NASDAQ: OBIO

Our Flagship Candidates

AVIM Therapy

AVIM Therapy is a bioelectronic therapy candidate designed to immediately, substantially and sustainably lower blood pressure. AVIM Therapy can be fully integrated as a firmware upgrade to standard cardiac pacemakers. HTN is the most common comorbidity in the pacemaker population affecting over 70% of the pacemaker-indicated patients, making AVIM Therapy a potentially highly attractive therapeutic solution for these patients. AVIM Therapy may offer therapeutic benefits to HTN patients not yet indicated for a pacemaker who have uncontrolled systolic blood pressure despite medical therapy and have high cardiovascular risk factors, such as Isolated System Hypertension (“ISH”), Diastolic Dysfunction (“DD”) and additional serious medical comorbidities including hypertensive patients with heart failure with preserved ejection fraction (“HFpEF”).

Although the safety and efficacy profile has not yet been established by any regulatory body, AVIM Therapy previously showed encouraging results in clinical studies conducted by Orchestra BioMed with its Moderato™ device, including the MODERATO II study, a prospective, multi-center, randomized, double-blind pilot study (the “MODERATO II study)” and in the MODERATO I study, a prospective, multi-center, single-arm open label study of patients with uncontrolled HTN and an indication for a pacemaker. We have also published additional clinical study results demonstrating favorable mechanistic and cardiac function effects of AVIM Therapy on patients with blood pressure above target thresholds.

On June 30, 2022, we entered into an exclusive license and collaboration agreement with Medtronic, one of the largest medical device companies in the world, for the development of AVIM Therapy for the treatment of HTN in pacemaker-indicated patients (the “Medtronic Collaboration”). The Medtronic Collaboration provides us with development, clinical and regulatory support for the BACKBEAT (BradycArdia paCemaKer with AVIM for Blood prEssure treAtmenT) global pivotal study (“BACKBEAT study”). Upon regulatory approval, if received, Medtronic will have the exclusive global rights to commercialize AVIM Therapy for this target population. If AVIM Therapy is approved and successfully commercialized, we will share meaningfully in the revenues generated from Medtronic’s sale of AVIM-enabled pacing systems. Medtronic has a right of first negotiation with respect to AVIM Therapy for the treatment of HTN in non-pacemaker patients.

On August 5, 2025, we announced that we and Medtronic had amended the Medtronic Collaboration to provide a pathway for potential integration of AVIM Therapy into future Medtronic leadless pacemakers. At the same time, we announced that Medtronic made an additional equity investment in the Company of $11.6 million and committed $20 million in exchange for a secured subordinated promissory note convertible to a capped revenue share credit. During 2022, Medtronic invested $40.0 million in the Series D Financing and entered into a $10.0 million forward purchase agreement in support of the Business Combination (as defined below).

We estimate that the total addressable market for pacemaker-indicated patients with HTN comprises more than 1,000,000 patients worldwide per year and represents a potential annual revenue opportunity for us and Medtronic of over $2.4 billion. We further estimate that the annual market for highly selected patients with uncontrolled hypertension that are not yet indicated for a pacemaker but have high cardiovascular risk and key co-morbidities, including HFpEF, comprises at least 3.7 million patients worldwide, or approximately 0.3% of the global HTN population, and represents a potential annual revenue opportunity for Orchestra BioMed and a strategic partner of over $15 billion.

On April 22, 2025, we announced that the FDA had granted Breakthrough Device Designation (“BDD”) for an implantable system for delivery of AVIM Therapy using conduction system pacing to reduce blood pressure in patients with preserved left ventricular systolic function and uncontrolled hypertension with increased high ten-year atherosclerotic cardiovascular disease (“ASCVD”) risk, despite the use of anti-hypertensive medications or in patients who may have intolerance to anti-hypertensive medications. Orchestra BioMed estimates that there are over 7.7 million patients in the U.S. that meet the criteria for the BDD for AVIM Therapy.

On September 19, 2023, we announced that the FDA granted us investigational device exemption (“IDE”) approval to initiate the BACKBEAT study to treat HTN in patients indicated for a pacemaker. The study is a double-blind, randomized study that is expected to enroll up to 500 patients that have previously been implanted with a Medtronic dual-chamber pacemaker (Azure® or Astra®) and have blood pressure above target despite medical therapy at up to 130 clinical sites worldwide. Patients will be randomized 1:1 to AVIM Therapy plus medical therapy (treatment) as compared to medical therapy alone (control). On January 8, 2024, we announced that the first patient was enrolled and randomized into the BACKBEAT study. We currently estimate completion of enrollment of the BACKBEAT study in mid-2026; however, there is no assurance that our current operating plan will be achieved. For a detailed description of the BACKBEAT study, see “—BIOELECTRONIC PRODUCT CANDIDATES —AVIM Therapy for Hypertension and CNT-HF for Heart Failure—Clinical Results—Clinical, Regulatory and Commercialization Pathway—The BACKBEAT Global Pivotal Study.”

Virtue SAB

Virtue SAB is a proprietary drug/device combination product candidate for the treatment of artery disease that is designed to deliver a large liquid dose of proprietary, investigational, extended-release formulation of sirolimus (“SirolimusEFR”) to the vessel wall during balloon angioplasty without the need for balloon coating or a permanent implant. Although the safety and efficacy profile has not yet been established by any regulatory body, Virtue SAB previously demonstrated promising three-year clinical data in the treatment of coronary ISR in the prospective, multi-center SABRE Study.

Virtue SAB was granted BDD by the FDA, for specific indications relating to the treatment of coronary ISR, coronary small vessel disease and peripheral artery disease below-the-knee. We estimate that these indications will represent an annual global addressable market opportunity of at least $10 billion, based on approximately 5 million procedures, as discussed below under “— INTERVENTIONAL THERAPIES — Virtue SAB for Artery Disease and SirolimusEFR for Local Inflammation in Multiple Indications. — Targeted Unmet Needs and Market Opportunity for Virtue SAB.”

On April 29, 2025, we announced IDE approval from the FDA for the Virtue Trial, a pivotal trial to be conducted at up to 75 sites in the U.S. that is expected to randomize approximately 740 patients 1:1 to either treatment with Virtue SAB or Boston Scientific Corporation’s AGENT™ paclitaxel-coated balloon (currently the only drug-coated balloon approved in the U.S. for a coronary indication) with a primary efficacy and safety endpoint of statistical non-inferiority of target lesion failure (“TLF”) at 12 months post index treatment.

On October 27, 2025, we announced that we had initiated enrollment of patients for the Virtue Trial. We currently estimate completion of enrollment of the Virtue Trial in mid-2027; however, there is no assurance that our current operating plan will be achieved.

On October 28, 2025, we entered into a termination and right of first refusal agreement (the “Termination and ROFR Agreement”) with Terumo Corporation and Terumo Medical Corporation (collectively, “Terumo”) with respect to Virtue SAB. The Termination and ROFR Agreement, which supersedes and terminates the prior Virtue SAB distribution agreement between us and Terumo (the “Terumo Agreement”), grants Terumo a right of first refusal (“ROFR”) to acquire the rights, or enter a distribution arrangement, with respect to Virtue SAB for the treatment of coronary artery disease, in exchange for an upfront payment of $10.0 million. For additional information relating to the Termination and ROFR Agreement, see the disclosure under the heading “Termination and Right of First Refusal Agreement” in Note 3 to the Consolidated Financial Statements included herein. In connection with the Termination and ROFR Agreement, on November 7, 2025, Terumo invested an additional $20.0 million in Orchestra BioMed through a new series of non-voting convertible preferred stock, par value $0.0001 per share (our “Series A Preferred Stock”), which is convertible into common stock in the future, subject to certain conditions, at a minimum of $12 per share pursuant to the terms of a securities purchase agreement (the “Terumo Securities Purchase Agreement”). Terumo previously made a $30.0 million non-refundable payment and $5.0 million common stock investment in Orchestra BioMed upon execution of the Terumo Agreement.

Ligand Pharmaceuticals Incorporated Revenue Participation Right Purchase and Sale Agreement and Purchase of Shares

On August 5, 2025, we announced that we had entered into a revenue participation right purchase and sale agreement (the “Revenue Purchase and Sale Agreement”) with Ligand Pharmaceuticals Incorporated (“Ligand”). Under the terms of the Revenue Purchase and Sale Agreement, in exchange for payment of $35.0 million (the “Investment Amount”), less certain reimbursable expenses, Ligand acquired from us the right to receive tiered revenue payments (the “Revenue Interest”) with respect to revenue (including certain licensing revenue) received by us in a calendar year in connection with worldwide net product sales, or other product revenue received by, by us and our licensees (“Annual Net Sales”) of (a) AVIM Therapy (the “Primary Product”) in the field of hypertension treatment and (b) the Virtue SAB (the “Secondary Product” and together with the Primary Product, the “Products”) in the field of coronary artery treatment. Ligand also made a $5.0 million equity investment in the Company. For additional information, see Note 15 to the Consolidated Financial Statements – “Royalty Purchase Agreement.”

History of Caliber and BackBeat

We were incorporated in Delaware in January 2017 and were formed to acquire operating and other assets as well as to raise capital to support further development of acquired assets. We had limited activity in 2017. In May 2018, we concurrently completed a recapitalization and mergers with Caliber Therapeutics, Inc., a Delaware corporation that has, among other things, the rights to the Virtue SAB product candidate and BackBeat Medical, Inc., a Delaware corporation that has, among other things, the rights to the AVIM Therapy product candidate. Caliber Therapeutics, Inc. was incorporated in Delaware in October 2005 and began development of its lead product candidate, Virtue SAB, in 2008. BackBeat Medical, Inc. was incorporated in Delaware in January 2010 and began development of its lead product candidate, AVIM Therapy, that same year.

Conversion of Caliber and BackBeat Limited Liability Companies

On December 26, 2019, we completed the conversions of Caliber Therapeutics, Inc., a Delaware corporation, to Caliber Therapeutics, LLC, a Delaware limited liability company, and BackBeat Medical, Inc., a Delaware corporation, to BackBeat Medical, LLC, a Delaware limited liability company. References in this Annual Report on Form 10-K to “Caliber” refer to Caliber Therapeutics, Inc. prior to its conversion to a limited liability company and to Caliber Therapeutics, LLC after its conversion to a limited liability company, as applicable. References in this Annual Report on Form 10-K to “BackBeat” refer to BackBeat Medical, Inc. prior to its conversion to a limited liability company and to BackBeat Medical, LLC after its conversion to a limited liability company, as applicable.

Merger with Health Sciences Acquisitions Corporation 2

We were incorporated in the Cayman Islands in 2020, as a special purpose acquisition company under the name Health Sciences Acquisitions Corporation 2 (“HSAC2”). On January 26, 2023, Orchestra BioMed, Inc. and HSAC2 consummated a business combination with HSAC2 pursuant to which, among other things, Orchestra BioMed, Inc. became a wholly owned subsidiary of HSAC2 and HSAC2 changed its name to Orchestra BioMed Holdings, Inc. (the “Business Combination”).

Partnership-Enabled Business Model

Our business was formed specifically to pursue a partnership-enabled business model that applies strategies typically used by the biopharmaceutical industry to the medical device market where product developers are often challenged with the financial and execution burdens of also commercializing the products they are developing to achieve a value inflection event for their shareholders.

Our goal is to accelerate and improve the likelihood of our product innovations reaching patients and providers worldwide by sharing the risks and rewards of developing and commercializing these product candidates with established multinational companies, such as Medtronic. Using this approach, we believe we can pursue multiple potentially lucrative innovation opportunities by focusing our efforts and resources on advancing promising therapeutic solutions, such as AVIM Therapy and Virtue SAB, through pivotal-stage clinical results. Meanwhile, our partners secure substantial new prospective growth opportunities with the potential to reduce risk and expense while leveraging their existing infrastructure to bring our partnered product candidates through regulatory approvals processes to global markets quickly and efficiently (assuming regulatory approval is obtained).

We believe our partnership-enabled business model can create value for its stakeholders and partners by:

•Optimizing development and commercialization of product candidates by pairing its research and development strengths and capabilities with the established commercial infrastructure of our partners;

•Enhancing capital efficiencies by sharing costs and responsibilities with our partners; and

•Maximizing the potential of future profitability by seeking to create multiple long-term high-margin royalty and revenue sharing arrangements with our partners.

Our Product Pipeline

Our pipeline is comprised of innovative therapeutic product candidates that we believe have the potential for value creation using our partnership-enabled business model, led by our flagship technologies, AVIM Therapy and Virtue SAB. We believe our product pipeline has the potential to improve clinical outcomes and provide distinct commercial advantages major cardiovascular indications in large and well-established global medical device markets with unmet medical needs: AVIM Therapy in cardiac rhythm management implants, an overall global market that Grand View Research valued at a $17.2 billion market worldwide in 2024; and Virtue SAB in interventional devices to treat coronary artery disease (“CAD”) and peripheral artery disease (“PAD”), an overall global market that IMARC Group, a leading market research company, valued at a $26.7 billion market worldwide in 2024. Our pipeline also includes additional product candidates for other significant medical conditions that we believe are attractive candidates for value creation using its partnership-enabled business model.

Our product candidates are based on platform technologies that each have late-stage lead clinical indications with attractive follow-on clinical indications that could add substantial future commercial potential. Moreover, our additional pipeline opportunities, such as Cardiac Neuromodulation Therapy (“CNT”) for heart failure, or potential treatment of clinical indications such as urology or osteoarthritis using SirolimusEFR, and the microporous AngioInfusion balloon technology used in the Virtue SAB leverage the same platform technologies and intellectual property already developed for its flagship product candidates. Generally, our product candidates target large, mature global markets in which there are several active multinational and regional corporations with established distribution capabilities in place. These product candidates are designed to potentially offer important clinical, health and economic benefits without changing established treatment paradigms such as physician techniques or patient referral and treatment patterns, providing a select strategic partner a potential means to differentiate their product portfolios from competitors, drive revenue growth and gain market share. Our strategic collaboration agreement with Medtronic for AVIM Therapy demonstrates our ability to align with a global market leader for the long-term development and commercialization of a product candidate.

The following table summarizes our material pipeline programs organized by product platform, as well as target indications, development status, market opportunity, strategic partners/collaborators and next milestones.

Advancing a High-Impact Pipeline

1Will seek to leverage data from the pilot and pivotal trials involving HTN in patients indicated for a cardiac pacemaker (the “HTN+P population” or the “Primary Field”) to support clinical and regulatory development for HTN with high cardiovascular risk in patients not yet indicated for a pacemaker indication given that age and other demographic factors of the target population are expected to be similar, the type of hypertension treated will likely be isolated systolic hypertension which is predominant in the HTN+P population, and other co-morbidities are also expected to be common to both target populations.

2Plan to leverage existing coronary ISR data to support potential pivotal studies, although there have only been limited discussions with the FDA or comparable foreign regulators in this regard.

3Virtue SAB has received Breakthrough Device Designation by the FDA for the balloon dilatation of the stenotic portion (up to 26 mm length) of a stented coronary artery (ISR) that is 2.25 to 4.0 mm in diameter, for the purpose of improving lumen diameter.

4Virtue SAB has received Breakthrough Device Designation by the FDA for the balloon dilatation of the de novo stenotic portion (up to 26mm in lesion length) of a native coronary artery of 2.0 mm to 2.5 mm in diameter (small coronary arteries), for the purpose of improving lumen diameter.

5Virtue SAB has received Breakthrough Device Designation by the FDA for the balloon dilatation of the stenotic portion (up to 18 mm length) of an infrapopliteal artery (P-3 segment or distal, below the knee, with reference vessel diameter (RVD) 2.25 – 4.0 mm), for the purpose of improving lumen diameter.

BIOELECTRONIC PRODUCT CANDIDATES —AVIM Therapy for Uncontrolled Hypertension and CNT-HF for Heart Failure

We are developing bioelectronic therapies based on patented CNT technology. Our product candidates are designed to use standard active implantable cardiac rhythm management systems, such as pacemakers, with changes to firmware and software only. Our flagship product candidate of the Bioelectronic Therapies Group is AVIM Therapy, a patented, potential bioelectronic treatment for uncontrolled HTN, the leading risk factor for death worldwide. We have an exclusive strategic collaboration with Medtronic for the development and commercialization of AVIM Therapy for the treatment of uncontrolled HTN in patients indicated for a cardiac pacemaker. We also believe AVIM Therapy may offer therapeutic benefit to select patients with uncontrolled HTN who are not indicated for a pacemaker, including those with increased cardiovascular risk and HFpEF. Medtronic has a right of first negotiation with respect to AVIM Therapy for the treatment of HTN in non-pacemaker patients.

We are also pursuing CNT-HF, a bioelectronic product candidate that aims to reduce chronic sympathetic nervous system activity in heart failure (“HF”) for which there is an estimated global patient population of 64 million people according to the AME Medical Journal.

Atrioventricular Interval Modulation (AVIM) Therapy Product Candidate

In the discussion below and elsewhere in this Annual Report on Form 10 K, we reference p-values, which are statistical calculations that relate to the probability that the observed difference between groups happened by chance, with a p-value of less than 0.05 (i.e., less than a 5% probability that the observed difference happened by chance) generally considered as the threshold to indicate statistical significance in clinical trials.

AVIM Therapy is a bioelectronic product candidate for uncontrolled HTN that is designed to immediately, substantially and sustainably reduce blood pressure. AVIM Therapy is delivered through programmed cardiac pacing algorithms and is designed to leverage standard rhythm management device procedures (dual-chamber pacemaker), utilizing the same implant procedure and lead positions while still enabling standard rhythm management (pacing) functions. While AVIM Therapy is designed to achieve certain results as described above, there is no guarantee that AVIM Therapy will prove to be safe and effective.

Clinical studies performed to date have been conducted using our proprietary Moderato system, a pacemaker system, incorporating AVIM therapy. Clinical results from two European clinical studies, the MODERATO I single-arm clinical study and the MODERATO II double-blind, randomized, controlled pilot study, demonstrated a significant and clinically meaningful reduction in systolic blood pressure in hypertensive patients also indicated for a pacemaker. In particular, the MODERATO II study met its primary efficacy endpoint, as patients randomized to AVIM Therapy showed a statistically significant 11.1 mmHg (p<0.01) reduction in mean 24-hour ambulatory systolic blood pressure (“aSBP”) at six months follow-up from activation, resulting in a statistically significant difference of 8.1 mmHg (p=0.01) of aSBP compared to control patients who were managed only with anti-hypertensive medications. The study also met its primary safety endpoint with no clinically meaningful differences in rate of major adverse cardiac events (“MACE”) between the two groups at six months follow-up. Further details on the results of the AVIM Therapy clinical studies performed to date are provided below.

Strategic Collaboration Agreement with Medtronic

In June 2022, we and Medtronic entered into the Medtronic Agreement for the development and commercialization of AVIM Therapy for the treatment of uncontrolled HTN in patients indicated for a cardiac pacemaker (the “HTN+P population” or the “Primary Field”). Under the terms of the Medtronic Agreement, we are the sponsor for the BACKBEAT study to support regulatory approval in the United States, European Union (the “EU”), Japan and other potential territories of AVIM Therapy in the Primary Field and we are financially responsible for development, clinical and regulatory costs associated with this pivotal study.

Medtronic has completed integration and associated validation and verification testing of AVIM Therapy algorithms as a field downloadable addition to its premium, commercially available dual-chamber pacemaker systems for use in the pivotal study. Medtronic is also providing clinical, regulatory, operational field clinical resources in support of the BACKBEAT study. We are reimbursing Medtronic at cost for these development, clinical and regulatory resources. Medtronic will integrate AVIM Therapy, at our cost, as a firmware component of a premium pacemaker for potential regulatory approval and commercialization of AVIM-enabled commercial devices following a successful outcome of the BACKBEAT study.

Medtronic is the global market leader in cardiac rhythm management (“CRM”), and pacemaker devices, with over 50% of the U.S. market share for such devices and typically having a leading share in all other global markets. Given Medtronic’s market leadership and the potential therapeutic benefits of AVIM Therapy, we believe AVIM-enabled pacemakers, if commercially approved, have the potential to be rapidly adopted into existing pacemaker-indicated patient care for addressable hypertensive patients. We further believe the substantial potential added clinical value and differentiation of AVIM-enabled pacemakers can help Medtronic potentially expand market share and grow revenue.

Under the terms of the Medtronic Agreement, Medtronic will have exclusive rights in the Primary Field to commercialize AVIM-enabled pacing systems globally following receipt of regulatory approvals. Medtronic would be entirely responsible for global commercialization following any receipt of regulatory approvals, including manufacturing, sales, marketing and distribution costs. Under the terms of the Medtronic Agreement, assuming that AVIM-enabled devices are sold at average selling prices supported by existing reimbursement structures worldwide (e.g., no higher or additional reimbursement is available), we are expected to receive between $500 and $1,600 per AVIM-enabled device sold based on a formula of the higher of (1) a fixed dollar amount per AVIM-enabled device (amount varies materially on a country-by-country basis) or (2) a percentage of the AVIM Therapy generated sales. This estimated range is derived from publicly available information, our management’s knowledge of the pacemaker market, our discussions with Medtronic, and the terms of the Medtronic Agreement. Based on our discussions with Medtronic, the global market leader in pacemakers, the terms of the Medtronic Agreement and our management’s knowledge of reimbursement codes for medical devices, we believe that AVIM-enabled pacemakers can be supported by existing reimbursement codes without the need for new codes.

Under the terms of the Medtronic Agreement, Medtronic has a right of first negotiation through FDA approval of AVIM Therapy for the Primary Field, to expand its global rights to AVIM Therapy for the treatment of uncontrolled HTN in patients not indicated for a pacemaker.

In addition to customary early termination provisions, the Medtronic Agreement will terminate on the date no further revenue share payments are due under the Medtronic Agreement, at which point Medtronic’s license under the Medtronic Agreement would become fully paid up, perpetual, irrevocable and royalty-free. Revenue share payments with respect to each applicable country (or group of countries) are to be paid for a minimum period of time determined by the latest to occur of (a) the expiration of the last valid claim of certain specified patents or (b) the date that is 12 years after the first commercial sale of any AVIM-enabled pacemakers in the applicable country or group of countries.

On July 31, 2025, Orchestra BioMed, Inc., BackBeat and Medtronic entered into an amendment to the Medtronic Agreement, which became effective on August 4, 2025 (the “Medtronic Agreement Amendment”), to provide, among other things, a development and commercialization framework for future AVIM-therapy integration into a dual-chamber leadless pacemaker. Pursuant to the Medtronic Agreement Amendment, we will, among other things, be required to reimburse Medtronic for certain expenses incurred in connection with the integration of AVIM-therapy into Medtronic’s dual-chamber leadless pacemaker, up to a specified cap.

Market Needs

Hypertension

HTN is elevated blood pressure that increases risk of major cardiac events like heart attack and stroke and can contribute to other significant conditions such as heart failure and kidney disease. According to the World Health Organization (the “WHO”), HTN is the leading global risk factor for death affecting an estimated 1.4 billion adults worldwide. Cardiovascular risk doubles for every 10 mmHg increase in office systolic blood pressure and the mortality rate doubles with an increase of 20 mmHg in office systolic blood pressure, according to the National Center for Biotechnology Information.

The Centers for Disease Control and Prevention (the “CDC”) estimates 119.9 million adults, or approximately 48% of all adults in the United States have HTN. Within this group only 1 in 4 adults have their condition under control. In 2025, the American Heart Association (“AHA”) and the American College of Cardiology (“ACC”) updated their High Blood Pressure Clinical Practice Guideline, maintaining the same blood pressure thresholds established in 2017 for diagnosing hypertension—Stage 1 hypertension is defined as a systolic blood pressure of 130–139 mm Hg or diastolic blood pressure of 80–89 mm Hg, and Stage 2 hypertension as a systolic blood pressure of ≥140 mm Hg or diastolic blood pressure of ≥90 mm Hg. However, the 2025 guideline introduces new clinical tools and recommendations that further refine management strategies, including use of the PREVENT risk calculator to guide treatment decisions and broaden the indication for earlier pharmacotherapy in patients with Stage 1 hypertension who do not achieve targets with lifestyle changes. Under these updated guidelines, the estimated prevalence of hypertension among U.S. adults increased to nearly 47%, equivalent to approximately 120 million adults. While many global guidelines have not yet adopted these specific U.S. thresholds and continue to use the traditional ≥ 140/90 mmHg definition for diagnosing hypertension, the 2025 ACC/AHA guideline emphasizes more intensive control and earlier intervention to reduce cardiovascular and related risks. Importantly, a large proportion of U.S. adults over age 65—who are most likely to require pacemakers—now meet the criteria for hypertension under the updated definition. Additionally, the guideline recommends that a substantial number of U.S. adults taking antihypertensive medication may benefit from more intensive blood pressure–lowering treatment to achieve a target of <130/80 mmHg for optimal risk reduction.

The CDC reported high blood pressure as the primary or contributing cause of death in 2022 for more than 685,000 people in the United States, equating to nearly 1,875 deaths per day. By 2035, the estimated direct cost of high blood pressure could increase to $220.9 billion (annual average), according to the AHA.

Non-adherence to antihypertensive treatment is a critical contributor to suboptimal blood pressure control and another important risk factor for adverse cardiovascular disease outcomes. Of U.S. patients aware of their HTN diagnosis, about 76% are believed to be taking anti-hypertensive medication, but only 52% of those have their condition controlled, according to the Journal of Clinical Hypertension. Therefore, approximately 60% of hypertensive U.S. adults have uncontrolled HTN. An estimated 31% of HTN patients are non-adherent to medications, according to the AHA. Thus, many medically responsive patients have high blood pressure simply because they do not take their medications, making medication non-compliance one of the most prominent challenges of HTN management. In addition, since HTN patients are typically older, they are more likely to be prescribed multiple medications for HTN and other medical conditions: polypharmacy (multiple medications) is associated with increased risk of adverse events (fall injury, heart failure, etc.), polypharmacy mismanagement, and drug-drug interactions. Furthermore, AHA estimates as much as 15% of the prevalent HTN population is resistant to medical therapy, and these patients are 47% more likely to suffer the combined outcomes of death, myocardial infarction, heart failure, stroke, or chronic kidney disease over the median 3.8 years of follow-up than other HTN patients. Because of the factors mentioned above, there is a significant need for alternative therapies to treat HTN, particularly, device-based therapies that do not require patient compliance for receiving treatment.

Isolated Systolic Hypertension, Elevated Pulse Pressure & Diastolic Dysfunction

Based on data from the CDC, 72% of U.S. adults over 60 years old have HTN, with over 65% of them suffering from isolated systolic hypertension (“ISH”). ISH patients have elevated systolic blood pressure (>140 mmHg), while their diastolic blood pressure remains normal or low (≤90 mmHg). ISH is a more difficult to treat form of HTN because anti-hypertensive medications generally impact both systolic and diastolic pressure. It is estimated that over 80% of medical treatment failure patients over 60 years old have ISH, according to the AHA. ISH patients experience elevated pulse pressure, which is the difference between systolic and diastolic pressures (“Pulse Pressure”). Pulse Pressure is a known, significant, independent risk factor for coronary heart disease. According to published literature, a 10 mmHg increase in Pulse Pressure is associated with a 32% increase in risk of heart failure and a 24% increase in risk of stroke (after controlling for systolic BP and other risk factors). In addition, in men ≥60 years old (the typical age of pacemaker patients), risk for coronary artery disease is three times larger in patients with Pulse Pressure of ≥70 mmHg compared to those with Pulse Pressure of 60 mmHg.

Long standing HTN leads to cardiac structural and functional changes that frequently result in left ventricular (“LV”) diastolic dysfunction (“DD”), a condition in which the left ventricle has impaired relaxation and filling, leading to increased pressure and reduced efficiency in pumping blood. It is a key contributor to heart failure with preserved ejection fraction (HFpEF), which accounts for approximately 50% of all heart failure cases. HTN is one of the primary causes of DD and the prevalence of DD increases with age, affecting over 50% of individuals over 70.

Hypertension among Patients with Pacemakers

Pacemakers are recommended for the management of symptomatic bradycardia (slow heart rate) due to sick sinus syndrome, atrio-ventricular block, a combination of these conditions or other situations in which patients are prone to brady-arrhythmias. Currently available devices have evolved from single-chamber, fixed-rate pacemakers to multi-chamber, rate-responsive units. In the United States, over 85% of pacemaker patients receive dual-chamber devices which have wires or leads implanted in the right atrium and right ventricle of the heart capable of sensing and stimulating the heart to control contraction timing of both chambers. There are projected to be approximately 1.4 million dual-chamber pacemaker implants performed worldwide in 2028 according to GlobalData & Life Science Intelligence. Global sales of dual-chamber pacemakers exceeded $3.6 billion in 2022 according to GlobalData, comprising over 20% of the overall $17.2 billion market for implantable cardiac rhythm management devices.

Based on ACC/AHA guidelines, we estimate that nearly 80% of U.S. patients that are indicated for the implant of a pacemaker have HTN. Among this group of patients, over 60% are estimated to have uncontrolled HTN based on the treatment goal per the 2025 ACC/AHA guidelines. Further, since the average age of pacemaker-indicated patients is approximately 73 years old and, in consideration of other demographic factors associated with this population, these patients are at elevated risk of ISH (over 80% of patients enrolled in prior clinical studies of AVIM Therapy had ISH). Furthermore, these patients are likely to suffer from DD, have increased overall cardiovascular risk as well as other co-morbidities such as atherosclerosis, hyperlipidemia, diabetes mellitus and chronic kidney disease. We believe these patients could benefit substantially from a HTN treatment like AVIM Therapy that can be administered via an already necessary pacemaker.

Target Patient Populations and Market Opportunity for AVIM Therapy

The initial target market for AVIM Therapy is the large population of patients with uncontrolled HTN who also require the implant or replacement of a pacemaker (the HTN+P population). Pursuing this patient population leverages the design of AVIM Therapy to address hypertension in patients who already require a pacemaker implant since it can be readily incorporated into standard cardiac rhythm management systems such as pacemakers, as Medtronic has already done for the BACKBEAT study. As a novel HTN therapy that can be completely integrated with an established existing commercially available device patients already require for a critical medical indication, we believe AVIM Therapy can be readily adopted into the existing care paradigm for hypertensive patients that already require a pacemaker implant. As described above, we believe there is a significant unmet need and commercial opportunity for more effective treatment of the HTN+P population.

AVIM-enabled pacemakers can be implanted using standard implant procedures, electrical leads and lead positions. Further, we believe any experienced and trained physicians who perform pacemaker implants, such as electrophysiologists and cardiologists, will be able to select an AVIM-enabled pacemaker for an appropriate patient without the need for another physician referral, if approved. AVIM Therapy features proprietary algorithms that are designed to enable physicians to non-invasively adjust the therapeutic parameters to optimize chronic blood pressure reduction to individual patient needs. In addition, AVIM Therapy is designed to be de-activated or reactivated by the physician as necessary, offering potential efficacy and safety advantages over other device-based therapies. Importantly, the delivery of AVIM Therapy does not rely on patient adherence or compliance, offering a significant complement to pharmaceutical therapies for which adherence and compliance are a key challenge.

We estimate that the addressable annual market for pacemaker-indicated patients with HTN will comprise more than 1,000,000 patients worldwide by 2028. We estimate that, if approved, commercialization of AVIM Therapy in hypertensive pacemaker patients can increase the commercial value of the global pacemaker device market by over $2.4 billion annually. This substantial annual opportunity is based on incorporating AVIM Therapy’s potentially potent and clinically impactful HTN treatment capabilities into a pacemaker to drive a meaningful increase in the average selling price (“ASP”) that can be supported by existing pacemaker procedure codes globally.

AVIM Therapy may also offer clinical utility for HTN patients not yet indicated for a pacemaker who have uncontrolled systolic blood pressure despite medical therapy and have increased cardiovascular risk factors such as ISH, DD and additional serious medical comorbidities. We estimate that this additional addressable annual market for select patients with uncontrolled hypertension and high cardiovascular risk not yet indicated for a pacemaker will comprise at least 3.7 million patients worldwide by 2025, or approximately 0.2% of the global HTN population. We calculate this estimated market using information from publicly available third-party sources that only includes those hypertensive patients who are (1) over 60 years of age with high (>20%) ASCVD score, (2) are currently being treated with at least one medication, (3) have high systolic blood pressure (greater than 160 mmHg oSBP) despite medical therapy, (4) have preserved ejection fraction (EF >50%), (5) have ISH and/or DD or HFpEF, and (5) do not have high burden atrial fibrillation or severe valvular disease. Using similar maximum ASP figures based on existing reimbursement codes for pacemaker implantation, we estimate that this calculated market represents a global potential annual revenue opportunity of over $15.4 billion using similar potential ASPs as AVIM-enabled pacemakers.

FDA Breakthrough Device Designation

On April 22, 2025, we announced that the FDA had granted BDD for an implantable system for delivery of AVIM Therapy using conduction system pacing to reduce blood pressure in patients with preserved left ventricular systolic function and uncontrolled hypertension with increased high ten-year ASCVD risk, despite the use of anti-hypertensive medications or in patients who may have intolerance to anti-hypertensive medications. Orchestra BioMed estimates that there are over 7.7 million patients in the U.S. that meet the criteria for the BDD for AVIM Therapy.

The FDA Breakthrough Devices Program, which reflects the FDA’s commitment to device innovation and protecting public health, is designed to expedite the development and provide priority review of innovative medical technologies that have the potential to significantly improve outcomes for patients with serious or life-threatening conditions. To be eligible for this designation, a device must demonstrate the potential to provide more effective treatment or diagnosis of a life-threatening or irreversibly debilitating condition. In addition, the device must meet at least one of the following criteria: it must represent breakthrough technology, have no approved or clear alternatives, offer significant advantages over existing options, or be determined by the FDA to be in the best interest of patients. Beyond regulatory acceleration, the BDD may also support favorable reimbursement pathways, including eligibility for incremental inpatient reimbursement through the New Technology Add-on Payment (“NTAP”) and outpatient Transitional Pass-Through payments (“TPT”) under the Center for Medicare & Medicaid Services (“CMS”) programs. These mechanisms may help facilitate more timely access to breakthrough technologies while supporting provider adoption and patient access.

Impact Potential of AVIM Therapy

AVIM Therapy is a bioelectronic product candidate for uncontrolled HTN that is designed to immediately, substantially and sustainably reduce blood pressure. AVIM Therapy is delivered through programmed cardiac pacing algorithms. These algorithms are specifically designed to reduce blood pressure by (1) lowering cardiac preload (ventricular filling volume) and maintaining reduced blood pressure and by (2) modulating sympathetic tone (the level of activity of the sympathetic nervous system) as well as reducing cardiac afterload (total peripheral resistance). AVIM Therapy is designed to leverage standard rhythm management devices (dual-chamber pacemakers), utilizing the same implant procedure and lead positions while still enabling standard rhythm management (pacing) functions. We believe that physicians such as implanting cardiologists and electrophysiologists who currently implant pacemakers and are responsible for the care of these patients can make the medical decision to implant an AVIM-enabled pacemaker in an eligible patient. Further, we believe that AVIM-enabled devices can garner meaningfully higher ASPs that can be supported by existing reimbursement without the need for new procedure codes. While AVIM Therapy is designed to achieve certain results as described above and below, there is no guarantee that AVIM Therapy will prove to be safe and effective.

AVIM Therapy is designed to deliver cardiac pacing to reduce blood pressure through two essential mechanisms:

1.Programmed pacing with short AV delays (shorter timeframe between contraction of the atria and the ventricle of the heart) designed to substantially reduce blood pressure by reducing cardiac preload. Cardiac preload is the amount of stretching of the ventricle of the heart driven by the volume of blood that fills the ventricle. Pacing with shorter AV delays reduces fill volume and, thereby, cardiac preload. Lower preload results in lower blood pressure.

2.Programmed variable blood pressure patterns (achieved using programmed pacing with a combination of short and intermittent longer AV delays) designed to maintain average blood pressure reduction by modulating sympathetic tone and reducing cardiac afterload. Sympathetic tone refers to the level of activity of the sympathetic nervous system response which is known to drive and maintain elevated blood pressures. Cardiac afterload is the vascular resistance against which the heart must contract to eject blood and is characterized by the diameter of arteries, otherwise known as total peripheral resistance.

1Kalarus et al. Journal of the American Heart Association. 2021;10:e020492ahajournals.org/doi/10.1161/JAHA.120.020492.

2Kuck, Hemodynamics Effects of AVIM Therapy, THT’24

Preclinical Data

The goal of the preclinical studies was to evaluate the feasibility of the use of AVIM Therapy in a canine model with surgically induced HTN and to provide a rationale for clinical use to persistently lower blood pressure in patients with HTN. AVIM Therapy was delivered via pacing algorithms in a prototype device in the canine model. Chronic delivery of AVIM Therapy significantly reduced 24-hour aSBP by an average of 32.5 mmHg over a one-month period (n=4).

The reduction occurred immediately upon activation of therapy and was maintained for the period that the therapy was active (approximately 30 days). Blood pressure did not meaningfully change in the study’s single control animal that had an AVIM Therapy device implanted but not activated. 24-hour aSBP was measured using an implanted blood pressure sensor.

The chart below shows the baseline 24-hour aSBP profile of one of the study animals prior to therapy activation as compared to the 24-hour aSBP profile of the same animal following activation of AVIM Therapy. The results are plotted as a histogram demonstrating the frequency of blood pressure levels over the course of the 24-hour period. The baseline aSBP histogram shows the percentage frequency of aSBP reaching different levels of pressure ranging from approximately 135 mmHg to 280 mmHg and a most frequent aSBP of approximately 180 mmHg. By contrast, the AVIM Therapy aSBP histogram shows the percentage frequency of aSBP reaching different levels of pressure ranging from approximately 120 mmHg to 260 mmHg and a most frequent aSBP of approximately 145 mmHg. The charts demonstrate the significant improvement in the entire 24-hour aSBP profile of the animal driven by AVIM Therapy as the entire aSBP histogram is shifted substantially downwards and to the left in terms of frequency of reaching lower SBP levels and the peak SBP frequency level is reduced by approximately 35 mmHg. These results are similar in the three AVIM Therapy study animals in terms of substantial improvement of the 24-hour aSBP profile while the one study control animal did not experience a shift in 24-hour aSBP profile.

The chart below on the left shows average aSBP per 24-hour period of the same study animal profiled above over the entire study period. This chart demonstrates that (1) AVIM Therapy drove a substantial reduction of 24-hour aSBP from baseline levels (shown in orange with each box representing a full 24-hour period of aSBP measurement); (2) this blood pressure reduction was maintained through the period that AVIM Therapy was active (as reflected in the orange line made up of orange boxes); and (3) blood pressure levels took more than 10 days to return to baseline levels after AVIM Therapy was turned off, indicating that sympathetic tone responses and afterload levels were potentially modulated by chronic delivery of AVIM Therapy since aSBP levels would be expected to return immediately to baseline levels if sympathetic tone and afterload were not modulated. These results are similar in all three AVIM Therapy study animals in terms of durable substantial improvement of the 24-hour aSBP profile and slow response over days to baseline aSBP levels. As shown in the chart below on the right, the one study control animal did not experience any significant changes in 24-hour aSBP during the study period as illustrated by the chart below.

Clinical Results

Acute Clinical Studies (Nanjing):

A short time-based study of the effects of AVIM Therapy in 18 patients with uncontrolled HTN who were already scheduled to undergo an invasive electrophysiology procedure was conducted at Jiangsu Province Hospital/The First Affiliated Hospital with Nanjing Medical University, Nanjing, China over a one year period ending March 2012. The study population consisted of patients with uncontrolled HTN and systolic blood pressure >140 mmHg despite at least one anti-hypertensive medication.

AVIM Therapy was applied for at least one minute in all patients and up to five minutes in certain patients based on whether the physician managing the primary electrophysiology procedure allowed for longer duration of treatment based on the time available to perform the AVIM Therapy acute clinical study versus the primary electrophysiology procedure for which the patient was being treated. Various signal parameters were evaluated. All patients exhibited reduction of >10 mmHg in systolic blood pressure. The average sustained reduction in blood pressure was 19.7 +/-7.4 mmHg systolic (p<0.001) and 4.3 +/-3.7 mmHg diastolic (p<0.001). No serious adverse effects were observed or reported in these studies. The study also demonstrated that reduction in blood pressure was titrated by modifying AVIM Therapy parameters as needed.

Acute Clinical Study (Prague):

On March 6, 2024, we announced the presentation of results from a pressure volume (“PV”) loop clinical study of AVIM Therapy in pacemaker-indicated patients with uncontrolled HTN despite the use of anti-hypertensive medication. These clinical data demonstrate the favorable hemodynamic impact of AVIM Therapy as compared to standard right ventricular (“RV”) pacing on systolic blood pressure and overall cardiac function when delivered using both conduction system as well as standard pacing lead locations. The PV loop study was conducted at Na Homolce Hospital in Prague by Petr Neužil, MD, CSc., FESC and the data were presented by Prof. Karl-Heinz Kuck, M.D., Medical Director at LANS Cardio Hamburg at the Technology and Heart Failure Therapeutics 2024 Meeting. On August 26, 2025, we announced that the results of this PV loop study were published in the Journal of the American College of Cardiology: Clinical Electrophysiology.

The PV loop study enrolled 16 patients indicated for a dual-chamber pacemaker that also had uncontrolled HTN despite taking anti-hypertensive medication who underwent invasive PV loop testing to evaluate cardiac function, measured by changes in LV volumes and pressures using a pressure-volume catheter placed in the LV. SBP was measured using a pressure transducer placed in the aorta, and baseline measurements were recorded using atrial pacing at a fixed rate. Normal conduction AVIM Therapy with pacing leads placed in AVIM RV locations, as well as in AVIM conduction system pacing (CSP) locations targeting the left bundle branch area (LBBA) regions, respectively, was compared to standard atrioventricular (AV) Pacing.

Overall mean results for each variable were calculated using paired measurements for each individual patient using AVIM RV, AVIM CSP and AV Pacing, respectively:

●AVIM Therapy generated statistically significant reductions (p<0.05) in systolic blood pressure (SBP), end diastolic volume (EDV), end diastolic pressure (EDP), and end systolic volume (ESV) using both AVIM RV and AVIM CSP pacing lead locations compared to AV Pacing

oSBP was reduced by 17.1 mmHg and 19.2 mmHg compared to 1.6 mmHg

oEDV was reduced by 12.6 mL and 18.6 mL compared to 1.4 mL

oEDP was reduced by 2.3 mmHg and 3.6 mmHg compared to an increase of 0.3 mmHg

oESV was reduced by 11.0 mL and 14.1 mL compared to an increase of 1.8 mL

●AVIM Therapy drove statistically significant (p<0.05) reductions in stroke work (SW) without significantly reducing stroke volume (SV)

oStroke work (SW) was reduced by 1596 mL and 1870 mL compared to 42 mL

oStroke volume (SV) was not significantly reduced by AVIM RV, AVIM CSP or AV Pacing

●AVIM Therapy drove statistically significant (p<0.05) reductions in total peripheral resistance (TPR or Ea) and no change in contractility (Ees)

oEffective arterial elastance (Ea, a measure of TPR) was reduced by 0.23 mmHg/mL and 0.31 mmHg/mL compared to an increase of 0.04 mmHg/mL

oEes remained unchanged with AVIM RV, AVIM CSP and AV Pacing

Chronic Clinical Studies:

MODERATO I Single Arm Study

The 27-patient, MODERATO I clinical study was conducted primarily in Europe (along with one clinical site in Chile) to evaluate the safety and efficacy of AVIM Therapy using our proprietary Moderato system, capable of delivering AVIM Therapy as well as performing the rhythm management function of a standard dual-chamber pacemaker. The Moderato system, comprised of the implantable pulse generator (“IPG”) and programmer, was manufactured under an original equipment manufacturer contract by a division of Integer Holdings Corporation (“Integer”), a leading supplier of cardiac rhythm management device components. The Moderato system was European Conformity (“CE”) marked in July 2019. However, we do not plan to commercialize the Moderato device but may consider utilizing the CE marked system to conduct additional clinical work in the EU.

The results from the MODERATO I study were published in December 2017 in the Journal of the American Heart Association. The main inclusion criteria required patients to have oSBP >150 mmHg despite taking at least two anti-hypertensive drugs as well as having a clinical indication for a dual-chamber pacemaker implant or replacement. Twenty-seven patients meeting all study entry criteria underwent a Moderato device implant, at which time only standard pacemaker functions were activated. Nearly 80% of the patients enrolled had ISH, making them a more difficult group of patients to treat. All enrolled patients were implanted with Moderato devices and then followed for a one-month observation period to evaluate any changes in blood pressure due to either the initiation of standard pacing alone or due to their participation in the study. At the end of the one-month period blood pressure was reassessed to ensure oSBP remained >140 mmHg for eligibility to enter the treatment phase of the study. Only 27 patients met the criteria and AVIM Therapy was activated in these patients. Patients were then reevaluated following three months of treatment for changes in blood pressure assessed by both office cuff measurements and by 24-hour ambulatory blood pressure recordings. The study’s co-primary efficacy endpoints were changes in oSBP and mean 24-hour aSBP (added as a study amendment) from pre-activation through three months post activation of therapy. All 27 patients completed the study’s three-month activation period and clinical follow-up. Twenty-one patients consented to be followed at 6, 12, 18 and 24 months after activation and only oSBP levels were measured at these longer follow-up time points due to the fact that measuring changes in aSBP over two- to six-month periods is generally deemed appropriate to assess HTN therapies and because additional aSBP measurements are highly burdensome for patients that participate in HTN studies as they require wearing a device that takes frequent blood pressure measurements over a 24-hour period. Two-year follow-up data available from these 21 patients was presented for the first time in October 2017 at the Transcatheter Cardiovascular Therapeutics (“TCT”) conference in Denver, Colorado.

The co-primary efficacy endpoint of changes in mean 24-hour aSBP was met successfully with AVIM Therapy activation driving a significant 11.6 mmHg reduction (p<0.001) from pre-activation levels during the first day of therapy. The reduction was maintained through the three-month activation period, representing a statistically significant reduction of 10.1 mmHg (p=0.007) from the pre-activation aSBP. Seventeen of the 27 study patients participated in the co-primary efficacy endpoint analysis which was included as amendment to the MODERATO I study design following initiation of the study given new evidence from other clinical studies regarding the potential importance of change in mean 24-hour aSBP in assessing the potential efficacy of HTN therapies.

The co-primary efficacy endpoint of changes in oSBP was also met successfully with AVIM Therapy driving a statistically significant reduction in oSBP, 16.1 mmHg (p<0.001) from pre-activation levels. This reduction in oSBP was maintained in patients who reached the later follow-up time points with a mean statistically significant reduction of 23.4 mmHg (p<0.001) in oSBP from baseline levels after 24 months of therapy.

1Neuzil et al. Journal of the Am Heart Assoc. 2017;6:e006974.

2Burkhoff MODERATO I Study 2-Year Results TCT 2018.

3Compared to pre-activation.

4aSBP (n=16) at pre-activation.

5AVIM (n=21) continued after completion of study at 3 months to be followed for 2 years.

Long-term (24-month) data showed results consistent with expected mechanism of action, including statistically significant reduction in heart rate (p<0.05), a key measure of sympathetic nervous system activation, and end-diastolic volume, a key safety measure. In addition, comparison of echocardiograms performed at baseline and following activation up to two years of AVIM Therapy showed that there were no significant changes in cardiac function (ejection fraction).

1Burkhoff MODERATO I Study 2-Year Results TCT 2018.

24-month Data Consistent with Expected Mechanism of Action

During the initial study period for MODERATO I, there were eleven serious adverse events (“SAEs”) in seven of the 27 study patients. Nine events in six patients were cardiac related. Two non-cardiac events were urinary tract infections and dyspnea treated with bronchodilator. No events were adjudicated as definitely or probably related to AVIM Therapy. One event was adjudicated as probably related to the implant procedure for the Moderato device. Four events in four patients were adjudicated as possibly related to the Moderato device (atrial fibrillation, myocardial infarction with symptoms of heart failure, cardiac asthma, and arrhythmia due to ventricular oversensing).

During the extended 21-month follow-up period that included 24 patients who continued with AVIM Therapy, there were 25 SAEs in twelve patients. No events were adjudicated as definitely or probably related to AVIM Therapy. Out of 25 events, 17 events in seven patients were cardiac related. There were eight non-cardiac events in eight patients. The non-cardiac events included two orthopedic events, two cases of cancer, a transient ischemic event, and three respiratory related events. Five events in three patients were adjudicated as possibly device related. These included two events of atrial fibrillation in the same patient, pneumonia with cardiac decompensation and dyspnea with cardiac decompensation in one patient, and cardiac decompensation in another patient.

MODERATO II Double-Blind, Randomized Study

The results of the MODERATO II study of AVIM Therapy in patients with uncontrolled HTN also indicated for a pacemaker were published in August 2021 in the Journal of the American Heart Association. All patients enrolled in the MODERATO II study, a European prospective, multi-center, double-blind, randomized pilot study of AVIM Therapy, had persistent HTN (aSBP ≥ 130 mmHg and oSBP ≥ 140 mmHg) despite one or more anti-hypertensive medications and a pacemaker indication, and were implanted with our Moderato System. Following a 30-day run-in period during which patients received only standard pacing along with anti-hypertensive medications, patients who met follow-up screening criteria for daytime aSBP were randomized to AVIM Therapy or control groups.

Prior to randomization, mean aSBP for both groups was 136.3 mmHg with patients, on average, treated with over three prescribed anti-hypertensive drugs. 88.5% of the patients in the AVIM Therapy treatment arm had ISH, making them a more challenging group of patients to treat. 71.4% of control arm patients also had ISH. The study met its primary efficacy endpoint of superiority of AVIM Therapy to control in terms of change in mean 24-hour aSBP at six months following randomization. After six months, mean aSBP was reduced by a statistically significant 11.1 mmHg in the AVIM Therapy group as compared to a non-significant reduction of 3.1 mmHg in the control group, resulting in a statistically significant difference of 8.1 mmHg (p=0.01) between groups.

The treatment group saw a high (85%) overall response rate, with approximately 54% of the AVIM-treated patients experiencing aSBP reduction at six months of greater than 10 mmHg, an amount associated with a clinically meaningful reduction in risk of heart attack and stroke.

The study met its secondary efficacy endpoint of superiority of AVIM Therapy to control in terms of change in oSBP at six months following randomization. After six months, oSBP was reduced by a statistically significant 12.4 mmHg in the AVIM Therapy group as compared to a non-significant reduction of 0.1 mmHg in the control group, resulting in a statistically significant difference of 12.3 mmHg (p=0.02) between groups.

The MODERATO II study also met its primary safety endpoint, which was no significant differences in rates of MACE. There were no MACE in the AVIM Therapy group and three MACE in two patients in the control group (one death from cancer and two cardiac events) at six months. Additionally, there were no notable differences in echo parameters between the two arms. During the randomized phase of the study, there were eight SAEs in four patients in the control group (n=21) and none in the treatment group (n=26). Two of the eight events were cardiac related. During the extended 18-month follow-up period that included treatment patients (n=26) and crossover-to-treatment patients (n=14), there were 26 SAEs in 16 patients. Out of 26 events, only 13 events (in eleven patients) were cardiac related. No events were adjudicated as possibly related to AVIM Therapy. The non-cardiac events included four cancer related events, four gastrointestinal disorder events, one COVID-19 death, one amputation, two inflammatory events, and a transient ischemic event.

AVIM-treated patients in the MODERATO II study continued to be followed through the 24-month period of the study, including control patients who crossed over to AVIM Therapy after the end of the six-month double-blind period of the study. Only oSBP measurements were taken at follow-up visits after the six-month aSBP primary endpoint was measured. Significant reduction in oSBP, a mean of 17.5 mmHg, was maintained in all AVIM-treated patients who completed the 24-month follow-up. The results for 24-hour aSBP and oSBP at six months post-randomization, as well as the oSBP results at 24 months are shown in the figure below:

124-Hr aSBP Control (n=19), 1 control patient could not be measured despite repeat measurement (patient had extremely high blood pressure);

Additionally, as shown in the chart below, the mean pre-activation 24-hour aSBP profile (systolic blood pressure plotted over a 24-hour period) for all 26 AVIM Therapy patients (prior to receiving AVIM Therapy) was significantly reduced at six months following AVIM Therapy activation at all time points.

Source: 1Burkhoff MODERATO II Study 2-Year Results TCT 2021.

Following completion of the randomized period and successful achievement of the primary endpoints, 14 control patients crossed over to active AVIM Therapy. Nine of the fourteen patients had ISH. The results in these patients were encouraging and consistent with the reductions in the AVIM Therapy group during the randomized portion of the study and are summarized below:

•Statistically significant mean reductions in aSBP (-10.3±9.3 mm Hg, p<0.01) and ambulatory pulse pressure (-11.7±5.5 mmHg, p<0.01) at six months post therapy activation compared to pre-crossover.

•Minimal changes in mean ambulatory diastolic blood pressure (+1.5±5.5 mmHg, p=NS) at six months post therapy activation compared to pre-crossover.

•Mean oSBP decreased by 13.1±26.6 and 13.8±28.7 mmHg at six and eighteen months post therapy activation, respectively, compared to pre-crossover.

MODERATO II Results in ISH Patients

In a subgroup of the MODERATO II study’s patients with ISH, a dangerous and challenging to treat form of HTN prevalent in older patients, treatment with AVIM Therapy resulted in clinically meaningful and statistically significant reductions of 7.4 mmHg in aSBP and 11.9 mmHg in oSBP when compared to control (continued medical therapy) patients at six months. Further, in patients with ISH, AVIM Therapy drove statistically significant reductions of 9.4 mmHg in ambulatory Pulse Pressure and 13.3 mmHg in office Pulse Pressure at six months as compared to control patients.

1Burkhoff MODERATO II Study 2-Year Results TCT 2021.

2Vaccarino V, et al. Am J Cardiol. 2001.

Definitions: aPP = ambulatory Pulse Pressure, oPP = office Pulse Pressure

1Compared to pre-activation.

224-Hr Ambulatory Pulse Pressure control (n=13) at 6 months. One died of cancer, and one had unsuccessful recording.

3Office Pulse Pressure control (n=14) at 6 months. One died of cancer.

4AVIM Therapy(n=21) at 24 months. One died of cancer, and one died from Covid-19.

MODERATO II Long-Term Follow Up & Therapy Washout Study:

On February 26, 2024, we announced new data demonstrating sustained, clinically meaningful reduction in 24-hour ambulatory systolic blood pressure (aSBP) in hypertensive pacemaker patients treated with AVIM Therapy for over 3 years. Reduction in aSBP measured at 6 months from randomization and therapy activation was the primary endpoint of the MODERATO II study, a European multi-center, double-blind, randomized pilot study involving 47 subjects. Patients randomized to AVIM Therapy and antihypertension medication in that study experienced an 11.1 mmHg (p<0.001) reduction in mean aSBP at 6 months follow-up, resulting in a statistically significant difference of 8.1 mmHg compared to control patients who were managed only with anti-hypertensive medications (p=0.01). Long-term blood pressure results are from a follow-up study of 16 patients originally enrolled in the MODERATO II study. This group included eight patients from the MODERATO II study’s AVIM treatment arm and eight control arm patients that crossed over to AVIM Therapy at the end of the 6-month double-blind phase. In this group of patients, aSBP was measured, on average, 3.6 (±0.6) years following initiation of AVIM Therapy. As a group and based on individual paired data, these patients continued to experience a statistically significant, clinically meaningful mean aSBP reduction of 8.9 mmHg at long-term follow up, which is similar to the mean aSBP reduction of 8.9 mmHg seen in this same group of patients when measured at the 6-month aSBP measurement.

1Kalaras et al. Journal of the American Heart Association. 2021;10:e020492 ahajournals.org/doi/10.1161/JAHA.120.020492.

2Burkhoff MODERATO II Study 2-Year Results TCT 2021.

3Fischer MODERATO Study Long-term Results ICI 2024.

4Patients re-consented for long-term follow-up.

On September 4, 2025, we announced the presentation of additional clinical results at the HRX Live 2025 Meeting, in Atlanta, GA, demonstrating that the sustained blood pressure-lowering effects of AVIM Therapy are reversible with no evidence of rebound hypertension or blood pressure exceeding initial baseline values, and can be restored upon reactivation. These data further support AVIM Therapy’s potential role as a controllable, programmable, and durable device-based therapy for uncontrolled hypertension. Key findings included:

●Reversible treatment effect following therapy deactivation:

oReturn to baseline: AVIM Therapy was turned off for a washout period of seven days. On Day 1, aSBP returned to 133.1 mmHg, consistent with original baseline hypertension (132.2 mmHg; p=NS).

oAbsence of rebound hypertension: No residual antihypertensive effects or rebound hypertension were observed.

●Immediate effect upon therapy reactivation:

oRestored reduction in aSBP: Following the 7-day washout period, aSBP was immediately and significantly reduced (124.4 mmHg; p<0.002) upon reactivation.

●Reproducible effect:

oNo statistically significant difference in the therapeutic effects of AVIM Therapy were observed between 6-month (122.8 mmHg), chronic 3.6-year follow-up (122.8 mmHg) and Day 8 reactivation (124.4 mmHg).

MODERATO II Results in Patients with Diastolic Dysfunction

In February 2025, we announced results from a retrospective analysis of the MODERATO II study’s data demonstrating favorable impact of AVIM Therapy on Echo markers of diastolic dysfunction (“DD”), a key driver of heart failure progression. The results were presented as late-breaking science at the Technology and Heart Failure Therapeutics (“THT”) 2025 Conference. HTN is the leading cause of DD; both conditions are common in older patients and contribute to the development of heart failure. On August 15, 2025, we announced that these results were published in the Journal of the American College of Cardiology: Advances.

The retrospective, treatment-blinded analysis of the MODERATO II study assessed the impact of 6 months on systolic blood pressure (“SBP”) and Echo markers of DD using core lab Echos with independent blinded adjudication. Patients were classified as with DD (“DD+”) or without DD (“DD-”) using ​the American Society of Echocardiography Guidelines. From the MODERATO II study cohort (n=47), 36 patients had technically sufficient Echo data, and 61% of this group (22/36) had Echo evidence of DD.

Using key measures of diastolic function, AVIM Therapy:

●Significantly reduced office and ambulatory SBP in patients ​with DD through 6 months

oAmbulatory SBP (“aSBP”) was reduced in AVIM-treated DD+ patients (N=12) by 8.3±9.7 mmHg (p<0.01 vs. baseline) compared to 2.2±9.8 mmHg in the control DD+ group (N=10)

oOffice SBP (“oSBP”) was reduced in AVIM-treated DD+ patients by 12.1±12.8 mmHg (p<0.01 vs. baseline) compared to an increase of 2.9±26.4 mmHg in the control DD+ group (N=10)

oSBP reduction was similar in patients with and without DD

●Significantly improved key measures of diastolic dysfunction​

oIn patients with DD, AVIM Therapy demonstrated favorable Echo changes consistent with improved myocardial relaxation and diastolic compliance. Specifically, in comparison to DD+ control patients, AVIM-treated DD+ patients experienced a significant increase in e’ (from 5.9±2.0 to 8.8±3.4cm/sec; P<0.01) consistent with an improvement in left ventricular relaxation and a significant increase in E/A (from 0.86±0.39 to 1.60±0.84; P<0.01) consistent with improved passive filling of the left ventricle despite reduced filling time (the designed effect of AVIM Therapy) with no significant changes in left atrial size.

These findings provide further evidence that AVIM Therapy, in addition to significantly reducing systolic blood pressure, may also favorably influence ventricular function in important ways for patients with DD and at risk for heart failure.

Clinical, Regulatory and Commercialization Pathway

The BACKBEAT Global Pivotal Study

On September 19, 2023, we announced that the FDA granted us IDE approval to initiate our planned BACKBEAT study to treat uncontrolled HTN in patients indicated for a pacemaker. On January 8, 2024, we announced that the first patient was enrolled and randomized into the BACKBEAT study in late December 2023. The BACKBEAT study is a global, multi-center, prospective, randomized, double-blind study investigating the efficacy and safety of AVIM Therapy in patients who have recently undergone implantation of a Medtronic dual-chamber cardiac pacemaker and have uncontrolled HTN despite the use of anti-hypertensive medications. We are actively screening patients for enrollment in the BACKBEAT study. Site activations are expected to continue throughout 2025 with a target of activating up to 130 centers in the United States and Europe. The study will randomize up to 500 patients 1:1 to AVIM Therapy combined with continued medical therapy (treatment) or continued medical therapy and standard pacing alone (control). The study’s primary efficacy endpoint will determine at three months post-randomization whether AVIM-treated patients experience a statistically significant reduction in daily average blood pressure (mean 24-hour aSBP) as compared to control patients. The primary safety endpoint will determine at three months post-randomization whether AVIM-treated patients experience serious adverse device effects that are not anticipated with cardiac pacing. Double-blind follow-up will continue through 12 months to enable the collection of additional clinical endpoints. All patients will be eligible to cross over upon completion of the 12-month blinded follow-up phase. The updated protocol also streamlines site coordinator and patient visit activities. We currently estimate completion of enrollment of the BACKBEAT study in mid-2026; however, there is no assurance that our current operating plan will be achieved.

The design of the BACKBEAT study is outlined in the chart below:

We utilize a four-pronged approach to support clinical activities for the BACKBEAT study: (1) full-time employees and consultants to directly manage the study in Europe; (2) U.S. based full-time employees who manage and oversee clinical trial work that is outsourced to contract research organizations (CROs), strategic partners, and service vendors, including site management and safety monitoring activities; (3) regional field clinical engineers (“FCEs”) who support site activations and on-site clinical activities in the U.S. and Europe, including AVIM programming support ; and (4) FCE and other clinical and regulatory resources from Medtronic, our strategic partner, to assist with certain clinical study activities.

In the third quarter of 2019, the Moderato implantable system that delivers AVIM Therapy for the treatment of uncontrolled HTN while also providing standard pacemaker functions was CE marked in the EU under the Active Implantable Medical Device Directive. We currently do not have plans to commercialize this system in the EU on our own but believe there is a significant opportunity for Medtronic to commercialize AVIM-enabled pacemakers in the EU post-marketing approval. We expect that the BACKBEAT study will include at least 20 clinical study sites in the EU, including several sites that participated in the MODERATO I and II studies.

For the clinical and regulatory development of AVIM Therapy for uncontrolled HTN with high cardiovascular risk, we will seek to leverage data from the BACKBEAT study given that age and other demographic factors of the target population are expected to be similar, the type of HTN treated will likely be isolated systolic HTN which is a predominant form of HTN in the HTN+P population, and other comorbidities are also expected to be similar to both target populations.

AVIM Therapy & CNT-HF for Heart Failure

Our Bioelectronic Therapies group is also seeking to develop a pipeline of additional treatments for development and future licensing based on its patented CNT technology. The lead follow-on therapy candidate is CNT-HF, a bioelectronic treatment for HF. According to the AME Medical Journal, HF affects an estimated 64 million people worldwide. According to the Journal of Cardiac Failure, 6.7 million Americans have HF costing nearly $31.0 billion annually. AHA projects the cost of HF will increase by 127% to $69.8 billion in 2030, amounting to approximately $244 for every U.S. adult. Heart failure was a contributing cause of death in the U.S., resulting in over 400,000 deaths in 2022 and accounted for about 45% of cardiovascular deaths that year, according to the Heart Failure Society of America. Approximately half of the patients with signs and symptoms of heart failure have largely normal left ventricular ejection fraction and are therefore considered Heart Failure patients with Preserved Ejection Fraction (“HFpEF”), according to the AHA. The prevalence of HFpEF compared with prevalence of HF with reduced ejection fraction (“HFrEF”), appears to be increasing over time along with aging of the population and the increasing prevalence of risk factors for HFpEF, such as obesity, HTN, and type 2 diabetes as well as improvements in diagnosis, according to the AHA. Those living with HFpEF experience frequent hospitalizations and high mortality rates. Nevertheless, there are currently no approved disease-modifying therapies for HFpEF. The success of existing HF therapies is mostly limited to treatment of HFrEF, not HFpEF, according to GlobalData.

We are exploring the benefits of AVIM Therapy in patients with HTN and/or ISH that are at high risk for the development of HFpEF or have early-stage HFpEF. We believe there is a likely physiological relationship between chronic HTN, particularly ISH, and other conditions such as DD, and the development of HF. We believe AVIM Therapy may play a beneficial role in the dynamic, helping to prevent progression of HFpEF. We are planning to initiate a pilot clinical study in 2026 of AVIM Therapy for the treatment of patients with HFpEF using our proprietary Moderato Plus IPG.

We have also conducted initial feasibility work with regard to CNT-HF, a modified cardiac neuromodulation therapy algorithm that, like AVIM Therapy, aims to achieve autonomic nervous system modulation with a primary focus on sympathetic down-regulation without substantial impact on blood pressure for the treatment of HFrEF. HFrEF is a syndrome characterized initially by left ventricular dysfunction that triggers countermeasures aimed to restore cardiac output. These responses are compensatory at first but eventually become part of the disease process itself, leading to further worsening cardiac function. Among these responses is the activation of the sympathetic nervous system (“SNS”), that provides inotropic support to the failing heart increasing stroke volume, and peripheral vasoconstriction to maintain mean arterial perfusion pressure, but eventually accelerates disease progression affecting survival. Activation of SNS has been attributed to the withdrawal of normal restraining influences and the enhancement of excitatory inputs, leading to worsening heart failure symptoms and progression of disease.

If shown to be safe and effective, we believe CNT-HF for the treatment of heart failure has the potential to be an attractive therapeutic candidate for licensing and collaboration with strategic partners that have established commercial cardiac rhythm management business. We anticipate that CNT-HF will run on a dual-chamber pacemaker, a three-chamber bi-ventricular pacemaker (also known as a cardiac resynchronization therapy or “CRT” device), as well as, potentially, a combined pacemaker/CRT/defibrillator, allowing potential strategic partners already in the cardiac rhythm management business to provide an entirely new HF treatment leveraging their existing manufacturing and commercialization infrastructure.

INTERVENTIONAL THERAPIES — Virtue SAB for Artery Disease and SirolimusEFR for Local Inflammation in Multiple Indications

We are developing high impact therapeutic product candidates designed to optimize focal drug delivery during well-established interventional procedures with the objective of improving clinical outcomes and reducing complications. Our flagship product candidate of the Interventional Therapies portfolio is Virtue SAB, a drug-device product candidate that is designed to enable targeted delivery of sirolimus, an approved pharmaceutical agent for preventing restenosis during interventional stent treatment of artery disease, the leading cause of death worldwide. We are also exploring multiple additional applications of SirolimusEFR, our proprietary, investigational extended focal release formulation of sirolimus used in Virtue SAB. Sirolimus is a widely used anti-proliferative, anti-inflammatory pharmaceutical. We believe its unique formulation has the potential for the treatment of local inflammation in target tissues other than coronary and peripheral arteries, and a broad array of additional indications in which we are conducting early exploratory work, such as urology.

Below is a detailed summary of Virtue SAB and an overview of potential future SirolimusEFR-based programs.

Virtue Sirolimus AngioInfusion Balloon

Virtue SAB is a novel, proprietary drug-device combination product candidate for the treatment of artery disease that is designed to deliver a large liquid dose of extended focal release formulation of sirolimus to the vessel wall during balloon angioplasty without the need for balloon coating or a permanent implant. Virtue SAB utilizes two key enabling technologies, our proprietary, investigational formulation of sirolimus, SirolimusEFR, and its patented microporous AngioInfusion Balloon, that work synergistically to optimize the clinical performance of the product candidate. Virtue SAB demonstrated promising clinical data from the SABRE trial, a multi-center, prospective, independent core lab-adjudicated pilot clinical study of 50 patients with coronary ISR conducted in Europe. We are currently enrolling patients in the Virtue Trial, a U.S. IDE pivotal trial to be conducted at up to 75 sites that is expected to randomize approximately 740 patients 1:1 to either treatment with Virtue SAB or Boston Scientific Corporation’s AGENTTM paclitaxel-coated balloon (currently the only drug-coated balloon approved in the U.S. for a coronary indication) with a primary efficacy and safety endpoint of statistical non-inferiority of target lesion failure (“TLF”) at 12 months post index treatment. The aim of this study is to support regulatory approval of Virtue SAB in the U.S. and other countries around the world. We believe Virtue SAB has the potential for further evaluation in follow-on clinical indications such as treatment of de novo coronary small vessel (“SV”) disease, below-the-knee peripheral disease (“BTK”), and other therapeutic areas such as urology.

Termination and ROFR Agreement with Terumo

On October 28, 2025, we entered into the Termination and ROFR Agreement with Terumo with respect to Virtue SAB. The ROFR Agreement, which supersedes and terminates the Terumo Agreement, grants Terumo a ROFR to acquire the rights, or enter a distribution arrangement, with respect to Virtue SAB for the treatment of coronary artery disease, in exchange for an upfront payment of $10.0 million. In connection with the Termination and ROFR Agreement, on November 7, 2025, Terumo invested an additional $20.0 million in Orchestra BioMed through our Series A Preferred Stock, which is convertible into common stock in the future, subject to certain conditions, at a minimum of $12 per share. Terumo previously made a $30.0 million non-refundable payment and $5.0 million common stock investment in Orchestra BioMed upon execution of the Terumo Agreement.

Market Needs — Coronary and Peripheral Artery Disease

Artery disease is caused by atherosclerosis, the hardening and narrowing of the arteries due to the build-up of fatty material and plaque that reduces blood flow through the blood vessels supplying the heart muscle (coronary artery disease or “CAD”) or limbs (peripheral artery disease or “PAD”). CAD reduces blood flow and oxygen supply to the heart muscle and can result in angina, heart attack and lead to heart failure and arrhythmias. PAD can happen in any blood vessel, but it is more common in the legs than the arms and can lead to pain, muscle weakness, wounds and ulcers that are difficult to heal and, eventually, amputation.

According to the WHO, cardiovascular diseases are the top cause of global death, resulting in over 19.8 million deaths annually worldwide. The CDC estimates 1 in 20 adults (approximately 5%) in the U.S. aged 20 and older have CAD and reported 370,000 CAD-driven deaths in the United States in 2022.

The AHA also estimates 10-12 million adults in the United States have PAD, including up to 15% of individuals older than age 70.

Interventional Cardiology

Interventional cardiology is a medical specialty that uses minimally invasive transcatheter, percutaneous technologies and techniques to treat artery disease and atherosclerosis. Catheter-based interventions using balloon angioplasty, stents and other technologies are the most common medical procedures used to treat artery disease and related conditions. There were over 6.4 million coronary and over 1.6 million peripheral catheter-based interventional procedures performed worldwide in 2022 according to Global Data & LSI Research. The global market for coronary interventional devices used to treat CAD, such as stent and balloon angioplasty systems, was valued at approximately $27.8 billion in 2024, and the global market for devices used to treat PAD, including angioplasty balloons, drug-coated balloons (“DCBs”), stents and atherectomy systems, was valued over $7.8 billion in 2022, according to market research firms Grand View Research and Straits Research.

The Evolution of Available Treatment Options

Balloon angioplasty is a procedure where small balloons integrated into catheters are introduced into the vascular system through a small puncture in the femoral artery in the leg or radial artery in the arm. Using specialized imaging technology called angiography, the balloon catheter is threaded through the vasculature to the site of blockage in an artery in the heart (coronary) or in the peripheral vessels. The balloon is then inflated using high pressures (up to 20 atmospheres) in order to crush the blockage (plaque) and expand the artery to restore blood flow.

While plain balloon angioplasty can offer significant clinical benefits, it also comes with drawbacks, such as elastic recoil, arterial remodeling or vascular smooth muscle cell excessive proliferation resulting in restenosis (vessel renarrowing) in response to balloon injury. These problems drove the development of bare metal stents (“BMS”) that are permanently implanted to hold a vessel open. These devices helped address elastic recoil and remodeling which helped reduce the impact of restenosis while also limiting the incidence of abrupt closure.

While the use of BMS helped address abrupt closure, it did not fully address the problem of restenosis in response to injury caused by the interventional procedure. Both angioplasty and stenting cause a stretch injury to the artery, resulting in a healing response whereby arterial smooth muscle cells proliferate and may block the artery again, a process known as restenosis. Restenosis can also occur over longer periods of time after a procedure because of the development of new atherosclerosis.

To help address the problems of restenosis, device manufacturers introduced drug-eluting stents (“DES”), which are stents coated with potent pharmaceutical agents that stop excessive cellular proliferation and thereby minimize ISR. The most commonly used drugs were sirolimus, ‘limus analogs and paclitaxel. Paclitaxel is a cytotoxic drug widely used in cancer chemotherapy. Paclitaxel interferes with cell division, leading to cell death. Sirolimus and other ‘limus analogs, on the other hand, are cytostatic drugs widely used as an immunosuppressant to prevent transplant rejection. Sirolimus works by blocking a key pathway critical to cell proliferation while allowing the cell to continue to function when sirolimus is no longer present. Sirolimus and its analogs, or ‘limus agents, can be administered in high doses without adverse effects, resulting in a low toxicity profile.

In a large meta-analysis of 76 studies in patients undergoing percutaneous coronary intervention, ‘limus-eluting stents outperformed paclitaxel-eluting stents. In a meta-analysis of 26 randomized controlled trials (“RCTs”), ‘limus-eluting stents demonstrated superior safety and efficacy with significantly lower MACE and target lesion revascularization, rates compared to paclitaxel-eluting stents (see figures below). Thus, ‘limus analog eluting stents have become the clear “gold standard,” with nearly 100% current global market share in the coronary DES marketplace.

Source: Xinlin Zhang, et. al. PLOS ONE 2014 May 20;9(5):e97934.

Definitions: Adj-OS = adjusted observational study; Cl = confidence interval; No. = number of the studies; Non-adj OS = non-adjusted observational study; PES = paclitaxel-eluting stents; RCT = randomized controlled trial; RR = relative risk; SES = sirolimus-eluting stent; TLR = target lesion revascularization

One clearly demonstrated requirement for the use of sirolimus and other ‘limus agents in DES for the prevention of restenosis is that they be bioavailable for approximately 30 days at the treated lesion for optimal efficacy. This 30-day period is considered the critical healing period following the baseline interventional procedure during which the DES is implanted. For commercially successful DES products marketed by leading companies such as Medtronic, Abbott and Johnson & Johnson, the drug elution profile, or rate at which drug is released from the stent, has been specifically engineered and demonstrated in published preclinical results to provide drug availability for approximately 30 days. The critical importance of this 30-plus day elution profile for sirolimus and ‘limus agents is best demonstrated by Medtronic’s experience with its first DES product called Endeavor. The Endeavor DES was designed to have a faster drug release profile resulting in an elution period of approximately 14 days. Clinical results with the Endeavor product were not favorable as compared to other commercially available DES. Subsequently, Medtronic developed and commercialized another DES product called Resolute that eluted Zotarolimus, a ‘limus agent proprietary to Medtronic, over more than 30 days. Medtronic conducted head-to-head clinical studies comparing Endeavor to Resolute demonstrating significantly superior clinical outcomes for Resolute in terms of Late Lumen Loss (“LLL”), and Target Lesion Failure (“TLF”). The figures below show the drug elution profile of the fast-eluting Endeavor DES compared to Resolute and the Cypher DES (Johnson & Johnson) and the Xience DES (Abbott), as well as clinical outcomes comparing Endeavor to Resolute.

1Tada, et. Al., Am Heart J. 2013 Jan; 165(1):80-6;

2Leon M. LBCT III, Session 3014. Presented at: ACC 60th Annual Scientific Sessions; April 2-5, 2011

While DES offer significant clinical improvements over plain balloon angioplasty and BMS, they have limitations, including the need for long-term use of dual antiplatelet therapy (having to use two types of antiplatelet agents) to address the new issues of late and very late stent thrombosis (formation of a blood clot) caused by delayed healing, local inflammation and impaired endothelial function around the stent. In addition, restenosis within a stent occurs in 5 – 10% of stented patients during the first year and continues at a rate of up to 3% per year thereafter, according to data from the National Cardiovascular Data Registry.

The limitations of DES prompted innovation for improved solutions that enable local delivery of anti-proliferative drugs while not leaving a permanent metal implant in the vessel. Bioabsorbable vascular scaffolds (“BVS”), were developed with the objective of performing like stents while eventually dissolving and leaving nothing behind after a few years. In July 2016, the first such device was approved by the FDA, Abbott’s Absorb Everolimus-eluting BVS. Unfortunately, this promising innovation has encountered several setbacks in clinical studies and upon commercialization. In September 2017, Abbott decided to pull Absorb from the market while other device manufacturers halted their in-progress programs. As a result, the attractive concept of “leave nothing behind” drug-eluting interventional therapy for coronary arteries remains unfulfilled. More recently, these devices are being explored for treatment of below-the-knee PAD, a challenging area of unmet need for which we believe Virtue SAB may warrant further development.

Drug-coated balloons have emerged during the last decade with the goal of providing the mechanical vessel expansion and anti-proliferative drug properties of DES while leaving nothing behind. We believe the concept of combining balloon angioplasty with simultaneous delivery of anti-proliferative medication may offer incremental benefits over available interventional therapies by (i) preserving the artery’s original anatomy; (ii) enabling treatment of vessels where DES delivery is challenging, such as small and bifurcated vessels; (iii) offering potential clinical improvement in lesions where available interventional devices have shown poor performance, including below-the-knee and restenotic lesions; and (iv) minimizing the dependency on long-term dual antiplatelet therapy and associated bleeding risks.

While having the potential to offer benefits over available interventional therapies, drug-coated balloons face some important challenges:

●The Use of Paclitaxel — Despite the inferior performance observed in DES, most of the drug-coated balloons in use or in development globally deliver paclitaxel. The primary reason paclitaxel is used on drug-coated balloon technology is that paclitaxel has shown to be an easier pharmaceutical agent for balloon-based delivery due to fast tissue absorption and long tissue retention. On the contrary, delivery of ‘limus agents has proven to be difficult based on two key reasons: (i) slow tissue absorption making it difficult to transfer the drug and ensure desired tissue absorption; and (ii) short half-life (the time it takes for the amount of drug present to be reduced by 50%) makes it challenging to ensure that therapeutic concentration of the drug is present for the critical, four-week healing period.

Comparison of ‘Limus Agents and Paclitaxel by Key Attributes Relevant to Drug-Coated Balloons

•Balloon Surface Coating — Drug-coated balloons utilize surface coatings for drug delivery which carry inherent limitations such as: (1) drug dosing that is constrained to what can incorporated in a balloon surface coating, (2) risk of emboli (e.g., a blood clot or other blockage) from large coating particulates that may cause downstream ischemia (an inadequate blood supply) in non-target tissues, and (3) significant drug loss during navigation of the balloon to the target lesion location in the artery. Published quantitative analysis of various drug-coated balloons showed a substantial number of large particles (>300μm). Large particles have the potential to occlude microvessels downstream following balloon inflation.

•In addition, third-party clinical data demonstrated that 50 – 80% of drug was washed or scraped off during transit to the target lesion prior to balloon inflation. Concerns of drug loss in transit and risk of particulates have prompted existing drug-coated balloon manufacturers to recommend balloon inflation within 30 seconds of balloon insertion into the patient, making it challenging for physicians to reach target lesions and ensure proper placement in such a short period of time, particularly in difficult coronary and peripheral lesions such ISR, small vessel disease, and below-the-knee disease.

Despite the limitations of paclitaxel-based DCBs, they are now widely used globally for the treatment of coronary ISR, coronary SV disease and other coronary indications. EU clinical guidelines recommend the use of DCBs for the treatment of coronary ISR based on clinical evidence. On March 1, 2024, Boston Scientific Corporation (“BSC”) announced FDA approval for its AGENT™ paclitaxel-coated balloon for the treatment of coronary ISR. BSC launched the AGENT DCB commercially in the US in late 2024 and has reported rapid commercial uptake since launch. We believe the AGENT DCB is currently becoming the new standard of care for coronary ISR in the US.

BSC has reported 2-year follow-up results from its US IDE study comparing the AGENT DCB to plain balloon angioplasty for the treatment of coronary ISR. These results showed statistical superiority for AGENT over plain balloon angioplasty with respect to the occurrence of TLF, the primary endpoint for the study. However, we believe the 17.9% reported rate of overall TLF at 1 year follow up is still high and creates a need and an opportunity for a differentiated, sirolimus-based product like Virtue SAB to demonstrate superior results and improve this standard of care. In the subgroup of patients that had single-layer ISR, AGENT DCB showed a TLF rate of 13.5% at 1 year follow up. This TLF result worsened by over 53% to 20.7% at 2-year follow-up.

At TCT 2025, Cordis reported preliminary results from its IDE study called SELUTION4ISR comparing the performance of its Selution SLR™ sirolimus-coated balloon to a “standard of care” control group including DES and plain old balloon angioplasty (“POBA”) for the treatment of coronary ISR. While the Selution DCB achieved statistical non-inferiority to the control group, its results were numerically inferior.

Further, while ‘limus-based DES consistently outperformed paclitaxel DES as described above, Selution DCB’s 13.2% TLF rate in single-layer ISR were equivalent to the AGENT DCB results. The SELUTION4ISR and AGENT studies involved significantly different rates of double-layer stent ISR, making comparisons of overall performance difficult.

Overall, we believe Virtue SAB’s performance in the SABRE study described below, particularly in the single-layer ISR per protocol population, reflects a promising opportunity for Virtue SAB in coronary artery treatment. However, please note that the AGENT study, the SELUTION4ISR study and the SABRE study are three separate studies conducted at different times and are not head-to-head comparisons of these therapies. Thus, the results of these studies may not be comparable.

1Yeh RW, Shlofmitz R, Moses J, et al. JAMA. 2024;331(12):1015–1024. doi:10.1001/jama.2024.136.

2Moses, J Two-Year Outcomes from the AGENT IDE Trial CRT 2025.

3Boston Scientific AGENT DCB Brochure 2017.

Definitions: Plain old balloon angioplasty (POBA), Standard of care (SOC), late lumen loss (LLL)

1Cutlip et al. SELUTION4ISR Clinical Trial TCT 2025.

Targeted Unmet Needs and Market Opportunity for Virtue SAB

We believe significant unmet needs remain in certain artery disease indications where treatment options are limited or fail to adequately improve patient outcomes, including ISR, SV, high bleeding risk patients undergoing percutaneous revascularization and BTK. We estimate these indications currently represent a total addressable global market opportunity of approximately 5.0 million treatable artery disease lesions. Further, based on estimated regional average selling prices, we believe the current aggregate annual global market opportunity for Virtue SAB is at least $10 billion. The bullets below outline key potential market opportunities, including their relative size and scope, for Virtue SAB.

•Coronary ISR: The majority of coronary artery interventional procedures involve the placement of a permanent stent at the site of stenotic lesion. According to the National Cardiovascular Data Registry, restenosis within a stent occurs in 5 – 10% of stented patients during the first year and continues at a rate of up to 3% per year thereafter, resulting in what we currently estimate to be an annual addressable global market of nearly 347,000 lesions that may require treatment. Until recently, the only device treatments approved by the FDA specifically for use in coronary ISR lesions were balloon angioplasty and intravascular radiation therapy known as brachytherapy. However, brachytherapy is considered a last resort treatment due to expense, limited availability, and long-term requirement for dual antiplatelet therapy, and hence represents a small proportion of ISR procedures, while traditional balloon angioplasty has poor outcomes with high retreatment rates. Although DES are not approved for ISR, it is commonly used off-label despite the problems associated with multiple stent layers within the lumen of the vessel along with other limitations. Despite the limitations of paclitaxel-based DCBs, they are now widely used in the EU and Japan for the treatment of coronary ISR, coronary SV disease and other coronary indications. EU clinical guidelines recommend the use of DCBs for the treatment of coronary ISR based on clinical evidence. We estimate that potentially more than 30% of coronary interventions in the EU and Japan utilize a paclitaxel DCB. On March 1, 2024, BSC announced FDA approval for its AGENT™ paclitaxel-coated balloon for the treatment of coronary ISR following preliminary results from its US pivotal study showing statistical superiority for AGENT over plain balloon angioplasty with respect to the occurrence of TLF. We believe the 17.9% reported rate of overall TLF is still high and creates a need and an opportunity for a differentiated, sirolimus-based product like Virtue SAB.

•De Novo Coronary Small Vessels (<=2.5 mm): DES are difficult to position in vessels measuring less than or equal to 2.5 mm in diameter and may reduce already limited luminal area thereby impacting blood flow. We estimate, based on published data relating to specific country-wide lesion incidences, that there are approximately 1,500,000 patients with lesions in small diameter vessels that may require treatment worldwide.

•De Novo Large Vessel (>2.5 mm): Percutaneous coronary intervention (“PCI”), with placement of DES requires prolonged (greater than six months) treatment with dual antiplatelet therapy (“DAPT”), which is intended to prevent stent thrombosis or the development of blood clots on or around the metal struts of a stent. Stent thrombosis can lead to major adverse events such as heart attacks and death. We estimate, based on published data relating to specific country-wide lesion incidences, that patients with vessel diameter greater than 2.75 mm currently have an estimated 1,850,000 treatable lesions worldwide.

•Below-the-Knee Lesions: BTK disease is a form of PAD and is a primary cause of critical limb ischemia or lack of sufficient blood flow to the legs and feet. This may lead to amputation and increased risk of death. Diagnosis and treatment of BTK disease is highly fragmented with patients being diagnosed by internists, podiatrists as well as interventionalists. The Rutherford score is often used to classify patients with peripheral artery disease with 0 being asymptomatic and 6 being severe ischemic ulcers or gangrene. The patients with Rutherford score of 3 – 5 are most likely to benefit from an effective interventional BTK treatment. We estimate there are currently 1,242,000 treatable BTK lesions worldwide. Available endovascular treatment options are limited and often provide limited benefit. Balloon angioplasty has generally poor outcomes with high restenosis rates that require frequent retreatment for these lesions. DES and bare metal stents are used off-label to treat BTK lesions but suffer from strut fractures and kinking due to high torsion and potential for a crush injury in arterial lesions that are located between the knee and ankle. Disappointingly, BTK trials with paclitaxel-coated balloons to date have shown limited improvement over plain balloons as well as, in some cases, increased risk of amputation. While the cause of increased amputation risk has not been attributed to a specific factor, we believe this may be due to drug toxicity and the impact of flakes and large particulates from the balloon coating itself causing blockage in downstream capillaries or the cytotoxic effect of paclitaxel in these downstream locations.

The above estimates are based on, among other factors, our engagement with an established market research firm to conduct market analysis of the Virtue SAB global opportunity. This third party employed primary and secondary data gathering and analysis methods. Primary analysis involved multiple Q&A calls with industry-leading key opinion leaders to help assess the addressable patient population and the most addressable patient segments. Secondary data analysis was conducted by mining numerous subscription-based market databases, Medicare data and published literature. After gathering initial disease prevalence data, both we and the third party spent extensive time collaborating on further delineating potential procedure volumes for coronary ISR, coronary SV disease, and BTK peripheral disease that can be addressed by Virtue SAB, taking into consideration patient treatment pathways, anticipated product benefits, competitive landscape and reimbursement. The market size calculations accounted for patients with high bleeding risk, which overlaps with all three target indications, and we believe will be an important driver of adoption. Our above estimate of 5.0 million treatable artery disease lesions is based on third-party data, combined with our knowledge of market dynamics and anticipated product differentiation.

Average selling price estimates were calculated by country or region based on existing competitive device prices, as well as estimated future pricing for Virtue SAB and future competitive devices. Reimbursement policies and coverage determinations for medical technologies are subject to evolving regulatory and market dynamics. The recent FDA approval and commercialization of BSC’s AGENT may establish a clearer reimbursement pathway for DCBs, potentially benefiting our future market access strategy. As payors define coverage policies, coding, and payment rates for AGENT, we may benefit from an established precedent and streamline our engagement with Medicare, Medicaid, and private insurers, facilitating broader and more predictable coverage upon regulatory approval. Additionally, the adoption of a reimbursement framework for AGENT may expedite decision-making among payors, potentially leading to more favorable reimbursement terms for similar technologies, like Virtue SAB. While the evolving landscape presents opportunities, reimbursement determinations remain subject to various factors, including clinical differentiation, cost-effectiveness assessments, and provider adoption. We will continue to monitor and engage with key stakeholders to ensure alignment with emerging reimbursement policies that could enhance market access for Virtue SAB.

Impact Potential of Virtue SAB

Virtue SAB is a proprietary drug-device combination product designed to deliver a large liquid dose of extended focal release SirolimusEFR during angioplasty for the treatment of atherosclerosis and prevention of restenosis. The patented Virtue SAB is specifically designed to perform angioplasty, a well-established interventional procedure where high-pressure balloon inflation mechanically re-opens a clogged artery. It also simultaneously enables protected delivery and extended focal release of therapeutic levels of proven sirolimus over the critical healing period following angioplasty, which we believe could revolutionize intra-procedural arterial drug delivery by leaving nothing permanent behind in the artery. While Virtue SAB is designed to achieve certain results as described above and below, there is no guarantee that Virtue SAB will prove to be safe and effective. Virtue SAB is designed to overcome the limitations of drug-coated balloons by:

•Delivering sirolimus without the need for a permanent implant or balloon coating;

•Protecting drug during transit to treatment site, preventing drug loss and reducing potential for downstream ischemia from large particulates;

•Performing angioplasty using standard catheter techniques without navigation and deployment time constraints; and

•Delivering the intended dose of sirolimus consistently

1Granada et al. EuroIntervention 2016;12:740-747.

2 Animals included in the analysis of distant organs received average dose of 20.4 mg ≈10X the largest clinical dose

The differentiated design of Virtue SAB was made possible by combining two key technologies:

•Our patented AngioInfusion Balloon is designed to offer protected delivery of SirolimusEFR by keeping the drug formulation contained within the Dose Unit until the time of inflation when it is delivered to the target lesion through micropores in the balloon surface. The AngioInfusion Balloon is designed to offer the following benefits:

•Enable high-pressure angioplasty to dilate artery, restoring blood flow;

•Protect SirolimusEFR in transit to deliver the intended therapeutic dose at the target lesion;

•Deliver SirolimusEFR simultaneously with angioplasty; and

•Leave no permanent implant behind.

•Our proprietary, investigational SirolimusEFR powered by Sostenocel, a fully bioabsorbable technology, is designed to enable extended focal release of a therapeutic dose of the anti-restenotic sirolimus over the critical healing period. SirolimusEFR is designed to offer the following benefits:

•Protection of sirolimus from rapid degradation;

•Extended release of therapeutic levels of sirolimus into the tissue during the critical healing period of approximately 30 days; and

•Elimination from the body, leaving no detectable residual drug or material behind.

Virtue SAB System Components and Deployment

The Virtue SAB product candidate is under development to be provided in two packages:

•AngioInfusion Balloon Package: This package includes the AngioInfusion Balloon along with a Compliance Card explaining the pressures needed for full balloon expansion, a Dose Chart which defines the dose of SirolimusEFR to be utilized for each balloon size, and the proposed Instructions for Use (“IFU”) for the system. To accommodate various vessel sizes and lesion diameters, we expect end users would need to stock an array of AngioInfusion Balloon sizes. The AngioInfusion Package is expected to be stored at room temperature with a target shelf-life of two years at commercial launch (shelf-life independent of SirolimusEFR Package), if approved.

•SirolimusEFR Package: This package includes SirolimusEFR in freeze-dried powder form in a vial with all components needed to reconstitute the formulation and set the desired dose to be delivered for the target lesion based on length and vessel diameter according to the Dose Chart and IFU provided in the package. The SirolimusEFR package is designed to be universal for all AngioInfusion Balloon sizes.

Since Virtue SAB is designed to work primarily as a balloon angioplasty catheter, the device most commonly used by interventional cardiologists, we believe it should be relatively easy for physicians to learn, adopt and use the device. The additional steps we expect will be required to reconstitute SirolimusEFR are straightforward and familiar to nurses and technicians. Following the standard preparation of the vessel and after identifying the appropriate balloon size, Virtue SAB is designed to be deployed in three easy steps:

1.Reconstitute the formulation and set dose

•SirolimusEFR is designed to be provided as a lyophilized (freeze-dried) powder that is reconstituted using provided components prior to the angioplasty procedure. Each balloon size is designed to deliver a specific volume of SirolimusEFR. Based on the balloon size selected, the required dose volume of the reconstituted liquid formulation is loaded into the Dose Unit. The SirolimusEFR-loaded Dose Unit is connected to the AngioInfusion Balloon catheter.

2.Prime the catheter

•The AngioInfusion Balloon is a semi-compliant microporous balloon. After the Dose Unit is connected, the AngioInfusion catheter is primed with the formulation using a standard endoflator device used in all catheterization labs prior to insertion into the patient and navigation to a target lesion. The dose remains protected in the catheter and the Dose Unit.

3.Position AngioInfusion Balloon and inflate

•Similar to standard angioplasty, a guidewire and guide catheter are placed, and the balloon is positioned at the lesion using radiopaque marker bands. When satisfied with device positioning, the physician inflates the AngioInfusion Balloon to perform standard high-pressure angioplasty. The intended dose of SirolimusEFR is delivered simultaneously through the micropores to the target lesion.

Preclinical Data

We have conducted extensive preclinical testing of Virtue SAB and its key enabling technologies (SirolimusEFR and the AngioInfusion Balloon), including feasibility work as well as Good Laboratory Practice (“GLP”) studies in support of regulatory filings and approvals. This work includes a variety of benchtop as well as small and large animal models. Large animal studies have been conducted in a porcine animal model, a widely used model for testing interventional cardiovascular devices. A particularly important series of preclinical studies involving 130 pigs and over 750 distinct artery treatment sites showed that Virtue SAB provided extended focal release of therapeutic levels of sirolimus through the critical healing period of approximately four weeks. The data from these preclinical studies was published in the peer-reviewed EuroIntervention Journal in 2016 and showed that Virtue SAB successfully delivered and enabled long-term focal delivery at the treatment site of a therapeutic sirolimus dose (above the 1ng of drug per mg of tissue). This therapeutic dose level has been clinically proven using DES to be safe and efficacious at reducing restenosis during the critical healing period of approximately 30 days post-procedure. These preclinical studies also showed very low systemic concentrations in cardiac tissue as well as critical organs, such as lungs, liver and kidneys, and did not show any adverse local or systemic effects.

In March 2024, we shared preclinical pharmacokinetic (“PK”) data demonstrating that SostenocelTM, the proprietary polymer system enabling Virtue SAB’s SirolimusEFR, was shown to be eliminated in SirolimusEFR-treated stented arteries without detectable degradation. In other polymer-based delivery systems, degradation prior to elimination is associated with adverse events, such as the development of localized tissue inflammation. Specifically, the presented PK data showed that Sostenocel was undetectable at 90 days in treated arteries and at 3 days in all non-target tissues, and the molecular weight of Sostenocel remained unchanged prior to elimination, showing no evidence of in-vivo degradation. This is achievable through the focal uptake extended release of Sostenocel technology.

Clinical Results

SABRE Study Results

The SABRE, or Sirolimus AngioInfusion Balloon for Coronary In-Stent Restenosis, first-in-human clinical study was initiated in November 2013 by Caliber Therapeutics, Inc., which is now our subsidiary. SABRE was a prospective, 50-patient feasibility study at nine European centers (Belgium, The Netherlands, Denmark and Latvia), following patients for three years after Virtue SAB treatment, including angiographic follow-up at six months and clinical follow-up at one, two and three years.

Twelve-month follow-up data from the SABRE study, published in JACC Intervention in October 2017, demonstrated the clinical study performance of Virtue SAB in what we believe was a very challenging patient population with predominantly long, diffuse restenotic lesions within stents that had been implanted, on average, nearly four years prior to the study enrollment.

Clinicians in the study reported a 100% procedural success rate on a per patient basis (which was defined as the ability to successfully deliver and deploy the device at the lesion site) with Virtue SAB, suggesting the ease of use of the system. The primary safety endpoint was TLF at 30 days. TLF is commonly defined as a combination of MACE, which include cardiac death, target vessel myocardial infarction, as well as clinically (symptom) driven target lesion revascularization. The primary performance endpoint was six-month in-segment LLL, measured as the difference in the vessel lumen diameter immediately after the procedure compared to the follow-up at six months.

Revised Per-Protocol Population

A revised per-protocol population was determined based on analysis of procedural data by an independent core lab. This analysis identified 14 cases out of the 50 patients treated in the SABRE study that represented serious violations of the established inclusion and exclusion criteria of the protocol for the study. Eight cases were excluded due to excessive proximity to the aorta or major side branches. Three cases were excluded due to treatment of lesions that were longer than the available Virtue SAB devices were designed to treat or because there were multiple lesions in the vessel where there was a target lesion. Finally, three cases were excluded due to double-layer stent ISR where Virtue SAB was used to treat to previously stented restenosis (i.e., the lesion already had two overlapping treatment stents). The remaining 36 patients with single-layer ISR are referred to herein as the revised per-protocol, population.

Virtue SAB met the primary performance endpoint of the SABRE study with Virtue SAB demonstrating six-month in-segment LLL was 0.12 mm, a positive result as compared to the study target of 0.43 mm. Virtue SAB met the primary safety endpoint with zero reported TLFs at 30 days. The secondary performance endpoint of binary restenosis was also met with Virtue SAB achieving a rate of 2.8%. Revised per-protocol analysis showed a low 2.8% rate of TLF at one-year follow-up and 5.6% at three-year follow-up. The increase in TLF after one year was because of the death of one study patient which was reported as multiple organ failure non-cardiac death and adjudicated as non-device and non-procedure related. Over the entire three-year period of the SABRE study, a total of 66 SAEs occurred in 32 of the 50 study patients (64.0%). A total of 29 SAEs in 18 patients were cardiac-related, of which:

•with respect to their relationship to the investigational device, the SAEs were adjudicated as follows: 19 as “unrelated,” three as “unlikely,” four as “possible”, two as “probable” and one as “highly probable;” and

•with respect to their relationship to the device treatment procedure, the SAEs were adjudicated as follows: 18 as “unrelated,” three as “unlikely,” two as “possible,” three as “probable” and three as “highly probable.”

A total of 37 SAEs in 25 patients were non-cardiac-related, none of them were adjudicated as “highly probable,” “probable,” or “possible” related to either the device treatment procedure or the investigational device. A total of eleven patients had both cardiac- and non-cardiac-related SAEs.

Intent to Treat Population

The intent-to-treat (“ITT”) population included all the patients enrolled in the study including those treated despite a significant protocol violation as noted above. The ITT analysis of the SABRE study demonstrated 0% MACE and TLF in hospital or at 30 days follow-up, 10.2% MACE and 8.2% TLF at six months, and 16.3% MACE and 14.3% TLF through three-year follow-up. LLL results were 0.31 mm at six months. We believe these results were encouraging given that the ITT population had a high percentage of difficult-to-treat diffuse lesions as well as lesions with an average time since original stent implantation of nearly four years which is substantially longer than typical ISR, which is most likely to occur 3 to 12 months after stenting.

Two-year and three-year clinical follow-up results from the SABRE study were presented at the TCT conference in 2017 and 2018, respectively. We believe the angiographic and clinical results of the SABRE trial are encouraging and provide the basis for it to conduct the upcoming Virtue ISR-US pivotal clinical study in coronary ISR. The diagrams below summarize the clinical results from this study.

Angiograms of Virtue SAB in Patients

The below images were best matched pairs of baseline and six-month follow-up angiograms identified and are included for illustrative purposes only to show the outcome of Virtue SAB administration in successfully treated patients. The images below are not intended to be representative of all the patients treated in the study and their respective outcomes.

Patient 1 (06-03): Patient presented with an 11.54 mm lesion in the mid-left circumflex artery. Lesion was previously treated with a BMS. The patient’s lesion was pre-dilated (a standard practice in drug-eluting balloon procedures) with a non-compliant balloon (a balloon that expands to one specific size independent of internal pressures commonly used to expand clogged arteries) and was treated with a 3.5 mm x 15 mm Virtue SAB. The patient had an excellent post-procedure outcome which was maintained through angiographic follow-up at 193 days. The LLL was measured at -0.03 mm.

Patient 2 (11-03): Patient presented with a 17.8 mm diffuse lesion of mid-left arterior descending artery following implantation of a DES seven months prior. After pre-dilatation with a scoring balloon (capable of achieving greater pressures and commonly used to open long, diffuse lesion), the lesion was treated with 3.25mm x 25mm Virtue SAB. The patient had an excellent post-procedure outcome, which was maintained through angiographic follow-up (at 175 days). The LLL was measured at -0.16mm.

The Virtue Trial, FDA Regulatory Status & Breakthrough Device

On April 29, 2025, we announced IDE approval from the FDA for the Virtue Trial, a pivotal trial to be conducted at up to 75 sites in the U.S. that is expected to randomize approximately 740 patients 1:1 to either treatment with Virtue SAB or Boston Scientific Corporation’s AGENTTM paclitaxel-coated balloon (currently the only drug-coated balloon approved in the U.S. for a coronary indication) with a primary efficacy and safety endpoint of statistical non-inferiority of target lesion failure (“TLF”) at 12 months post index treatment.

On October 27, 2025, we announced that we had initiated enrollment of patients for the Virtue Trial. We currently estimate completion of enrollment of the Virtue Trial in mid-2027; however, there is no assurance that our current operating plan will be achieved. To execute and support clinical activities for the Virtue Trial we plan to use (1) full-time employees as well as full- and part-time consultants to directly manage clinical studies and supervise external providers; (2) an external contact research organization (“CRO”), that serves as the authorized and legal representative of the study sponsor, submits study protocol for approval by clinical site review boards and ethics committees, and reports adverse events; and (3) an independent core lab and independent imaging analysis lab.

We currently anticipate using the Virtue Trial results to support regulatory approval for Virtue SAB for the treatment of coronary ISR. The FDA previously confirmed that Virtue SAB will be regulated as a combination product candidate, with the FDA’s Center for Devices and Radiological Health as the lead review center of a marketing application. In addition, Virtue SAB has been granted Breakthrough Device designation in:

•Coronary ISR — for the balloon dilatation of the stenotic portion (up to 26 mm in length) of a stented coronary artery that is 2.25 mm to 4.0 mm in diameter, for the purpose of improving lumen diameter;

•Coronary SV — for the balloon dilation of the de novo stenotic portion (up to 26 mm in lesion length) of a native coronary artery of 2.0 mm to 2.5 mm in diameter (small coronary arteries), for the purpose of improving lumen diameter; and

•Peripheral BTK — for the balloon dilatation of the stenotic portion (up to 18 cm in length) of an infrapopliteal artery (P-3 segment or distal, below the knee, with reference vessel diameter 2.25 – 4.0 mm), for the purpose of improving lumen diameter.

SirolimusEFR — Additional Interventional Therapies Product Candidates and Development Initiatives

We believe we have a future opportunity to establish a pipeline of additional targeted therapeutic product candidates for development and licensing based on our proprietary SirolimusEFR formulation as well as, potentially, the microporous AngioInfusion balloon technology used in the Virtue SAB. SirolimusEFR is an investigational, extended focal release formulation of sirolimus, enabled by our proprietary Sostenocel technology. We believe the ability of its Sostenocel technology to enable localized, targeted delivery and extended tissue release of sirolimus offers the potential for new and impactful therapeutic applications of SirolimusEFR. Sirolimus, a pharmaceutical agent also known as rapamycin, is a macrolide compound that is used to treat artery disease (drug-eluting stents or drug-coated balloons), prevent organ transplant rejection, treat rare lung disease called lymphangioleiomyomatosis, and shown to be effective against various tumor types. In addition to these approved indications, sirolimus and its analogs have been studied for potential clinical benefit in a broad array of medical conditions.

Sirolimus and its analogs act to inhibit the mammalian target of rapamycin, which regulates cellular metabolism, growth, and proliferation. Through its cystostatic mechanism of action, sirolimus prevents cell replication and proliferation while the drug is present in cells and tissues. Unlike cytotoxic agents such as paclitaxel, however, sirolimus does not kill the cells it affects, and these cells return to normal function once the drug is no longer present. This safer anti-proliferative mechanism makes sirolimus a valuable pharmaceutical agent to suppress undesirable immune system activity, which is why systemic use of high doses of sirolimus is the primary treatment to prevent rejection of transplanted organs. It also makes sirolimus useful as an anti-inflammatory and anti-fibrotic agent, which is one of the primary reasons it was chosen as an anti-restenotic drug to coat on the surface of a permanent arterial stent. However, the therapeutics effects of sirolimus are limited by the amount of time sirolimus is present at a therapeutic concentration. The known half-life of sirolimus is short, approximately 62 hours. Sirolimus has an attractive safety profile and a wide therapeutic window which allows for relatively high dosing thresholds before risk of toxicity. However, using systemic delivery of the drug to achieve therapeutic effects in targeted tissues or organs requires regular systemic dosing, increasing the risk of off-target effects and toxicity.

Our proprietary Sostenocel technology is designed to facilitate a localized tissue depot of sirolimus and enable extended focal release of sirolimus over typical critical healing period of approximately 30 days, potentially overcoming the challenges of sirolimus’ short half-life. While our Sostenocel technology is designed to achieve certain results as described above, there is no guarantee that it will prove to be safe and effective.

We believe we have a future opportunity to develop additional therapies using our proprietary SirolimusEFR to potentially treat focal inflammation outside of coronary and peripheral vascular indications. Further, we are currently working on all chemistry, manufacturing and controls (“CMC”) testing for our IDE submission for the combination product Virtue SAB that includes populating a drug master file (“DMF”). We believe this DMF will be helpful in supporting additional vascular regulatory indications for Virtue SAB as well as future potential non-vascular indications for SirolimusEFR, with or without our microporous angioinfusion balloon technology. Depending on the indication, we may be able to leverage some of the biocompatibility and CMC data in the DMF, while providing additional data depending on the indication selected. Leveraging CMC data in the DMF, as well as other preclinical, clinical and device testing work related to Virtue SAB, may allow us to advance development of additional SirolimusEFR-based product candidates at an accelerated pace and at reduced cost, although no assurances can be given that development will proceed faster or at lower expense than otherwise expected.

We are evaluating the use of SirolimusEFR through a balloon device treatment and delivery system similar to our AngioInfusion Balloon, through next generation non-balloon-based delivery systems or simply as a direct focal injection for treatment of additional indications associated with major medical conditions for which mature procedure-based markets already exist. We will seek to identify and initiate discussions with potential strategic partners when we believe sufficient data and evidence is available to support a potential business collaboration.

Our Future Growth Strategy

Our growth strategy is primarily focused on the execution of key development initiatives and partnership opportunities within our existing product pipeline, with the objective to advance these product candidates to key value inflection points and to form strategic partnerships for commercial value realization. This includes advancing clinical study activities for our flagship product candidates, as well as moving earlier stage product candidates further into clinical development. In the future, we may look to potentially expand our pipeline through collaborations or spinouts with corporate partners, targeted acquisitions that are made in parallel to forming strategic collaborations, royalty-based research and development partnerships, as well as highly selective organic development or intellectual property licensing.

We carefully screen new opportunities utilizing our focused innovation selection criteria to ensure a fit with our partnership-enabled business model.

•Target mature therapeutic device markets with significant unmet needs. Product innovations that address known unmet clinical and procedural needs in established medical markets with entrenched leaders and slowed product innovation.

•Provide high-impact, procedure-based solutions with rapid adoption potential. Transformative technology solutions with the potential to improve clinical outcomes and lower costs of care while fitting existing treatment paradigms and having well-defined development pathways.

•Offer strategic and financial benefits to a commercial partner and us. Innovative technologies that are protected by strong intellectual property offer distinct advantages that can be leveraged to disrupt competitive dynamics and have the potential to provide attractive profit margins to support favorable partnership economics.

Our Team and Innovation History

We are led by a highly accomplished, multidisciplinary management team with extensive experience and strong expertise in all phases of therapeutic product development. Our senior management team, including the vice president-level and above, has over 300 years of combined experience, with an average tenure of 25 plus years in the development and commercialization of procedure-based innovations for major clinical indications. Our team’s expertise includes clinical need and market analysis, product design and intellectual property prosecution, clinical and regulatory execution, as well as supply chain and quality system development. Members of our senior management team have been personally involved in the development and regulatory approval or clearance of over 100 products and have helped author over 600 patent applications. Our executive team is guided by a seasoned and highly accomplished board of directors with knowledge and experience in the healthcare industry, including medical devices, biotechnology and clinical medicine, as well as business operations, strategy, finance and capital markets. Further, our product development efforts are supported by world-renowned medical advisors who are physicians and scientists recognized for their knowledge of specific disease states and treatment options available, as well as their ability to quickly assess new technologies for clinical feasibility and likelihood of adoption.

All the product candidates in our pipeline were conceived and developed by our management team and employees through predecessor companies founded by a medical device accelerator, Accelerated Technologies, Inc. (“ATI”). ATI was originally founded in 2000 and employed active collaboration with industry-leading physicians to identify and purpose-build transformational therapeutic devices. Our founders and senior executives, Mr. David Hochman, our Chief Executive Officer, and Mr. Darren Sherman, our President and Chief Operating Officer, joined ATI in 2006 and 2008, respectively. Prior to their joining, ATI was associated with the development of approved devices such as transcatheter aortic valve replacement (Percutaneous Valve Technologies, Inc., which was acquired by Edwards Lifesciences Corp. in 2003) and catheter-based temporary ventricular support (Impella CardioSystems AG, which was acquired by ABIOMED, Inc. in 2005). Mr. Hochman and Mr. Sherman assumed control of ATI in 2009 and proceeded to found new companies that developed Virtue SAB (Caliber Therapeutics), AVIM Therapy (BackBeat Medical), and the FreeHold Duo and Trio Retractors (FreeHold Surgical). Orchestra BioMed, Inc.’s business was formed in May 2018 upon the merger of these three entities and a concurrent recapitalization. ATI was subsequently acquired by Orchestra BioMed, Inc. in December 2019.

Our Strategic Holdings

We own outright or maintain ownership of minority equity interests, convertible debt and/or royalty-stream interests in additional therapeutic device assets currently undergoing early-stage commercialization and further product development that we believe have growth and value appreciation potential. Our objective is to create and realize additional stockholder value through ownership in innovative therapeutic product solutions in core, adjacent and synergistic medical segments. Our strategic holdings include:

•FreeHold Surgical — we own 100% of FreeHold Surgical, LLC, which has developed and commercialized on a pilot basis in the U.S. patented single-use FreeHold Hands-Free Intracorporeal Retractions (“FreeHold Devices”) designed to help reduce required incisions and enhance laparoscopic and robotic procedures. FreeHold Trio and Duo hands-free intracorporeal retractors are regulated as Class I medical devices by the FDA and are generally indicated for internal organ or tissue retraction during minimally invasive procedures. We believe FreeHold devices are the only fully and continuously adjustable, completely intracorporeal devices specifically designed to address limitations of the available retraction methods. These devices are designed to enable a variety of advanced robotic and laparoscopic surgical procedures for the treatment of obesity, GI disorders and other indications. Their versatile design makes retractors appropriate for a broad range of minimally invasive procedures, including bariatric and foregut surgeries, nephrectomies, colectomies, cholecystectomies, paraaortic node dissections, hysterectomies, and other procedures. We believe FreeHold devices are designed to offer several potential advantages over existing retraction options:

•Improve Patient Care

•No additional incisions required as they are deployed through same access incisions as used in standard procedures;

•Minimize complications from suboptimal visualization and additional incisions; and

•Avoid trauma associated with the use of Nathanson-type retractors

•Enable Full Surgeon Autonomy

•Surgeon controls positioning and adjustment of retractor;

•Once positioned, surgeon has full use of both hands to perform surgery; and

•No coordination with circulator required

•Optimize Visualization

•Easily adjustable throughout the procedure for sustained visibility; and

•Low profile design minimizes procedural clutter and collisions

Targeted Commercialization — We estimate over 20,000 procedures using FreeHold devices have been performed in the United States to date, primarily in bariatric (obesity) and foregut (GI, metabolic) surgeries with some initial experience in paraaortic node dissections (gynecologic oncology), nephrectomies (kidney removal) and cholecystectomies (gallbladder removal). FreeHold’s targeted commercial development program involves only two dedicated sales representatives targeting hospitals in the United States to demonstrate clinical utility and commercial demand for FreeHold Devices.

Strategic Potential — We believe FreeHold devices have been optimized for strategic partnership because they are highly differentiated, enabling products that fit into the current treatment paradigms, are easy to use with a relatively short learning curve and have sufficiently high profit margins that provide potential for partnering to enable a revenue sharing arrangement.

Formation and Conversion to a Limited Liability Company — In May 2018, Orchestra BioMed, Inc. completed its acquisition of FreeHold Surgical, Inc., a Delaware corporation that has, among other things, the rights to our FreeHold Devices. FreeHold Surgical, Inc. was incorporated in Delaware in May 2010 and began development of its hands-free, intracorporeal retractors for minimally invasive surgery in 2012. In December 2019, Orchestra BioMed, Inc. converted FreeHold Surgical, Inc., a Delaware corporation, to FreeHold Surgical, LLC, a Delaware limited liability company. References in this annual report to FreeHold refer to FreeHold Surgical, Inc. prior to its conversion to a limited liability company and to FreeHold Surgical, LLC after its conversion to a limited liability company, as applicable.

•Motus GI — We own 100% of Motus GI Medical Technologies Ltd., an Israeli corporation (“Motus GI Technologies”) and Motus GI, LLC, a Delaware limited liability company (“Motus Delaware” and, collectively, with Motus GI Technologies, the “Motus Entities”), which has developed the Pure-Vu® System, a medical device that has been approved by the FDA to facilitate the cleansing of a poorly prepared gastrointestinal tract during colonoscopy and to help facilitate upper gastrointestinal (GI) endoscopy procedures. The Pure-Vu® System is also CE marked in the EU for use in colonoscopy. The Pure-Vu® System integrates with standard and slim colonoscopes, as well as gastroscopes, to improve visualization during colonoscopy and upper GI procedures while preserving established procedural workflow and techniques. Through irrigation and evacuation of debris, the Pure-Vu® System is designed to provide better-quality exams as well as enable the completion of exams that otherwise could not be completed due to obstructed visualization. Challenges exist for inpatient colonoscopy and endoscopy, particularly for patients who are elderly, with comorbidities, or active bleeds, where the ability to visualize, diagnose and treat is often compromised due to debris, including fecal matter, blood, or blood clots. We believe this is especially true in high acuity, high risk patients, like those experiencing GI bleeding where the existence of blood and blood clots can impair a physician’s view and removing them can be critical in allowing a physician the ability to identify and treat the source of bleeding on a timely basis.

Market Opportunity & Commercial Experience — We estimate that there are approximately 1.5 million inpatient colonoscopy procedures that were performed in the U.S. and approximately 4.8 million worldwide annually, based on our analysis of market data and projections from iData Research Inc. Upper GI bleeds occurred in the U.S. at a rate of approximately 400,000 cases per year in 2019, according to iData Research Inc. The Pure-Vu System has been assigned an ICD-10 reimbursement classification code in the U.S., and we believe the clinical and health economic benefits offered by the Pure-Vu System make its use financially supportable under existing reimbursement payments for inpatient procedures. The Pure-Vu System does not currently have unique or dedicated reimbursement codes for specific additional reimbursement with any private or governmental third-party payors in any other country or for any other use; however, we may pursue reimbursement activities in the future. The Pure-Vu® System is designed to reduce the time required to complete colonoscopy procedures, which may make it attractive to closed healthcare systems, such as the Veterans Affairs hospital system (“VA”), that are insured by their constituents and bear the cost burden of lengthened hospital stays due to colonoscopy preparation. The Pure-Vu System is designed to reduce hospital stays through more efficient colonoscopy procedures, potentially saving money and expediting care. Additionally, VA patients may have increased complications with colonoscopy preparation due to the co-morbidities that veterans can experience. Thus, the potential clinical benefit to VA patients of the Pure-Vu product may be important as well, as the system is designed to remove debris and enhance the field of view during a colonoscopy procedure in the event the pre-procedure preparation was not optimal. The Pure-Vu System is currently in pilot commercial use in 8 hospitals in the U.S., including two VA hospitals. We anticipate increasing Pure-Vu System pilot use to approximately 20 U.S. hospitals in 2025, with a particular focus on the VA where we anticipate conducting structured clinical evaluations aimed at supporting broader VA system adoption. We also expect to obtain CE Mark approval for the next generation of the system with both the upper and lower indication and introduce the system to a few select hospitals in the EU and Israel.

Strategic Potential — We believe use of the Pure-Vu® System has the potential to help achieve better clinical outcomes and lower costs for hospitals by safely and quickly improving visualization of the colon and upper GI tract, potentially enabling effective diagnosis and treatment without delay. In multiple clinical studies to date, involving the treatment of challenging inpatient and outpatient cases, the Pure-Vu® System has consistently helped achieve adequate bowel cleanliness rates greater than 95% for inpatients and outpatients following a reduced prep regimen. We also believe that the technology may be useful in the future as a tool to help reduce user dependency on conventional pre-procedural bowel prep regimens and enhance the treatment of acute upper GI bleeding. We believe the Pure-Vu System is potentially attractive for strategic partnership because it is a proprietary enabling technology that addresses significant unmet needs in a large established global market, its usage fits into current treatment paradigms and is easy enough to use with a relatively short learning curve, and its disposable component has sufficiently high profit margins that provide potential for partnering to enable a revenue sharing arrangement.

Acquisition of Motus Entities — In October 2024, we entered a Share and Membership Interest Purchase Agreement with the previously publicly traded company, Motus GI Holdings, Inc. and its lender, Kreos Capital VI, LP. to acquire the Motus Entities for the rights to the intellectual property of the Pure-Vu® System.

•Vivasure Medical — As of December 31, 2025, we owned a minority equity interest, representing approximately 10.9% in Vivasure Medical Limited (“Vivasure”), a Galway, Ireland-based company that develops advanced polymer implants and delivery systems, primarily focused on minimally invasive vessel closure in cardiology, interventional radiology and vascular surgery. On January 9, 2026, Haemonetics Corporation (“Haemonetics”), a U.S. medical device company, closed on an acquisition of Vivasure in which we expect to receive up to $21.0 million in cash proceeds. We can receive up to $10.7 million of proceeds in 2026 made up of a $4.7 million upfront, which was received on January 9, 2026, and approximately $6.0 million in a first milestone payment. The remainder of the proceeds may be received in future revenue earnouts based on the achievement of certain milestones in a period greater than one year.

Our Research and Development

We invest in research and development efforts that advance and expand our product pipeline. Our goals are to: (1) deliver on clinical, regulatory and commercial development objectives for Virtue SAB; (2) deliver on clinical, regulatory and commercial development objectives for AVIM Therapy set forth in collaboration with our strategic partner, Medtronic; and (3) further develop pipeline product candidates towards future partnerships with potential strategic partners. Our research and development expenses totaled $58.2 million for the year ended December 31, 2025 and $42.8 million for the year ended December 31, 2024.

We believe our ability to rapidly develop innovative product candidates is attributable to the dynamic product innovation process that we have implemented, the versatility and leveragability of our core technologies and our partnership-enabled business model that drives our innovation objectives and research and development process. We have recruited and retained engineers and scientists with significant experience in the development of medical devices. We have a pipeline of product candidates in various stages of development that are expected to provide additional strategic opportunities. Our research and development efforts are based at our facilities in New Hope, Pennsylvania and Fort Lauderdale, Florida.

Our Manufacturing and Supply

Bioelectronic Therapies (AVIM Therapy and CNT-HF)

Our wholly owned subsidiary, BackBeat Medical previously contracted with a business unit of Integer under an agreement (the “Integer Agreement”) to develop and manufacture the Moderato device. The Moderato device consists of an IPG powered by a primary battery, a programming system integrated by a programmer interface, a telemetry wand and a software application capable of programming standard pacing functions as well as the different parameters of AVIM Therapy. All intellectual property that Integer developed for BackBeat Medical during the performance of the Integer Agreement, whether developed independently or jointly, and that resulted from or uses BackBeat Medical’s technology or intellectual property are owned by BackBeat Medical. Under the Integer Agreement, Integer provided BackBeat Medical a perpetual, royalty-free, fully paid, assignable, world-wide, non-exclusive license for the device-incorporated Integer property, allowing the use of the incorporated Integer property only within BackBeat Medical’s field of use (electrical therapies, particularly cardiac pacing for (i) treatment of HTN and (ii) rhythm management in patients that were implanted with a device for the treatment of HTN). We also utilize the services of external consultancy firms for quality and regulatory services related to Moderato devices to supplement its internal capabilities. As of the date of this filing, we do not anticipate receiving any new Moderato devices under the Integer Agreement.

Medtronic has completed integration and associated validation and verification testing of AVIM Therapy algorithms as a field downloadable addition to its premium, commercially available dual-chamber pacemaker systems for use in the BACKBEAT study. Medtronic is also providing clinical and regulatory resources in support of the pivotal study. We are reimbursing Medtronic at cost for these development, clinical and regulatory resources. Medtronic will integrate AVIM Therapy, at our cost, as a firmware component of a premium pacemaker for potential regulatory approval and commercialization of AVIM-enabled commercial devices following a successful outcome of the BACKBEAT study.

In February 2023, we also contracted with MEDICO S.R.L. to develop a dual chamber pacemaker device that meets our specifications for running our cardiac neuromodulation therapies as well as standard pacing algorithms. This new device platform is designed to allow us to conduct CNT program studies for potential expanded indications and populations, including certain heart failure patients. Initial devices have been delivered, and we are actively engaging centers with a new protocol to conduct clinical evaluations which commenced in 2025.

Interventional Therapies (Virtue SAB, SirolimusEFR and Sostenocel)

Microporous AngioInfusion Balloon and other device components of Virtue SABs

Currently, we manage the supply chain, and these devices are manufactured by a selected group of third parties contracted by us. All of Virtue SAB’s key suppliers and vendors carry the proper quality system certification and/or FDA approvals for the activity they are providing in support of the manufacturing, testing, storage and distribution of components, materials, services or final product.

SirolimusEFR

We have internal capabilities for small scale production (300 vials per run), lyophilization, and characterization testing for SirolimusEFR. Clinical and commercial production has been contracted through an established clinical manufacturing organization with large scale current Good Manufacturing Practice (“cGMP”) production capabilities. We have scaled clinical production with an external manufacturing partner to achieve a capacity of approximately 3,000 vials per run with further scaling planned to reach planned commercial production capacity. Additional contract vendors provide polymer synthesis capabilities based on world-class polymer expertise in order to supply enabling components to the Sostenocel technology used to create SirolimusEFR. cGMP syntheses have been performed, with extensive analytical method, and quality control development complete. Synthesis of custom polymers has successfully achieved clinical scale with ongoing work to scale processes to commercial scale.

FreeHold Devices

We utilize an FDA-registered and ISO 13485-certified U.S.-based manufacturing partner to manufacture FreeHold Duo and FreeHold Trio intracorporeal retractors. Our manufacturing partner also provides warehousing and distribution of its products to qualified customers based on orders placed by customers to its FreeHold Surgical subsidiary. We have utilized the same manufacturing partner since the time of FDA product registration. Further, our manufacturing partner has achieved a greater than 99% on-time order delivery rate to our customers.

Motus Devices

We have established relationships with research facilities, contract manufacturing organizations, or CMOs, and our collaborators to manufacture and supply our product for our initial U.S. market development efforts targeting early adopter hospitals and selective closed systems like the Veterans Affairs hospital system. Currently, the workstation component of our Pure-Vu® System is manufactured by Sanmina Corporation at their facilities in Israel. The disposable portion of the Pure-Vu EVS is manufactured by Sterling Industries in their Michigan, U.S. facility. These manufacturing suppliers have extensive experience in medical devices and in dealing with regulatory bodies and other competent entities. These suppliers have ISO 13485 certified quality systems. We have an agreement in place with a third-party logistics provider in the U.S. who is ISO 13485 certified and specializes in medical devices and equipment. They provide warehousing, shipping and back-office support to meet our commercial needs with respect to our Pure-Vu® System.

Our Competition

The medical device industry is intensely competitive, subject to rapid change and significantly affected by new product introductions and other market activities of industry participants. We compete or plan to compete with developers, manufacturers and distributors of cardiovascular and other medical devices. Regarding Virtue SAB, our most notable competitors in the highly competitive interventional cardiology field include Boston Scientific Corporation, Medtronic plc, Becton Dickinson, Philips N.V., B. Braun, Abbott Laboratories, Cordis, Teleflex, Inc., Concept Medical, Inc., MicroPort, Eurocor Tech GmbH, iVascular, S.L.U., Biosensors International Group, Ltd., Balton, Invamed, Inc., and others. Regarding AVIM Therapy, our potential competitors in the field of cardiac rhythm management devices include Abbott Laboratories, Boston Scientific Corporation, BIOTRONIK, Inc., and MicroPort CRM and others.

Many of these competitors are large, well-capitalized companies with significantly greater market share and resources than we have. Consequently, they are able to spend more on product development, marketing, sales and other product initiatives than we can. We also compete with smaller medical device companies that have single products or a limited range of products. Some of these competitors have:

•significantly greater name recognition;

•broader or deeper relations with healthcare professionals, customers and third-party payors;

•more established distribution networks;

•additional lines of products and the ability to offer rebates or bundle products to offer greater discounts or other incentives to gain a competitive advantage;

•greater experience in conducting research and development, manufacturing, clinical studies, marketing and obtaining regulatory clearance, certification or approval for products; and

•greater financial and human resources for product development, sales and marketing and patent prosecution.

We believe that our proprietary AVIM Therapy, Virtue SAB and other pipeline technologies, our partnership-enabled business model, our strategic partnerships, such as the Medtronic Collaboration for AVIM Therapy and our organizational culture and strategy will be important factors in our future success. We compete primarily on the basis that our products are designed to improve outcomes, reduce complications and provide distinct commercial advantages that can be leveraged by us and our strategic partners. Our continued success depends on our, and in some cases, our strategic partners’ ability to:

•develop innovative, proprietary products that can cost-effectively address significant clinical needs in a manner that is safe and effective for patients and easy to use for physicians;

•continue to innovate and develop scientifically advanced technology;

•forge risk and reward sharing partnerships with established commercial market leaders to help support product development and commercialization;

•obtain and maintain regulatory clearances, certifications or approvals;

•demonstrate efficacy in sponsored and third-party clinical studies;

•obtain and maintain adequate reimbursement for procedures using its products;

•apply technology to develop pipeline product candidates for additional clinical indications;

•attract and retain skilled research and development and sales personnel; and

•cost-effectively manufacture and successfully market and sell products.

Our Intellectual Property

Our success depends in part on our ability to obtain, maintain, protect and enforce our proprietary technology and intellectual property rights, and, in particular, our patent rights, as well as our ability to preserve the confidentiality of our trade secrets, and operate without infringing, misappropriating or otherwise violating the valid and enforceable patents and other intellectual property rights of third parties. We rely on a combination of patent, trademark, trade secret, copyright and other intellectual property rights and take measures to protect the intellectual property rights that we consider important to our business.

The term of individual patents depends upon the legal term for patents in the countries in which they are granted. In most countries, including the United States, the patent term is 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country. In the United States, a patent’s term can be extended to recapture a portion of the United States Patent and Trademark Office’s (the “USPTO”) delay in processing the patent to issue as well as restore a portion of the term effectively lost as a result of the FDA regulatory review period. However, as to the FDA component, the restoration period cannot be longer than five years and the total patent term including the restoration period must not exceed 14 years following FDA approval. The duration of patents outside of the United States varies in accordance with provisions of applicable local law but typically is also 20 years from the earliest effective filing date. However, the actual protection afforded by a patent varies on a product-by-product basis, from country to country and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent. We cannot be sure that our pending patent applications that we have filed or may file in the future will result in issued patents, and we can give no assurance that any patents that have issued or might issue in the future will protect our current or future products, will provide us with any competitive advantage, and will not be challenged, invalidated, or circumvented.

We also rely on trade secret know-how and continuing technological innovation to develop and maintain our competitive position. We seek to protect our proprietary rights through a variety of methods, including confidentiality agreements with suppliers, consultants and others who may have access to our proprietary information and proprietary information and inventions agreements with our employees. However, trade secrets and proprietary information can be difficult to protect. While we take measures to protect and preserve our trade secrets and proprietary information, such measures can be breached, and we may not have adequate remedies for any such breach. In addition, our competitors may independently discover or develop the same trade secrets and proprietary information as us. To the extent that our suppliers, employees, consultants and others use intellectual property owned by others in their work for us, we may be subject to allegations of infringement and further disputes may arise as to the rights in related or resulting improvements, know-how and inventions.

Our success also depends in part on not infringing the intellectual property rights of third parties. It is uncertain whether the issuance of any third-party patent would require us to alter our development or commercial strategies, or our product candidates or processes, obtain licenses or cease certain activities. Our breach of any license agreements or failure to obtain a license to intellectual property rights that we may require to develop or commercialize our future product candidates may have an adverse impact on the business. If third parties have prepared and filed patent applications in the United States prior to March 16, 2013 (the date when U.S. patent law changed from granting rights to the first-to-invent to the first-to-file) that also claim technology to which we have rights, we may have to participate in interference proceedings in the USPTO to determine priority of invention. Assuming that other requirements for patentability are met, prior to March 2013, in the United States, the first to invent the claimed invention was entitled to the patent, while outside the United States, the first to file a patent application was entitled to the patent. After March 2013, under the America Invents Act, enacted in September 2011, the United States transitioned to a first inventor to file system in which, assuming that other requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an invention regardless of whether a third party was the first to invent the claimed invention. For more information regarding the risks related to our intellectual property, please see the section titled “Risk Factors — Risks Related to Our Intellectual Property.”

Trademarks

As of December 31, 2025, we have 8 trademarks that are approved in the United States: “Orchestra BioMed,” “Moderato,” “Virtue”, “FreeHold Surgical,” “FreeHold Duo,” “FreeHold Trio,” “Pure-Vu System,” and “Motus GI.” A further 10 applications for trademark registration are pending, covering “OBIO,” “SirolimusEFR,” “AngioInfusion,” “Virtue Sirolimus AngioInfusion Balloon,” “BackBeat Medical,” “BackBeat CNT,” “BackBeat Cardiac Neuromodulation Therapy,” “Moderato Plus,” “Sostenocel,” and “MICRO-PREP.” The trademark “Orchestra Biomed Inc.” is approved in Japan (only). This Annual Report on Form 10-K contains references to our trademarks and service marks and to those belonging to other entities. Solely for convenience, trademarks and trade names referred to in this Annual Report on Form 10-K, including logos, artwork, and other visual displays, may appear without the ® or ™ symbols, but such references are not intended to indicate in any way that we will not assert, to the fullest extent under applicable law, our right or the rights of the applicable licensor to these trademarks and trade names. We do not intend our use or display of other entities’ trade names, trademarks, or service marks to imply a relationship with, or endorsement or sponsorship of us by, any other entity.

Material Patents

As of December 31, 2025, we owned 241 patents globally, of which 82 were issued U.S. patents and 159 were patents outside of the United States.

Our issued patents expire between March 2026 and April 2041. Despite the near-term expiration of certain of our material patents, we believe that our other patents, as well as our trade secrets and continuing technological know-how, provide us with sufficient intellectual property protection to develop our product candidates and protect our intellectual property.

Below is a more specific overview of our intellectual property as it relates to our pipeline programs by modality:

Bioelectronic Therapies (AVIM Therapy and CNT-HF)

AVIM Therapy and CNT-HF are protected by an intellectual property portfolio which currently includes 44 issued U.S. patents and 94 issued patents in countries outside of the United States encompassing devices, algorithms, and methods. These issued patents, and any patents granted from such applications, will, or are expected to, expire between 2026 and 2041, without taking potential patent term extensions or adjustments into account. Additional patent applications are filed on a regular basis. BackBeat issued patents are divided between CNT and CNT-HF as follows: 40 issued U.S. patents and 80 issued patents in countries outside of the United States protect CNT, and which are exclusively licensed to Medtronic in the Primary Field pursuant to the Medtronic Agreement; four issued U.S. patents and 14 issued patents in countries outside of the United States protect CNT-HF; and a further 38 patent applications were filed protecting AVIM Therapy.

In addition to customary early termination provisions, the Medtronic Agreement will terminate on the date no further revenue share payments are due under the Medtronic Agreement and Medtronic’s license under the Medtronic Agreement would become fully paid up, perpetual, irrevocable and royalty-free. Revenue share payments with respect to each applicable country (or group of countries) are to be paid for a minimum period of time determined by the latest to occur of (a) the expiration of the last valid claim of certain specified patents (as well as any patents claiming priority to, from or through such patents) (the “Patent-Based Expiration”) or (b) the date that is 12 years after the first commercial sale of any AVIM-enabled pacemakers in the applicable country or group of countries (the “Time-Based Revenue Share Expiration”). Accordingly, to the extent AVIM-enabled pacemakers receive regulatory approval and are sold commercially, Medtronic’s obligation to make payments to us will extend to at least approximately 2041 under the Time-Based Revenue Share Expiration, regardless of the expiration of any of our patents. Further, such date may be extended up to an additional five years based on the Medtronic Agreement which provides that the Patent-Based Expiration may be extended until the expiration of patents that may be issued based on additional patent applications that we have filed prior to entering into the Medtronic Agreement, although no assurance can be given that such patents will be issued or any claims associated with newly issued patents will be valid. To the extent there are revenue share payments made under the Medtronic Agreement after the Time-Based Revenue Share Expiration and prior to the Patent-Based Expiration, those payments would likely be based on intellectual property we develop in the future, and not the current patents held by us.

AVIM Therapy and CNT-HF are also protected by trade secrets and proprietary know-how. We seek to protect its proprietary technology and processes, in part, by confidentiality agreements and invention assignment agreements with its employees, consultants, scientific advisors, contractors and commercial partners.

We will continue to endeavor to obtain and maintain patent protection worldwide on select patentable aspects of AVIM Therapy and CNT-HF as well as to protect our trade secrets and proprietary know-how.

The following table lists our material patents relating to AVIM Therapy and CNT-HF as of December 31, 2025, their jurisdiction and expiration date:

Jurisdiction

Patent No.

Expiration Date

Related Product

United States

9,008,769

8/31/2033

AVIM Therapy

United States

9,333,352

3/14/2033

AVIM Therapy

United States

9,526,900

8/31/2033

AVIM Therapy

United States

9,370,662

8/31/2033

AVIM Therapy

United States

9,656,086

3/14/2033

AVIM Therapy

United States

9,878,162

8/31/2033

AVIM Therapy

United States

9,937,351

7/4/2034

AVIM Therapy

United States

10,071,250

3/14/2033

AVIM Therapy

United States

10,252,061

8/31/2033

AVIM Therapy

United States

10,441,794

3/14/2033

AVIM Therapy

United States

10,485,658

5/16/2037

AVIM Therapy

United States

10,610,689

3/14/2033

AVIM Therapy

United States

10,967,188

7/21/2034

AVIM Therapy

United States

11,097,108

12/19/2033

AVIM Therapy

United States

11,426,589

3/17/2038

AVIM Therapy

United States

11,452,875

3/14/2033

AVIM Therapy

United States

11,712,567

8/31/2033

AVIM Therapy

United States

11,969,598

4/20/2037

AVIM Therapy

United States

11,986,661

3/14/2033

AVIM Therapy

United States

12,208,271

6/17/2034

AVIM Therapy

United States

12,246,180

6/17/2034

AVIM Therapy

United States

12,485,805

3/14/2033

AVIM Therapy

Europe

EP2934669

12/19/2033

AVIM Therapy

Great Britain

EP2934669

12/19/2033

AVIM Therapy

France

EP2934669

12/19/2033

AVIM Therapy

Germany

EP2934669

12/19/2033

AVIM Therapy

Switzerland

EP2934669

12/19/2033

AVIM Therapy

Sweden

EP2934669

12/19/2033

AVIM Therapy

Italy

EP2934669

12/19/2033

AVIM Therapy

Spain

EP2934669

12/19/2033

AVIM Therapy

Europe

EP3082949

6/17/2034

AVIM Therapy

Great Britain

EP3082949

6/17/2034

AVIM Therapy

France

EP3082949

6/17/2034

AVIM Therapy

Germany

EP3082949

6/17/2034

AVIM Therapy

Switzerland

EP3082949

6/17/2034

AVIM Therapy

Sweden

EP3082949

6/17/2034

AVIM Therapy

Europe

EP3238777

12/19/2033

AVIM Therapy

Great Britain

EP3238777

12/19/2033

AVIM Therapy

France

EP3238777

12/19/2033

AVIM Therapy

Germany

EP3238777

12/19/2033

AVIM Therapy

Switzerland

EP3238777

12/19/2033

AVIM Therapy

Sweden

EP3238777

12/19/2033

AVIM Therapy

Europe

EP3461531

6/17/2034

AVIM Therapy

Great Britain

EP3461531

6/17/2034

AVIM Therapy

France

EP3461531

6/17/2034

AVIM Therapy

Germany

EP3461531

6/17/2034

AVIM Therapy

Switzerland

EP3461531

6/17/2034

AVIM Therapy

Sweden

EP3461531

6/17/2034

AVIM Therapy

Europe

EP3639888

12/19/2033

AVIM Therapy

Great Britain

EP3639888

12/19/2033

AVIM Therapy

France

EP3639888

12/19/2033

AVIM Therapy

h

Jurisdiction

Patent No.

Expiration Date

Related Product

Germany

EP3639888

12/19/2033

AVIM Therapy

Switzerland

EP3639888

12/19/2033

AVIM Therapy

Sweden

EP3639888

12/19/2033

AVIM Therapy

Europe

EP3445443

4/21/2037

AVIM Therapy

Great Britain

EP3445443

4/21/2037

AVIM Therapy

France

EP3445443

4/21/2037

AVIM Therapy

Germany

EP3445443

4/21/2037

AVIM Therapy

Switzerland

EP3445443

4/21/2037

AVIM Therapy

Sweden

EP3445443

4/21/2037

AVIM Therapy

Europe

EP3954429

4/17/2041

AVIM Therapy

Great Britain

EP3954429

4/17/2041

AVIM Therapy

France

EP3954429

4/17/2041

AVIM Therapy

Germany

EP3954429

4/17/2041

AVIM Therapy

Switzerland

EP3954429

4/17/2041

AVIM Therapy

Sweden

EP3954429

4/17/2041

AVIM Therapy

China

ZL201380072479.3

12/18/2033

AVIM Therapy

China

ZL201480075987.1

6/16/2034

AVIM Therapy

China

ZL2017109301826

12/18/2033

AVIM Therapy

China

ZL2018113777986

6/16/2034

AVIM Therapy

China

ZL201780034227X

4/20/2037

AVIM Therapy

Hong Kong

HK1226016

6/16/2034

AVIM Therapy

Hong Kong

HK1243968

12/18/2033

AVIM Therapy

Australia

AU2013361318

12/19/2033

AVIM Therapy

Australia

AU2014367229

6/17/2034

AVIM Therapy

Australia

AU2018217270

12/18/2033

AVIM Therapy

Australia

AU2019204758

6/17/2034

AVIM Therapy

Australia

AU2017252310

4/21/2037

AVIM Therapy

Australia

AU2022246435

4/21/2037

AVIM Therapy

Canada

CA2893222

12/19/2033

AVIM Therapy

Canada

CA2933278

6/17/2034

AVIM Therapy

Japan

JP6457530

6/17/2034

AVIM Therapy

Japan

JP6510421

12/19/2033

AVIM Therapy

Japan

JP6381087

12/19/2033

AVIM Therapy

Japan

JP6839163

6/17/2034

AVIM Therapy

Japan

JP7050693

4/21/2037

AVIM Therapy

Japan

JP7138202

12/19/2033

AVIM Therapy

Japan

JP7222962

6/17/2034

AVIM Therapy

Japan

JP7395638

4/21/2037

AVIM Therapy

Japan

JP7672471

4/21/2037

AVIM Therapy

Japan

JP7759859

12/19/2033

AVIM Therapy

Korea

KR10-2221586

12/19/2033

AVIM Therapy

Korea

KR10-2323562

6/17/2034

AVIM Therapy

Korea

KR10-2367191

12/19/2033

AVIM Therapy

Korea

KR10-2471841

6/17/2034

AVIM Therapy

India

401318

12/19/2033

AVIM Therapy

India

409845

4/21/2037

AVIM Therapy

India

516531

4/21/2037

AVIM Therapy

India

566889

12/19/2033

AVIM Therapy

United States

7,869,874

11/7/2028

AVIM Therapy

United States

8,515,536

3/15/2028

AVIM Therapy

United States

8,340,763

3/25/2031

AVIM Therapy

United States

8,165,674

7/13/2029

AVIM Therapy

United States

8,521,280

3/1/2026

AVIM Therapy

United States

9,370,661

9/25/2030

AVIM Therapy

United States

9,427,586

11/15/2027

AVIM Therapy

United States

9,687,636

3/1/2026

AVIM Therapy

United States

9,731,136

9/8/2029

AVIM Therapy

United States

10,252,060

9/8/2029

AVIM Therapy

United States

10,369,333

9/27/2026

AVIM Therapy

United States

11,083,894

9/8/2029

AVIM Therapy

United States

11,577,059

9/27/2026

AVIM Therapy

United States

11,759,639

10/30/2029

AVIM Therapy

United States

12,239,839

9/8/2029

AVIM Therapy

United States

12,440,653

3/1/2026

AVIM Therapy

United States

8,086,315

7/3/2026

AVIM Therapy

United States

11,406,829

10/4/2026

AVIM Therapy

Jurisdiction

Patent No.

Expiration Date

Related Product

United States

10,596,380

11/15/2027

CNT-HF

United States

11,389,658

9/8/2036

CNT-HF

United States

10,342,982

9/8/2036

CNT-HF

United States

11,529,520

11/15/2027

CNT-HF

Australia

AU2016319787

9/9/2036

CNT-HF

Japan

JP6999545

9/9/2036

CNT-HF

China

ZL2016800526048

9/9/2036

CNT-HF

Europe

EP3347090

9/9/2036

CNT-HF

Great Britain

EP3347090

9/9/2036

CNT-HF

France

EP3347090

9/9/2036

CNT-HF

Germany

EP3347090

9/9/2036

CNT-HF

Switzerland

EP3347090

9/9/2036

CNT-HF

Sweden

EP3347090

9/9/2036

CNT-HF

Italy

EP3347090

9/9/2036

CNT-HF

Spain

EP3347090

9/9/2036

CNT-HF

Korea

KR10-2630590

9/9/2036

CNT-HF

India

514118

9/9/2036

CNT-HF

Canada

CA2996312

9/9/2036

CNT-HF

Interventional Therapeutics (Virtue SAB, SirolimusEFR and Sostenocel)

We rely on intellectual property protection for Virtue SAB and its enabling technologies, including SirolimusEFR and the AngioInfusion Balloon, based on protection of proprietary particle drug encapsulation technology through trade secrets and proprietary know-how; and through issued patents and patent applications in process covering key aspects of Virtue SAB’s micro-porous balloon system and integration of its drug encapsulation formulation with the device.

Virtue SAB is currently protected by 7 issued U.S. patents and 20 issued patents outside the United States with additional patent applications pending in the United States and in countries outside of the United States covering key aspects of Virtue SAB product design, clinical application and enabling technology. These issued patents, and any patents granted from such applications, will, or are expected to, expire between 2030 and 2032, without taking potential patent term extensions or adjustments into account. We will continue to selectively advance certain aspects of Virtue SAB toward submission of appropriate patent applications. A further three published patent applications were filed to protect Virtue SAB.

Our Sostenocel technology and SirolimusEFR are intentionally protected by trade secrets and proprietary know-how, as we believe the design and manufacture of this formulation would be highly difficult to develop or reverse engineer. Seeking patent protection for these processes would have required detailed publication of proprietary information without certainty of patent claim issuance or protection.

Development and production of SirolimusEFR have been refined and scaled to support the Virtue ISR-US trial and other trials we plan to conduct to support commercialization of SirolimusEFR. Production scaling and manufacturing processes are central components of the proprietary trade secret and proprietary know-how of the intellectual property protection of Virtue SAB and other future product candidates involving SirolimusEFR.

Virtue SAB is also protected by trade secrets and proprietary know-how that was intentionally not made public or published in patent applications. We believe the strategy to avoid publication of proprietary methods as long as possible has been an important part of maintaining the differentiation and advantages of Virtue SAB. Trade secrets and proprietary know-how include aspects of formulation, materials production, and manufacturing of Virtue SAB. Such trade secrets and proprietary information is used to develop and maintain our competitive position. We seek to protect our proprietary technology and processes, in part, by confidentiality agreements and invention assignment agreements with its employees, consultants, scientific advisors, contractors and commercial partners.

We will continue to endeavor to obtain and maintain patent protection worldwide on select patentable aspects of Virtue SAB as well as to protect our trade secrets and proprietary know-how.

The following table lists our material patents relating to Virtue SAB as of December 31, 2025, their jurisdiction and expiration:

Jurisdiction

Patent No.

Expiration Date

Related Product

United States

8,696,644

3/9/2032

Virtue SAB

United States

8,715,230

12/30/2030

Virtue SAB

United States

9,649,478

12/30/2030

Virtue SAB

United States

9,649,479

12/30/2030

Virtue SAB

United States

10,207,084

1/6/2031

Virtue SAB

United States

10,806,909

1/6/2031

Virtue SAB

United States

12,144,945

1/6/2031

Virtue SAB

Australia

AU2010339379

12/30/2030

Virtue SAB

Australia

AU2014202452

12/30/2030

Virtue SAB

Australia

AU2016202636

12/30/2030

Virtue SAB

Australia

AU2017225072

12/30/2030

Virtue SAB

Australia

AU2019202994

12/30/2030

Virtue SAB

Australia

AU2020281081

12/30/2030

Virtue SAB

China

ZL201080064442.2

12/30/2030

Virtue SAB

Japan

JP5553908

12/30/2030

Virtue SAB

Canada

CA02786282

12/30/2030

Virtue SAB

Canada

CA3065396

12/30/2030

Virtue SAB

India

IN385350

12/30/2030

Virtue SAB

Europe

EP2603274

12/30/2030

Virtue SAB

Great Britain

EP2603274

12/30/2030

Virtue SAB

France

EP2603274

12/30/2030

Virtue SAB

Germany

EP2603274

12/30/2030

Virtue SAB

Switzerland

EP2603274

12/30/2030

Virtue SAB

Sweden

EP2603274

12/30/2030

Virtue SAB

Italy

EP2603274

12/30/2030

Virtue SAB

Spain

EP2603274

12/30/2030

Virtue SAB

Netherlands

EP2603274

12/30/2030

Virtue SAB

FreeHold Devices

Our FreeHold Devices and additional minimally invasive surgery enabling devices are protected by an intellectual property portfolio which currently includes issued U.S. patents and issued patents and pending applications in countries outside of the United States covering methods and apparatus for intracorporeal retraction and removal of organs, internal adjustment of device and retraction, as well as design for safe device removal. Specifically, this portfolio includes 10 issued U.S. patents, 12 issued patents in countries outside the United States, and one pending application. These issued patents, and any patents granted from such applications, will, or are expected to, expire between 2030 and 2037, without taking potential patent term extensions or adjustments into account. A further three published patent applications were filed to protect FreeHold devices.

Motus Devices

Our Pure-Vu® System and related highly innovative technologies rooted in systems and methods for cleaning body cavities with or without the use of an endoscope are protected by an intellectual property portfolio which includes 21 granted or allowed patents in the U.S., 20 patents in Asia (Japan, China and Hong Kong), and 13 patents in the EU, with patent protection until at least 2040. In addition, we have 6 pending patent applications in various regions of the world with a focus on the U.S., EU and Japan. We have registered trademarks for Motus GI and for the Pure-Vu® System in the U.S., EU and other international jurisdictions. We also have a pending trademark application in the U.S. to MICRO-PREP.

Government Regulation

Our AVIM Therapy and CNT-HF product candidates and our FreeHold Devices, as well as the PerQSeal and Pure-Vu products, are regulated as medical devices. Our Virtue SAB product candidate is a proprietary drug/device combination product candidate in development for the treatment of artery disease. In the United States, products composed of constituent parts that individually would be regulated under different regulatory pathways, and frequently by different centers at the FDA, are known as combination products. In the case of Virtue SAB, if marketed individually, the balloon angioplasty device would be regulated by FDA as a medical device while SirolimusEFR would be regulated by the FDA as a drug. However, under the Federal Food, Drug, and Cosmetic Act (the “FDCA”), the FDA is charged with assigning a center with primary jurisdiction, or a lead center, for review of a combination product. The designation of a lead center generally obviates the need for separate approval of each component of a combination product. The determination of which center will be the lead center is based on the “primary mode of action” of the combination product. Thus, if the primary mode of action of a drug/device combination product is attributable to the device constituent, the FDA center responsible for pre-market review of the device product would have primary jurisdiction for the combination product. A combination product with a medical-device primary mode of action generally would be reviewed and approved or cleared pursuant to the medical device approval and clearance processes set forth under the FDCA. In reviewing the marketing application for such a product, however, FDA reviewers in the drug center could consult with their counterparts in the device center to ensure that the drug component of the combination product met applicable requirements regarding safety and effectiveness. In addition, under FDA regulations, drug/device combination products are subject to cGMP requirements applicable to both drugs and devices, including the Quality Management System Regulation (the “QMSR”) applicable to medical devices.

In 2019, the FDA confirmed that Virtue SAB will be regulated as a combination product candidate, with the FDA’s Center for Devices and Radiological Health as the lead review center of a marketing application. We expect to seek FDA approval of each proposed indication of Virtue SAB through submission of a PMA, reviewed by the FDA’s Center for Devices and Radiological Health and do not expect that the FDA will require a separate marketing authorization for each constituent component of Virtue SAB. We anticipate that our standalone SirolimusEFR product candidate for certain potential indications such as ophthalmic inflammatory conditions (uveitis) and chronic joint inflammation (osteoarthritis) will be regulated by the FDA as a drug.

Medical Device Regulation

United States

Medical devices are subject to extensive and ongoing regulation by the FDA under the FDCA and its implementing regulations, as well as other federal and state regulatory bodies in the United States and comparable authorities in other countries under other statutes and regulations. The laws and regulations govern, among other things, product design and development, preclinical and clinical testing, manufacturing, packaging, labeling, storage, recordkeeping and reporting, clearance or approval, marketing, distribution, promotion, import and export and post-marketing surveillance. Failure to comply with applicable requirements may subject a device and/or its manufacturer to a variety of administrative sanctions, such as issuance of warning letters, recalls, import detentions, suspension of manufacturing or distribution, civil monetary penalties and/or judicial sanctions, such as product seizures, injunctions and criminal prosecution.

FDA’s Approval Requirements

Unless an exemption applies, each medical device commercially distributed in the United States generally requires either FDA clearance of a 510(k) pre-market notification, or approval of a PMA application. The AVIM Therapy and CNT-HF product candidates will be regulated as Class III medical devices and will require submission of a PMA supplement or a PMA. We anticipate that our Virtue SAB product candidate will be regulated as a drug/device combination product that will require submission of a PMA.

PMA Pathway

In the United States, medical devices are classified into one of three classes — Class I, Class II or Class III — depending on the degree of risk associated with each medical device and the extent of manufacturing and regulatory control needed to provide reasonable assurance of safety and effectiveness. Class I devices are deemed to be low risk and are those for which safety and effectiveness can be assured by adherence to the FDA’s General Controls for medical devices, which include compliance with the applicable portions of the QMSR, facility registration and product listing, reporting of adverse medical events and truthful and non-misleading advertising and promotion. Most Class I devices are classified as exempt from pre-market notification requirements and therefore may be commercially distributed without obtaining prior authorization from the FDA. Class II devices are subject to the FDA’s General Controls and special controls intended to provide reasonable assurance of safety and effectiveness of the device. Special controls can include performance standards, post-market surveillance, patient registries and guidance documents. Manufacturers of most Class II devices are required to submit to the FDA a pre-market notification under Section 510(k) of the FDCA demonstrating that the device to be marketed is as safe and effective, that is, substantially equivalent, to a legally marketed device and requesting permission to commercially distribute the device. Pursuant to the Medical Device User Fee Amendments of 2022 (MDUFA V), unless a specific exemption applies, 510(k) premarket notification submissions require payment of user fees. Devices deemed by the FDA to pose the greatest risk, such as life-sustaining, life-supporting or implantable devices, devices that utilize new technology, or devices deemed not substantially equivalent to a previously cleared 510(k) device, are placed in Class III, generally requiring approval of a PMA application.

Class III devices such as the AVIM Therapy and CNT-HF product candidates require PMA approval before they can be marketed, although some pre-amendment Class III devices for which FDA has not yet required a PMA are cleared through the 510(k) process. The PMA application process is much more demanding than the 510(k) clearance process. A PMA application must be supported by extensive data, including but not limited to technical, preclinical, clinical studies, manufacturing and labeling, to demonstrate to the FDA’s satisfaction reasonable evidence of safety and effectiveness of the device. The PMA application must also contain a full description of the device and its components, a full description of the methods, facilities and controls used for manufacturing and proposed labeling. PMA applications (and supplemental PMA applications) are subject to substantially higher user fees under MDUFA V than are 510(k) premarket notifications.

After a PMA application is submitted, the FDA has 45 days to determine whether the application is sufficiently complete to permit a substantive review and thus whether the FDA will file the application for review. The FDA then has 180 days under the FDCA to review a filed PMA application, although the review of an application generally occurs over a significantly longer period of time and can take up to several years. During this review period, the FDA may request additional information or clarification of the information already provided.

Also, an advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA as to the approvability of the device. Although the FDA is not bound by the advisory panel’s decision, the panel’s recommendations are important to the FDA’s overall decision-making process. In addition, the FDA may conduct a pre-approval inspection of the manufacturing facility to ensure compliance with the QMSR. The agency also may inspect one or more clinical sites to assure compliance with FDA’s regulations.

Upon completion of the PMA review, the FDA may: (i) approve the PMA which authorizes commercial marketing with specific prescribing information for one or more indications, which can be more limited than those originally sought; (ii) issue an approvable letter which indicates the FDA’s belief that the PMA is approvable and states what additional information the FDA requires, or the post-approval commitments that must be agreed to prior to approval; (iii) issue a “not approvable” letter which outlines steps required for approval, but which are typically more onerous than those in an approvable letter, and may require additional clinical studies that are often expensive and time consuming and can delay approval for months or even years; or (iv) deny the application. If the FDA issues an approvable or not approvable letter, the applicant has 180 days to respond, after which the FDA’s review clock is reset.

The FDA will generally approve the new device for commercial distribution if it determines that the data and information in the PMA constitute valid scientific evidence and that there is reasonable assurance that the device is safe and effective for the use(s) indicated in the proposed labeling. The FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution, and collection of long-term follow-up data from patients in the clinical study that supported PMA approval or requirements to conduct additional clinical studies post-approval. The FDA may condition PMA approval on some form of post-market surveillance when deemed necessary to protect the public’s health or to provide additional safety and efficacy data for the device in a larger population or for a longer period of use. In such cases, the manufacturer might be required to follow certain patient groups for a number of years and to make periodic reports to the FDA on the clinical status of those patients. Failure to comply with the conditions of approval can result in material adverse enforcement action, including withdrawal of the approval.

Certain changes to an approved device, such as changes in manufacturing facilities, methods, or quality control procedures, or changes in the design performance specifications, which affect the safety or effectiveness of the device, require submission of a PMA supplement. PMA supplements often require submission of the same type of information as a PMA, except that the supplement is limited to information needed to support any changes from the device covered by the original PMA and may not require as extensive clinical data or the convening of an advisory panel. Certain other changes to an approved device require the submission of a new PMA, such as when the design change causes a different intended use, mode of operation, and technical basis of operation, or when the design change is so significant that a new generation of the device will be developed, and the data that were submitted with the original PMA are not applicable for the change in demonstrating a reasonable assurance of safety and effectiveness.

Clinical Studies

Clinical studies are almost always required to support pre-market approval and are sometimes required for 510(k) clearance. All clinical investigations of investigational devices designed to determine safety and effectiveness must be conducted in accordance with the FDA’s IDE regulations, which govern investigational device labeling, prohibit promotion of the investigational device, and specify an array of recordkeeping, reporting and monitoring responsibilities of study sponsors and study investigators. If the device presents a “significant risk” to human health, as defined by the FDA, the FDA requires the device sponsor to submit an IDE application to the FDA, which must become effective prior to commencing human clinical studies. A significant risk device is one that presents a potential for serious risk to the health, safety or welfare of a patient and either is implanted, used in supporting or sustaining human life, substantially important in diagnosing, curing, mitigating or treating disease or otherwise preventing impairment of human health, or otherwise presents a potential for serious risk to a subject. An IDE application must be supported by appropriate data, such as animal and laboratory test results, showing that it is safe to test the device in humans and that the testing protocol is scientifically sound. The IDE will automatically become effective 30 days after receipt by the FDA unless the FDA notifies the company that the investigation may not begin. If the FDA determines that there are deficiencies or other concerns with an IDE for which it requires modification, the FDA may permit a clinical study to still proceed under a conditional approval. Acceptance of an IDE for review does not guarantee that the FDA will allow the IDE to become effective and, if it does become effective, the FDA may or may not determine that the data derived from the trials support the safety and effectiveness of the device or warrant the continuation of clinical studies.

Regardless of the degree of risk presented by the medical device, clinical studies must be approved by, and conducted under the oversight of, an Institutional Review Board (IRB), for each clinical study site. An IRB is an appropriately constituted group that has been formally designated to review and monitor medical research involving subjects and which has the authority to approve, require modifications in, or disapprove research to protect the rights, safety and welfare of human research subjects. If an IDE application is approved by the FDA and one or more IRBs, human clinical studies may begin at a specific number of investigational sites with a specific number of patients, as approved by the FDA. If the evaluation of the device presents a non-significant risk to the patient, a sponsor may begin the clinical study after obtaining approval for the study by one or more IRBs without separate approval from the FDA. However, the clinical study must still be conducted in compliance with abbreviated IDE and human subject protection requirements, such as monitoring the investigation, ensuring that the investigators obtain informed consent, and labeling and recordkeeping requirements. During a study, the sponsor is required to comply with the applicable FDA requirements, including, for example, trial monitoring, selecting clinical investigators and providing them with the investigational plan, ensuring IRB review, adverse event reporting, recordkeeping, and prohibitions on the promotion of investigational devices or on making safety or effectiveness claims for them. The clinical investigators in the clinical study are also subject to FDA regulations and must obtain patient informed consent, rigorously follow the investigational plan and study protocol, control the disposition of the investigational device, and comply with all reporting and recordkeeping requirements. Additionally, after a trial begins, the sponsor, the FDA or the IRB could suspend or terminate a clinical study at any time for various reasons, including a belief that the risks to study subjects outweigh the anticipated benefits, or failures to follow applicable regulations.

Sponsors of certain clinical studies of medical devices are required to register their studies with clinicaltrials.gov, a public database of clinical study information. Information related to the device, patient population, phase of investigation, study sites and investigators and other aspects of the clinical study is made public as part of the registration.

Breakthrough Devices Program

Following passage of the 21st Century Cures Act, the FDA implemented the Breakthrough Devices Program, which is a voluntary program offered to manufacturers of certain medical devices and device-led combination products that may provide for more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions. The goal of the program is to provide patients and healthcare providers with more timely access to qualifying devices by expediting their development, assessment and review, while preserving the statutory standards for PMA approval, 510(k) clearance and de novo classification. The program is available to medical devices that meet certain eligibility criteria, including that the device provides more effective treatment or diagnosis of life-threatening or irreversibly debilitating diseases or conditions, and that the device meets one of the following criteria: (i) the device represents a breakthrough technology, (ii) no approved or cleared alternatives exist, (iii) the device offers significant advantages over existing approved or cleared alternatives, or (iv) the availability of the device is in the best interest of patients. Breakthrough Device designation provides certain benefits to device developers, including more interactive and timely communications with FDA staff, use of post-market data collection, when scientifically appropriate, to facilitate expedited and efficient development and review of the device, opportunities for efficient and flexible clinical study design, and prioritized review of premarket submissions.

Ongoing Regulation by the FDA

Even after a device receives clearance or approval and is placed on the market, numerous regulatory requirements apply. These include:

•establishment registration and device listing;

•labeling regulations, which require that promotion is truthful, not misleading, fairly balanced, provides adequate directions for use, and that all claims are substantiated, and the FDA prohibitions against the promotion of products for uncleared, unapproved or “off-label” uses and other requirements related to promotional activities;

•medical device reporting regulations, which require that manufacturers report to the FDA if their device may have caused or contributed to a death or serious injury, or if their device malfunctioned and the device or a similar device marketed by the manufacturer would be likely to cause or contribute to a death or serious injury if the malfunction were to recur;

•corrections and removal reporting regulations, which require that manufacturers report to the FDA field corrections or removals if undertaken to reduce a risk to health posed by a device or to remedy a violation of the FDCA that may present a risk to health;

•requirements for Unique Device Identifiers on devices and the submission of certain information about each device to the FDA’s Global Unique Device Identification Database;

•the FDA’s recall authority, whereby the FDA can order device manufacturers to recall a medical device from the market if the FDA finds that there is a reasonable probability that the device would cause serious, adverse health consequences or death; and

•post-market surveillance regulations, which apply to certain Class II or Class III devices when necessary to protect the public’s health or to provide additional safety and effectiveness data for the device.

Manufacturing of medical devices is required to comply with the applicable portions of the QMSR, which cover the methods and the facilities, controls for the design, manufacture, testing, production, processes, controls, quality assurance, labeling, packaging, distribution, installation, and servicing of finished devices intended for human use. The QMSR also requires, among other things, maintenance of a device master file, device history file, and complaint files. The QMSR incorporates by reference requirements of the international standard specific for medical device quality management systems set by the International Organization for Standardization (ISO), ISO 13485:2016. Our facilities, records, and manufacturing processes, as well as those of our contract manufacturers, are subject to periodic scheduled or unscheduled inspections by the FDA. Our or our contract manufacturers’ failure to maintain compliance with the QMSR or other applicable regulatory requirements could result in the shut-down of, or restrictions on, its manufacturing operations and the recall or seizure of its products. The discovery of previously unknown problems with any marketed products, including unanticipated adverse events or adverse events of increasing severity or frequency, whether resulting from the use of the device within the scope of its clearance or off-label by a physician in the practice of medicine, could result in restrictions on the device, including the removal of the product from the market or voluntary or mandatory device recalls.

The FDA has broad regulatory compliance and enforcement powers. If the FDA determines that a manufacturer has failed to comply with applicable regulatory requirements, it can take a variety of compliance or enforcement actions, which may result in any of the following sanctions:

•warning or untitled letters, fines, injunctions, consent decrees and civil penalties;

•customer notifications, voluntary or mandatory recall or seizure of products;

•operating restrictions, partial suspension or total shutdown of production;

•refusals or delays in processing submissions or applications for new products or modifications to existing products;

•refusal to grant export or import approvals for products;

•withdrawing approvals that have already been granted; and

•criminal prosecution.

European Union

We believe our Virtue SAB, AVIM Therapy and CNT-HF product candidates as well as our FreeHold Devices would be regulated in the EU as medical devices.

The EU has adopted specific directives and regulations regulating the design, manufacture, clinical investigation, conformity assessment, labeling and adverse event reporting for medical devices (including active implantable medical devices).

Until May 25, 2021, medical devices (including active implantable medical devices) were regulated by Council Directive 93/42/EEC and Council Directive 90/385/EEC (the “EU Medical Devices Directives”), which have been repealed and replaced by Medical Devices Regulation (EU) No 2017/745 (the “EU Medical Devices Regulation”). Our current certificates have been granted under the EU Medical Devices Directives whose regimes are described below. However, as of May 26, 2021, some of the EU Medical Devices Regulation requirements apply in place of the corresponding requirements of the EU Medical Devices Directives with regard to registration of economic operators and of devices, post-market surveillance and vigilance requirements. If we want to market our medical devices in the EU, it will notably require that our devices be certified under the new regime set forth in the EU Medical Devices Regulation.

Medical Devices Directives

Under the EU Medical Devices Directives, all medical devices (including active implantable medical devices) placed on the market in the EU must meet the relevant essential requirements laid down in Annex I to the EU Medical Devices Directives, including the requirement that a medical device must be designed and manufactured in such a way that it will not compromise the clinical condition or safety of patients, or the safety and health of users and others. In addition, the device must achieve the performance intended by the manufacturer and be designed, manufactured, and packaged in a suitable manner. The European Commission has adopted various standards applicable to medical devices. These include standards governing common requirements, such as sterilization and safety of medical electrical equipment and product standards for certain types of medical devices. There are also harmonized standards relating to design and manufacture. While not mandatory, compliance with these standards is viewed as the easiest way to satisfy the essential requirements as a practical matter as it creates a rebuttable presumption that the device satisfies that essential requirement.

To demonstrate compliance with the essential requirements laid down in Annex I to the EU Medical Devices Directives, medical device manufacturers must undergo a conformity assessment procedure, which varies according to the type of medical device and its (risk) classification. As a general rule, demonstration of conformity of medical devices and their manufacturers with the essential requirements must be based, among other things, on the evaluation of clinical data supporting the safety and performance of the products during normal conditions of use. Specifically, a manufacturer must demonstrate that the device achieves its intended performance during normal conditions of use, that the known and foreseeable risks, and any adverse events, are minimized and acceptable when weighed against the benefits of its intended performance, and that any claims made about the performance and safety of the device are supported by suitable evidence. Except for low-risk medical devices (Class I non-sterile, non-measuring devices), where the manufacturer can self-assess the conformity of its products with the essential requirements (except for any parts which relate to sterility or metrology), a conformity assessment procedure requires the intervention of a notified body. Notified bodies are independent organizations designated by EU member states to assess the conformity of devices before being placed on the market. A notified body would typically audit and examine a product’s technical dossiers and the manufacturers’ quality system (the notified body must presume that quality systems which implement the relevant harmonized standards — which is ISO 13485:2016 for Medical Devices Quality Management Systems — conform to these requirements). If satisfied that the relevant product conforms to the relevant essential requirements, the notified body issues a certificate of conformity, which the manufacturer uses as a basis for its own declaration of conformity. The manufacturer may then apply the CE mark to the device, which allows the device to be placed on the market throughout the EU.

Throughout the term of the certificate of conformity, the manufacturer will be subject to periodic surveillance audits to verify continued compliance with the applicable requirements. In particular, there will be a new audit by the notified body before it will renew the relevant certificate(s).

Medical Devices Regulation

The regulatory landscape related to medical devices in the EU recently evolved. On April 5, 2017, the EU Medical Devices Regulation was adopted with the aim of ensuring better protection of public health and patient safety. The EU Medical Devices Regulation establishes a uniform, transparent, predictable and sustainable regulatory framework across the EU for medical devices and ensure a high level of safety and health while supporting innovation. Unlike the EU Medical Devices Directives, the EU Medical Devices Regulation is directly applicable in EU member states without the need for member states to implement into national law. This aims at increasing harmonization across the EU.

The EU Medical Devices Regulation became effective on May 26, 2021. The new regulation, among other things:

•strengthens the rules on placing devices on the market (e.g., reclassification of certain devices and wider scope than the EU Medical Devices Directives) and reinforces surveillance once they are available;

•establishes explicit provisions on manufacturers’ responsibilities for the follow-up of the quality, performance and safety of devices placed on the market;

•establishes explicit provisions on importers’ and distributors’ obligations and responsibilities;

•imposes an obligation to identify a responsible person who is ultimately responsible for all aspects of compliance with the requirements of the new regulation;

•improves the traceability of medical devices throughout the supply chain to the end-user or patient through the introduction of a unique identification number, to increase the ability of manufacturers and regulatory authorities to trace specific devices through the supply chain and to facilitate the prompt and efficient recall of medical devices that have been found to present a safety risk;

•sets up a central database (Eudamed) to provide patients, healthcare professionals and the public with comprehensive information on products available in the EU; and

•strengthens rules for the assessment of certain high-risk devices, such as implants, which may have to undergo a clinical evaluation consultation procedure by experts before they are placed on the market.

Devices lawfully placed on the market pursuant to the EU Medical Devices Directives prior to May 26, 2021 may generally continue to be made available on the market or put into service until May 26, 2025, provided that the requirements of the transitional provisions are fulfilled. In particular, the certificate in question must still be valid. However, even in this case, manufacturers must comply with a number of new or reinforced requirements set forth in the EU Medical Devices Regulation, in particular the obligations described below. The EU Medical Devices Regulation requires that before placing a device, other than a custom-made device, on the market, manufacturers (as well as other economic operators such as authorized representatives and importers) must register by submitting identification information to the electronic system (Eudamed), unless they have already registered. The information to be submitted by manufacturers (and authorized representatives) also includes the name, address and contact details of the person or persons responsible for regulatory compliance. The new regulation also requires that before placing a device, other than a custom-made device, on the market, manufacturers must assign a unique identifier to the device and provide it along with other core data to the unique device identifier (“UDI”) database. These new requirements aim at ensuring better identification and traceability of the devices. Each device — and as applicable, each package — will have a UDI composed of two parts: a device identifier specific to a device, and a production identifier to identify the unit producing the device. Manufacturers are also notably responsible for entering the necessary data on Eudamed, which includes the UDI database, and for keeping it up to date. The obligations for registration in Eudamed will become applicable at a later date (as Eudamed is not yet fully functional). Until Eudamed is fully functional, the corresponding provisions of the EU Medical Devices Directive continue to apply for the purpose of meeting the obligations laid down in the provisions regarding exchange of information, including, and in particular, information regarding registration of devices and economic operators.

All manufacturers placing medical devices on the market in the EU must comply with the EU medical device vigilance system which has been reinforced by the EU Medical Devices Regulation. Under this system, serious incidents and Field Safety Corrective Actions (“FSCAs”) must be reported to the relevant authorities of the EU member states. These reports will have to be submitted through Eudamed — once functional — and aim to ensure that, in addition to reporting to the relevant authorities of the EU member states, other actors such as the economic operators in the supply chain will also be informed. Until Eudamed is fully functional, the corresponding provisions of the EU Medical Devices Directives continue to apply. A serious incident is defined as any malfunction or deterioration in the characteristics or performance of a device made available on the market, including use-error due to ergonomic features, as well as any inadequacy in the information supplied by the manufacturer and any undesirable side-effect, which, directly or indirectly, might have led or might lead to the death of a patient or user or of other persons or to a temporary or permanent serious deterioration of a patient’s, user’s or other person’s state of health or a serious public health threat. Manufacturers are required to take FSCAs defined as any corrective action for technical or medical reasons to prevent or reduce risk of a serious incident associated with the use of a medical device that is made available on the market. An FSCA may include the recall, modification, exchange, destruction or retrofitting of the device. FSCAs must be communicated by the manufacturer or its legal representative to its customers and/or to the end users of the device through Field Safety Notices. For similar serious incidents that occur with the same device or device type and for which the root cause has been identified or a FSCA implemented or where the incidents are common and well documented, manufacturers may provide periodic summary reports instead of individual serious incident reports.

The advertising and promotion of medical devices is subject to some general principles set forth in EU legislation. According to the EU Medical Devices Regulation, only devices that are CE-marked may be marketed and advertised in the EU in accordance with their intended purpose. Directive 2006/114/EC concerning misleading and comparative advertising and Directive 2005/29/EC on unfair commercial practices, while not specific to the advertising of medical devices, also apply to the advertising thereof and contain general rules, for example, requiring that advertisements are evidenced, balanced and not misleading. Specific requirements are defined at a national level. EU member states’ laws related to the advertising and promotion of medical devices, which vary between jurisdictions, may limit or restrict the advertising and promotion of products to the general public and may impose limitations on promotional activities with healthcare professionals.

Many EU member states have adopted specific anti-gift statutes that further limit commercial practices for medical devices, in particular vis-à-vis healthcare professionals and organizations. Additionally, there has been a recent trend of increased regulation of payments and transfers of value provided to healthcare professionals or entities and many EU member states have adopted national “Sunshine Acts” which impose reporting and transparency requirements (often on an annual basis), similar to the requirements in the United States, on medical device manufacturers. Certain countries also mandate implementation of commercial compliance programs.

The aforementioned EU rules are generally applicable in the European Economic Area (the “EEA”), which consists of the 27 EU Member States plus Norway, Liechtenstein and Iceland.

United Kingdom

In the United Kingdom (“UK”), the medical devices market is regulated by the Medicines and Healthcare products Regulatory Agency, which performs market surveillance of medical devices on the UK market. Devices are regulated under the Medical Devices Regulations 2002, which gave effect in UK law to the following EU directives: Directive 90/385/EEC on active implantable medical device; Directive 93/42/EEC on medical devices; and Directive 98/79/EC on in vitro diagnostic medical devices. The UK Conformity Assessed (“UKCA”) marking is a UK product marking used for medical devices being placed on the Great Britain market. It is not recognized in the EU, so these products require a CE marking as well. CE marketed devices will be accepted on the Great Britain market until June 30, 2023. From July 1, 2023, devices placed on the Great Britain market will need to conform to UKCA marketing requirements.

We may need to support clinical and/or regulatory requirements in the UK for its AVIM Therapy product candidate, and potentially others.

Other Regions

Most major markets have different levels of regulatory requirements for medical devices. Modifications to the approved or certified products may require a new regulatory submission in all major markets. The regulatory requirements, and the review time, vary significantly from country to country. Products can also be marketed in other countries that have minimal requirements for medical devices.

Drug Regulation

United States

In the United States, our SirolimusEFR product candidate is subject to extensive regulation by the FDA, which regulates drugs under the FDCA and its implementing regulations, and other federal, state, and local regulatory authorities. The process of obtaining regulatory approvals and certifications and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations requires the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending applications, withdrawal of an approval, imposition of a clinical hold, issuance of warning or untitled letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

The process required by the FDA before a drug may be marketed in the United States generally involves the following:

•completion of preclinical laboratory tests, animal studies and formulation studies in compliance with the FDA’s GLP regulations;

•submission to the FDA of an investigational new drug (“IND”) application, which must become effective before human clinical studies may begin;

•approval by an independent IRB or ethics committee at each clinical site before each trial may be initiated;

•generation of data from adequate and well-controlled human clinical studies in accordance with Good Clinical Practice (“GCP”) requirements to establish the safety and efficacy of the proposed drug product for its intended use;

•submission to the FDA of a new drug application (an “NDA”) after completion of all pivotal trials;

•satisfactory completion of an FDA advisory committee review, if applicable;

•satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the product is produced to assess compliance with current cGMP requirements and to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

•satisfactory completion of an FDA inspection of selected clinical sites to assure compliance with GCPs and the integrity of the clinical data, if applicable;

•payment of user fees; and

•FDA review and approval of the NDA.

We have performed CMC testing in support of our IDE approval for the combination product Virtue SAB that includes populating a DMF. We intend to follow up post-IDE approval for the Virtue SAB with exploring additional pre-clinical work to support additional indications. Depending on the indication, we may be able to leverage some of the biocompatibility and CMC data in the DMF, while providing additional data depending on the indication selected.

Preclinical Studies

Preclinical studies include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies to assess potential safety and efficacy. An IND sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data and any available clinical data or literature, among other things, to the FDA as part of an IND. Some preclinical testing may continue even after the IND is submitted. An IND automatically becomes effective and a clinical study proposed in the IND may begin 30 days after the FDA receives the IND, unless before that time the FDA raises concerns or questions related to one or more proposed clinical studies and places the clinical study on a clinical hold. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical study can begin. As a result, submission of an IND may not result in the FDA allowing clinical studies to commence.

We believe that additional preclinical studies will be necessary for evaluating SirolimusEFR in new indications.

Clinical Studies

Clinical studies involve the administration of the new investigational drug to human subjects under the supervision of qualified investigators in accordance with GCP and human subject protection requirements, which include the requirement that all research subjects provide their informed consent in writing for their participation in any clinical study. Clinical studies are conducted under protocols detailing, among other things, the objectives of the trial, the parameters to be used in monitoring safety, and the effectiveness criteria to be evaluated. A protocol for each clinical study and any subsequent protocol amendments must be submitted to the FDA as part of the IND. An IRB at each institution participating in the clinical study must review and approve the plan for any clinical study before it commences at that institution, and the IRB must continue to oversee the clinical study while it is being conducted. Some trials also include oversight by an independent group of qualified experts organized by the clinical study sponsor, known as a Data Safety Monitoring Board, which provides authorization for whether or not a study may move forward at designated check points based on access to certain data from the study and may halt the clinical study based on prespecified criteria, for example, if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. Information about certain clinical studies must be submitted within specific timeframes for public dissemination on the www.clinicaltrials.gov website.

Human clinical studies are typically conducted in three or four sequential phases, which may overlap or be combined:

•Phase 1: The drug is initially introduced into healthy human subjects or patients with the target disease or condition and tested for safety, dosage tolerance, absorption, metabolism, distribution, excretion and, if possible, to gain an early indication of its effectiveness.

•Phase 2: The drug is administered to a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage.

•Phase 3: The drug is administered to an expanded patient population, generally at geographically dispersed clinical study sites, in well-controlled clinical studies to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

•Phase 4: In some cases, the FDA may condition approval of an NDA for a product candidate on the sponsor’s agreement to conduct additional clinical studies after NDA approval. In other cases, a sponsor may voluntarily conduct additional clinical studies post-approval to gain more information about the drug. Certain post-approval trials may be typically referred to as Phase 4 clinical studies.

Progress reports detailing the results of the clinical studies, among other information, must be submitted at least annually to the FDA, and more frequently if serious adverse events occur. Furthermore, the FDA or the sponsor may suspend or terminate a clinical study at any time on various grounds, including a finding that the research subjects are being exposed to an unacceptable health risk or the failure to meet the trial’s objectives. Similarly, an IRB can suspend or terminate approval of a clinical study at its institution if the clinical study is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

Concurrent with clinical studies, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the product and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its shelf life.

We believe that additional clinical studies will be necessary for evaluating SirolimusEFR in new indications.

Marketing Approval

Assuming successful completion of the required clinical testing in accordance with all applicable regulatory requirements, the results of the preclinical and clinical studies, together with detailed information relating to the product’s chemistry, manufacture, controls and proposed labeling, among other things, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications. In most cases, the submission of an NDA is subject to a substantial application user fee. Under the Prescription Drug User Fee Act guidelines that are currently in effect, the FDA has a goal of 10 months to review and act on an NDA designed for standard review and six months to review and act on an NDA designed for priority review, measured from the “filing” date for an NDA for a new molecular entity (“NME”) or from the receipt date for an NDA for a non-NME product. Measuring from the “filing” date typically adds approximately two months to the timeline for review and decision, because the FDA has sixty days from receipt to make a “filing” decision, as described below.

In addition, under the Pediatric Research Equity Act of 2003 as amended and reauthorized, certain NDAs or supplements to an NDA must contain data that are adequate to assess the safety and effectiveness of the drug for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective. The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or partial waivers from the pediatric data requirements as relevant.

Under certain circumstances, the FDA also may require submission of a risk evaluation and mitigation strategy (“REMS”) plan to ensure that the benefits of the drug outweigh its risks. The REMS plan could include medication guides, physician communication plans, assessment plans, and/or elements to assure safe use, such as restricted distribution methods, patient registries, or other risk minimization tools.

The FDA conducts a preliminary review of all NDAs within the first 60 days after submission, before accepting them for filing, to determine whether they are sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to review before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA reviews an NDA to determine, among other things, whether the drug is safe and effective and whether the facility in which it is manufactured, processed, packaged or held meets standards designed to assure the product’s continued safety, quality and purity.

The FDA may refer an application to an advisory committee. An advisory committee is a panel of independent experts, including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured. The FDA will not approve an application unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications. Additionally, before approving an NDA, the FDA may inspect one or more clinical study sites to assure compliance with GCP requirements.

The FDA generally accepts data from foreign clinical studies in support of an NDA if the trials were conducted under an IND. If a foreign clinical study is not conducted under an IND, the FDA nevertheless may accept the data in support of an NDA if the study was conducted in accordance with GCP requirements and the FDA is able to validate the data through an on-site inspection, if deemed necessary. The FDA may accept foreign clinical data as the sole clinical basis for marketing approval if (1) the foreign data are demonstrated to be applicable to the U.S. population and U.S. medical practice, (2) the studies were performed by clinical investigators with recognized competence, and (3) the data may be considered valid without the need for an on-site inspection or, if the FDA considers the inspection to be necessary, the FDA is able to validate the data through an on-site inspection or other appropriate means.

After evaluating the NDA and all related information, including the advisory committee recommendation, if any, and inspection reports regarding the manufacturing facilities and clinical study sites, if any, the FDA may issue an approval letter, or, in some cases, a Complete Response Letter. A Complete Response Letter indicates that the review cycle of the application is complete, and the application will not be approved in its present form. A Complete Response Letter contains a statement of all deficiencies identified in the NDA and the specific conditions that must be met to secure final approval of the NDA and may require additional clinical testing, preclinical testing, manufacturing or formulation modifications or other changes in order for the FDA to reconsider the application. Even with submission of this additional information, the FDA ultimately may decide that a resubmitted application does not satisfy the regulatory criteria for approval. If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter. An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

Even if the FDA approves a product, it may limit the approved indications or other conditions of use for use of the product, require that contraindications, warnings or precautions be included in the product labeling, require that post-approval studies, including Phase 4 clinical studies, be conducted to further assess a drug’s safety after approval, require testing and surveillance programs to monitor the product after commercialization, or impose other conditions, including distribution and use restrictions or other risk management mechanisms under a REMS, which can materially affect the potential market and profitability of the product. The FDA may take steps to prevent or limit further marketing of a product based on the results of post-marketing studies or surveillance programs. After approval, some types of changes to the approved product, such as adding new indications, manufacturing changes, and additional labeling claims, may be subject to further testing requirements and FDA review and approval.

SirolimusEFR is the drug product component of our combination product Virtue SAB. On April 29, 2025, we announced that we had received FDA approval for an IDE amendment to initiate an updated design of our planned Virtue Trial for our Virtue SAB product candidate for the treatment of Coronary ISR.

The Hatch-Waxman Amendments

Our current regulatory strategy is to pursue development of a standalone SirolimusEFR product candidate for potential indications such as ophthalmic inflammatory conditions (uveitis) and chronic joint inflammation (osteoarthritis) as a Section 505(b)(2) NDA. As an alternative path to FDA approval for modifications to formulations or uses of drugs previously approved by the FDA, an applicant may submit an NDA under Section 505(b)(2) of the FDCA. Section 505(b)(2) was enacted as part of the Hatch-Waxman Amendments. A Section 505(b)(2) NDA is an application that contains full reports of investigations of safety and effectiveness, but where at least some of the information required for approval comes from studies not conducted by, or for, the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted. This type of application permits reliance for such approvals on literature or on the FDA’s previous findings of safety, effectiveness or both for an approved drug product. As such, under Section 505(b)(2), the FDA may rely, for approval of an NDA, on data not developed by or for the applicant and for which the applicant does not contain a right of reference. If the 505(b)(2) applicant can establish that reliance on FDA’s previous findings of safety and effectiveness is scientifically appropriate, it may eliminate the need to conduct certain preclinical or clinical studies of the product candidate. The FDA may also require companies to perform additional bridging studies or measurements, including clinical studies, to support the change from the approved listed drug. The FDA may then approve the new product candidate for all, or some, of the labeled indications and conditions of use for which the listed drug has been approved, as well as for any new indications and conditions of use sought by the 505(b)(2) applicant.

Orange Book Listing

In seeking approval for a drug through an NDA, including a 505(b)(2) NDA, applicants are required to list with the FDA certain patents whose claims cover the applicant’s product. Upon approval of an NDA, each of the patents listed in the application for the drug is then published in the FDA’s Approved Drug Products with Therapeutic Equivalence Evaluations, known as the Orange Book. Any applicant who files an Abbreviated New Drug Application (“ANDA”) seeking approval of a generic equivalent version of a drug listed in the Orange Book or a 505(b)(2) NDA referencing a drug listed in the Orange Book must certify, for each patent listed in the Orange Book for the referenced drug, to the FDA that (1) no patent information on the drug product that is the subject of the application has been submitted to the FDA, (2) such patent has expired, (3) the date on which such patent expires or (4) such patent is invalid or will not be infringed upon by the manufacture, use or sale of the drug product for which the application is submitted. The fourth certification described above is known as a paragraph IV certification. A notice of the paragraph IV certification must be provided to each owner of the patent that is the subject of the certification and to the holder of the approved NDA to which the ANDA or 505(b)(2) application refers. The applicant may also elect to submit a “section viii” statement certifying that its proposed label does not contain (or carves out) any language regarding the patented method-of-use rather than certify to a listed method-of-use patent. This section viii statement does not require notice to the patent holder or NDA owner. There might also be no relevant patent certification.

If the reference NDA holder and patent owners assert a patent challenge directed to one of the Orange Book listed patents within 45 days of the receipt of the paragraph IV certification notice, the FDA is prohibited from approving the application until the earlier of 30 months from the receipt of the paragraph IV certification expiration of the patent, settlement of the lawsuit, or a decision in the infringement case that is favorable to the applicant. Even if the 45 days expire, a patent infringement lawsuit can be brought and could delay market entry, but it would not extend the FDA-related 30-month stay of approval.

The ANDA or 505(b)(2) application also will not be approved until any applicable non-patent exclusivity listed in the Orange Book for the branded reference drug has expired. Specifically, the holder of the NDA for the listed drug may be entitled to a period of non-patent exclusivity, during which the FDA cannot approve an ANDA or 505(b)(2) application that relies on the listed drug. For example, a pharmaceutical manufacturer may obtain five years of non-patent exclusivity upon NDA approval of a NCE, which is a drug that contains an active moiety that has not been approved by FDA in any other NDA. An “active moiety” is defined as the molecule or ion responsible for the drug substance’s physiological or pharmacologic action. During the five-year NCE exclusivity period, the FDA cannot accept for filing and cannot approve any ANDA seeking approval of a generic version of that drug or any 505(b)(2) NDA for the same active moiety and that relies on the FDA’s findings regarding that drug, except that the FDA may accept an application for filing after four years (and may initiate a review of the application, but still may not approve it for five years) if the follow-on applicant makes a paragraph IV certification. This exclusivity period may be extended by an additional six months if certain requirements are met to qualify the product for pediatric exclusivity, including the receipt of a written request from the FDA that the NDA holder conduct certain pediatric studies, the submission of study reports from such studies to the FDA after receipt of the written request and satisfaction of the conditions specified in the written request.

In addition, a drug, including one approved under Section 505(b)(2), may also obtain a three-year period of market exclusivity for a particular condition of approval, or change to a marketed product, such as a new formulation for a previously approved product, if one or more new clinical studies (other than bioavailability or bioequivalence studies) was essential to the approval of the application and was conducted/ sponsored by the applicant. Should this occur, the FDA would be precluded from approving any ANDA or 505(b)(2) application that relies on the information supporting the approval of the drug, or the change to the drug for which the information was submitted and the exclusivity granted, until after that three-year exclusivity period has run. However, unlike for NCE exclusivity, the FDA can accept an application and begin the review process during the exclusivity period.

Post-Approval Requirements

Drugs manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA and other government authorities, including, among other things, requirements relating to recordkeeping, periodic reporting, product sampling and distribution, product tracking and tracing, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the approved product, such as adding new indications, manufacturing changes or other labeling claims, are subject to prior FDA review and approval. There also are continuing annual program fee requirements for any marketed products.

The FDA may impose a number of post-approval requirements as a condition of approval of an NDA. For example, the FDA may require post-marketing testing, including Phase 4 clinical studies, and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization.

In addition, drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and state authorities and are subject to periodic unannounced inspections by the FDA and these state authorities for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated and often require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP requirements and impose reporting and documentation requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

Once an approval is granted, the FDA may withdraw the approval if certain conditions are met, for example, if clinical or other experience, tests, or other scientific data show that such drug is unsafe for use. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks; or imposition of distribution or other restrictions under a REMS program.

Other potential consequences include, among other things:

•restrictions on the marketing or manufacturing of the product or complete withdrawal of the product from the market;

•fines, warning letters or holds on ongoing or proposed clinical studies;

•refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product license approvals;

•product seizure or detention, or refusal to permit the import or export of products;

•consent decrees, corporate integrity agreements, debarment or exclusion from federal healthcare programs;

•mandated modification of promotional materials and labeling and the issuance of corrective information;

•the issuance of safety alerts, Dear Healthcare Provider letters, press releases and other communications containing warnings or other safety information about the product; or

•injunctions or the imposition of civil or criminal penalties.

The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. A company generally can make only claims with respect to FDA-approved uses of a drug and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products. The federal government has levied large civil and criminal fines against companies for alleged improper promotion of off-label use and has enjoined companies from engaging in off-label promotion. The FDA and other regulatory agencies have also required that companies enter into consent decrees or permanent injunctions under which specified promotional conduct is changed or curtailed. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labeling.

In addition, the distribution of prescription pharmaceutical products is subject to the Prescription Drug Marketing Act (the “PDMA”), which regulates the distribution of drug samples at the federal level. Title II of the Federal Drug Quality and Security Act of 2013, known as the Drug Supply Chain Security Act (DSCSA), has also imposed “track and trace” requirements on the distribution of prescription drug products by manufacturers, distributors, and other entities in the drug supply chain. The DSCSA requires product identifiers (i.e., serialization) on prescription drug products in order to establish an electronic interoperable system to identify and trace certain prescription drugs distributed in the United States and preempts existing state drug pedigree laws and regulations on this topic.

Foreign Regulation

In addition to regulations in the United States, we will be subject to a variety of foreign regulations governing clinical studies and commercial sales and distribution of its products. Whether or not we obtain FDA approval for a product, it must obtain approval or certification by the comparable regulatory authorities of foreign countries before it can commence clinical studies, and approval or certification from regulatory authorities in foreign countries, such as the EU, before it may market products in those countries. The requirements and process governing the conduct of clinical studies, approval process, product licensing, pricing and reimbursement vary from country to country. Failure to comply with applicable foreign regulatory requirements, may be subject to, among other things, fines, suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution.

Non-clinical studies and clinical studies

Similarly to the United States, the various phases of non-clinical and clinical research in the EU are subject to significant regulatory controls.

Non-clinical studies are performed to demonstrate the health or environmental safety of new chemical or biological substances. Non-clinical studies must be conducted in compliance with the principles of GLP as set forth in EU Directive 2004/10/EC. In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies. These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical studies of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Conference on Harmonization’s GCPs, as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If the sponsor of the clinical study is not established within the EU, it must appoint an EU entity to act as its legal representative. The sponsor must take out a clinical study insurance policy, and in most EU member states, the sponsor is liable to provide ‘no fault’ compensation to any study subject injured in the clinical study.

The regulatory landscape related to clinical study in the EU has been subject to recent changes. The EU Clinical Trials Regulation (“CTR”), which was adopted in April 2014 and repeals the EU Clinical Trials Directive (the “Clinical Trials Directive”), became applicable on January 31, 2022. Unlike directives, the CTR is directly applicable in all EU member states without the need for member states to further implement it into national law. The CTR notably harmonizes the assessment and supervision processes for clinical studies throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.

While the Clinical Trials Directive required a separate clinical trial application (“CTA”) to be submitted in each member state, to both the competent national health authority and an independent ethics committee, much like the FDA and IRB respectively, the CTR introduces a centralized process and only requires the submission of a single application to all member states concerned. The CTR allows sponsors to make a single submission to both the competent authority and an ethics committee in each member state, leading to a single decision per member state. The CTA must include, among other things, a copy of the trial protocol and an investigational medicinal product dossier containing information about the manufacture and quality of the medicinal product under investigation. The assessment procedure of the CTA has been harmonized as well, including a joint assessment by all member states concerned, and a separate assessment by each member state with respect to specific requirements related to its own territory, including ethics rules. Each member state’s decision is communicated to the sponsor via the centralized EU portal. Once the CTA is approved, clinical study development may proceed.

The CTR foresees a three-year transition period. The extent to which ongoing and new clinical studies will be governed by the CTR varies. For clinical studies whose CTA was made under the Clinical Trials Directive before January 31, 2022, the Clinical Trials Directive will continue to apply on a transitional basis for three years. Additionally, sponsors may still choose to submit a CTA under either the Clinical Trials Directive or the CTR until January 31, 2023 and, if authorized, those will be governed by the Clinical Trials Directive until January 31, 2025. By that date, all ongoing trials will become subject to the provisions of the CTR.

Medicines used in clinical studies must be manufactured in accordance with GMP. Other national and EU-wide regulatory requirements may also apply.

Marketing Authorization

In order to market our future product candidates in the EU and many other foreign jurisdictions, we must obtain separate regulatory approvals. More concretely, in the EU, medicinal product candidates can only be commercialized after obtaining a marketing authorization (“MA”). To obtain regulatory approval of a product candidate under EU regulatory systems, we must submit a MA application (“MAA”). The process for doing this depends, among other things, on the nature of the medicinal product. There are two types of MAs:

•“Centralized MA” are issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Product for Human Use (“CHMP”) of the European Medicines Agency (“EMA”) and are valid throughout the EU. The centralized procedure is mandatory for certain types of product candidates, such as: (i) medicinal products derived from biotechnology processes, such as genetic engineering, (ii) designated orphan medicines, (iii) medicinal products containing a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases and (iv) advanced therapy medicinal products such as gene therapy, somatic cell therapy or tissue-engineered medicines. The centralized procedure is optional for product candidates containing a new active substance not yet authorized in the EU, or for product candidates that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.

•“National MAs” are issued by the competent authorities of the EU member states, only cover their respective territory, and are available for product candidates not falling within the mandatory scope of the centralized procedure. Where a product has already been authorized for marketing in an EU member state, this national MA can be recognized in another member state through the mutual recognition procedure. If the product has not received a national MA in any member state at the time of application, it can be approved simultaneously in various member states through the decentralized procedure. Under the decentralized procedure an identical dossier is submitted to the competent authorities of each of the member states in which the MA is sought, one of which is selected by the applicant as the reference member state.

Under the centralized procedure the maximum timeframe for the evaluation of a MAA by the EMA is 210 days.

In exceptional cases, the CHMP might perform an accelerated review of a MAA in no more than 150 days (not including clock stops). Innovative products that target an unmet medical need and are expected to be of major public health interest may be eligible for a number of expedited development and review programs, such as the Priority Medicines (“PRIME”) scheme, which provides incentives similar to the breakthrough therapy designation in the U.S. In March 2016, the EMA launched an initiative, the PRIME scheme, a voluntary scheme aimed at enhancing the EMA’s support for the development of medicines that target unmet medical needs. It is based on increased interaction and early dialogue with companies developing promising medicines, to optimize their product development plans and speed up their evaluation to help them reach patients earlier. Product developers that benefit from PRIME designation can expect to be eligible for accelerated assessment but this is not guaranteed. Many benefits accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical study designs and other development program elements, and accelerated MAA assessment once a dossier has been submitted. Importantly, a dedicated contact and rapporteur from the CHMP is appointed early in the PRIME scheme facilitating increased understanding of the product at EMA’s committee level. An initial meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide guidance on the overall development and regulatory strategies.

Moreover, in the EU, a “conditional” MA may be granted in cases where all the required safety and efficacy data are not yet available. The conditional MA is subject to conditions to be fulfilled for generating the missing data or ensuring increased safety measures. It is valid for one year and has to be renewed annually until fulfillment of all the conditions. Once the pending studies are provided, it can become a “standard” MA. However, if the conditions are not fulfilled within the timeframe set by the EMA, the MA ceases to be renewed. Furthermore, MA may also be granted “under exceptional circumstances” when the applicant can show that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use even after the product has been authorized and subject to specific procedures being introduced. This may arise in particular when the intended indications are very rare and, in the present state of scientific knowledge, it is not possible to provide comprehensive information, or when generating data may be contrary to generally accepted ethical principles. This MA is close to the conditional MA as it is reserved to medicinal products to be approved for severe diseases or unmet medical needs and the applicant does not hold the complete data set legally required for the grant of a MA. However, unlike the conditional MA, the applicant does not have to provide the missing data and will never have to. Although the MA “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually and the MA is withdrawn in case the risk-benefit ratio is no longer favorable.

MAs have an initial duration of five years. After these five years, the authorization may be renewed for an unlimited period on the basis of a reevaluation of the risk-benefit balance.

Data and marketing exclusivity

The EU also provides opportunities for market exclusivity. Upon receiving MA, reference products generally receive eight years of data exclusivity and an additional two years of market exclusivity. If granted, the data exclusivity period prevents generic or biosimilar applicants from relying on the pre-clinical and clinical study data contained in the dossier of the reference product when applying for a generic or biosimilar MA in the EU during a period of eight years from the date on which the reference product was first authorized in the EU. The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial MA of the reference product in the EU. The overall 10-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those 10 years, the MA holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. However, there is no guarantee that a product will be considered by the EU’s regulatory authorities to be a new chemical entity, and products may not qualify for data exclusivity.

Post-Approval Requirements

Similar to the United States, both MA holders and manufacturers of medicinal products are subject to comprehensive regulatory oversight by the EMA, the European Commission and/or the competent regulatory authorities of the member states. The holder of a MA must establish and maintain a pharmacovigilance system and appoint an individual qualified person for pharmacovigilance who is responsible for oversight of that system. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (“PSURs”).

All new MAAs must include a risk management plan describing the risk management system that the company will put in place and documenting measures to prevent or minimize the risks associated with the product. The regulatory authorities may also impose specific obligations as a condition of the MA. Such risk-minimization measures or post-authorization obligations may include additional safety monitoring, more frequent submission of PSURs, or the conduct of additional clinical studies or post-authorization safety studies.

The advertising and promotion of medicinal products is also subject to laws concerning promotion of medicinal products, interactions with physicians, misleading and comparative advertising and unfair commercial practices. All advertising and promotional activities for the product must be consistent with the approved summary of product characteristics, and therefore all off-label promotion is prohibited. Direct-to-consumer advertising of prescription medicines is also prohibited in the EU. Although general requirements for advertising and promotion of medicinal products are established under EU directives, the details are governed by regulations in each member state and can differ from one country to another.

The aforementioned EU rules are generally applicable in the EEA.

Failure to comply with EU and member state laws that apply to the conduct of clinical studies, manufacturing approval, MA of medicinal products and marketing of such products, both before and after grant of the MA, manufacturing of pharmaceutical products, statutory health insurance, bribery and anti-corruption or with other applicable regulatory requirements may result in administrative, civil or criminal penalties. These penalties could include delays or refusal to authorize the conduct of clinical studies, or to grant MA, product withdrawals and recalls, product seizures, suspension, withdrawal or variation of the MA, total or partial suspension of production, distribution, manufacturing or clinical studies, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

Regulation of Combination Products in the EU

The EU regulates medical devices and medicinal products separately, through different legislative instruments, and the applicable requirements will vary depending on the type of drug-device combination product. EU guidance has been published to help manufacturers select the right regulatory framework.

Drug-delivery products intended to administer a medicinal product where the medicinal product and the device form a single integral product are regulated as medicinal products in the EU. The EMA is responsible for evaluating the quality, safety and efficacy of MAAs submitted through the centralized procedure, including the safety and performance of the medical device in relation to its use with the medicinal product. The EMA or the EU member state national competent authority will assess the product in accordance with the rules for medicinal products described above but the device part must comply with the EU Medical Devices Regulation (including the general safety and performance requirements provided in Annex I). The MAA must include — where available — the results of the assessment of the conformity of the device part with the Medical Devices Regulation contained in the manufacturer’s EU declaration of conformity of the device or the relevant certificate issued by a notified body. If the MAA does not include the results of the conformity assessment and where for the conformity assessment of the device, if used separately, the involvement of a notified body is required, the competent authority must require the applicant to provide a notified body opinion on the conformity of the device.

By contrast, in case of drug-delivery products intended to administer a medicinal product where the device and the medicinal product do not form a single integral product (but are e.g., co-packaged), the medicinal product is regulated in accordance with the rules for medicinal products described above while the device part is regulated as a medical device and will have to comply with all the requirements set forth by the EU Medical Devices Regulation.

The characteristics of non-integral devices used for the administration of medicinal products may impact the quality, safety and efficacy profile of the medicinal products. To the extent that administration devices are co-packaged with the medicinal product or, in exceptional cases, where the use of a specific type of administration device is specifically provided for in the product information of the medicinal product, additional information may need to be provided in the MAA for the medicinal product on the characteristics of the medical device(s) that may impact on the quality, safety and/or efficacy of the medicinal product.

The requirements regarding quality documentation for medicinal products when used with a medical device, including single integral products, co-packaged and referenced products, are outlined in the EMA guideline of July 22, 2021, which became applicable as of January 1, 2022.

The aforementioned EU rules are generally applicable in the EEA.

Coverage and Reimbursement

Sales of any pharmaceutical and medical device product depend, in part, on the extent to which such product will be covered by third-party payors, such as federal, state and foreign government healthcare programs, commercial insurance and managed healthcare organizations, and the level of reimbursement for such product by third-party payors. Significant uncertainty exists as to the coverage and reimbursement status of any newly approved product. Decisions regarding the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. One third-party payor’s decision to cover a particular product does not ensure that other payors will also provide coverage for the product. As a result, the coverage determination process can require manufactures to provide scientific and clinical support for the use of a product to each payor separately and can be a time-consuming process, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance. For products administered under the supervision of a physician, obtaining coverage and adequate reimbursement may be particularly difficult because of the higher prices often associated with such drugs. Additionally, separate reimbursement for the product itself or the treatment or procedure in which the product is used may not be available, which may impact physician utilization.

In addition, third-party payors are increasingly reducing reimbursements for medical devices, pharmaceutical products and services. The U.S. government and state legislatures have continued implementing cost-containment programs, including price controls, restrictions on coverage and reimbursement and requirements for substitution of generic products. Third-party payors are more and more challenging the prices charged, examining the medical necessity and reviewing the cost-effectiveness of medical devices and pharmaceutical products, in addition to questioning their safety and efficacy. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product. Decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product could reduce physician usage and patient demand for the product.

In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific products and therapies. For example, the EU provides options for its member states to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and to control the prices of medicinal products for human use. A member state may approve a specific price for the medicinal product or it may instead adopt a system of direct or indirect controls on the profitability of the company placing the medicinal product on the market. Pharmaceutical products may face competition from lower-priced products in foreign countries that have placed price controls on pharmaceutical products and may also compete with imported foreign products. Furthermore, there is no assurance that a product will be considered medically reasonable and necessary for a specific indication, will be considered cost-effective by third-party payors, that an adequate level of reimbursement will be established even if coverage is available or that the third-party payors’ reimbursement policies will not adversely affect the ability for manufacturers to sell products profitably.

Fraud and Abuse and Other Healthcare Regulations

Federal and state governmental agencies and equivalent foreign authorities subject the healthcare industry to intense regulatory scrutiny, including heightened civil and criminal enforcement efforts. These laws constrain the sales, marketing and other promotional activities of medical device manufacturers by limiting the kinds of financial arrangements we may have with hospitals, physicians and other potential purchasers of its products. Federal healthcare fraud and abuse laws apply to our business when a customer submits a claim for an item or service that is reimbursed under Medicare, Medicaid or other federally funded healthcare programs. Patient privacy statutes and regulations by foreign, federal and state governments may also apply in the locations in which we do business. Descriptions of some of the U.S. laws and regulations that may affect our ability to operate follow.

Federal Healthcare Anti-Kickback Statute

The federal Anti-Kickback Statute prohibits, among other things, persons or entities from knowingly and willfully soliciting, offering, receiving or paying any remuneration, directly or indirectly, overtly or covertly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchasing, leasing, ordering, or arranging for or recommending the purchase, lease, or order of any good or service for which payment may be made, in whole or in part, by federal healthcare programs, such as the Medicare and Medicaid programs. The term “remuneration” has been broadly interpreted to include anything of value, and the government can establish a violation of the Anti-Kickback Statute without proving that a person or entity had actual knowledge of the law or a specific intent to violate it. In addition, the government may assert that a claim, including items or services resulting from a violation of the Anti-Kickback Statute, constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. The Anti-Kickback Statute is subject to evolving interpretations and has been applied by government enforcement officials to a number of common business arrangements in the medical device industry. There are a number of statutory exceptions and regulatory safe harbors protecting certain business arrangements from prosecution under the Anti-Kickback Statute; however, those exceptions and safe harbors are drawn narrowly and there is no exception or safe harbor for many common business activities, such as reimbursement support programs, educational and research grants or charitable donations. The failure of a transaction or arrangement to fit precisely within one or more applicable statutory exceptions or regulatory safe harbors does not necessarily mean that it is illegal or that prosecution will be pursued. However, conduct and business arrangements that do not fully satisfy all requirements of an applicable safe harbor may result in increased scrutiny by government enforcement authorities and will be evaluated on a case-by-case basis based on a cumulative review of all facts and circumstances.

Federal Civil False Claims Act

The federal civil False Claims Act prohibits, among other things, persons or entities from knowingly presenting, or causing to be presented, a false or fraudulent claim for payment of government funds, or knowingly making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to avoid, decrease or conceal an obligation to pay money to the federal government. A claim including items or services resulting from a violation of the Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. Actions under the federal civil False Claims Act may be brought by the government or as a qui tam action by a private individual in the name of the government. These individuals, sometimes known as “relators” or, more commonly, as “whistleblowers,” may share in any amounts paid by the entity to the government in fines or settlement. The number of filings of qui tam actions has increased significantly in recent years. Qui tam actions are filed under seal and impose a mandatory duty on the U.S. Department of Justice to investigate such allegations. Most private citizen actions are declined by the Department of Justice or dismissed by federal courts. However, the investigation costs for a company can be significant and material even if the allegations are without merit. Various states have adopted laws similar to the federal civil False Claims Act, and many of these state laws are broader in scope and apply to all payors, and therefore, are not limited to only those claims submitted to the federal government. Medical device manufacturers and other healthcare companies also are subject to other federal false claims laws, including, among others, federal criminal healthcare fraud and false statement statutes that extend to non-government health benefit programs.

Healthcare Fraud Statute

The Health Insurance Portability and Accountability Act of 1996, as amended by the Health Information Technology for Economic and Clinical Health Act of 1996 (“HIPAA”) and its implementing regulations created federal criminal statutes that prohibit, among other things, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement or representation, or making or using any false writing or document knowing the same to contain any materially false, fictitious or fraudulent statement or entry, in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the Anti-Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a violation.

Sunshine Act

The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health Insurance Program to report annually with certain exceptions to the Centers for Medicare & Medicaid Services, or CMS, information related to payments or other transfers of value made to physicians (as defined by statute), certain non-physician practitioners, including physician assistants, nurse practitioners, clinical nurse specialists, certified nurse anesthetists, anesthesiology assistants and certified nurse-midwives, and teaching hospitals, either directly or indirectly through a third party at the request of such physician, non-physician practitioner or teaching hospital, as well as ownership and investment interests held by physicians and their immediate family members.

Other State Laws

Certain states also mandate implementation of commercial compliance programs, impose restrictions on device manufacturer marketing practices and/or require tracking and reporting of gifts, compensation and other remuneration to healthcare professionals and entities.

State and federal regulatory and enforcement agencies continue to actively investigate violations of healthcare laws and regulations, and the U.S. Congress continues to strengthen the arsenal of enforcement tools. The Bipartisan Budget Act of 2018 (the “BBA”) increased the criminal and civil penalties that can be imposed for violating certain federal healthcare laws, including the Anti-Kickback Statute. Enforcement agencies also continue to pursue novel theories of liability under these laws. In particular, government agencies recently have increased regulatory scrutiny and enforcement activity with respect to manufacturer reimbursement support activities and other patient support programs, including bringing criminal charges or civil enforcement actions under the Anti-Kickback Statute, federal civil False Claims Act and violations of healthcare fraud and HIPAA privacy provisions.

Enforcement and Penalties for Noncompliance with Fraud and Abuse Laws and Regulations

Compliance with these federal and state laws and regulations requires substantial resources. If our operations are found to be in violation of any of the laws described above or any other governmental regulations that apply to it, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment, disgorgement, exclusion from participation in government healthcare programs such as the Medicare and Medicaid programs, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of its operations. Companies settling federal civil False Claims Act, Anti-Kickback Statute and other fraud and abuse cases also may be required to enter into a Corporate Integrity Agreement with the U.S. Department of Health and Human Services Office of Inspector General in order to avoid exclusion from participation (i.e., loss of coverage for their products) in federal healthcare programs such as Medicare and Medicaid. Corporate Integrity Agreements typically impose substantial costs on companies to ensure compliance.

For additional information regarding obligations under federal healthcare statues and regulations, please see the section titled “Risk Factors — Risks Related to Government Regulation and Our Industry — Our relationships with physicians, patients and payors in the United States and elsewhere may be subject, directly or indirectly, to applicable anti-kickback, fraud and abuse, false claims, transparency, and other healthcare laws and regulations.”

United States Healthcare Reform

There have been and continue to be proposals by the federal government, state governments, regulators and third-party payors to control or manage the increased costs of healthcare and, more generally, to reform the U.S. healthcare system.

For example, in the United States, in March 2010, the Patient Protection and the Affordable Care Act, as amended by the Health Care and Education and Reconciliation Act (collectively, the “ACA”), was enacted. The ACA contained a number of significant provisions, including those governing enrollment in federal healthcare programs, reimbursement changes and fraud and abuse measures, all of which impacted existing government healthcare programs and resulted in the development of new programs. The ACA also imposed an excise tax of 2.3% on the sale of most medical devices, which was suspended, effective January 1, 2016, and subsequently repealed, effective January 1, 2020.

In addition, other legislative changes have been proposed and adopted since the ACA was enacted. On August 2, 2011, the Budget Control Act of 2011 was signed into law, which, among other things, includes reductions to Medicare payments to providers, which went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, including the BBA, will remain in effect through 2032, unless additional Congressional action is taken. On January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, reduced Medicare payments to several providers, including hospitals, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years. The Inflation Reduction Act of 2022 included, among other things, provisions that impose new manufacturer financial liability on certain drugs under Medicare Part D, allowing the U.S. government to negotiate Medicare Part B and Part D price caps for certain high-cost drugs and biologics without generic or biosimilar competition. Similarly, the One Big Beautiful Bill Act of 2025 will reduce Medicaid funding significantly.

Further, recently there has been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products, which has resulted in several U.S. Congressional inquiries and proposed and enacted federal and state legislation designed to bring transparency to product pricing and reduce the cost of products and services under government healthcare programs. Additionally, regional healthcare authorities and individual hospitals are increasingly using bidding procedures to determine what products to purchase and which suppliers will be included in their healthcare programs.

We expect additional state, federal and foreign healthcare reform measures to be adopted in the future, any of which could limit the amounts that federal, state and foreign governments will pay for healthcare products and services, which could result in reduced demand for our products or additional pricing pressure.

For instance, in December 2021, the EU Regulation No 2021/2282 on Health Technology Assessment (the “HTA”), amending Directive 2011/24/EU, was adopted. This regulation which entered into force in January 2022 intends to boost cooperation among EU member states in assessing health technologies, including some medical devices, and providing the basis for cooperation at the EU level for joint clinical assessments in these areas. The regulation foresees a three-year transitional period and will permit EU member states to use common HTA tools, methodologies, and procedures across the EU, working together in four main areas, including joint clinical assessment of the innovative health technologies with the most potential impact for patients, joint scientific consultations whereby developers can seek advice from HTA authorities, identification of emerging health technologies to identify promising technologies early, and continuing voluntary cooperation in other areas. Individual EU member states will continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technologies, and making decisions on pricing and reimbursement.

Data Privacy and Security Laws

Numerous state, federal and foreign laws, regulations and standards govern the collection, use, access to, confidentiality and security of health-related and other personal information, and could apply now or in the future to our operations or the operations of our partners. In the United States, numerous federal and state laws and regulations, including data breach notification laws, health information privacy and security laws and consumer protection laws and regulations govern the collection, use, disclosure, and protection of health-related and other personal information. In addition, certain foreign laws govern the privacy and security of personal data, including health-related data. Privacy and security laws, regulations, and other obligations are constantly evolving, may conflict with each other to complicate compliance efforts, and can result in investigations, proceedings, or actions that lead to significant civil and/or criminal penalties and restrictions on data processing.

Our Employees

As of December 31, 2025, we had 86 employees engaged in finance, clinical, research and development, engineering, regulatory and administration functions. We anticipate that the number of employees will grow as we scale our research and development and clinical organizational capabilities. In addition, we utilize and will continue to utilize consultants, clinical research organizations and third parties to perform our analytical and test method development, component and sub-assembly design and manufacturing, as well as preclinical studies, clinical studies, manufacturing and regulatory functions. We will use consultants and third-party analytical and design houses to complement internal capabilities and will utilize external manufacturing partners that have extensive experience in medical devices and dealing with regulatory bodies to provide components, assemblies and final product. Our suppliers will have ISO 13485 approved quality systems (or have been approved for GMP manufacturing of pharmaceutical products).

None of our employees are represented by a labor union or covered under a collective bargaining agreement. We consider our employee relations to be good.

Available Information

We maintain a website at www.orchestrabiomed.com. We are providing the address to our website solely for the information of investors. The information contained on, or accessible through, our website is not a part of, nor is it incorporated by reference into this Form 10-K. Through our website, we make available, free of charge, our annual proxy statement, annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act of 1934, as amended (the “Exchange Act”), as soon as reasonably practicable after we electronically file such material with, or furnish it to the SEC. The SEC maintains a website that contains these reports at www.sec.gov.