NASDAQ: GUTS

The Revita DMR System (“Revita”), our lead product candidate, is based on our insights surrounding the potential role of the gut in obesity. Revita is designed to remodel the duodenal lining via hydrothermal ablation (i.e. duodenal mucosal resurfacing) to reverse damage to intestinal nutrient sensing and signaling mechanisms caused by chronic high-fat and high-sugar diets that are a root cause of metabolic disease. Revita has U.S. FDA Breakthrough Device designation in weight maintenance for people with obesity who discontinue GLP-1 based therapy. We have received favorable FDA feedback on our De Novo classification request for Revita and anticipate submitting a potential De Novo marketing application in the late fourth quarter of 2026. We are evaluating Revita in the REMAIN-1 weight maintenance program, which is designed to evaluate Revita’s potential to maintain weight loss following GLP-1 based therapy discontinuation. The REMAIN-1 study includes three distinct participant cohorts that are conducted under a single IDE: the REVEAL-1 Cohort, the REMAIN-1 Midpoint Cohort and the REMAIN-1 Pivotal Cohort, which are designed to collectively establish the clinical and regulatory foundation for Revita in weight maintenance.

The REVEAL-1 Cohort (n=22) is an open-label study in individuals with obesity who have lost at least 15% of their total body weight on a GLP-1 medication and who either need or choose to discontinue GLP-1 based therapy.

The REMAIN-1 Midpoint Cohort (n=45) is a randomized, double-blind, sham-controlled pilot study to assess the potential of Revita to maintain weight loss after GLP-1 based therapy discontinuation.

The REMAIN-1 Pivotal Cohort (n=315) is a randomized, double-blind, sham-controlled pivotal study to evaluate the safety and efficacy of Revita in maintaining weight loss.

The REMAIN-1 study was initiated in the third quarter of 2024. Enrollment of all three cohorts is complete and the REMAIN-1 Midpoint Cohort and REMAIN-1 Pivotal Cohort are fully randomized, as described further under “Ongoing REMAIN-1 Clinical Study” below.

We are also developing Rejuva, our novel and locally administered, adeno-associated virus (“AAV”)-delivered pancreatic gene therapy platform. Rejuva is designed to enable long-term remission of T2D and obesity by durably reprogramming

pancreatic islet cells to endogenously produce metabolic hormones. Rejuva leverages advanced delivery systems and proprietary screening methods to identify and develop metabolically active gene therapy candidates targeting the pancreas.

Our lead candidate from the Rejuva platform, RJVA-001, is designed to be delivered to the pancreas via a single endoscopic intervention to enable pancreatic beta cells to express GLP-1 locally via nutrient-responsive control. This gene therapy approach enables physiologic GLP-1 secretion without the high circulating levels that contribute to side effects seen with systemic GLP-based drugs.

Our second candidate from the Rejuva platform, RJVA-002, is a dual GIP/GLP-1 gene therapy and is currently in preclinical development. RJVA-002 expands the Rejuva platform into obesity, targeting dual incretin biology with the goal of achieving durable, well-tolerated, weight loss from a single intervention.

Additional information regarding the Rejuva platform is described under “Rejuva Platform Description” and “Preclinical Data Overview: Rejuva Gene Therapy Platform” below.

We believe Revita and Rejuva have the potential to revolutionize treatment across the spectrum of obesity and T2D, align the clinical and economic interests of key stakeholders around the long-term regression of metabolic disease, and, at their fullest potential, significantly reduce the burden of metabolic disease globally.

Our Development Pipeline

Our development pipeline for Revita and Rejuva pancreatic gene therapy (“PGTx”) candidates target large market indications in obesity and T2D and aim to transform treatment from chronic symptom management to disease-modifying therapies that target the organ-level root causes of metabolic disease.

The following table summarizes our development pipeline and potential clinical opportunities across the spectrum of metabolic disease, from obesity (with or without prediabetes) to advanced T2D.

What Sets Us Apart

Our vision is to develop transformative therapies that can prevent and eliminate metabolic disease. We plan to achieve this by creating disease-modifying therapies targeting the gut and pancreas, driving broad adoption of our innovative approach and improving real-world outcomes for patients and health systems. Our vision is supported by the following strengths:

Pioneering New Approaches Based on Deep Understanding of Metabolic Diseases

We are pioneering the development of disease-modifying therapies targeting the organ level root cause of metabolic disease. Our approach builds on over a decade of our research and the accumulation of independently published, supportive preclinical and clinical evidence, all implicating the gut and pancreas as validated, untapped targets in obesity and T2D. We

aim to restore and preserve the health of the key organs required for metabolic fitness and reduce the burden of metabolic disease for patients.

Developing Disease-Modifying Therapies that Provide Long-Term Metabolic Benefits and the Potential to Shift the Treatment Paradigm in Obesity and T2D

Our Revita and Rejuva programs are designed to target dysfunction in the duodenum and pancreas, respectively, to provide long-term metabolic benefits from a single administration. For this reason, we believe Revita and Rejuva offer the potential to address metabolic diseases in ways we believe current therapies do not, including the prevention and remission of the diseases. Specifically, Revita has the potential to support long-term, durable weight maintenance, while Rejuva offers the potential to drive T2D remission and achieve durable weight loss.

Rigorous Approach to Clinical Development

The Revita clinical program is designed to advance the development of Revita as a foundational outpatient procedural therapy for obesity. By targeting duodenal dysfunction, Revita aims to provide durable weight maintenance solutions, addressing a critical gap in current long-term obesity care. To date, we have evaluated Revita in over 500 participants across multiple clinical studies at sites in South America, Europe and the U.S., with favorable safety and tolerability, glycemic control and weight maintenance data. Our Rejuva platform with GLP-1 PGTx candidates has been evaluated in small and large animal models, as well as ex vivo murine and human islets. In preclinical head-to-head studies, Rejuva gene therapy candidates demonstrated weight reduction in a disease-relevant diet-induced obesity (“DIO”) mouse model, along with improvement in glycemic control and delayed T2D progression in a disease-relevant db/db mouse model compared to chronic administrations of semaglutide (the active agent in Ozempic and Wegovy). We are leveraging our extensive clinical therapeutic endoscopy experience with Revita to inform our clinical plans with our RJVA-001 and RJVA-002 T2D and obesity candidates, respectively. We believe our clinical and preclinical programs are supported by a robust intellectual property position, including issued patents and pending applications, intended to protect core elements of our technology and assets and provide meaningful barriers to entry.

Aligning Interests of Key Stakeholders: Patients, Referring Physicians, Providers, and Payors

We believe Revita and Rejuva, if approved, have the potential to offer clinical and economic benefits while reducing the burden of disease management compared to the current standard of care in obesity and T2D. We believe both programs have the potential to broadly align interests across key stakeholders involved in the treatment of obesity and T2D, and may have the following benefits to these groups:

Patients. Improving weight loss maintenance and glycemic control, while reducing the number and burden of therapies required to adequately manage obesity and T2D.

Referring Physicians. Preventing weight gain and lowering HbA1c for specific patient populations with a procedural therapy that reduces the workload in disease management and improves quality metrics associated with the disease.

Providers. Straightforward, easy to train outpatient procedures, which we believe could be safely deployed at scale across a large patient population. Intended to seamlessly integrate into existing endoscopist workflows and provide a new, potentially profitable service line for hospitals with a patient-friendly therapeutic option for a significant portion of their patients.

Payors. Significant health economic benefits for payors who are currently struggling with the increasing expenses of obesity and T2D, driven primarily by unchecked disease progression and the lack of disease-modifying therapies.

Purpose-Built Leadership Team with Shared Mission to Advance Patient Care in Metabolic Disease

Our diverse leadership team, combining product development know-how, therapeutic expertise and commercial readiness, has over 150 years of collective experience in therapeutic development. We are mission-driven to develop novel

disease-modifying therapies that can potentially reverse metabolic diseases for patients and for health systems. Our team aims to continuously advance and expand upon our body of knowledge in order to establish and maintain a scientific leadership position in our therapeutic areas of focus. We do so by collaborating with expert advisors who are leaders in metabolic disease, weight maintenance, endocrine signaling, endoscopy and gene therapy.

Growth Strategies

Our mission is to develop transformative therapies that prevent and eliminate metabolic disease. To achieve this goal, we plan to employ the following strategies:

Establish Practice-Changing Levels of Evidence for Revita Across the Spectrum of Obesity

Our stepwise approach to regulatory marketing authorization will initially focus on patients with the highest unmet need in obesity, those who need to maintain weight loss after GLP-1 medication discontinuation and then progress to other unmet needs in the treatment and prevention of metabolic diseases, including T2D.

We believe our Revita clinical program, including our ongoing REMAIN-1 study, will provide comprehensive clinical evidence to support the potential of Revita as an investigational, potential disease-modifying procedural therapy for weight maintenance in obesity.

Rejuva Gene Therapy Platform to Enable Long-Term Remission of T2D and Obesity

To further our core strategy to treat and significantly reduce the burden of T2D and obesity, we are developing the Rejuva gene therapy platform, which is designed to enable long-term remission of T2D and obesity by durably reprogramming pancreatic islet cells to endogenously produce metabolic hormones. Based on this mechanism, we believe Rejuva could be a potentially first-in-class, nutrient-responsive (“smart”), gene therapy that durably improves metabolic control. Our platform utilizes a novel investigational pancreatic delivery device to administer gene therapy candidates directly to the pancreas (body and tail). We believe that our approach allows for the precise mechanical and molecular confinement of targeted, low dose gene therapy medicines that can address many of the challenges that limit the use of gene therapy in the pancreas and systemic GLP-1-based drugs today.

Execute Targeted and Efficient Go-to-Market Strategy for Revita

If Revita is approved in the U.S. for a weight maintenance indication, we plan to execute an efficient “hub-and spoke” commercialization strategy to capitalize on the aligned incentives of key stakeholders and drive rapid adoption. Leveraging key learning and insights from the Revita clinical program and from the commercial pilot in Germany, we plan to assemble a targeted sales force initially focusing on a center of excellence model, working closely with gastrointestinal (“GI”) endoscopist “early adopters,” with a dedicated interest in bariatric and metabolic endoscopy. In parallel, we plan to leverage our letter of intent (“LOI”) with Everself (formerly Bariendo) as this potential partnership will bring a scalable, physician-driven platform designed to deliver metabolic endoscopic solutions at the nation’s largest network of high-volume hospital and ambulatory endoscopy centers across the U.S. We intend to roll out a robust procedural training and support program for GI endoscopists, which we believe will ensure seamless integration into their workflow and practice. We will also work with CMS and private insurers to seek to establish coverage and reimbursement for procedures using our Revita product candidate, a key strategy to support the commercial viability of Revita with providers.

Broaden the Indication and Use of Revita

If Revita is approved for a weight maintenance indication in the U.S., we plan to leverage our platform, technology, core capabilities and the data gathered from our prior clinical studies and the Revita clinical program to expand the indication and use of Revita within other unmet needs in the treatment and prevention of other serious metabolic diseases, including T2D.

Because of our broadly accessible and disease-modifying approach, we intend to make Revita a backbone procedural therapy with the potential to significantly reduce the burden of obesity, T2D and prediabetes. As we expand the adoption of Revita, we may seek regulatory allowance to evaluate additional indications and uses of Revita, as well as partnerships and/or distributor relationships for its commercialization in other global geographies.

Expand Application of Rejuva Platform to Other Metabolic Targets Beyond GLP-1

The Rejuva platform is modular and designed to enable local pancreatic production of key metabolic hormones important for proper beta cell function and incretin signaling. Our initial gene therapy candidates will include an AAV9 vector with a transgene that expresses GLP-1 (RJVA-001) and glucose-dependent insulinotropic polypeptide (“GIP”)/GLP-1 (RJVA-002) hormones from an insulin promoter. The modular nature of our platform can enable production of a number of additional metabolic hormones, including but not limited to, peptide YY (“PYY”) and amylin. The versatility of the Rejuva platform has the potential to underpin a comprehensive, next-generation modality capable of targeting the root causes of various metabolic diseases.

Addressing Interlinked Metabolic Conditions: Obesity and T2D

Metabolic syndrome represents a spectrum of disorders that are primarily characterized by disturbances in the body’s ability to properly metabolize glucose, lipids, and other essential molecules. One of the most prevalent and ubiquitous manifestations of metabolic syndrome is obesity, a condition where excessive body fat accumulates to a degree that has the potential to adversely impact health. The presence of excess body fat in obesity helps predispose at-risk individuals to other manifestations of metabolic disease, notably T2D, cardiovascular disease (“CVD”), metabolic dysfunction-associated steatohepatitis (“MASH”) (formerly known as non-alcoholic steatohepatitis).

Whereas our ancestors lived and adapted over centuries to ensure adequate energy supply in environments with limited nutrition, many people now live in a modern world with abundant access to calories and levels of nutrition for which we believe our bodies were never designed. The mismatch between our ancestral genetics and modern diets that are high in fat and sugar is a primary driver of metabolic diseases in the recent past. Emerging scientific consensus links these high fat and sugar diets to dysfunction in key metabolic organs that increase the risk of the development of obesity and T2D, including the gut and pancreas. There is a high degree of overlap between obesity and T2D. Obesity is a key factor in poor metabolic function in patients with T2D, and weight loss is seen as a critical therapeutic goal for T2D patients. According to the American Diabetes Association Standards of Medical Care in Diabetes—2022, management of obesity is an important factor in the treatment of diabetes. According to the American Diabetes Association, even a 5% weight loss can improve blood glucose levels and reduce the need for medication. Therapeutic strategies that can both lower blood glucose and help with weight management could have longer-term benefits in prevention and remission of metabolic diseases.

Our Market Opportunity in Obesity

Obesity is a disorder of altered metabolic setpoint and nutritional excess characterized by progressive weight gain and metabolic dysfunction that sits at the apex of a diverse range of negative health conditions, including T2D, CVD, MASH, PCOS and certain types of cancer. The International Diabetes Federation estimates that there are over 800 million people globally today who suffer from obesity and prediabetes, with nearly 100 million people in the U.S. alone. With new innovations achieving greater degrees of potency than earlier agents, the obesity market is poised for immense growth, with industry expectations of approximately $250 billion in drug sales by the end of the decade.

The human body has complex mechanisms to regulate weight, often compared to a thermostat that sets a “weight setpoint.” This setpoint is determined by a variety of factors, including genetics, environment and behavior, and is regulated by a multitude of neural and hormonal signals originating in the intestine, pancreas, and adipose tissue, converging in the hypothalamus and other regions of the brain.

In individuals with obesity, the weight setpoint might be set or defended at a higher level, which is a key challenge in the management of this disease. When an individual with obesity loses weight (either by behavior changes or with medications, including GLP-1 drugs), the body perceives the weight loss as a state of calorie deficit and risk of starvation. For this reason, the brain triggers a set of compensatory mechanisms, including increased hunger and decreased energy expenditure to try to restore the previous higher weight setpoint. The potential correction of the body’s altered metabolic setpoint can enable lasting benefits and translate to superior real-world outcomes.

The Current Treatment Paradigm in Obesity

Guidelines today focus on addressing excess weight in obesity, rather than developing strategies to lower or reset the body’s altered weight setpoint. Initial interventions focus on dietary changes and lifestyle modifications. The American College of Cardiology (“ACC”) and American Association of Clinical Endocrinologists (“AACE”) recommend that patients with obesity should initially be prescribed aerobic exercise and resistance training, a reduced calorie diet, and

behavioral intervention. The AACE and ACC guidelines recommend that behavioral interventions be escalated for patients who do not achieve 2.5% weight loss within one month of beginning lifestyle modifications. If lifestyle modifications are not successful, treatment may move into therapeutic involvement and surgery. The AACE guidelines recommend that pharmacotherapy combined with lifestyle modifications be considered in individuals with a BMI of at least 27 kg/m2.

The GLP-1 class of medicines have proven clinical efficacy in obesity. Wegovy (semaglutide), Saxenda (liraglutide), and Zepbound (tirzepatide) are GLP-1 based therapies currently FDA-approved for obesity, with additional candidates in various development stages. In August 2023, Novo Nordisk’s SELECT trial demonstrated that treatment with semaglutide as an adjunct to the standard of care reduced the risk of heart attack, stroke, or heart disease-related death by 20% in overweight or obese individuals with CVD and no prior history of T2D. Current prescription trends suggest widespread usage of GLP-1s in obesity, demonstrating extensive patient interest in access to this class of drugs.

A critical unmet need remains in obesity despite the potency of GLP-1s. As with glucose control, GLP-1s have a “rebound effect” in obesity, in which weight loss is not maintained once medication is stopped. A 2022 third-party study exploring weight regain and cardiometabolic effects after withdrawal of 2.4 mg of once-weekly semaglutide found that participants regained two-thirds of their prior weight loss one year after treatment discontinuation, with similar changes in cardiometabolic variables. In July 2023, results from Eli Lilly’s SURMOUNT trials for tirzepatide demonstrated similar results. We believe there remains a critical unmet need in obesity for a therapeutic option that provides long-term weight and metabolic benefit even after treatment discontinuation.

In an era of potent but non-durable weight loss therapies, we believe goals for anti-obesity medications should be 1) weight maintenance, defined as minimal weight regain over the course of at least one year after the discontinuation of therapy, and 2) obesity remission, defined as achieving durable weight loss without the need for ongoing obesity-specific pharmacologic or surgical treatments. Therapeutic strategies that can achieve weight maintenance and obesity remission have the potential to provide a step change in outcomes for patients with obesity.

Our Market Opportunity in Type 2 Diabetes

The International Diabetes Federation estimates that diabetes currently affects approximately over 500 million adults worldwide, with nearly 1.3 billion people expected to be living with T2D globally by 2050. In the U.S. alone, approximately 27 million people live with T2D on medical therapy and 5 million people live with advanced T2D on insulin therapy.

The Current Treatment Paradigm in T2D

The current standard of care for T2D is defined by life-long symptomatic management, focused on blood glucose control instead of disease modification. Even though T2D affects a significant fraction of the global population, there has not been a novel modality introduced to treat T2D in over a decade. While therapeutic advances in T1D have led to the approval of Tzield (teplizumab-mzwv) for the prevention of progression of T1D in 2022, and novel cell-based approaches to replacing beta cells in T1D, there has been an absence of therapeutic strategies tackling the root cause pathology of T2D. This lack of innovation is evidenced by the stubborn persistence of inadequate T2D control in patients. There are no approved disease-modifying therapies that target the organ-level root causes of T2D today.

The standard initial therapy in T2D is preventive care: dietary and lifestyle interventions aimed at altering the risk factors that contribute to progression of disease. While alterations to lifestyle are important, even intensive diets have not demonstrated sufficiently durable effectiveness to favorably impact long-term health in most patients due to lack of persistence and adherence. The Look AHEAD trial, conducted by the National Institute of Diabetes and Digestive and Kidney Diseases, was a randomized controlled trial comparing an intensive lifestyle program to standard diabetes education in overweight and obese T2D patients to track the development of CVD over time. The trial was stopped for futility after a median follow-up of 9.6 years. Eventually, even with diet and lifestyle interventions, blood glucose often worsens as ongoing insulin resistance causes progressive failure of pancreatic beta cells. At this point, symptomatic therapy to manage hyperglycemia is needed and most patients advance to medications and the chronic-care therapeutic model we see today.

Several classes of oral and injectable drugs exist for the management of hyperglycemia, and the sequential addition of medications on top of one another is directed by patient preference and payor pressure to minimize costs. Most patients with T2D will remain on an expanding list of medications to lower their blood glucose throughout the remainder of their lives. The sodium-glucose cotransporter-2 inhibitor (“SGLT2i”) (e.g., empagliflozin), and GLP-1RA (e.g., semaglutide), classes emerged over ten years ago as important new therapies in T2D with benefits beyond glucose lowering alone,

including broader metabolic benefits on CVD and kidney disease risk. Guidelines call for patients to typically try SGLT2i and GLP-1RA if affordable before progressing to insulin therapy, helping to make the SGLT2i class an estimated $12 billion market and the GLP-1RA class an estimated $20 billion market in 2022. The significant market uptake of these drugs has come despite important shortcomings. SGLT2i and GLP-1RA medicines have a black box warning associated with significant safety risks, as well as tolerability challenges affecting medication adherence. For example, GLP-1RAs impact several physiological processes and result in a variety of side effects, including nausea, vomiting and diarrhea.

The advent of the GLP-1RA class of medicines for T2D has led to an explosion in prescriptions of these drugs due to their impressive potency, cardiovascular benefits, and favorable weight loss profile. According to a report by Trilliant Health, physicians signed more than nine million GLP-1RA prescriptions in the U.S. for Ozempic, Mounjaro and Saxenda in the last three months of 2022 alone. However, a retrospective study conducted by Polonsky et al. analyzing medical claims data between July 2012 and January 2019 demonstrated that a majority of patients on a weekly GLP-1RA (i.e., semaglutide, dulaglutide or exenatide extended release) discontinued therapy at 12 months (Polonsky et al. Diabetes Ther (2022) 13:175–187). Discontinuation of these agents typically leads to an immediate loss of metabolic benefit and weight rebound, as seen in Eli Lilly’s SURMOUNT-4 study with tirzepatide and Novo Nordisk’s STEP-1 extension study with semaglutide. This lack of persistence to therapy and subsequent loss of benefit in both blood glucose and weight suggests that these agents do not offer durable disease modification and help explain the increasing burden of T2D in society, even with the availability of these potent drugs.

We believe the current symptom-driven approach to T2D management is misdirected and unreasonable. It asks patients for dietary and lifestyle changes in the face of an altered physiologic set-point in the body, rigorous and lifelong patient adherence and persistence to medicines, and unquestioning willingness to accede to increasingly complex therapies. This burdensome approach to care is often unmanageable and may leave many patients at risk, potentially resulting in chronic elevations in blood glucose that increase the likelihood of microvascular and macrovascular complications of T2D, and even death. There are no therapies that are approved today in T2D that offer disease modification, which we define as ongoing and durable preservation of pancreatic insulin production capacity even after therapy is discontinued.

We believe the same attention toward disease modification should be applied to T2D as is now already evident in T1D therapeutic development with goals of 1) diabetes prevention, defined as whether the treatment delays progression of diabetes, and 2) diabetes remission, defined as achieving a blood glucose level below the diabetic range for at least one year in the absence of active pharmacotherapy or ongoing procedures.

Our Approach

We design and develop novel, differentiated, disease-modifying therapies that precisely target and alter the function of the diseased organs responsible for obesity and T2D. Despite the development of highly potent medicines that can improve glucose control and weight loss, significant unmet needs remain in these diseases due to high rates of drug discontinuation over time, the loss of metabolic benefit upon drug discontinuation, and the inability of medicines to arrest the progressive nature of these conditions. Our vision is to develop transformative therapies that have the potential to prevent and eliminate metabolic diseases.

Our product candidates have the potential to offer a major advance in healthcare because they are designed as disease-modifying treatments that provide long-term metabolic benefits from a single administration, and are therefore potentially positioned to target the prevention and remission of disease. These critically important categories in obesity and T2D treatment cannot be addressed with current pharmacology. To be maximally impactful, these therapies must also be delivered at a scale that can match the incidence and prevalence of metabolic disease around the world. We believe our product candidates are not only unique in their potential for disease modification, but also in their design for broad accessibility for large populations. Accordingly, we believe our candidates have the capacity to revolutionize treatment of obesity and T2D and, at their fullest potential, significantly reduce the burden of metabolic disease globally.

Our Solutions

We believe there is a significant market opportunity for disease-modifying treatments that provide long-term metabolic benefits across the spectrum of obesity and T2D and we are developing a suite of product candidates that will target different phases of these metabolic diseases.

Overview of Revita

Revita is an investigational outpatient procedural therapy designed to durably modify duodenal dysfunction, a major pathologic consequence of a high fat high sugar diet, which can initiate obesity and T2D in humans. The duodenum is the first segment of the small intestine and the first site of nutrient absorption within the body. The duodenal mucosa regulates the human metabolic response to food intake, and chronic exposure to modern diets high in fat and sugar drive a functional maladaptation of stem cells in the duodenum and lead to dysfunctional hyperplasia of the duodenal mucosa. These diet-induced changes to the structure and function of the duodenal mucosa disrupt physiologic nutrient sensing and signaling mechanisms from the gut to the brain, with resulting alterations to systemic metabolic activity that affect glucose control and satiety through multiple downstream organ systems. Emerging scientific consensus has identified this dysfunction in the gut as a root cause of obesity and metabolic dysfunction and therefore propose targeting gut dysfunction to address downstream metabolic diseases. There are no therapies approved today that target the duodenal mucosa for regeneration and renewal.

The Revita system is designed to enable durable and repeatable metabolic improvement by targeting duodenal dysfunction with an outpatient, endoscopic procedural therapy. Revita uses heat energy to ablate the dysfunctional duodenal mucosa, including the duodenal stem cells residing at the base of the mucosa, to enable regeneration and renewal of the duodenum and restore normal metabolic signaling from the gut. The Revita procedure provides thermal protection to the duodenum before ablating the superficial mucosa by (1) isolating the mucosa from the deeper muscle layer of the duodenum and then (2) hydrothermally ablating the superficial layer of the duodenal lining with a proprietary balloon catheter and control console. The procedure takes less than 45 minutes and can be conducted in an outpatient setting in a manner that allows immediate return to daily life for patients. In the days following the ablation procedure, the duodenal mucosa regenerates, which we believe leaves the duodenal lining revitalized and better able to properly coordinate the gut’s metabolic signaling mechanisms.

Revita is designed to treat patients ranging from those who are living with obesity and at risk of developing metabolic complications of obesity, such as T2D, to those who have advanced T2D and have exhausted medical therapies. For individuals with obesity and prediabetes, Revita is designed to address upstream metabolic dysfunction that puts them at risk for the progression of obesity and at risk for the development of T2D.

Potential Benefits of Revita

We believe that Revita’s unique individual features combine to provide a significantly differentiated solution to obesity, offering the following potential benefits:

Durable and Repeatable Benefit. Revita is designed to improve metabolic health, blood glucose levels, and weight in patients living with obesity and/or T2D. A pooled analysis of data collected on secondary endpoints assessing weight in our previously conducted controlled clinical studies across the U.S. and Europe demonstrated a 3.4% (n=100) mean reduction in total body weight loss at four weeks in patients with T2D on multiple ADAs after undergoing a single Revita DMR procedure and showed a sustained mean body weight loss of 4.0% (n=94) at 48 weeks. We believe this is an important and differentiated therapeutic profile in obesity management. In addition, we believe our Revita system has the potential to enable repeat Revita procedures over time.

Tolerability. In clinical studies to date, Revita has been observed to be generally well tolerated, with most patients resuming normal daily activities one day after the procedure and none requiring prescription pain medications. Our proprietary Revita technology is designed to provide thermal protection before ablation, enabling isolation of the mucosa from deeper tissue structures and sparing pain fibers in the muscle while reducing risk of tissue injury.

Broad Implementation. Revita is a modular system that can potentially be incorporated into the endoscopist workflow by leveraging familiar skillsets of advanced endoscopists. Revita is intended to fit into most

endoscopy suites and typically requires fewer than four cases for the endoscopist to acquire proficiency. It is designed to be an outpatient procedure that can be performed by a trained therapeutic endoscopist in less than an hour. Today, approximately over 25 million endoscopies are performed each year in the U.S., including over 600,000 advanced endoscopic procedures. Of the estimated 30 million people potentially on GLP-1s in the U.S. today, approximately 3 million will undergo an endoscopy this year. The Revita DMR procedure is designed to be a simple add-on procedure to-these, and other endoscopies already performed on patients living with obesity and T2D annually.

Real-World Outcomes. Because it is designed as a procedural therapy, Revita does not rely on perfect patient adherence or persistence to chronic therapy for its anticipated clinical effects. Unlike diet and lifestyle interventions or pharmacologic management, the benefits of Revita are intended to be conferred at the time of the procedure and not reliant upon ongoing therapeutic maintenance. This allows a shift in patient focus from escalating chronic disease management burden to ongoing health maintenance after the procedure.

Patient Friendly. Revita is designed to offer a straight-forward, outpatient experience requiring less than a half-day visit, and allowing patients to typically return to their normal daily lives the very next day. Furthermore, initial interim data suggest that the Revita DMR procedure has thus far been observed to be compatible with other current interventions for obesity in broad use, including diet and lifestyle, as well as existing and emerging pharmacologic therapies.

Overview of Rejuva

Rejuva is a novel, endoscopically administered, adeno-associated virus (“AAV”) pancreatic gene therapy platform designed to enable long-term remission of T2D and obesity by durably altering metabolic hormone production in the pancreatic islet cells of patients with T2D and obesity. Pancreatic islets are tiny clusters of cells distributed throughout the pancreas that play a crucial role in endocrine function and metabolism. There are several cell types within the pancreatic islet, including alpha cells responsible for glucagon production and beta cells responsible for insulin production. Metabolic dysfunction in obesity and prediabetes can lead to progressive beta cell dysfunction and eventual failure, loss of insulin production and secretion, and the development of metabolic disease. There are no therapies approved today that target the pancreatic islet in T2D or obesity.

The Rejuva platform is modular and consists of three key elements designed to enable successful pancreatic gene therapy delivery and expression with limited off-target biodistribution: (1) a novel, proprietary, investigational endoscopic device designed to enable local, low-dose therapeutic delivery directly to the pancreas (body and tail), (2) vectors with tropism for the pancreatic islet to enable successful transduction and (3) transgenes with tissue-restricted promoters driving the expression of metabolically active peptides that can durably impact glucose and weight control.

These peptides are intended to rejuvenate beta cell health, restore insulin production, and activate incretin signaling pathways in a nutrient-responsive (“smart”) manner. The first gene therapy candidate, RJVA-001, is comprised of an AAV9 viral vector that expresses a human GLP-1 hormone from an insulin promoter designed for the remission of T2D. The second candidate, RJVA-002, is designed to treat obesity and is composed of an AAV9 vector that expresses both human GIP and GLP-1 hormones driven by an insulin promoter. Activation of both GIP and GLP-1 receptors may improve body weight and blood sugar regulation.

Potential Benefits of Rejuva

We believe that Rejuva’s individual features combine to provide a significantly differentiated solution to T2D and obesity, offering the following potential benefits:

A Compelling, Substantial Commercial Model in Gene Therapy. We believe the Rejuva platform, if approved, has the potential to provide a differentiated market offering within the gene therapy space. We believe this potential for differentiation could be enabled by a large patient population (approximately 27 million people are living with T2D in the U.S.; approximately 100 million people are living with obesity in the U.S.), low cost of goods (local delivery of a validated AAV capsid enables a cost of goods sold of potentially less than $10,000 per patient), and a development space where the high economic value is

substantial and well understood (approximately $10,000 price per year under the Institute for Clinical and Economic Review price benchmark).

Novel Approach to a Highly Validated Target. Our Rejuva platform candidates leverage well established and understood hormone signaling known to be central to metabolic regulation. Our platform’s endoscopic pancreatic delivery, pancreas-targeted AAV capsid, and insulin promotor driven transgene expression enables nutrient-responsive (“smart”) production of GLP-1 (RJVA-001) and GIP/GLP-1 (RJVA-002) from beta-cells. Unlike GLP-1-based drugs, Rejuva candidates allow for durable physiologic metabolic hormone signaling.

Precise Local Delivery. Our Rejuva gene therapy platform is designed to provide precise local delivery of gene therapy to the pancreas in a single endoscopic procedure. Our Rejuva platform leverages standard-of-care techniques for pancreatic tissue access and possesses key proprietary device elements and procedure steps, thereby reducing procedural risk. We believe our Rejuva gene therapy candidates will benefit from

localized administration, potentially avoiding the risk of high dose systemic administration that has been observed with other gene therapy candidates or GLP-1 receptor analogs.

Building Upon Clinical and Real-World Experience with Revita. The gene therapy candidates from our Rejuva platform benefit from the extensive clinical and real-world experience that we have accumulated through our Revita program. Rejuva PGTx candidates can be delivered by the same treating physicians and in the same setting as the Revita DMR procedure, utilizing the same distribution network. Moreover, we believe the metabolic benefits of Rejuva PGTx candidates have the potential to be complementary to, and perhaps synergistic with, the Revita DMR procedure.

Rigorous Development Plan. We completed key preclinical in vivo studies to support a CTA for RJVA-001 and subsequently submitted CTAs for RJVA-001 in T2D to regulators in the EU (Netherlands) and Australia in the second half of 2025, advancing the program toward its anticipated first-in-human study. We expect to receive regulatory feedback in the second quarter of 2026 and, subject to CTA authorization, to initiate first-in-human dosing of RJVA-001 and expected reporting of preliminary data in the second half of 2026.

Interchangeable Platform for Metabolic Therapy. The Rejuva platform enables selection of multiple metabolically active peptide hormones (GLP-1, GIP, PYY, amylin, glucagon, etc.), either individually or in combination, with the same local delivery and plasmid construct for differential therapeutic profiles over time.

By employing Revita and Rejuva to target the prevention and remission of obesity and T2D, we believe it is possible to provide a step change in outcomes for patients above and beyond the current chronic management strategies that exist today. If we are able to obtain marketing authorization for these product candidates in the U.S., we believe these therapies will enable us to chart a course towards significantly reducing the burden of obesity and T2D globally.

Our Targets: the Gut and Pancreas

“All disease begins in the gut.”

- Hippocrates

The Role of the Gut in the Central Regulation of Metabolism

In recent years, there has been an increase in research tying gut health to diseases throughout the body, ranging from obesity to T2D to dementia. An emerging consensus identifies the impact of modern diets on the gut as one of the body’s critical metabolic control systems as an important root cause of metabolic disease. The gut possesses the largest nervous system outside the brain, the largest hormone-producing endocrine system, a complex microbiome, and the largest immune system in the body. Different segments of the intestine have different endocrine-producing cells and different neurohormonal effects on the brain’s response to a meal. These mechanisms work together to provide an early warning detection system that helps the body prepare for and respond to the food we ingest.

Diets have changed significantly over the past several decades, shifting from relatively calorie-poor, fiber-rich, natural foods to an inexpensive and abundant supply of ultra-processed foods high in simple fats and sugars. Our founders, along

with several scientific groups around the world, have detailed the specific changes that these modern diets cause in the gut and the downstream impact on the body and brain. While the gut has long been recognized as an acute nutrient sensor, its role in regulating the body’s metabolic status over longer periods of time has been underappreciated. Recent advances have demonstrated that chronic exposure of the intestine to high levels of fats and sugars leads to structural and functional changes of the lining of the proximal gut that may signal a metabolic shift to the brain and body. These diet-induced changes are geographically confined to the upper small intestine, particularly the duodenum, an area directly accessible via routine upper endoscopy. This research provides, for the first time, an accessible potential target of pathology within the gut that sits at the apex of the complex metabolic changes underlying obesity and T2D.

Structural and functional changes in the duodenal lining

Studies analyzing the small intestine in diabetic patients and animal models have identified functional maladaptation of the intestinal mucosa after chronic dietary exposure to high concentrations of fat and sugar. Geltrude Mingrone (a consultant to the Company), et al. showed in 2010 that a high-fat diet in rats can cause overgrowth of the duodenal mucosa. Working with colleagues at King’s College London, we extended these observations to show that mucosal overgrowth may occur in the duodenum and proximal jejunum but does not extend to further segments of the intestine, such as the ileum (West et al. bioRxiv preprint doi: https://doi.org/10.1101/822122). Aliluev and colleagues observed that high-fat, high-sugar diets alter intestinal stem cell homeostasis leading to hyperplasia of the duodenal mucosa (Aliluev et al. Nat Metab. 3(9):1202-1216). Studies in rodents chronically fed a high-fat diet have demonstrated up to a 50% increase in mucosal surface area compared with rodents fed a normal diet, illustrating diet-induced structural overgrowth over time. This finding of a nutrient-induced stem cell division process that causes structural and functional changes of the duodenal mucosa has been replicated by multiple independent groups in the U.S. and Europe, and across organism species and disease models. Michael Theodorakis et al. demonstrated similar observations in diabetic humans, showing through duodenal biopsies that the mucosa in the duodenum of patients with T2D becomes thickened and exhibits changes to the hormone-producing cell populations (Theodorakis et al. Am J Physiol Endocrinol Metab 290: E550–E559, 2006).

Hyperplasia and dysfunction of the duodenum is associated with a greater surface area for nutrient absorption and altered neurohormonal signaling, changing the body’s metabolic response from the gut. According to Duca et al., enteroendocrine cells in the duodenum respond to ingested nutrients by secreting hormones, including GLP-1 and cholecystokinin, which enter the circulation and trigger local nervous system activation. The brain receives these neurohormonal signals and uses the integrated information to regulate blood glucose levels and weight. In a healthy state, intraduodenal lipids trigger satiety and suppression of blood glucose, but chronic high-fat diets impair this gut-brain feedback, leading to metabolic dysfunction (Duca et al. Cell Metab. 2015 Sep 1;22(3):367-80, Duca et al., Nat Commun. 2021; 12: 903).

We believe that this preclinical and clinical evidence demonstrates that abnormal neurohormonal signaling from the duodenum is an important contributor to metabolic dysfunction, broadening conventional wisdom that excess weight and physical inactivity are the sole drivers of T2D.

Avoiding Nutrient Contact with the Duodenum can Reduce Insulin Resistance in T2D

The pancreas is a hormone-producing organ in the retroperitoneum surrounded by the duodenum, immediately below the stomach, with functions related to the secretion of digestive enzymes (exocrine pancreas) and hormones including insulin and glucagon from pancreatic islets (endocrine pancreas). Within the pancreatic islet, alpha cells secrete glucagon into the bloodstream and beta cells secrete insulin. Glucagon and insulin are counter-regulatory hormones that act in opposite directions to raise or lower blood glucose levels, respectively.

Most people can compensate for metabolic dysfunction by increasing insulin production to maintain normal blood glucose levels. Patients who develop T2D eventually experience a gradual loss of beta cell function, driven by two principal causes: (1) exhaustion of beta cell function in the face of longstanding metabolic dysfunction and chronically elevated blood glucose, and (2) damage to beta cells from the toxicity of circulating lipids (lipotoxicity). By the time the diagnosis of diabetes is made, patients have lost over 80% of their beta cell function, making early and aggressive intervention essential.

Increasing GLP-1 Levels in the Pancreas Can Improve Islet Metabolic Function

GLP-1 is a potent hormone produced in the distal intestine and secreted into the circulation in response to nutrient intake, and also produced in the pancreatic islets by alpha cells. The role of GLP-1 within the pancreatic islet in beta cell function and insulin production is one of the best understood hormonal mechanisms in medicine. The GLP-1 receptor is expressed in

beta cells, where activation acutely stimulates insulin secretion in response to blood glucose elevations and chronically stimulates insulin gene transcription and islet cell survival. The GLP-1 receptor is also expressed in alpha cells, where activation regulates glucagon expression. Studies have shown impaired GLP-1 signaling in the pancreatic islet in T2D, and that increased GLP-1 signaling can compensate for impaired insulin secretion, preserve beta cell function and survival, and improve glucose homeostasis. The beneficial effects of GLP-1 on islet function have been further demonstrated by the GLP-1RA class of medicines.

Revita and Rejuva are designed to treat obesity and T2D by directly targeting the gut and pancreas, respectively, addressing root causes of metabolic disease within these organs. By leveraging our expertise in developing novel, differentiated, disease-modifying therapies, and our insights into the biology of the gut and pancreas, we believe our therapeutic approaches, if approved, have the ability to alter the paradigm for treating obesity and T2D.

Revita Product Description

Revita Device Overview

Revita comprises (i) the Revita console that houses our proprietary technology and software, and (ii) a single-use Revita DMR catheter. The console’s touchscreen-based graphical user interface is designed to provide ease-of-use and clear guidance on the performance and progress of the procedure for the physician. The console is designed to control the flow, pressure and temperature of the ablative and cooling fluid, vacuum suction, facilitate the delivery of saline for the submucosal lift. In addition, the console houses sensors that are designed to monitor temperature, pressure and procedure status. We believe the console enables a targeted ablation process by enabling a proprietary safety mechanism that reduces penetration of heat to deeper tissues during the hydrothermal ablation procedure, and potentially reduces the risk of physician error by automating certain steps of the treatment process by guiding the physician step-by-step through the procedure. The image below depicts a prototype rendering of the modular Revita commercial console and catheter. The catheter and graphical user interface are currently being used in our REMAIN-1 and REVITALIZE-1 clinical studies, but the Revita console hardware below is not. We plan to seek FDA clearance of the proposed commercial system as part of our FDA De Novo process. The Revita DMR catheter comprises three outward-facing ports on the exterior of our novel ablation balloon with a control handle on the proximal end. Each port on the catheter has an opening whose size and shape is designed to enable suction to selectively pull only the mucosal and submucosal tissue into the port. The catheter is designed to be deliverable and trackable across the stomach into the small intestine over a standard endoscopic guidewire or the Revita procedurally optimized guidewire. In the first quarter of 2025, we began offering the FDA 510K cleared Revita

Guidewire to principal investigators to support ongoing Revita clinical studies. The Revita Guidewire is specifically designed for ease of delivery of the Revita DMR catheter.

Modular Revita Console

Revita Procedure Overview

The Revita DMR procedure is designed to be a minimally invasive, outpatient, endoscopic procedural therapy using a proprietary balloon catheter that is uniquely designed for the duodenal mucosa in a procedure that typically lasts less than an hour. Revita is designed to target the mucosal surface for ablation and induce intestinal stem cell-mediated regeneration. The procedure is performed by a trained endoscopist while the patient is under conscious sedation or general anesthesia. With the help of the Revita console, certain steps of the procedure are designed to be highly automated, which we believe minimizes the risk of physician error.

The procedure involves inserting the distal end of the single-use Revita catheter through the mouth over a guidewire past the stomach and into the duodenum, using fluoroscopy to assist placement. The catheter is then positioned distal to the ampulla of Vater (i.e., the hepatopancreatic duct where bile salts and pancreatic enzymes enter the GI tract) under direct endoscopic visualization. The procedure then involves a repeated sequence of thermal safety and hydrothermal ablation steps.

Thermal Safety. Our proprietary thermal safety procedural step involves an automated, circumferential injection of saline into the submucosal space of the duodenum. This step is initiated through the user interface of the console and enables the

lifting of the mucosa away from the underlying muscle layer. The catheter balloon is expanded with fluid to allow the catheter to engage with the mucosa and a vacuum connected to the console draws the mucosa into each of three injection ports on the catheter. The user interface of the console is then used to initiate saline delivery to the submucosal space via needles within the vacuum ports. This procedure step is designed to create a thermal barrier between the mucosa and the underlying muscular layer in order reduce the risk of discomfort or unintended thermal injury, and to enable repeated procedures by ensuring that the mucosa can be safely lifted before performing thermal ablation.

Designed to Create a Protective Thermal Barrier

Hydrothermal Ablation. After the thermal safety step is completed in a region of the duodenum, hydrothermal ablation is initiated through the console user interface. The ablation cycle involves the introduction and recirculation of water within the balloon. We believe this sequence of steps provides a controlled, uniform, “thin layer” ablation of the mucosa and superficial submucosa and potentially further reduces the risk of injuring deeper tissues. The first step fills the balloon with cold water to cool the duodenal tissue below body temperature prior to ablation. The second step is intended to deliver a precise dose of hydrothermal energy to the tissue to create a controlled coagulative ablation. The third step is intended to remove any residual heat from the tissue and to prevent unintended conduction of heat within the tissue.

The thermal safety and hydrothermal ablation steps are continued sequentially along the length of the duodenum, extending from just beyond the ampulla of Vater and proceeding distally until the full length of the duodenum is treated. The sequential thermal safety and hydrothermal ablation steps are designed to ensure the spatial and temporal alignment of the ablation within the previously lifted region before the thermal protective saline barrier dissipates. We have designed Revita’s hydrothermal ablation to be coagulating, where the proteins in the tissue are denatured but the tissue remains in place. In addition, our ablation procedure is designed to prevent bleeding and to allow overlapping ablations without excessive depth of ablation.

Upon completion of the procedure, the guidewire, catheter and endoscope are removed, leaving no long-term implant in the GI tract. The patient is typically discharged on the same day and is prescribed a graduated post-procedure diet, starting with liquids and progressing to pureed foods and soft foods. Similar to other routine upper-GI endoscopic procedures, if Revita is approved, we anticipate that patient will resume normal activities the day after their procedure, which is supported by our observations to date.

Clinical Data Overview: Revita

We have evaluated the Revita DMR procedure in over 500 participants across multiple clinical studies at sites in South America, Europe and the U.S. To date, we have observed the Revita DMR procedure, when added to certain ADAs and lifestyle counseling, to be generally well tolerated and demonstrated durable blood glucose lowering and weight stabilization in patients for two years post-procedure. We are currently evaluating the Revita DMR procedure in the REMAIN-1 weight maintenance program, which is designed to evaluate Revita’s potential to maintain weight loss following GLP-1 based therapy discontinuation.

Pursuant to our Strategic Reprioritization, announced on January 31, 2025, we paused investment in Revita for T2D, including the REVITALIZE-1 study and the Germany Real-World Registry study. Our decision to pause these studies was not driven by any safety or efficacy concerns. We continue to follow existing participants per protocol and report outcomes on an ongoing basis for these studies. For additional detail on REVITALIZE-1, see our Annual Report on Form 10-K for the fiscal year ended December 31, 2024. For additional detail on the Germany Real-World Registry study, see “Germany Real-World Registry Study” below.

The table below summarizes our ongoing, paused and completed clinical studies for the Revita DMR procedure.

Study and Status

Study Design

Primary Objectives

Upcoming Milestones

Ongoing

REMAIN-1. Pivotal clinical study in participants who have lost at least 15% of their total body weight on GLP-1 therapy and wish to discontinue their GLP-1 without weight regain (ongoing)

Three Cohorts, multi-center, parallel cohort, randomized (2:1), open-label

REVEAL-1/open-label: up to 40 participants

Randomized midpoint analysis of 45 participants

Randomized pivotal analysis: 315 participants (DMR and sham)

To demonstrate superiority of the Revita DMR procedure to sham in weight maintenance after discontinuation of tirzepatide at 26 weeks

To demonstrate that a majority of Revita DMR participants maintain clinically significant weight loss after discontinuing tirzepatide therapy at 26 weeks

February 2026: Completed randomization in REMAIN-1 Pivotal Cohort

Q2 2026: 1-year REVEAL-1 Cohort data

Q3 2026: 1-year REMAIN-1 Midpoint Cohort randomized data

Early Q4 2026: Topline 6-month randomized data from REMAIN-1 Pivotal Cohort

Late Q4 2026: Potential FDA De Novo marketing application submission in post-GLP-1 weight maintenance.

Paused due to Strategic Reprioritization

Germany Real‑World Registry. Study in participants with inadequately controlled T2D on at least one ADA

Commenced in April 2023

Announced on January 31, 2025 that Company paused investment

Prospective, post‑market, clinical five‑year follow‑up of participants who have received the Revita DMR procedure in a real‑world setting

To assess the safety and clinical effectiveness, quality of life and participant reported outcomes, and healthcare utilization expenditure of the Revita DMR procedure

Follow-up of participants who have received the Revita DMR procedure in a real-world setting and report data on an ongoing basis per protocol

REVITALIZE‑1. Pivotal clinical study in participants with inadequately controlled T2D despite being on at least one GLA

Commenced in March 2021

Announced on January 31, 2025 that Company has paused investment

Converted to a safety only study, approved by FDA July 24, 2025

Stage 1: open-label, single-arm training stage

Stage 2: Randomized, double‑blind, crossover, sham‑controlled, multi‑center

~10-14 cm DMR

Two arms: DMR and sham

Stage 1: up to 140 participants

Stage 2: up to 320 participants

To demonstrate safety and tolerability of the Revita device and procedure 24 weeks post DMR

Close study and report on safety H1 2027

Study and Status

Study Design

Primary Objectives

Milestones

Completed

U.S. Pilot. Pilot study in participants with suboptimally controlled T2D despite being on metformin in combination with one to two additional OADs

Completed (prematurely ended)

Randomized (2:1), double-blind, crossover, sham controlled, multi‑center

Two arms: DMR and sham

9 participants

~10 cm DMR

No formal statistical powering

Evaluate the safety and efficacy of the Revita DMR procedure on certain glycemic endpoints

The Revita DMR procedure was generally well tolerated

As agreed with the FDA, the study was prematurely ended due to the COVID‑19 pandemic and subsequent authorization to proceed with the REVITALIZE-1 study

Revita‑2. Clinical study in participants with suboptimally controlled T2D despite being on an OAD and/or metformin

Completed

Randomized, double-blind, crossover, sham controlled, multi‑center

~10 cm DMR

Two arms: DMR and sham

108 participants

Evaluate the safety and efficacy of the Revita DMR procedure on certain T2D related endpoints

Baseline reduction of HbA1c, MRI‑PDFF, HOMA‑IR and weight when compared to the sham arm (p*=<0.05)

The Revita DMR procedure was generally well tolerated

INSPIRE. Investigator initiated pilot study in T2D participants on long‑acting insulin

Completed

Open-label, single‑center

~15 cm DMR

Single arm

16 participants

Evaluate the feasibility of eliminating insulin therapy in T2D participants by combining the Revita DMR procedure with a GLP‑1 and lifestyle counseling

69%, 56% and 53% of participants at 24 weeks, 48 weeks and 72 weeks, respectively, were off insulin therapy with an HbA1c of 7.5% or less

Revita‑1. Feasibility study in participants with poorly controlled T2D despite at least one OAD

Completed

Open-label, multi‑center

~9 cm DMR

Single arm

46 participants

Evaluate the safety and effectiveness of the Revita DMR procedure on certain glycemic endpoints

Baseline mean HbA1c reduction of 0.9% at 24 weeks (p*=<0.001)

Baseline mean reduction in total body weight of 3.1% sustained through two years (p=0.01)

The Revita DMR procedure was generally well tolerated

Revita. First‑in‑Human. Clinical study in participants with poorly controlled T2D despite at least one OAD

Completed

Open‑label, single‑ center

Single arm: LSDMR (~9 cm) and SSDMR (~3 cm)

57 participants

Evaluate the safety and feasibility of the Revita DMR procedure over variable lengths of the duodenum

Baseline mean HbA1c reduced by 2.5% at 12 weeks (LS‑DMR) (p*=<0.05)

Baseline mean HbA1c reduced by 1.2% at 12 weeks (SS‑DMR) (p*=<0.05)

The Revita DMR procedure was generally well tolerated; duodenal stenosis observed in three participants with good resolution post‑ balloon dilation

* p-value represents the chance that the observed results occurred by chance alone. A p-value of less than 0.05 is considered statistically significant.

Key Metrics

The outcomes of our clinical studies are evaluated by a number of well-known validated glycemic metrics, including:

Total Body Weight Change. A physical measurement from baseline weight identifying alteration in weight due to caloric excess or deficit. Total body weight change can include weight gain (from energy excess) or weight loss (from energy expenditure exceeding caloric intake).

Glycosylated Hemoglobin (HbA1c %). HbA1c reflects average levels of blood glucose over the previous two to three months and is the most widely used clinical test to estimate mean blood glucose and monitor glycemic control.

Fasting Plasma Glucose (mg/dL or mmol/L). FPG measures the serum glucose concentration after an overnight fast of at least eight hours providing an instantaneous measure of glucose homeostasis.

Oral Glucose Tolerance Test. A oral glucose tolerance test (“OGTT”), evaluates beta cell function after a participant ingests a fixed glucose solution. To perform the test, blood glucose is measured immediately prior to consumption and typically every 30 minutes two hours after consumption. Area under the curve, OGTT is the calculation of the total excess of blood glucose measured during the course of the OGTT.

Revita Clinical Program Insights

Our Revita clinical program design has been informed by our prior clinical studies and expertise in the field of metabolic diseases, including obesity and T2D. We are evaluating and/or have evaluated the Revita DMR procedure in over 500 participants, 30 clinical centers, with the procedure performed by more than 30 different endoscopists. We have followed most Revita-1 and Revita-2 participants beyond 12 months post-procedure to observe the long-term safety of the Revita DMR procedure, including its effects on glucose homeostasis and weight. Based on these experiences, we believe the Revita DMR procedure has the potential to:

enable weight maintenance in patients living with obesity;

reduce the risk of developing diabetes in patients with high-risk prediabetes;

improve glycemic control in T2D patients on insulin; and

improve glycemic control in T2D patients on one or more ADAs who are not yet on insulin.

We are focused on developing Revita to treat patients ranging from those who are living with obesity and at risk of developing metabolic complications of obesity, such as T2D, to those who have advanced T2D and have exhausted medical therapies. For individuals living with obesity and prediabetes, Revita is designed to address upstream metabolic dysfunction that puts them at risk for the progression of obesity and at risk for the development of T2D.

Ongoing REMAIN-1 Clinical Study

We are evaluating Revita in the REMAIN-1 weight maintenance program, which is designed to evaluate Revita’s potential to maintain weight loss following GLP-1 based therapy discontinuation. The REMAIN-1 program includes three distinct participant cohorts that are conducted under a single IDE:

The REVEAL-1 Cohort (n=22): an open-label study in individuals with obesity who have lost at least 15% of their total body weight on a GLP-1 medication and who either need or choose to discontinue GLP-1 therapy. After stopping the GLP-1 based therapy, participants receive Revita treatment in an open-label setting and take part in a structured diet and lifestyle program. REVEAL-1 is designed to provide early, real-world insights on how Revita performs after GLP-1 discontinuation.

The REMAIN-1 Midpoint Cohort (n=45): a randomized, double-blind, sham-controlled pilot study to assess the potential of Revita to maintain weight loss after GLP-1 based therapy discontinuation. Participants with obesity who have not yet taken GLP-1 drugs, are initiated on tirzepatide at the time of enrollment, and treated with the drug to achieve at least 15% total body weight loss. Participants then discontinue tirzepatide and are randomized to undergo either Revita or a sham procedure with a 2:1 treatment randomization. The key efficacy endpoint is total body weight change in Revita versus sham

at 3 months. The randomized Midpoint Cohort serves as an important early randomized readout to assess Revita’s potential to maintain weight loss after GLP-1 based therapy discontinuation. All participants enrolled in the study will receive diet and lifestyle counseling.

The REMAIN-1 Pivotal Cohort (n=315): a randomized, double-blind, sham-controlled pivotal study to evaluate the safety and efficacy of Revita in maintaining weight loss after GLP-1 based therapy discontinuation. Participants with obesity who have not yet taken GLP-1 drugs, are initiated on tirzepatide at the time of enrollment, and treated with the drug to achieve at least 15% total body weight loss. Participants then discontinue tirzepatide and are randomized to undergo either Revita or a sham procedure with a 2:1 treatment randomization. The first co-primary endpoint is defined as the percent of total body weight regain from the time of tirzepatide discontinuation in Revita versus sham participants through 6-month follow up. The primary objective is to demonstrate a benefit of Revita versus sham for weight maintenance after GLP-1 based therapy discontinuation. The second co-primary endpoint evaluates a responder rate among the Revita treated participants at 1 year to demonstrate the durability of the Revita procedure for weight maintenance after discontinuation of a GLP-1 based therapy. The responder rate is defined as the percentage of participants who received the Revita procedure who maintain at least 5% total body weight loss from pre‑tirzepatide (week -21) to week 52. Secondary objectives will include evaluation of the effectiveness of the Revita DMR procedure on the change in blood glucose levels, CVD risk factors, body composition and pre-diabetes status. All participants enrolled in the study will receive diet and lifestyle counseling.

Enrollment of all three cohorts is complete. We completed randomization of 307 participants in the REMAIN-1 Pivotal Cohort in February 2026, with topline six-month data anticipated in the early fourth quarter of 2026. In March 2026 we received pre-submission feedback from the FDA in which it acknowledged that the safety profile of the Revita DMR System, based on clinical data from over 300 procedures, is consistent with a Class II device classification. We anticipate submitting a potential De Novo marketing application in post-GLP-1 weight maintenance in the late fourth quarter of 2026.

In September 2024, the FDA approved an amendment to the clinical study protocol for the REMAIN-1 study of our Revita device, which aligns the co-primary endpoint with a weight maintenance indication for Revita and adds a midpoint analysis at three months allowing us to analyze and report on approximately 45 randomized participants. In the third quarter of 2024, we initiated REMAIN-1.

In July 2024, we obtained Breakthrough Device designation from the FDA for the Revita system, as an adjunct to diet and exercise, to perform hydrothermal ablation of the duodenal mucosa, or the Revita DMR procedure, for use in the maintenance of weight loss after discontinuation of GLP-1-based therapy on participants who cannot tolerate long-term GLP-1 therapy and who are not candidates for endoscopic remodeling procedure or bariatric surgery.

We gained FDA approval for the IDE in the first quarter of 2024 to initiate the pivotal REMAIN-1 study.

The table below depicts the REMAIN-1 pivotal clinical study design.

REVEAL-1 Cohort:

In December 2025, we announced 22 participants had been treated in the REVEAL-1 cohort, with up to six months of follow-up data available for 17 participants. As of December 2, 2025, no safety or tolerability concerns were reported, consistent with Revita’s safety profile observed in prior clinical experience. Participants maintained stable weight after a single Revita procedure, with a mean total body weight change of 1.5% ± 1.3% (SEM; n=17) at 6 months. Published

third-party studies report ~10% weight regain by this time point after GLP-1 withdrawal alone. Minimal change in HbA1c levels was observed after the Revita procedure (0.04% ± 0.08%; SEM; n=17), compared to the ~0.4% increase in HbA1c seen post-GLP-1 based therapy discontinuation in the STEP-1 trial extension of GLP-1 withdrawal. These results indicate the potential for Revita to help stabilize cardiometabolic parameters beyond weight loss alone. Mean body weight and HbA1c curves showed a stable and durable trajectory over time, consistent with prior Revita clinical study and real-world experience. No procedure-related serious adverse events were observed; 8 of 22 participants (36%) experienced mild treatment-emergent adverse events which were transient, and self-limited; all consistent with prior Revita experience and similar to routine upper endoscopy findings.

In June 2025, we announced positive 3-month data from the REVEAL-1 Cohort. As of June 23, 2025, 22 participants had been treated in the REVEAL-1 Cohort, with 3-month follow-up data available for 13 individuals. The profile of the REVEAL-1 Cohort closely mirrors that of the REMAIN-1 Midpoint and Pivotal Cohorts, with an average age of 49 and a gender distribution of 11 women and 2 men. All participants had previously been treated with a GLP-1 therapy for durations ranging from approximately 5 months to 3 years, with a median total body weight (“TBW”) loss of 20.9% while on therapy. Fifteen percent of participants had pre-diabetes at baseline. At 3 months, 12 of 13 participants either lost or maintained their weight after GLP-1 based therapy discontinuation and a single Revita procedure. Notably, 6 of 13 experienced further weight loss. Median weight remained stable through 3 months (TBW change of 0.46% / ~ 1 pound was within the margin of error for daily weight measurement), compared to the typical 5-6% (10–15 pounds) rebound seen in other third party clinical studies such as SURMOUNT-4. Only one participant experienced weight regain similar to that seen after tirzepatide withdrawal. Early signs also point to excellent weight stability following Revita procedure, with essentially no weight change between 1 and 3 months (median weight gain at 1 month: 0.43% and 3 months: 0.46%). Consistent with prior studies of Revita, the procedure was well tolerated, with no unanticipated or serious adverse effects reported. No new safety concerns were observed.

In April 2025, we announced additional positive early data from the REVEAL-1 Cohort. As of April 1, 2025, 15 participants had been treated with Revita, with 1-month follow-up data available for the first 7 participants. There were not any safety or tolerability concerns reported in the 15 participants treated to date, consistent with Revita’s favorable safety profile from pooled data across more than 100 treated participants. At 1-month post-procedure, 7 participants experienced an average weight regain of just 1.2%, compared to the ~3% typically observed at this time period after GLP-1 based therapy discontinuation based on prior clinical studies.

In January 2025, we reported positive preliminary results from the REVEAL-1 open-label cohort. Initial findings from the first participant, as of a cutoff date of January 13, 2025, showed successful weight maintenance at one month following GLP-1 based therapy discontinuation and Revita DMR procedure.

REMAIN-1 Midpoint Cohort:

In January 2026, we announced 6-month randomized data. As of January 29, 2026, across the prespecified efficacy population (n=40, with five participants excluded per protocol due to diet and lifestyle noncompliance and only included in the safety population), Revita-treated participants experienced a 4.5% weight regain vs 7.5% in the sham arm at 6 months (p=0.07, one-sided), consistent with meaningful and sustained attenuation of the expected post-GLP-1 rebound trajectory. An exploratory analysis of participants who achieved above median weight loss during GLP-1 run-in (n=20) showed that Revita-treated participants experienced 4.2% weight regain versus 13.3% with sham at 6 months, corresponding to an approximately 70% relative reduction in post-GLP-1 weight regain (LS mean difference -9.1%; p=0.004, one-sided). As expected, treatment-by-run-in weight loss interaction terms suggested a meaningful relationship between degree of GLP-1-associated weight loss and the magnitude of Revita benefit. Further post-hoc analysis in March 2026 demonstrated a statistically significant correlation between ablation length and weight maintenance in the Revita arm and that more complete duodenal ablation drives greater treatment effect (n=29; p=0.048). Putting both together, in participants with above median GLP-1-induced weight loss who received greater than 14 cm duodenal ablation, Revita participants retained 88% of GLP-1 induced weight loss at six months compared to only 60% in sham participants. Revita continued to demonstrate favorable safety and tolerability results through six months, with no treatment-emergent serious adverse events related to the device or procedure, and no study discontinuations due to adverse events No new related adverse events were observed between 3- and 6-month follow up.

In September 2025, we announced positive 3 -month results from the randomized REMAIN‑1 Midpoint Cohort (n=45), demonstrating Revita’s potential to maintain weight loss after discontinuation of GLP-1 based therapy. Enrollment for this cohort had been previously completed, and as of September 26, 2025, all participants had been treated. The study met its 3-month efficacy endpoint with strong statistical significance (p=0.014), delivering 2.5% further weight loss with Revita (n=29) even after stopping tirzepatide, versus 10% weight regain in sham-treated participants (n=16). These results are

clinically and statistically significant and provide randomized, blinded evidence that drug-free, durable weight maintenance is possible. No Revita-related SAEs or Grade II+ AEs were observed. Side effects were infrequent, mild, and transient, consistent with prior Revita clinical study experience.

In the fourth quarter of 2024, we completed enrollment of the 45 participants of the randomized REMAIN-1 Midpoint Cohort.

REMAIN-1 Pivotal Cohort:

We completed enrollment of the REMAIN-1 Pivotal Cohort in July 2025. We completed randomization of the REMAIN-1 Pivotal Cohort in February 2026, with topline six-month data anticipated in the early fourth quarter of 2026. In March 2026 we received favorable FDA feedback on our De Novo classification request for Revita and anticipate submitting a potential De Novo marketing application in Post-GLP-1 weight maintenance in the late fourth quarter of 2026.

Germany Real-World Registry Study

In April 2023, we initiated the Germany Real-World Registry study, a prospective, post-market, clinical follow-up study to evaluate the Revita DMR procedure in participants with inadequately controlled T2D. Our inclusion criteria included participants ages 18 and over, with a baseline HbA1c between 7.0% and 10.0%, a BMI of less than or equal to 45 and on at least one ADA. The study assessed change in HbA1c, change in number of ADAs, safety and tolerability, quality of life and participant reported outcomes, and healthcare utilization expenditure over five years in participants with T2D after receiving the Revita DMR procedure in a real-world setting.

On January 31, 2025, we announced that pursuant to the Strategic Reprioritization, we have paused investment in the Germany Real-World Registry study. We expect to continue to follow the existing participants per protocol and continue to report on clinical, health economic, and participant-relevant outcomes from this study on an ongoing basis.

As of October 31, 2025, the first 30 participants with 1 year of follow-up had, at baseline, a mean age of 60 years, a mean weight of 102 kg (225 lbs; BMI 33 kg/m²), and a mean HbA1c of 8.8%, despite being on up to three glucose-lowering agents (“GLAs”).

After a single Revita procedure, these 30 participants achieved a mean total body weight loss of 8.0% with weight decreasing from 102 kg to 94 kg at 3 months, a result that was sustained throughout 1 year post-procedure (94 kg) (Table 1, Figure 3). Notably, 28 of 30 participants lost weight, 20 of 30 participants experienced at least a 5% weight reduction, and 12 of 30 participants saw weight reductions of 10% or more. In parallel, mean HbA1c decreased by 1.0% at 3 months, from 8.8% at baseline to 7.7%, and this improvement was sustained throughout 1 year post-procedure (7.9%) (Table 1) with 83% (25/30) of participants on stable or reduced GLAs. In this cohort, weight loss and glucose improvements began as early as one month after the Revita procedure and were sustained through 1 year of follow-up (Table 1).

Table 1. Germany Real-World Registry Study Weight and Blood Sugar Data Post-Revita Procedure (n=30)

Endpoint

Baseline

3 Months

6 Months

1 Year

Weight (kg)

102 ± 3.4

94 ± 3.3

94 ± 3.3

94 ± 3.3

HbA1c (%)

8.8 ± 0.2

7.7 ± 0.4

7.9 ± 0.3

7.9 ± 0.2

Mean ± standard error of the mean (“SEM”) values shown. Fractyl Health internal data.

Of these 30 participants, 14 have now been followed for 2 years post-procedure. These 14 participants had a mean age of 62 years, mean weight of 104 kg (229 lbs; BMI 34 kg/m²), and a mean HbA1c of 9.1%, despite being on up to three GLAs. These 14 participants achieved a mean weight loss of 7.9% at 1 year with weight decreasing from 104 kg to 95 kg, an improvement that was maintained through 2 years post-procedure (94 kg) (Table 2). Mean HbA1c reduced by 1.2% at 1 year, from 9.1% at baseline to 7.8%, and this improvement was sustained throughout 2 years post procedure (7.4%) (Table 2), with 86% (12/14) of participants on stable or reduced GLAs.

Table 2. Germany Real-World Registry Study Weight and Blood Sugar Data Post-Revita Procedure (n=14)

Endpoint

Baseline

3 Months

6 Months

1 Year

2 Years

Weight (kg)

104 ± 5.7

96 ± 5.5

96 ± 5.3

95 ± 5.3

94 ± 5.3

HbA1c (%)

9.1 ± 0.4

8.1 ± 0.7

8.2 ± 0.5

7.8 ± 0.3

7.4 ± 0.3

Mean ± SEM values shown. Fractyl Health internal data.

Figure 1: Germany Real-World Registry Study Total Body Weight Change from Baseline

Medication use was recorded at baseline and each follow-up visit. Changes were categorized as initiation or discontinuation of any GLA or anti-obesity medication class. In this Germany Real-World Registry study, treatment adjustments reflected routine clinical management and were not protocol-mandated. At baseline, participants were on up to 3 GLAs prior to treatment with Revita with inadequately controlled T2D.40% of participants were already receiving a glucagon‑like peptide-1 receptor agonist (“GLP-1RA”) for glucose control and remained inadequately controlled despite treatment. During follow-up, 14 of 30 (47%) participants remained on stable GLAs through their last follow-up period, 11 of 30 (37%) participants decreased the number of GLAs from baseline, and only 5 of 30 (17%) participants increased the number of GLAs from baseline. Analyses of weight and HbA1c were stratified by the change in the number of GLAs from baseline to account for the potential confounding effects of concomitant pharmacotherapy.

When stratifying for medication adjustments post-baseline, participants who were on either stable or reduced medications (n=25) had similar effects on weight and HbA1c at 1 year and 2 years post-procedure compared to the entire cohort. Those participants on stable or reduced medications had a mean weight reduction of 8.4±1.3% and 8.8±2.2% compared to 8.0±1.2% and 8.9±1.9% for the entire cohort (Figure 1 above) at 1 year and 2 years post-procedure, respectively. Likewise, participants on stable or reduced medications had a mean HbA1c reduction of 0.9±0.3% and 1.7±0.4% compared to 0.8±0.3% and 1.7±0.4% for the entire cohort at 1 year and 2 years post-procedure, respectively. Thus, the sustained improvement in weight and HbA1c observed after Revita occurred despite a substantial reduction in average GLA use and cannot be attributed to new medication use during the Germany Real-World Registry study follow up period.

Participant-reported outcomes (“PROs”) revealed that Revita was valued by participants and improved T2D management. At 1 year and 2 years post-procedure, 97% and 93% of participants, respectively, reported that they would undergo the Revita procedure again, and 100% and 93% of participants, respectively, would recommend the procedure to a family member or friend (n=30 at 1 year; n=14 at 2 years post-procedure). Revita received a mean score of 9.8±0.1 and 10±0.0 (1-10 scale, 10 highest) for its ability to improve T2D management. Revita’s ability to improve quality of life was scored a mean of 9.6±0.2 and 10±0.0 by Germany Real-World Registry study participants at 1 and 2 years post-procedure, respectively.

No device- or procedure-related serious adverse events have been reported to date.

Collectively, these findings highlight the potential of a single Revita treatment to deliver durable weight maintenance, glucose improvement, and reduction in medication utilization without significant adverse events in a real-world setting out to 2 years post-procedure. Parallel PROs demonstrate durable participant-perceived value and improvement in T2D management.

As of February 15, 2025, we had treated 39 participants with Revita DMR and enrolled 34 participants in the Real-World Registry study with 12-month follow-up data from 17 participants. At baseline, prior to Revita DMR procedure, these participants (n=17) were a mean age of 61 years, with obesity and advanced T2D, a mean body weight of 106 kilograms (234 pounds; BMI 34 kg/m2) and mean baseline fasting blood glucose (FBG) and HbA1c of 181 mg/dL and 9.1%, respectively, despite using up to three GLAs. Approximately 65% of these participants were male. At three months, participant mean weight was reduced by 7.2 kilograms (16 pounds) and this reduction was maintained through 6 and 12 months post-procedure (see the table below for absolute values). Nearly all participants lost weight with 65% and 29% losing >5% and >10% of their body weight at 12 months post-Revita DMR procedure, respectively. Weight loss was observed as early as one-month post-Revita DMR procedure, and weight loss was generally maintained through one year of follow-up, further underscoring in a real-world setting the potential for a single Revita DMR procedure to be a compelling and durable weight maintenance solution.

FBG and HbA1c also improved, with mean decreases of 50, 47, and 49 (n=17) mg/dL and 1.0, 1.0, and 1.2% (n=17), at 3, 6, and 12 months, respectively. In addition, at 12 months post-procedure, 82% of participants stabilized or reduced their GLA usage in addition to losing weight and improving their hyperglycemia (n=17). PROs revealed that Revita was valued by participants and improved T2D management. At 12 months post-procedure, 94% of participants reported they would undergo the Revita DMR procedure again and 100% would recommend the procedure to a family member or friend (n=17). Revita scored a 9.7 and 9.3 (1-10, 10 highest) for its ability to improve T2D management and quality of life, respectively (n=17). As of February 15, 2025, no device or procedure-related serious adverse events have been reported.

The table below reflects the Germany Real-World Registry study Weight and Blood Sugar Data Over Time Post-Revita DMR procedure.

Endpoint

Baseline

3 Months

6 Months

12 Months

Weight (kg)

106

99

99

99

FBG (mg/dL)

181

130

133

132

HbA1c (%)

9.1

8.1

8.0

7.9

Mean values shown. Company data on file, n=17. NCT06256497. HbA1c=glycated hemoglobin.

REVITALIZE-1 Pivotal Clinical Study

We obtained Breakthrough Device designation from the FDA for the Revita DMR System to perform the Revita DMR procedure to improve glycemic control and reduce insulin needs in T2D patients who are inadequately controlled on long-acting insulin. In granting Breakthrough Device designation, the FDA found the following: there is a reasonable expectation that Revita will provide for more effective treatment of T2D patients who are inadequately controlled on long-acting insulin therapy; Revita represents a breakthrough technology; Revita, if found to be safe and effective, could offer significant advantages over existing approved or cleared alternatives; and the availability of Revita, if found to be safe and effective, would be in the best interest of patients.

On January 31, 2025, we announced that pursuant to the Strategic Reprioritization, we paused investment in REVITALIZE-1, and our decision to do so was not driven by any safety or efficacy concerns for Revita in T2D. At that time, enrollment was paused and on July 24, 2025 FDA agreed to and approved the final study revision converting the study to safety only and reducing the overall size to those participants already enrolled, establishing participant follow-up to 24 weeks post Revita procedure. Participants previously enrolled and randomized were those with inadequately controlled T2D, and who were on at least one GLA. Participants randomized to the sham arm were offered an opportunity to receive the Revita DMR procedure (crossover) once unblinded. Participants who elected to crossover and undergo the Revita DMR procedure are being followed per protocol.

In June 2024, the FDA approved an amendment to the protocol of the REVITALIZE-1 study of our Revita device, which expanded eligibility to participants with T2D who are inadequately controlled on any GLA, including GLP-1 drugs and/or insulin.

In March 2021, we commenced REVITALIZE-1 (formerly known as REVITA-T2Di), a randomized, double-blind, crossover, sham-controlled, multi-center pivotal clinical study in participants with inadequately controlled T2D despite being on up to three ADAs and 20 to 100 units of insulin daily.

Rejuva Platform Description

Rejuva is a modular, physiologic gene therapy platform with three key elements designed to enable successful pancreatic gene therapy: (1) a proprietary delivery catheter designed to enable local, low dose therapeutic delivery directly to the pancreas via endoscopic access, (2) vectors with tropism for the pancreatic islet to enable successful transduction and gene delivery with limited biodistribution via this route of administration, and (3) transgenes with tissue-restricted promoters and metabolically active peptides that can durably impact glucose and weight control. Rejuva is designed to directly administer a gene therapy into the pancreas with both mechanical and molecular confinement of the therapeutic candidate with local administration and tissue-specific promoters.

Rejuva Device Overview

The Rejuva catheter leverages a single-use Rejuva PGTx catheter with a pressure-regulated and flow rate-controlled automated delivery mechanism. We believe the catheter enables a targeted delivery process by enabling a proprietary safety mechanism that controls the parameters of delivery that are required to ensure minimal disruption to the pancreatic tissue, and potentially reduces the risk of physician error by automating certain steps of the treatment process by guiding the fluid delivery mechanism. The Rejuva catheter is further composed of a narrow 27-gauge needle catheter that can be delivered through the working channel of a standard endoscopic ultrasound in which needle size, bevel shape, and aperture are designed to minimize risk of injury to the pancreas upon needle insertion.

Rejuva Drug Overview

The Rejuva drug platform is designed to be a modular, interchangeable platform composed of delivery vectors with high tissue tropism for the pancreatic islet and tissue-restricted promoters confining metabolically active transgene expression to islet cells. In the first quarter of 2024, we nominated RJVA-001, our first clinical candidate to emerge from the Rejuva platform for the remission of T2D. RJVA-001 combines a novel, proprietary Rejuva catheter for delivery, an AAV9 serotype vector, and a proprietary transgene construct, which features a modified human insulin promoter and a proprietary coding sequence that enables secretion of active human GLP-1.

In the fourth quarter of 2024, we nominated our first smart GIP/GLP-1 pancreatic gene therapy lead candidate, RJVA-002, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating blood sugar and body weight.

Our GLP-1 PGTx candidates are designed to express GLP-1 specifically in beta cells in a manner that will allow beta cells to produce, package, and secrete GLP-1 hormone in a similar method to insulin. In this way, the GLP-1 transgene product can act within the pancreatic islet on adjacent alpha and beta cells to augment local GLP-1 receptor activation and signaling. Because of this local expression, our GLP-1 PGTx candidates are designed to improve beta-cell health and function and thereby provide durable weight loss and glycemic control while minimizing the side effects of systemic exposure to GLP-1.

Rejuva Delivery Overview

Our Rejuva PGTx candidates are locally administered using a proprietary needle catheter that is uniquely designed for pancreas delivery in an outpatient, endoscopic procedure that lasts approximately twenty minutes. The procedure is performed by a trained endoscopist while the patient is under conscious sedation or general anesthesia. With the help of the Rejuva catheter handle, certain steps of the procedure are designed to be highly automated, which we believe minimizes the risk of physician error.

The procedure involves inserting the distal end of the single-use Rejuva catheter through the working channel of an endoscopic ultrasound imaging device and into the stomach. Ultrasound will be used to direct needle placement through the stomach wall into the body and tail of the pancreas after identifying the pancreatic duct and other key anatomical structures. The needle is then advanced into the distal pancreas. The physician will confirm needle placement before enabling a precise dose of the drug candidate to be delivered into the pancreas by an automated syringe pump system in the console. During the administration, the catheter handle will control the pressure and flow rate of the delivered fluid to prevent injury to the tissue and regulate the volume of delivery to control the precise dose of administration. A favorable benefit-risk profile of the delivery device can be enabled by directing the needle toward the body and tail of the pancreas, where a majority of pancreatic islets reside, and by avoiding the pancreatic duct in the head of the pancreas.

Preclinical Data Overview: Rejuva Gene Therapy Platform

We have evaluated potential GLP-1 PGTx candidates in large and small animal studies. In survival studies in over 100 large animals, we have observed 100% technical success with our Rejuva device using our proposed clinical route of administration with no device-related adverse events observed thus far. In small animal pharmacology studies, we observed that our potential GLP-1 PGTx candidates were generally well tolerated, reduced weight, improved glycemic control, and delayed T2D progression compared to vehicle or control and semaglutide. Given the data observed in our preclinical studies thus far, we believe that our Rejuva gene therapy candidates have the potential to provide superior clinical benefit in T2D and people living with obesity who currently have limited treatment options that provide long-term benefit even after treatment discontinuation.

Preclinical Studies: Proof-of-Concept

RJVA-001:

The lead product candidate from this platform, RJVA-001, is being advanced for patients with inadequately controlled T2D. RJVA-001 is designed to durably reprogram pancreatic beta cells to locally produce GLP-1 under nutrient-responsive

control, potentially enabling physiologic hormone secretion without the high circulating levels that contribute to side effects seen with systemic GLP-1 drugs.

In the second half of 2025, we completed preclinical chemistry, manufacturing, and controls activities and lot release for our RJVA-001 drug product, as well as key preclinical in vivo studies to support a CTA. During the same period, we submitted CTAs for RJVA-001 in T2D to regulators in the EU (Netherlands) and Australia, advancing the program toward its anticipated first-in-human study. We expect to receive regulatory feedback in the second quarter of 2026 and, subject to CTA authorization, to initiate first-in-human dosing of RJVA-001 and expected reporting of preliminary data in the second half of 2026.

In June 2025, we presented new preclinical data from Rejuva at the American Diabetes Association’s (“ADA”) 85th Scientific Sessions. We demonstrated that a single dose of GLP-1 PGTx was well-tolerated in healthy normal weight mice and prevented weight gain and hyperglycemia following a switch to a high-fat diet. Importantly, these data highlight Rejuva’s distinct mechanism of action. The Smart GLP-1TM design of Rejuva enables nutrient-responsive secretion, exerting minimal physiologic effect under healthy metabolic conditions and only activating in the presence of metabolic stress. This targeted activity, which mimics the body’s endogenous GLP-1 physiology, highlights the potential for Rejuva to offer superior potency and tolerability.

In May 2025, we presented new preclinical data from Rejuva in an oral session at the American Society of Gene and Cell Therapy 2025 Annual Meeting. These data showed that a single-dose RJVA-001 led to durable, dose-dependent metabolic improvements in a well-established mouse model of diabetes (db/db). Additionally, these data highlight the platform’s potential to deliver durable, nutrient-responsive GLP-1 secretion from pancreatic beta cells, mimicking natural hormone regulation with low circulating levels of GLP-1, offering a potentially profound mechanistic advantage over pharmacologic GLP-1 drugs.

Rejuva Shows Nutrient Responsive, Dose-Responsive GLP-1

Expression and Secretion in Transduced Human Beta Cells

Rejuva GLP-1 Improves Metabolic Control in db/db/ Mice

Dose-responsive improvement in body weight, blood glucose, and insulin levels

In a porcine route-of-administration safety model, RJVA-001 also showed strong efficacy, targeted delivery, and a favorable safety profile with no serum, biodistribution, or histopathologic findings of concern reinforcing its readiness for first-in-human studies.

Rejuva AAV Effectively Delivered to Pancreas Via Targeted ROA

Transgene DNA, RNA, active GLP-1 protein enriched in targeted pancreatic splenic lobe

No Toxicity Observed Following Rejuva Treatment

No serum, biodistribution, or histopathologic findings of concern

In the first quarter of 2025, we achieved alignment with European authorities on a patient population and study design for the RJVA-001 first-in-human study. The upcoming Phase 1/2 first in human study is designed to be an open-label, multicenter, single ascending dose study evaluating the safety, tolerability, and preliminary efficacy of RJVA-001 in adults with inadequately controlled T2D despite use of multiple glucose-lowering agents, including GLP-1 receptor agonists. Participants will undergo a standardized medication run-in and GLP-1 washout before receiving RJVA-001 delivered via endoscopic ultrasound-guided intrapancreatic infusion utilizing our investigational delivery device. The preliminary study design comprises three escalating dose cohorts (up to 3 participants each) which will be followed by an optional expansion cohort of up to 20 additional participants treated at the selected optimal dose. Participants will be monitored for 12 months for safety, glucose control, immune response, and GLP-1 expression, and enrolled in a long-term follow-up study for up to five years. Primary endpoints include safety and tolerability. Secondary endpoints include change in HbA1c, fasting plasma

glucose, and time-in-range as measured by continuous glucose monitoring. Exploratory endpoints assess beta-cell function, metabolic biomarkers, cardiovascular risk markers, and transgene expression.

We have conducted multiple proof-of-concept studies with GLP-1 PGTx candidates consisting of AAV-delivered transgenes carrying an insulin promoter driving GLP-1RA sequences in in vitro, ex vivo human islets, ex vivo mouse islets, and in vivo survival studies in a db/db mouse model of T2D and obesity. In db/db mice 10 weeks after a single administration of a GLP-1 PGTx candidate, we observed dose-dependent expression of the GLP-1RA protein in whole pancreas explants and in isolated islets from animals sacrificed at that time point. Isolated pancreatic islets from treated mice grown ex vivo demonstrated increased insulin content and improved glucose-stimulated insulin secretion (“GSIS”), a hallmark of improved beta cell function.

In the human EndoC-BH5 beta cell line, a GLP-1 PGTx candidate demonstrated dose-dependent increases in GLP-1RA secretion into the cell supernatant and improved GSIS. The improvement in GSIS was blocked by the administration of a GLP-1 receptor antagonist (exendin-9), demonstrating that improvements to beta cell function by the GLP-1 PGTx candidate were achieved through GLP-1 receptor binding and activation, and demonstrating the potential for pharmacologic agents that block the GLP-1 receptor to abrogate the effects of RJVA-001.

In ex vivo human islets, a GLP-1 PGTx candidate demonstrated dose-dependent transduction of up to 25% of beta cells within islets along with a doubling of GSIS. Taken together, we believe the results from EndoC-BH5 and healthy (non-diseased) human islets indicate that GLP-1 PGTx candidates have the potential to successfully transduce human beta cells and improve beta cell function even in healthy, non-diseased islets.

In proof-of concept preclinical in vivo studies in a db/db mouse model, we evaluated escalating doses of GLP-1 PGTx candidates in glucose lowering potency compared to vehicle. We observed dose-dependent improvements in FPG that were sustained for 64 days after a single administration of a GLP-1 PGTx candidate compared to vehicle control, along with sustained increases in fasting insulin at the same time point. We believe these results indicate that GLP-1 PGTx candidates have the potential to improve glucose control and beta cell insulin production and secretion in a durable manner.

In a head-to-head preclinical in vivo study in a db/db mouse model, we evaluated a GLP-1 PGTx candidate compared to semaglutide. By four weeks post treatment, we observed a statistically significant average reduction of FPG of 73% (p <0.0001), a statistically significant increase in fasting insulin of 478% (p < 0.01), and a statistically significant decrease in total body weight of 14% (p <0.001) relative to vehicle treated mice after a single administration of a GLP-1 PGTx candidate. Based on these data, we believe this study suggests that a single administration of a GLP-1 PGTx candidate can achieve greater improvements in blood glucose control and weight loss and delayed T2D progression in db/db mice compared to semaglutide.

In a head-to-head preclinical in vivo study in a DIO mouse model, we evaluated weight loss after a single administration of GLP-1 PGTx candidate compared to semaglutide 10 nmol/kg daily. At 28 days after administration, we observed a statistically significant reduction of total body weight of 27% for the GLP-1 PGTx candidate compared to 21% for semaglutide (p < 0.05 for the difference between GLP-1 PGTx candidate and semaglutide). Semaglutide-treated animals were then randomized on day 29 to withdrawal of semaglutide or a single administration of the GLP-1 PGTx candidate, and both groups were followed for an additional 4 weeks. On day 57, we observed weight loss of 25% in the obese rodents initially treated with the GLP-1 PGTx candidate, compared to weight gain of 4% in vehicles. Animals withdrawn from semaglutide regained weight to a net 2% body weight loss on day 57, while animals who crossed over from semaglutide to a single dose of the GLP-1 PGTx candidate maintained body weight loss on day 57 with 22% weight loss from baseline. Based on this data, we believe that a single administration of a GLP-1 PGTx candidate can achieve greater improvements in weight loss than semaglutide at the tested dose, durable improvements in weight loss compared to vehicle control, and can offer a potential weight maintenance therapeutic solution to prevent weight regain after semaglutide discontinuation.

In vivo studies of GLP-1 PGTx candidates in DIO and db/db mice have demonstrated high specificity of transgene expression for the pancreatic islets with no detectable transgene expression in off-target tissues (e.g., the exocrine pancreas). Quantification of GLP-1RA immunoreactivity in mouse islet beta cells indicates that potent efficacy can be achieved with only a small fraction (< 10%) of beta cells expressing GLP-1RA.

We observed that promoter and regulatory element optimization in GLP-1 PGTx candidates demonstrated the potential for a broad dynamic range of transgene protein production at eight to nine weeks after a single administration of a GLP-1 PGTx candidate. We believe these results indicate that GLP-1 PGTx candidates have the potential to provide durable metabolic benefits after a single administration with limited systemic exposure.

No abnormal findings were observed in animal behavior or clinical chemistries. Histopathologic analysis showed no evidence of inflammation, pancreatitis or pancreatic cancer.

RJVA-002:

The Company’s second candidate from the Rejuva platform, RJVA-002, is a dual GIP/GLP-1 gene therapy and is currently in preclinical development. RJVA-002 expands the Rejuva platform into obesity, targeting dual incretin biology with the goal of achieving durable, well-tolerated, weight loss from a single intervention.

In October 2025, we announced new preclinical potency data from RJVA-002 at the 2025 Cell & Gene Meeting on the Mesa. These data expand the potential of the Rejuva platform from the durable treatment of T2D to obesity. In this ongoing preclinical study, male mice engineered to express a humanized GIP receptor (“Biocytogen”) were fed a 60% high-fat diet (“HFD”) to induce obesity and were then randomized into one of four treatment cohorts: vehicle control, RJVA-001 mid-dose, RJVA-002 mid-dose, and RJVA-002 high-dose (n=7 per group). A single administration of RJVA002 led to approximately 30% weight loss over five weeks in a translational obesity model in male mice, with weight loss not yet plateaued and no observed adverse effects. In this preclinical trial, all mice were continued on HFD for the duration of the study. Treatment with RJVA-002 resulted in a robust, dose dependent reduction in body weight compared to vehicle control. By day 35, mice in mid- and high-dose cohorts had lost a mean of 18% (p<0.01) and 29% (p<0.0001) of their body weight after a single dose of RJVA-002, respectively. These findings highlighted the potential for a durable, one-time gene therapy approach to obesity that could match or exceed best-in-class chronic drug therapy. Results from this ongoing study at longer time points and with associated metabolic measurements will be presented at an upcoming scientific congress.

Clinical Development Overview: Rejuva Gene Therapy Platform

We completed key preclinical in vivo studies to support a CTA for RJVA-001 and subsequently submitted CTAs for RJVA-001 in T2D to regulators in the EU (Netherlands) and Australia in the second half of 2025, advancing the program toward its anticipated first-in-human study. We expect to receive regulatory feedback in the second quarter of 2026 and, subject to

CTA authorization, to initiate first-in-human dosing of RJVA-001 and expected reporting of preliminary data in the second half of 2026.

In addition, in the fourth quarter of 2024, we nominated our first smart GIP/GLP-1 pancreatic gene therapy lead candidate, RJVA-002, designed for the treatment of obesity. RJVA-002 is a locally administered AAV9 viral vector that expresses human GLP-1 and GIP hormones from a human insulin promoter. RJVA-002 is designed to activate both GIP and GLP-1 receptors, which play crucial roles in regulating blood sugar and body weight.

Commercialization Strategy

The Revita DMR System is approved in Europe as a medical device under a CE Mark and has received reimbursement authorization through NUB in Germany for the treatment of T2D. After securing reimbursement for Revita in 2022, in the first half of 2023 we initiated a limited commercial pilot in a single center in Dusseldorf, Germany, along with a Germany Real-World Registry study, designed to evaluate real-world evidence of Revita’s safety and effectiveness in people with inadequately controlled T2D. We have paused investment in this commercial pilot, as well as in ongoing enrollment in the Germany Real-World Registry study.

In the U.S., we have obtained Breakthrough Device designation from the FDA for the Revita DMR System, as an adjunct to diet and exercise, to perform hydrothermal ablation of the duodenal mucosa, or the Revita DMR procedure, for use in the maintenance of weight loss after discontinuation of GLP-1-based therapy on patients who cannot tolerate long-term GLP-1 therapy and who are not candidates for endoscopic remodeling procedure or bariatric surgery. 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 market authorizations but does not alter or confer any advantage in the regulatory review, approval, or clearance standard for medical devices.

We intend to submit a De Novo classification request with FDA for Revita after we complete the REMAIN-1 study, including participant follow-up through 52 weeks. If our De Novo request is granted, we believe longer-term follow-up studies beyond 52 weeks will likely be performed as part of a post-market study, which may include studying the safety and effectiveness of repeat procedures, should they be necessary. Based on regulatory precedent, we believe such post-market studies may be conducted in parallel with the commercial launch of Revita. If our De Novo request is granted, we intend to execute a targeted, efficient go-to-market strategy for Revita, driven by a stepwise approach that will build brand awareness, position Revita as a novel procedural therapy alternative to ongoing maintenance use of GLP-1s, and ultimately expand procedure volume as an attempt to validate Revita in endocrine and endoscopy communities as a durable and potentially repeatable option for patients living with obesity, prediabetes and other metabolic diseases.

As we progress our Revita clinical program and generate clinical evidence in support of Revita, we will invest in building a U.S. based direct sales force to support our U.S. launch to prepare for Revita’s potential FDA marketing authorization. We will seek to strategically recruit representatives with strong backgrounds and experience in the management of obesity and metabolic disease, as well as those with a deep understanding of therapeutic GI endoscopy. We expect to grow our field force over time to accelerate broad market adoption of Revita, building on the foundational brand awareness we aim to achieve through our initial educational efforts.

As we generate additional clinical data and insights through our Revita clinical program, we plan to carry out an organized medical education effort to inform gastroenterologists and endoscopic surgeons around the compelling solution provided by our product candidates, as we believe they will serve as the primary customers for our therapies. We believe that the clinical evidence generated from our program will continue to support our messaging to key leaders in the field of metabolic endoscopy. In parallel, we plan to leverage our LOI with Everself (formerly Bariendo) as this potential partnership will bring a scalable, physician-driven platform designed to deliver metabolic endoscopic solutions at the nation’s largest network of high-volume hospital and ambulatory endoscopy centers across the U.S.

If Revita receives marketing authorization, we intend to commercially launch with our next generation commercial console, which has been designed for scalability and ease-of-use. We plan to execute an efficient “hub-and spoke” commercialization strategy to position Revita as a novel procedural therapy to treat obesity and T2D and drive its rapid adoption. Leveraging key learning and insights from our Revita clinical program, we plan to have a targeted sales force initially focusing on centers of excellence with metabolically focused GI endoscopists and surgical endoscopists with a dedicated interest in bariatric and metabolic endoscopy. We plan to initially target participating physicians from our clinical

studies, as we believe their familiarity with our therapies will make them early adopters. Our multi-channel commercialization strategy will include a focus on patients directly with GI endoscopy suites and practices, as well as direct marketing campaigns to raise awareness amongst patients for a compelling new treatment alternative in weight maintenance and obesity.

We also plan to roll out a robust procedural training and support program for GI and surgical endoscopists, ensuring seamless integration of Revita into their workflow. These education and training efforts will be critical in building an installed base in metabolic endoscopy that will begin with providers at large hospitals and expand to outpatient endoscopy centers over time.

Our initial approach will be to focus on people living with obesity who desire an off-ramp from GLP-1 drugs, and progress to other unmet needs in the treatment and prevention of metabolic diseases, including T2D. Once we are established in obesity and prediabetes through clinical validation, medical education and training, strong procedure volumes and a robust installed base, we plan to leverage our foundational platform, technology and core capabilities to expand indications to other metabolic diseases, CVD, and others.

As we expand the adoption of Revita, we will evaluate potential partnerships and/or distributor relationships for its commercialization in other global geographies. Given the high prevalence and rapidly growing incidence of obesity and prediabetes in international markets, we believe there is a significant unmet need for a scalable, disease-modifying therapy globally. We plan to pursue regulatory authorizations, approvals and geographic expansion into international markets with reimbursement and a need for procedure-based solutions in obesity and prediabetes, as part of our long-term growth strategy.

Because Rejuva is designed to leverage the same patient referral pathways, physicians, skill sets and commercialization footprint of Revita, we believe that a successful launch of Revita, if authorized will enable a more rapid commercialization of Rejuva into that same channel, if both products receive marketing authorization in the U.S.

Research and Development

We have an experienced research and development team with the scientific, engineering, software, operations and clinical talent that we believe is required to grow our business. We have committed, and expect to continue to commit, significant resources to improve product candidate performance and reliability and reduce costs. As of March 1, 2026, our research and development team was comprised of 73 employees. For the years ended December 31, 2025 and 2024, we incurred research and development expenses of approximately $74.5 million and $70.5 million, respectively. Major components of the research and development expenses included salaries and benefits, engineering, preclinical and clinical study expenses.

We continuously seek to improve Revita, the DMR procedure and our Rejuva gene therapy platform, including improvements in our technology and its accessibility. We believe that technical advantage is important to achieve or sustain a competitive advantage, and therefore our research and development efforts are focused on the continued enhancement of Revita, the DMR procedure and Rejuva. We are dedicated to ongoing innovation with respect to Revita, the DMR procedure, Rejuva, and to expanding our pipeline of product candidates and their applications to treat obesity, T2D and other metabolic diseases.

Competition

The medical device and biopharmaceutical industries are characterized by rapid advancement of novel technologies, significant competition and a strong defense of intellectual property rights. While we believe that our product candidates and scientific expertise provides us with competitive advantages, we face competition from multiple sources, including larger and better-funded medical device and biopharmaceutical companies, academic institutions, lifestyle and diet service centers, hospitals, surgical centers, governmental agencies and public and private research institutions. We also may face competition from companies developing endoscopic and other procedure-based metabolic interventions, including duodenum-targeted therapies. Any product candidates that we successfully develop and commercialize will compete with currently approved therapies, services and procedures, including lifestyle and diet services, bariatric surgeries, in particular gastric bypass surgeries, and new therapies that may become available in the future. Key factors that would affect our ability to effectively compete with other therapeutics include safety, efficacy, ease of administration, pricing, brand recognition and availability of reimbursement and coverage by third party payors.

There are a number of new classes of agents and combination agents approved or in development for obesity and T2D, such as oral GLP-1s, other nutrient-stimulated hormones and novel mechanisms, which may offer evidence of significant weight loss and broad metabolic benefit. Pharmaceutical companies are heavily invested in their existing and future product platforms for obesity and T2D. They have strong relationships within the clinical community and with prescribing physicians in particular.

Intellectual Property

Our ability to obtain and maintain intellectual property protection for our product candidates and technology is fundamental to the long-term success of our business. We rely on a combination of intellectual property protection strategies, including patents, trademarks, trade secrets, confidentiality policies and procedures, non-disclosure agreements, invention assignment agreements and technical measures designed to protect the intellectual property and commercially valuable confidential information and data used in our business.

As of March 1, 2026, we own: 36 issued U.S. patents; 34 pending U.S. non provisional patent applications; five pending U.S. provisional patent applications; two patent cooperation treaty (“PCT”), applications that have not entered national stage; 51 issued foreign patents in Australia, Brazil, Canada, China, Europe, Israel, Japan, Korea, and Russia; and 26 pending foreign patent applications in Australia, Canada, China, Europe, Israel, India, Japan, and Korea. Patent counts reflect the patents we maintain. We may allow patents and applications that are not material to our business to lapse. The subject matter covered by our owned patents and patent applications include: Revita and components thereof, methods of using Revita, Rejuva and components thereof, methods of using Rejuva, and other exploratory product candidates. Excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable: our owned issued U.S. patents are expected to expire between January 2032 and January 2041; our owned issued foreign patents are expected to expire between January 2032 and October 2040; any patents that may issue from our owned pending U.S. patent applications are expected to expire between January 2032 and February 2047; any patents that may issue from our owned pending foreign patent applications or PCT applications are expected to expire between January 2032 and January 2045.

With respect to Revita, as of March 1, 2026, we own: 34 issued U.S. patents; 27 pending U.S. patent applications; one pending U.S. provisional patent applications; one PCT application that has not entered national stage; 51 issued foreign patents in Australia, Brazil, Canada, China, Europe, Israel, India, Japan, Korea, and Russia; and 17 pending foreign patent applications in Australia, Canada, China, Europe, Israel, Japan, and Korea. The issued patents and any patents that may issue from our pending patent applications related to Revita are expected to expire between January 2032 and July 2046, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

With respect to Rejuva, as of March 1, 2026, we own: six pending U.S. patent applications; six pending U.S. provisional patent applications; one PCT application that has not entered national stage; and nine pending foreign patent applications in Australia, Canada, China, Europe, Japan and Korea. Any patents that may issue from our pending patent applications related to Rejuva are expected to expire between February 2042 and February 2047, excluding any possible patent term adjustments or extensions and assuming payment of all appropriate maintenance, renewal, annuity or other governmental fees, as applicable.

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 U.S., the patent term is 20 years from the earliest claimed filing date of a non-provisional patent application in the applicable country. In the U.S., a patent’s term may, in certain cases, be lengthened by patent term adjustment, which compensates a patentee for administrative delays by the USPTO in examining and granting a patent, or may be shortened if a patent is terminally disclaimed over a commonly owned patent or a patent naming a common inventor and having an earlier expiration date. 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 intend to pursue additional intellectual property protection to the extent we believe it would be beneficial and cost-effective. Our ability to stop third parties from making, using or commercializing any of our patented inventions will depend in part on our success in obtaining, defending and enforcing patent claims that cover our technology, inventions, and improvements. With respect to our owned intellectual property, we cannot provide any assurance that any of our current or future patent applications will result in the issuance of patents in any particular jurisdiction, or that any of our

current or future issued patents will effectively protect any of our product candidates or technology from infringement or prevent others from commercializing infringing products or technology.

Our commercial success depends significantly on our ability to operate without infringing, misappropriating or otherwise violating the intellectual property rights of third parties. The medical device industry is subject to rapid technological change and substantial litigation regarding patent and other intellectual property rights. Numerous third-party patents exist in the fields relating to our product candidates, and it is difficult for industry participants, including us, to identify all third-party patent rights relevant to our product candidates and technologies. We are aware of third-party patents, and patent applications that if issued, may be construed to cover our product candidates or technologies, including Revita.

In addition to our reliance on patent protection for our inventions, products and technologies, we also seek to protect our brand through the procurement of trademark rights. As of March 1, 2026, we own 44 registered trademarks and three pending trademark applications for FRACTYL, FRACTYL HEALTH, FRACTYL HEALTH LOGO, REVITA, REVITA DMR, REJUVA and other product related brand names in the U.S. and certain foreign jurisdictions. Furthermore, we rely on trade secrets, know-how, unpatented technology and other proprietary information, to strengthen our competitive position. We have determined that certain technologies, including certain aspects of our software, are better kept as trade secrets. To mitigate the chance of trade secret misappropriation, we enter into non-disclosure and confidentiality agreements with parties who have access to our trade secrets, such as our employees, consultants, advisors and other third parties. We also enter into invention assignment agreements with our employees and consultants that obligate them to assign to us any inventions they have developed while working for us. We generally control access to our proprietary and confidential information through the use of internal and external controls that are subject to periodic review.

Although we take steps to protect our proprietary information and trade secrets, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. As a result, we may not be able to meaningfully protect our trade secrets. For further discussion of the risks relating to intellectual property, see Part I, Item 1A, “Risk Factors—Risks Related to Our Intellectual Property.”

Manufacturing and Supply

We currently perform final assembly and acceptance testing of Revita at our headquarters in Burlington, Massachusetts. We rely upon third-party suppliers for the manufacture of sub-assembly components, the sterilization of final components of the Revita system, the device component of the Rejuva product and the Rejuva gene therapy candidates. We do not have long-term supply agreements with any of our suppliers, some of which are single- or sole-source suppliers. Our purchase order arrangements are terminable at will. We have not yet identified and qualified second-source replacements for many of our critical single-source suppliers. Thus, in the event that our relationship with any of our single- or sole-source suppliers terminates in the future, we may have difficulty maintaining sufficient supplies of key components of our product candidate. Where practicable, we are currently seeking, or intend to seek, second-source manufacturers for our single-source components. We believe that our existing facilities and those of our third-party suppliers are adequate to meet our current manufacturing needs.

Manufacturing facilities that produce drug products, medical devices or their component parts are subject to regulation and periodic unannounced inspection by the FDA and other domestic and international regulatory agencies. In the U.S., we and some of our sub-assembly component manufacturers will be required to manufacture any products that we sell in compliance with the FDA’s Quality Management System Regulation (“QMSR”), and the FDA’s current good manufacturing practices (“cGMPs”), which cover the methods used in, and the facilities used for, the design, testing, control, manufacturing, sterilization, labeling, quality assurance, packaging, storage and shipping of our product candidates. In international markets, we and some of our sub-assembly component manufacturers are and will be required to obtain and maintain various quality assurance and quality management certifications, and are and will continue to be periodically inspected by international regulatory authorities for certification purposes. Our manufacturing operations, and those of our suppliers, are designed to be in compliance with applicable regulations of the FDA or other applicable regulatory authorities.

Government Regulation

Our product candidates and our operations are subject to extensive regulation by the FDA and other federal and state authorities in the U.S., as well as comparable authorities in foreign jurisdictions. For example, certain of our product candidates are subject to regulation as medical devices in the U.S. under the Federal Food, Drug, and Cosmetic Act (“FDCA”), as implemented and enforced by the FDA, and other product candidates we intend to develop are regulated as

biologic-device combination products subject to regulation by the FDA under the FDCA and the Public Health Service Act (“PHSA”), and comparable foreign laws and regulations.

United States Regulation of Medical Devices

The FDA regulates the development, design, non-clinical and clinical research, manufacturing, safety, efficacy, labeling, packaging, storage, installation, servicing, record keeping, premarket clearance or approval, adverse event reporting, advertising, promotion, marketing and distribution, and import and export of medical devices to ensure that medical devices distributed domestically are safe and effective for their intended uses and otherwise meet the requirements of the FDCA.

FDA Premarket Clearance and Approval Requirements

Unless an exemption applies, each medical device commercially distributed in the U.S. requires either FDA clearance of a premarket notification submitted under Section 510(k) of the FDCA, classification under FDA’s de novo classification process or approval of a PMA application. Under the FDCA, 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 manufacturer and regulatory control needed to ensure its safety and effectiveness. Class I includes devices with the lowest risk to the patient 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, establishment registration and device listing, reporting of adverse medical events and certain device malfunctions, known as medical device reporting (“MDR”), and truthful and non-misleading labeling, advertising, and promotional materials. Class II devices are subject to the FDA’s General Controls, and special controls as deemed necessary by the FDA to ensure the safety and effectiveness of the device. These special controls can include among other things performance standards, post-market surveillance, patient registries and additional labeling requirements.

While most Class I devices are exempt from the 510(k) premarket notification requirement, manufacturers of most Class II devices are required to submit to the FDA a premarket notification under Section 510(k) of the FDCA requesting permission to commercially distribute the device. The FDA’s permission to commercially distribute a device subject to a 510(k) premarket notification is generally known as 510(k) clearance and is granted upon a determination that the device is substantially equivalent to a legally marketed predicate device. For novel devices that are low to moderate risk but for which no legally marketed predicate device exists, a manufacturer may instead seek marketing authorization through the De Novo classification process. If granted, a De Novo request results in classification of the device as Class I or Class II and may establish special controls applicable to the device type, after which the device may serve as a predicate for future 510(k) submissions. Devices deemed by the FDA to pose the greatest risks, such as life-sustaining, life-supporting or certain implantable devices, or devices that present risks that cannot be adequately controlled through general and special controls, are placed in Class III and generally require approval of a PMA prior to commercialization. Some pre-amendment devices remain unclassified but are subject to the FDA’s premarket notification and clearance requirements in order to be commercially distributed.

510(k) Clearance Marketing Pathway

To obtain 510(k) clearance, the manufacturer must submit to the FDA a premarket notification submission demonstrating that the proposed device is “substantially equivalent” to a legally marketed predicate device. A predicate device is a legally marketed device that is not subject to premarket approval, i.e., a device that was legally marketed prior to May 28, 1976 (pre-amendments device) and for which a PMA is not required, a device that has been reclassified from Class III to Class II or I, or a device that was found substantially equivalent through the 510(k) process. The FDA’s 510(k) clearance process usually takes from three to twelve months, but may take longer. The FDA may require additional information, including clinical data, to make a determination regarding substantial equivalence. In addition, FDA collects user fees for certain medical device submissions and annual fees for medical device establishment registration.

If the FDA agrees that the device is substantially equivalent to a predicate device currently on the market, it will grant 510(k) clearance to commercially market the device. If the FDA determines that the device is “not substantially equivalent” to a previously cleared device, the device is automatically designated as a Class III device. The device sponsor must then fulfill more rigorous PMA requirements, or can request a risk-based classification determination for the device in accordance with the “de novo” classification process, which is a route to market for novel medical devices that are low to moderate risk and are not substantially equivalent to a predicate device.

After a device receives 510(k) clearance, any modification that could significantly affect its safety or effectiveness, or that would constitute a major change or modification in its intended use, will require a new 510(k) clearance or, depending on the modification, PMA approval or grant of a de novo request for classification. The FDA requires each manufacturer to determine whether the proposed change requires submission of a 510(k) in the first instance, but the FDA can review any such decision and disagree with a manufacturer’s determination. If the FDA disagrees with a manufacturer’s determination, the FDA can require the manufacturer to cease marketing and/or request the recall of the modified device until such marketing authorization has been granted. Also, in these circumstances, the manufacturer may be subject to significant regulatory fines or penalties.

De Novo Classification Pathway

The De Novo classification process is a marketing pathway for novel medical devices that are low to moderate risk and for which there is no legally marketed predicate device. A manufacturer may submit a De Novo request directly if no appropriate predicate exists, or after receiving a “not substantially equivalent” determination in response to a 510(k) submission. In a De Novo request, the manufacturer must provide sufficient information to demonstrate reasonable assurance of safety and effectiveness for the device's intended use and to show that general controls alone, or general and special controls, are adequate to mitigate identified risks. Submissions typically include a detailed device description, nonclinical performance testing, risk analysis, proposed labeling, and, where necessary, clinical data.

Based on clinical safety data generated to date and provided to the FDA, the FDA has indicated that Revita may be appropriate for classification as a Class II device, and we intend to seek a De Novo classification order from the FDA as our pathway to marketing authorization. There can be no assurance, however, that the FDA will grant the De Novo request, that the FDA will not require additional information or clinical data before completing its review, or that unforeseen safety events arising from our ongoing clinical studies will not cause the FDA to reassess Revita's risk classification. If the FDA determines that safety events identified during the REMAIN-1 study or otherwise warrant reclassification to Class III, we may be required to pursue PMA approval rather than De Novo classification, which would significantly increase the time, cost, and data requirements necessary to obtain marketing authorization. See “—PMA Approval Pathway” below.

Following submission, the FDA conducts an acceptance review and substantive review of the De Novo request. Although the statute provides the FDA with 150 review days, the total review timeline is often longer due to requests for additional information and sponsor response time. De Novo submissions are subject to user fees, which are generally higher than 510(k) fees but lower than PMA fees. If the FDA grants the De Novo request, the device is classified as Class I or Class II, and the FDA may establish special controls necessary to provide reasonable assurance of safety and effectiveness. The granted De Novo classification creates a new device type that may serve as a predicate for future 510(k) submissions.

After a device receives a De Novo classification, the manufacturer is subject to general medical device regulatory requirements, including establishment registration and device listing, QMSR compliance, medical device reporting, labeling requirements, and other post-market controls. Unlike PMA-approved devices, De Novo-classified devices are not subject to routine annual reporting requirements, although the FDA may impose post-market surveillance requirements as special controls or conditions of the classification order. Modifications that could significantly affect the safety or effectiveness of the device, or that constitute a major change in intended use, may require submission of a new 510(k), a new De Novo request, or a PMA, and the FDA may take enforcement action if it determines that a required marketing authorization was not obtained.

PMA Approval Pathway

Although we are currently pursuing De Novo classification for Revita based on the FDA's assessment of Revita as a Class II device, we may be required to seek PMA approval if the FDA determines, based on unforeseen safety events arising from the REMAIN-1 study or other ongoing clinical activities, that Revita poses risks inconsistent with Class II designation and should be reclassified as a Class III device. A Class III device requires PMA approval before it can be commercially marketed. The PMA process is substantially more demanding than the De Novo classification process and would significantly extend the time and resources required to obtain marketing authorization for Revita.

In a PMA, the manufacturer must demonstrate that the device is safe and effective, supported by extensive data from preclinical studies and human clinical trials. The PMA 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. Following receipt of a PMA application, the FDA determines whether the application is sufficiently complete to permit substantive review. If the FDA accepts the application for review, it has 180 days under the FDCA to complete its review,

although in practice the FDA's review often takes significantly longer and can take up to several years. An advisory panel of experts from outside the FDA may be convened to review and evaluate the application and provide recommendations to the FDA regarding approvability. The FDA may or may not accept the panel's recommendation. The FDA will generally conduct a pre-approval inspection of the applicant's or its third-party manufacturers' or suppliers' manufacturing facility or facilities to ensure compliance with the QMSR. PMA applications are also subject to user fees, which are higher than those applicable to De Novo submissions.

The FDA will approve a 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 its intended use. The FDA may approve a PMA with post-approval conditions intended to ensure the safety and effectiveness of the device, including restrictions on labeling, promotion, sale, and distribution, and requirements to collect long-term follow-up data from clinical study participants or to conduct additional post-approval studies. Failure to comply with the conditions of approval can result in material adverse enforcement action, including withdrawal of 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. None of our medical device products have been approved through the PMA process.

Clinical Trials

Clinical trials are almost always required to support a PMA or a de novo request, and are sometimes required to support a 510(k) submission. All clinical investigations of devices conducted in the U.S. to determine safety and effectiveness must be conducted in accordance with the FDA’s IDE regulations which among other things govern investigational device labeling, prohibit promotion of the investigational device, and specify an array of record keeping, 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 trials. If the device under evaluation does not present a significant risk to human health, then the device sponsor is not required to submit an IDE application to the FDA before initiating human clinical trials, but must still comply with abbreviated IDE requirements when conducting such trials. 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 trial to proceed under a conditional approval.

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 site. The IRB is responsible for the initial and continuing review of the IDE, and may impose additional requirements for the conduct of the study. If an IDE application is approved by the FDA and one or more IRBs, human clinical trials may begin at a specific number of investigational sites with a specific number of participants, as approved by the FDA. If the device presents a non-significant risk to the participant, a sponsor may begin the clinical trial after obtaining approval for the trial by one or more IRBs without separate approval from the FDA, but must still follow abbreviated IDE requirements, such as monitoring the investigation, ensuring that the investigators obtain informed consent, and complying with labeling and record-keeping requirements. In some cases, an IDE supplement must be submitted to, and approved by, the FDA before a sponsor or investigator may make a change to the investigational plan that may affect its scientific soundness, study plan or the rights, safety or welfare of human subjects.

During a study, the sponsor is required to comply with applicable FDA requirements, including, for example, trial monitoring, selecting clinical investigators and providing them with the investigational plan, ensuring IRB review, adverse event reporting, record keeping 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’s regulations and must obtain participant informed consent, rigorously follow the investigational plan and study protocol, control the disposition of the investigational device, and comply with all reporting and record keeping requirements. Additionally, after a trial begins, the sponsor, the FDA or the IRB could suspend or terminate a clinical trial at any time for various reasons, including a belief that the risks to study subjects outweigh the anticipated benefits.

Expedited Development and Review Programs

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 health care 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 postmarket 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.

Post-Market Regulation of Medical Devices

After a product is placed on the market, numerous regulatory requirements continue to apply. These relate to:

device listing and establishment registration, which helps facilitate FDA inspections and other regulatory action;

the QMSR, which currently requires manufacturers, including third-party manufacturers, to follow stringent design, validation, testing, control, documentation and other quality assurance procedures during all aspects of the design and manufacturing process;

labeling regulations, including regulations pertaining to Unique Device Identification, and FDA prohibitions against the promotion of products for uncleared or unapproved use or indication;

clearance of product modifications for 510(k)-cleared products that could significantly affect safety or effectiveness or that would constitute a major change in intended use or approval of supplemental PMAs for certain changes to an approved device;

compliance with MDR regulations, which require that a manufacturer report to the FDA if a device it markets may have caused or contributed to a death or serious injury, or has malfunctioned and the device or a similar device that it markets would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur;

correction and removal reporting regulations, which require that manufacturers report to the FDA certain corrections and removals;

post-market restrictions or conditions, including post-market study commitments;

complying with the laws and regulations requiring Unique Device Identifiers on commercialized devices and also requiring the submission of certain information about each device to the FDA’s Global Unique Device Identification Database;

post-market surveillance regulations, which apply, when necessary, to protect the public health or to provide additional safety and effectiveness data for the medical product;

the FDA’s recall authority, whereby it can ask, or under certain conditions order, device manufacturers to recall from the market a product that is in violation of governing laws and regulations; and

regulations pertaining to voluntary recalls.

Manufacturing processes for medical devices are required to comply with the applicable portions of the QMSR, which currently cover the methods and the facilities and 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. Manufacturers of medical devices are subject to periodic scheduled and unscheduled inspections by the FDA. Failure to maintain compliance with the QMSR requirements could result in the shut-down of, or restrictions on, manufacturing operations and the recall or seizure of marketed 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 marketing authorization, 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 letters, untitled letters, fines, injunctions, consent decrees and civil penalties;

recalls, withdrawals, or administrative detention or seizure of our products, when and if approved;

operating restrictions or partial suspension or total shutdown of production;

refusing or delaying requests for 510(k) clearance, de novo classification or PMA approvals of new products or modified products;

withdrawing PMA approvals that have already been granted;

refusal to grant export approvals for our products, when and if approved; or

criminal prosecution.

Advertising and promotion of medical devices, in addition to being regulated by the FDA, are also regulated by the Federal Trade Commission and by state regulatory and enforcement authorities. Promotional activities for FDA-regulated products of other companies have been the subject of enforcement action brought under healthcare reimbursement laws and consumer protection statutes.

Furthermore, under the federal U.S. Lanham Act and similar state laws, competitors and others can initiate litigation relating to advertising claims. In addition, we are required to meet regulatory requirements in countries outside the U.S., which can change rapidly with relatively short notice.

United States Regulation of Biologics and Combination Biologic/Device Products

In the U.S., biological products, or biologics, such as those gene therapy candidates we intend to develop through our proprietary Rejuva gene therapy platform, are subject to regulation under the FDCA, PHSA, and other federal, state, local and foreign statutes and regulations.

Combination Biologic/Device Products

We expect our gene therapy candidates developed through our Rejuva gene therapy platform to be subject to regulation in the U.S. as combination products comprised of a biologic product candidate and a device delivery system. A combination product is the combination of two or more regulated components, such as biologic/device, that are combined or mixed and produced as a single entity, packaged together in a single package or as a unit or a biologic or device packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified biologic or device where both are required to achieve the intended use, indication or effect. If marketed individually, each component would be subject to different regulatory pathways and would require approval of independent marketing applications by the FDA – one for the device component and one for the biologic component of the combination.

A combination product, however, is assigned to a center within FDA that will have primary jurisdiction over its regulation based on a determination of the combination product’s primary mode of action, which is the single mode of action that provides the most important therapeutic action. To determine which FDA center or centers will review a combination product candidate submission, companies may submit a request for assignment to the FDA. Those requests may be handled formally or informally. In some cases, jurisdiction may be determined informally based on FDA experience with similar products. However, informal jurisdictional determinations are not binding on the FDA. Companies also may submit a formal Request for Designation to the FDA Office of Combination Products. The Office of Combination Products will review the request and make its jurisdictional determination within 60 days of receiving a Request for Designation.

In the case of our Rejuva gene therapy candidates, we believe that the primary mode of action will be attributable to the biologic component of the combination product. We therefore would expect to seek approval of any such combination biologic/device product candidate through a single Biologics License Application (“BLA”), and we do not expect that the FDA will require a separate marketing authorization for the device component.

U.S. Biologics Regulation

The process required by the FDA before biologics may be marketed in the U.S. generally involves the following:

completion of certain preclinical laboratory tests and animal studies performed in accordance with the FDA’s Good Laboratory Practice requirements (“GLPs”);

submission to the FDA of an IND, which must become effective before clinical trials may begin;

approval by an IRB or ethics committee at each clinical site before the trial is commenced;

performance of adequate and well-controlled human clinical trials to establish the safety, purity and potency of the proposed biologic product candidate for its intended use in accordance with good clinical practice requirements (“GCPs”);

preparation of and submission to the FDA of a BLA;

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

a determination by the FDA within 60 days of its receipt of a BLA to file the application for review;

satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities at which the proposed product is produced to assess compliance with cGMPs (including the QMSR in the case of the device component of any biologic/device combination product), and to assure that the facilities, methods and controls are adequate to preserve the biological product’s continued safety, purity and potency,

satisfactory completion of potential FDA inspection of selected clinical investigation sites to assess compliance with GCPs; and

FDA review and approval of the BLA to permit commercial marketing of the product for particular indications for use in the U.S.

The preclinical developmental stage generally involves laboratory evaluations of chemistry, formulation and stability, as well as studies to evaluate the product candidate’s toxicity in animals, in an effort to support subsequent clinical testing. The conduct of preclinical studies is subject to federal regulations and requirements, including GLP regulations for certain in vivo studies.

Prior to beginning the first clinical trial with a product candidate in the U.S., the trial sponsor must submit an IND to the FDA. The central focus of an IND submission is on the general investigational plan and the protocol(s) for clinical studies. The IND also includes results of animal and in vitro studies assessing the toxicology, pharmacokinetics, pharmacology, and pharmacodynamic characteristics of the product candidate, chemistry, manufacturing, and controls information, and any available human data or literature to support the use of the product candidate. An IND must become effective before human clinical trials may begin. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA, within the 30-day time period, raises safety concerns or questions about the proposed clinical trial. In such a case, the IND may be placed on clinical hold and the IND sponsor and the FDA must resolve any outstanding concerns or questions before the clinical trial can begin. Submission of an IND therefore may or may not result in FDA authorization to begin a clinical trial.

While the IND is active, progress reports summarizing the results of the clinical trials and nonclinical studies performed since the last progress report, among other information, must be submitted at least annually to the FDA, and written IND safety reports must be submitted to the FDA and investigators for serious and unexpected suspected adverse events, findings from other studies suggesting a significant risk to humans exposed to the same or similar drugs, findings from animal or in vitro testing suggesting a significant risk to humans, and any clinically important increased incidence of a serious suspected adverse reaction compared to that listed in the protocol or investigator brochure.

In addition to the IND submission process, under the National Institutes of Health (“NIH”), Guidelines for Research Involving Recombinant DNA Molecules (“NIH Guidelines”), supervision of human gene transfer trials includes evaluation and assessment by an institutional biosafety committee (“IBC”), a local institutional committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution. The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such review may result in some delay before initiation of a clinical trial. While the NIH Guidelines are not mandatory unless the research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines voluntarily follow them.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include among other things, the requirement that all research subjects provide their informed consent for their participation in any clinical study. Clinical trials are conducted under protocols detailing, among other things, the objectives of the study, the parameters to be used in monitoring subject safety and the effectiveness criteria to be evaluated. A separate submission to the existing IND must be made for each successive clinical trial conducted during product development and for any subsequent protocol amendments.

Furthermore, an independent IRB for each site proposing to conduct the clinical trial must review and approve the plan for any clinical trial and its informed consent form before the clinical trial begins at that site, and must monitor the study until completed. Regulatory authorities, the IRB or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the subjects are being exposed to an unacceptable health risk or that the trial is unlikely to meet its stated objectives. Some studies 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 trial if it determines that there is an unacceptable safety risk for subjects or other grounds, such as no demonstration of efficacy. There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries, including clinicaltrials.gov.

For purposes of BLA approval, human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

Phase 1—The investigational product is initially introduced into healthy human subjects or patients with the target disease or condition. These studies are designed to test the safety, dosage tolerance, absorption, metabolism and distribution of the investigational product in humans, the side effects associated with increasing doses, and, if possible, to gain early evidence on effectiveness.

Phase 2—The investigational product is administered to a limited patient population with a specified disease or condition to evaluate the preliminary efficacy, optimal dosages and dosing schedule and to identify possible adverse side effects and safety risks.

Phase 3—The investigational product is administered to an expanded patient population to further evaluate dosage, to provide substantial evidence of clinical efficacy and to further test for safety, generally at multiple geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the investigational product and to provide an adequate basis for product labeling.

In some cases, the FDA may require, or sponsors may voluntarily pursue, additional clinical trials after a product is approved to gain more information about the product within the approved indication. These so-called Phase 4 studies may also be made a condition to approval of the BLA.

In addition, during the development of a biologic product candidate, sponsors are given opportunities to meet with the FDA at certain points, including prior to submission of an IND, at the end of Phase 2, and before a BLA is submitted. Meetings at other times may be requested. These meetings can provide an opportunity for the sponsor to share information about the data gathered to date, for the FDA to provide advice, and for the sponsor and the FDA to reach alignment on the next phase of development.

Concurrent with clinical trials, sponsors may complete additional animal studies and develop additional information about the biological characteristics of the product candidate, and must 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, 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.

BLA Submission and Review by the FDA

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, including results from preclinical studies and clinical trials are submitted to the FDA as part of a BLA requesting approval to market the product candidate for one or more indications. The BLA must include all relevant data available from preclinical and clinical studies, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry, manufacturing, controls, and proposed labeling, among other things. Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of a use of the product candidate, or from a number of alternative sources, including studies initiated by independent investigators. The submission of a BLA requires payment of a substantial application user fee to the FDA, unless a waiver or exemption applies.

In addition, the Pediatric Research Equity Act (“PREA”), requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration. Under PREA, BLAs and certain supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver. The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is deemed safe and effective. The sponsor or FDA may request a deferral of pediatric clinical trials for some or all of the pediatric subpopulations. A deferral may be granted for several reasons, including a finding that the drug is ready for approval for use in adults before pediatric clinical trials are complete or that additional safety or effectiveness data needs to be collected before the pediatric clinical trials begin. The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, keep a deferral current or fails to submit a request for approval of a pediatric formulation.

Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially complete before the FDA accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted with the additional information. Once a BLA has been accepted for filing, the FDA’s goal is to review standard applications within ten months after the filing date, or, if the application qualifies for priority review, six months after the FDA accepts the application for filing. In both standard and priority reviews, the review process may also be extended by a period of three months for FDA to respond to information deemed a “major amendment” to the application.

The FDA reviews a BLA to determine, among other things, whether the product candidate is safe, pure and potent for the proposed indication, and the facility in which it is manufactured, processed, packed or held meets standards designed to assure the product’s continued safety, purity and potency. During its review of the application, the FDA may also convene an advisory committee to provide clinical insight on application review questions. The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.

Before approving a BLA, the FDA will typically 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 and adequate to assure consistent production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.

After the FDA evaluates a BLA and conducts any required inspections of manufacturing facilities where the investigational product and/or its drug substance will be produced, the FDA may issue an approval letter or a Complete Response Letter (“CRL”). An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications. A CRL will generally describe all of the deficiencies that the FDA has identified in the BLA, except that where the FDA determines that the data supporting the application are inadequate to support approval, the FDA may issue the CRL without first conducting required inspections, testing submitted product lots, and/or reviewing proposed labeling. In issuing the CRL, the FDA may recommend actions that the applicant might take to place the BLA in condition for approval, including requests for additional information or clarification. The FDA may delay or refuse approval of a BLA if applicable regulatory criteria are not satisfied, require additional testing or information and/or require post-marketing testing and surveillance to monitor safety or efficacy of a product.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may include limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the BLA with a Risk Evaluation and Mitigation Strategy (“REMS”), to ensure the benefits of the product outweigh its risks. A REMS is a safety strategy implemented to manage a known or potential serious risk associated with a product and to enable patients to have continued access to such medicines by managing their safe use, and could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools. The FDA also may condition approval on, among other things, changes to proposed labeling or the development of adequate controls and specifications. Once a BLA is approved, the FDA may withdraw such approval if compliance with pre-and post-marketing requirements is not maintained or if problems occur after the product reaches the marketplace. The FDA may require one or more post-market studies and surveillance programs to further assess and monitor the product’s safety, purity and potency after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.

Expedited Development and Review Programs

The FDA offers a number of expedited development and review programs for qualifying product candidates. For example, the fast track program is intended to expedite or facilitate the process for developing and reviewing product candidates that are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition. Fast track designation applies to the combination of the product candidate and the specific indication for which it is being studied. The sponsor of a fast track-designated product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once a BLA is submitted, the application may be eligible for priority review. A fast track-designated product candidate may also be eligible for rolling review, where the FDA may consider for review sections of the BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the BLA, the FDA agrees to accept sections of the BLA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the BLA.

A product candidate intended to treat a serious or life-threatening disease or condition may also be eligible for breakthrough therapy designation to expedite its development and review. A product candidate can receive breakthrough therapy designation if preliminary clinical evidence indicates that the product candidate, alone or in combination with one or more other drugs or biologics, may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. The designation includes all of the fast track program features, as well as more intensive FDA interaction and guidance beginning as early as Phase 1 and an organizational commitment to expedite the development and review of the product candidate, including involvement of senior managers.

Certain investigational biologics may also be eligible for regenerative medicine advanced therapy (“RMAT”), designation. This designation may be available where the product candidate qualifies as an RMAT, meaning that, with limited exceptions, the investigational drug: (1) is a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product using such therapies or products; (2) is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition; and (3) preliminary clinical evidence indicates that the product candidate has the potential to address unmet medical needs for such a disease or condition. The RMAT designation provides all the benefits of a breakthrough therapy designation, including more frequent meetings with the FDA to discuss the development plan for the product candidate and eligibility for rolling review and priority review of a BLA submission. Product candidates granted RMAT designation may also be eligible for accelerated approval on the basis of a surrogate or intermediate endpoint reasonably likely to predict long-term clinical benefit, as discussed below, or through reliance upon data obtained from a meaningful number of clinical trial sites, including through expansion of trials to additional sites.

Any marketing application for a biologic product candidate submitted to the FDA for approval, including a product candidate with a fast track designation, RMAT designation and/or breakthrough therapy designation, may be eligible for other types of FDA programs intended to expedite the FDA review and approval process, such as priority review. A BLA is eligible for priority review if the product candidate is designed to treat a serious or life-threatening disease or condition, and if approved, would provide a significant improvement in safety or effectiveness compared to available alternatives for such disease or condition. For original BLAs, priority review designation means the FDA’s goal is to take action on the marketing application within six months of the 60-day filing date (as compared to ten months under standard review).

Additionally, depending on the design of the applicable clinical studies, product candidates studied for their safety and effectiveness in treating serious or life-threatening diseases or conditions may receive accelerated approval upon a determination that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonably likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments. As a condition of accelerated approval, the FDA will generally require the sponsor to perform adequate and well-controlled confirmatory clinical studies to verify and describe the anticipated effect on irreversible morbidity or mortality or other clinical benefit. The FDA may require, that such confirmatory studies be underway prior to approval or within a specific time period after the date of approval for a product granted accelerated approval. Under the FDORA, the FDA has increased authority for expedited procedures to withdraw approval of the product receiving accelerated approval if the sponsor fails to conduct the required post-marketing studies in a timely manner or if such studies fail to verify the predicted clinical benefit. In addition, the FDA requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast track designation, breakthrough therapy designation, RMAT Designation, priority review, and accelerated approval do not change the standards for approval but may expedite the development or approval process. Even if a product candidate qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Post-Approval Requirements

Biologics are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements relating to record-keeping, reporting of adverse experiences, periodic reporting, product sampling and distribution, and advertising and promotion of the product. After approval, most changes to the approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual program fees for any marketed products. Biologic manufacturers and their subcontractors are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP, which impose certain procedural and documentation requirements upon them. Changes to the manufacturing process are strictly regulated, and, depending on the significance of the change, may require prior FDA approval before being implemented. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting requirements. Accordingly, manufacturers must continue to expend time, money and effort in the area of production and quality control to maintain compliance with cGMP and other aspects of regulatory compliance.

The FDA may withdraw approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches the market. 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 revisions to the approved label to add new safety information; imposition of post-market studies or clinical studies to assess new safety risks; or imposition of distribution restrictions or other restrictions under a REMS. Other potential consequences include, among other things:

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

fines, warning letters, or untitled letters;

clinical holds on clinical studies;

refusal of the FDA to approve pending applications or supplements to approved applications, 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 closely regulates the marketing, labeling, advertising and promotion of biologics. A company can make only those claims that are 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 legally available products for uses that are not described in the product’s labeling and that differ from those tested and approved by the FDA. Such off-label uses are common across medical specialties. 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 a manufacturer’s communications on the subject of off-label use of their products.

Biosimilars and Reference Product Exclusivity

The Affordable Care Act, signed into law in 2010, includes a subtitle called the Biologics Price Competition and Innovation Act (“BPCIA”), which created an abbreviated approval pathway for biological products that are biosimilar to or interchangeable with an FDA-licensed reference biological product.

Biosimilarity, which requires that the biological product be highly similar to the reference product notwithstanding minor differences in clinically inactive components and that there be no clinically meaningful differences between the biological product and the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical study or studies. Interchangeability requires that a product is biosimilar to the reference product and the product can be expected to produce the same clinical results as the reference product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.

Under the BPCIA, an application for a biosimilar product may not be submitted to the FDA until four years following the date that the reference product was first licensed by the FDA. In addition, the approval of a biosimilar product may not be made effective by the FDA until 12 years from the date on which the reference product was first licensed. During this 12-year period of exclusivity, another company may still market a competing version of the reference product if the FDA approves a full BLA for the competing product containing that applicant’s own preclinical data and data from adequate and well-controlled clinical trials to demonstrate the safety, purity and potency of its product. The BPCIA also created certain

exclusivity periods for biosimilars approved as interchangeable products. Whether products deemed “interchangeable” by the FDA are readily substituted by pharmacies is governed by state pharmacy law.

A biological product can also obtain pediatric market exclusivity in the U.S. Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other existing exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” for such a study.

Foreign Government Regulation

In addition to U.S. regulations, we are subject to a variety of foreign government regulations applicable to medical devices, medicinal products and combination products.

Regulation of Medical Devices in the European Union

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

Until May 25, 2021, medical devices were regulated by the Council Directive 93/42/EEC (“Medical Devices Directive”), which has been repealed and replaced by Regulation (EU) No 2017/745 (“Medical Devices Regulation”). In accordance with the Medical Devices Regulation’s recently extended transitional provisions, both (i) devices lawfully placed on the market pursuant to the Medical Devices Directive prior to May 26, 2021, and (ii) legacy devices lawfully placed on the EU market after May 26, 2021 in accordance with the Medical Devices Regulation transitional provisions may generally continue to be made available on the market or put into service, provided that the requirements of the transitional provisions are fulfilled. However, even in this case, manufacturers must comply with a number of new or reinforced requirements set forth in the Medical Devices Regulation with regard to registration of economic operators and of devices, post-market surveillance and vigilance requirements. Pursuing marketing of medical devices in the EU will notably require that our devices be certified under the new regime set forth in the Medical Devices Regulation.

In the EU, there is currently no premarket government review of medical devices. However, the EU requires that, all medical devices placed on the market in the EU must meet the safety and performance requirements laid down in Annex I to the Medical Devices Regulation, including the requirement that a medical device must be designed and manufactured in such a way that during normal conditions of use, it is suitable for its intended purpose. Medical devices must be safe and effective and must not compromise the clinical condition or safety of patients, or the safety and health of users and – where applicable – other persons, provided that any risks which may be associated with their use constitute acceptable risks when weighed against the benefits to the patient and are compatible with a high level of protection of health and safety, taking into account the generally acknowledged state of the art. 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 general safety performance requirements as a practical matter as it creates a rebuttable presumption that the device satisfies that essential requirement general safety and performance.

Compliance with the general safety and performance requirements of the Medical Devices Regulation is a prerequisite for European conformity marking (“CE mark”), without which medical devices cannot be marketed or sold in the EU. To demonstrate compliance with the general safety and performance requirements laid down in Annex I to the Medical Devices Directive, 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 general safety and performance 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 issue an EU declaration of conformity based on a self-assessment of the conformity of its products with the general safety and performance 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 manufacturer’s 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 general safety and performance 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 EC 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).

The 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 Medical Devices 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 (“UDI-DI”), specific to the manufacturer and the device, and a production identifier (“UDI-PI”), to identify the unit of device production. Manufacturers are also notably responsible for entering the necessary data on EUDAMED, which includes the UDI database, and for keeping it up to date. Certain obligations for registration in EUDAMED are expected to become applicable in Q1 2026 (as EUDAMED is not yet fully functional). Until EUDAMED is fully functional, the corresponding provisions of the 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 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 Medical Devices Directive continue to apply. Manufacturers are required to take FSCAs, which are defined as any corrective action for technical or medical reasons to prevent or reduce a risk of a serious incident associated with the use of a medical device that is made available on the market. A serious incident is any malfunction or deterioration in the characteristics or performance of a device on the market (e.g., inadequacy in the information supplied by the manufacturer, undesirable side-effect), which, might lead to either the death or serious deterioration of the health of a patient, user, or other persons, or to a serious public health threat. 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.

Among the new requirements, manufacturers (and authorized representatives) must have available within their organization at least one person responsible for regulatory compliance (“PRRC”), who possesses the requisite expertise in the field of medical devices. The PRRC is notably responsible for compliance with post-market surveillance and vigilance requirements.

The advertising and promotion of medical devices is subject to some general principles set forth in EU legislation. According to the 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.

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

Brexit and the Regulation of Medical Devices in the United Kingdom

From January 1, 2021 onwards, the Medicines and Healthcare products Regulatory Agency (“MHRA”), has been the sovereign regulatory authority responsible for the Great Britain (“GB”) (i.e. England, Wales and Scotland) medical device market according to the requirements provided in the Medical Devices Regulations 2002 (SI 2002 No 618, as amended), or UK Medical Devices Regulations, that sought to give effect to the three pre-existing EU directives governing active implantable medical devices, general medical devices and in vitro diagnostic medical devices whereas, broadly, Northern Ireland continues to be governed by EU rules according to the Northern Ireland Protocol. Following the end of the Brexit transition period on January 1, 2021, new regulations require medical devices to be registered with the MHRA before being placed on the GB market. The MHRA will only register devices where the manufacturer or their United Kingdom (“UK”), Responsible Person has a registered place of business in the UK. Manufacturers based outside the UK need to appoint a UK Responsible Person that has a registered place of business in the UK to register devices with the MHRA. Furthermore, on December 16, 2024, the UK government published an amendment to the UK Medical Devices Regulations to clarify and strengthen the post-market surveillance requirements for medical devices in GB. This amendment will come into force on June 16, 2025 and aims to facilitate greater traceability of incidents and trends enabling the MHRA to act swiftly when needed to address safety issues and support the entire health system in better protecting patients. In addition, the MHRA launched a consultation between November 14, 2024 and January 5, 2025 on proposals to update the pre-market requirements for medical devices in GB, covering four topics, namely: (1) a new international reliance scheme to enable swifter market access for certain devices that have already been approved in a comparable regulator country; (2) the UKCA mark and, in particular, proposals to remove the requirement to place such UKCA mark on devices; (3) conformity assessment procedures for in vitro diagnostic devices; and (4) maintaining in UK law certain pieces of “assimilated” EU law which are due to sunset in 2025. This consultation builds on the MHRA’s previous consultation between September and November 2021, and the UK government’s response to that consultation which was published on June 26, 2022. The MHRA has stated that it will incorporate feedback to its recent consultation into new legislation on pre-market requirements for medical devices in GB. The new legislation is expected to be implemented in 2026 and aims to enable greater international collaboration and practices, with more patient-centered, proportionate requirements for medical devices which are responsive to technological advances.

Under the UK Medical Devices Regulations, certain medical devices need to be “UKCA” certified by a UK approved body in order to be lawfully placed on the GB market. However, certain medical devices in compliance with: (1) the (EU) Medical Devices Directive can continue to be placed on the GB market until the sooner of certificate expiration or June 30, 2028 or (2) the (EU) Medical Devices Regulation can continue to be placed on the GB market until the sooner of certificate expiration or June 30, 2030.

In addition, the Trade and Cooperation Agreement (“TCA”), between the UK and the EU generally provides for cooperation and exchange of information between the parties in the areas of product safety and compliance, including market surveillance, enforcement activities and measures, standardization-related activities, exchanges of officials, and coordinated product recalls. As such, processes for compliance and reporting should reflect requirements from regulatory authorities.

Coverage and Reimbursement

In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific product lines and procedures. In the EU and UK, member states impose controls on whether products are reimbursable by national or regional health service providers and on the prices at which devices are reimbursed under state-run healthcare schemes. More and more, local, product specific reimbursement law is applied as an overlay to Medical Devices Regulation, which has provided an additional layer of clearance requirement.

Regulation of Medicinal Products in the European Union

In addition to regulations in the U.S., we are subject to a variety of regulations in other jurisdictions governing, among other things, clinical studies, commercial sales, and distribution of our future products. Because biologically sourced raw materials are subject to unique contamination risks, their use may be restricted in some countries. In addition, ethical, social and legal concerns about gene-editing technology, gene therapy, genetic testing and genetic research could result in additional regulations restricting or prohibiting the processes we may use.

Most countries outside of the U.S., including the EU, require that CTAs, be submitted to and approved by the local regulatory authority for each clinical study. In addition, whether or not we obtain FDA approval for a product candidate, we must obtain the requisite approval from comparable regulatory authorities outside the U.S. before we can commence clinical studies or marketing of the product candidate in those countries. The requirements and process governing the conduct of clinical trials, approval, 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 Trials

Similarly to the U.S., 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 (pharmaco-toxicological) studies must be conducted in compliance with the principles of GLP as set forth in EU Directive 2004/10/EC (unless otherwise justified for certain particular medicinal products – e.g., radio-pharmaceutical precursors for radio-labeling purposes). GLP principles define a set of rules and criteria for a quality system concerned with the organizational process and the conditions under which these non-clinical studies are planned, performed, monitored, recorded, archived and reported. These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Council on Harmonization, of Technical Requirements for Pharmaceuticals for Human Use (“ICH”), guidelines on good clinical practices (“GCP”), as well as the applicable regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. Additional GCP guidelines from the European Commission, focusing in particular on traceability, apply to clinical trials of advanced therapy medicinal products (“ATMPs”). If the sponsor of the clinical trial 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 trial 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 trial.

The regulatory landscape related to clinical trials 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, 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 trials throughout the EU via a Clinical Trials Information System, which contains a centralized EU portal and database.

While the EU Clinical Trials Directive required a separate CTA to be submitted in each member state in which the clinical trial takes place, 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 for multi-center trials. 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 transition period ended on January 31, 2025, and all clinical trials and related applications are now fully subject to the provisions of the CTR.

Medicines used in clinical trials 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 in 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 (including an investigational biological product) under EU regulatory systems, we must submit a marketing authorization 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 MAs” are issued by the European Commission through the centralized procedure, based on the opinion of the Committee for Medicinal Products for Human Use (“CHMP”), of the European Medicines Agency (“EMA”), and is valid throughout the EU. It is compulsory for certain types of products, such as (i) medicinal products derived from biotechnological processes, (ii) designated orphan medicinal products, (iii) ATMPs, such as gene therapy, somatic cell-therapy or tissue-engineered medicines and (iv) medicinal products containing a new active substance indicated for the treatment of HIV/AIDS, cancer, neurodegenerative diseases, diabetes, auto-immune and other immune dysfunctions and viral diseases. The centralized procedure is optional for any other medicinal products containing new active substances not authorized in the EU or for product candidates which constitute a significant therapeutic, scientific, or technical innovation or for which the granting of authorization would be in the interests of public health in the EU.

“National MAs,” which are issued by the competent authorities of the EU member states and only cover their respective territory, 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.

The Committee for Advanced Therapies (“CAT”), is responsible in conjunction with the CHMP for the evaluation of ATMPs. The CAT is primarily responsible for the scientific evaluation of ATMPs and prepares a draft opinion on the quality, safety and efficacy of each ATMP for which a MAA is submitted. The CAT’s opinion is then taken into account by the CHMP when giving its final recommendation regarding the authorization of a product in view of the balance of benefits and risks identified. Although the CAT’s draft opinion is submitted to the CHMP for final approval, the CHMP may depart from the draft opinion, if it provides detailed scientific justification. The CHMP and CAT are also responsible for providing guidelines on ATMPs and have published numerous guidelines, including specific guidelines on gene therapies and cell therapies. These guidelines provide additional guidance on the factors that the EMA will consider in relation to the development and evaluation of ATMPs and include, among other things, the preclinical studies required to characterize ATMPs; the manufacturing and control information that should be submitted in a marketing authorization application; and post-approval measures required to monitor patients and evaluate the long term efficacy and potential adverse reactions of ATMPs.

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/or 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 trial 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 product candidates 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 preclinical and clinical trial 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.

In the EU, there is a special regime for biosimilars, or biological medicinal products that are similar to a reference medicinal product but that do not meet the definition of a generic medicinal product, for example, because of differences in raw materials or manufacturing processes. For such products, the results of appropriate preclinical or clinical trials must be provided, and guidelines from the EMA detail the type of quantity of supplementary data to be provided for different types of biological product. There are no such guidelines for complex biological products, such as gene or cell therapy medicinal products, and so it is unlikely that biosimilars of those products will currently be approved in the EU. However, guidance from the EMA states that they will be considered in the future in light of the scientific knowledge and regulatory experience gained at the time.

Post-Approval Requirements

Similar to the U.S., 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 the establishment and maintenance of that system, and oversees the safety profiles of medicinal products and any emerging safety concerns. Key obligations include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports (“PSURs”).

All new MAA 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 trials 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 trials, 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 trials, 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 trials, operating restrictions, injunctions, suspension of licenses, fines and criminal penalties.

Brexit and the Regulation of Medicinal Products in the United Kingdom

The TCA, agreed between the UK and the EU has been provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 2021. The TCA includes specific provisions concerning pharmaceuticals, which include the mutual recognition of GMP inspections of manufacturing facilities for medicinal products and GMP documents issued, but does not foresee wholesale mutual recognition of UK and EU pharmaceutical regulations. While the TCA has avoided a “no deal” Brexit scenario, and provides for quota and tariff free trading of goods in principle, it is nevertheless expected that the TCA will result in the creation of non-tariff barriers (such as increased shipping and regulatory costs and complexities) to the trade in goods between the UK and EU. Further, the TCA does not provide for the continued free movement of services between the UK and EU and also grants each of the UK and EU the ability, in certain circumstances, to unilaterally impose tariffs on one another.

EU laws which have been transposed into UK law through secondary legislation continue to be applicable as “retained EU law.” However, new legislation such as the EU Clinical Trial Regulation (Regulation (EU) No 536/2014) will not be applicable in GB. The Medicines and Medical Devices Act 2021 has introduced delegated powers in favor of the Secretary of State or an ‘appropriate authority’ to amend or supplement existing regulations in the area of medicinal products and medical devices. This allows new rules to be introduced in the future by way of secondary legislation, which aims to allow flexibility in addressing regulatory gaps and future changes in the fields of human medicines, clinical trials and medical devices.

As of January 1, 2021, the MHRA is the UK’s standalone medicines and medical devices regulator. As a result of the Northern Ireland Protocol, different rules applied in Northern Ireland than in GB (i.e., England, Wales, and Scotland); broadly, Northern Ireland continued to follow the EU regulatory regime. However, on January 1, 2025, a new arrangement called the “Windsor Framework” came into effect and reintegrated Northern Ireland under the regulatory authority of the MHRA with respect to medicinal products. The Windsor Framework removes EU licensing processes, and EU labeling and serialization requirements in relation to Northern Ireland, and introduces a UK-wide licensing process for medicinal products.

MAs in the UK are governed by the Human Medicines Regulations (SI 2012/1916), as amended. All existing EU MAs for centrally authorized products were automatically converted or grandfathered into UK MAs, effective in GB (only), free of charge on January 1, 2021, unless the MA holder chose to opt-out. Under the terms of the Windsor Framework, these MAs became valid for the whole of the UK from January 1, 2025. In order to use the EU centralized procedure to obtain an MA that will be valid throughout the EEA, companies must be established in the EEA. Therefore, since Brexit, companies established in the UK can no longer use the EU centralized procedure and instead an EEA entity must hold any centralized MAs. In order to obtain a UK MA to commercialize products in the UK, an applicant must be established in the UK and must follow one of the UK national authorization procedures or one of the remaining post-Brexit international cooperation procedures. Applications are governed by the Human Medicines Regulations (SI 2012/1916), as amended, and are made electronically through the MHRA Submissions Portal. The MHRA has introduced changes to national licensing procedures, including procedures to prioritize access to new medicinal products that will benefit patients, including a 150-day assessment (subject to clock-stops) and a rolling review procedure. In addition, an international recognition procedure (“IRP”), has been in place since January 1, 2024, whereby the MHRA will have regard to decisions on the approval of MAs

made by the EMA and certain other regulators when determining an application for a new UK MA. Pursuant to the IRP, the MHRA will take into account the expertise and decision-making of trusted regulatory partners (i.e., the regulators in Australia, Canada, Switzerland, Singapore, Japan, the U.S. and the EU). The MHRA will conduct a targeted assessment of IRP applications but retain the authority to reject applications if the evidence provided is considered insufficiently robust. The IRP allows medicinal products approved by such trusted regulatory partners that meet certain criteria to undergo a fast-tracked MHRA review to obtain and/or update an MA in the UK. Applications should be decided within a maximum of 60 days if there are no major objections identified that cannot be resolved within such 60-day period and the approval from the trusted regulatory partner selected has been granted within the previous 2 years, or if there are such major objections identified or such approval has not been granted within the previous 2 years within 110 days. Applicants can submit initial MAAs to the IRP but the procedure can also be used throughout the lifecycle of a product for post-authorization procedures including line extensions, variations and renewals. In the UK, the initial duration of an MA is five years and following renewal will be valid for an unlimited period unless the MHRA decides on justified grounds relating to pharmacovigilance, to proceed with only one additional 5-year renewal. Any authorization which is not followed by the actual placing of the medicinal product on the market in the UK within 3 years shall cease to be in force.

There is no pre-MA orphan designation in the UK. Instead, the MHRA reviews applications for orphan designation in parallel to the corresponding MA application. The criteria are essentially the same, but have been tailored for the market, i.e., the prevalence of the condition in the UK, rather than the EU, must not be more than five in 10,000. Should an orphan designation be granted, the period or market exclusivity will be set from the date of first approval of the product in the UK.

Coverage and Reimbursement in Foreign Countries

In some foreign countries, the proposed pricing for a product candidate must be approved before it may be lawfully marketed. The requirements governing product pricing vary widely from country to country. For example, in the EU pricing and reimbursement of pharmaceutical products are regulated at a national level under the individual EU member states’ social security systems. Some foreign countries provide options to restrict the range of medicinal products for which their national health insurance systems provide reimbursement and can control the prices and reimbursement levels of medicinal products for human use. Some jurisdictions operate positive and negative list systems under which products may only be marketed once a reimbursement price has been agreed. To obtain reimbursement or pricing approval, some of these countries may require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently available therapies. A country 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. There can be no assurance that any country that has price controls or reimbursement limitations for products will allow favorable reimbursement and pricing arrangements for any of our product candidates. Even if approved for reimbursement, historically, product candidates launched in some foreign countries, such as some member states in the EU, do not follow price structures of the U.S. and prices generally tend to be significantly lower.

Other Healthcare Laws

Healthcare Fraud and Abuse Laws

In the U.S., we are subject to a number of federal and state healthcare regulatory laws that restrict business practices in the healthcare industry. These laws include, but are not limited to, federal and state anti-kickback, false claims, transparency and other healthcare fraud and abuse laws.

The U.S. federal Anti-Kickback Statute prohibits, among other things, any person or entity from knowingly and willfully offering, paying, soliciting, receiving or providing any remuneration, directly or indirectly, overtly or covertly, to induce or in return for purchasing, leasing, ordering, or arranging for or recommending the purchase, lease, or order of any good, facility, item or service reimbursable, in whole or in part, under Medicare, Medicaid or other federal healthcare programs. The term “remuneration” has been broadly interpreted to include anything of value, including cash, improper discounts, and free or reduced price items and services. Among other things, the Anti-Kickback Statute has been interpreted to apply to arrangements between medical device manufacturers on the one hand and prescribers and purchasers on the other. Although there are a number of statutory exceptions and regulatory safe harbors protecting some common activities from prosecution, the exceptions and safe harbors are drawn narrowly. The government can exercise enforcement discretion in taking action against unprotected activities. Further, 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. Violations are subject to civil and criminal fines and penalties for each violation, plus up to three times the remuneration involved, imprisonment, and exclusion from government healthcare programs. In addition, the government may assert that a claim including items or services resulting from a violation of the

federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal False Claims Act or federal civil monetary penalties. The majority of states also have anti-kickback laws, which establish similar prohibitions, and in some cases may apply to items or services reimbursed by any third-party payor, including commercial insurers and self-pay patients.

The federal false claims laws, including the civil False Claims Act, prohibit, among other things, any person or entity from knowingly presenting, or causing to be presented, a false, fictitious or fraudulent claim for payment to, or approval by, the federal government, knowingly making, using, or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or knowingly making a false statement to avoid, decrease or conceal an obligation to pay money to the U.S. federal government. A claim includes “any request or demand” for money or property presented to the U.S. government. Manufacturers can be held liable under the federal False Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims. Actions under the civil False Claims Act may be brought by the Attorney General or as a qui tam action by a private individual in the name of the government. Moreover, a claim including items or services resulting from a violation of the U.S. federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act. In addition, various states have enacted false claim laws analogous to the federal False Claims Act, although many of these state laws apply where a claim is submitted to any third-party payor and not merely a federal healthcare program.

The federal Health Insurance Portability and Accountability Act of 1996 (“HIPAA”), created additional federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program, including private third-party payors, knowingly and willfully embezzling or stealing from a healthcare benefit program, willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false, fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the U.S. federal 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.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (“HITECH”), and their respective implementing regulations, including the Final Omnibus Rule published in January 2013, which impose requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses as well as their respective business associates, independent contractors or agents of covered entities, that perform services for them that involve the creation, maintenance, receipt, use, or disclosure of, individually identifiable health information relating to the privacy, security and transmission of individually identifiable health information and their covered subcontractors. HITECH also created new tiers of civil monetary penalties, amended HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, there may be additional federal, state and non-U.S. laws which govern the privacy and security of health and other personal information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect, thus complicating compliance efforts.

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, with specific exceptions, to report annually to CMS, information related to payments or other transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and chiropractors), certain non-physician providers (such as physician assistants and nurse practitioners), and teaching hospitals and physician ownership and investment interests, including such ownership and investment interests held by a physician’s immediate family members.

Federal price reporting laws, which require manufacturers to calculate and report complex pricing metrics to government programs, where such reported prices may be used in the calculation of reimbursement and/or discounts on approved products.

Federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm consumers.

Additionally, we are subject to state and foreign equivalents of each of the healthcare laws and regulations described above, among others, some of which may be broader in scope and may apply regardless of the payor. Some state and local laws require certain regulatory licenses to manufacture or distribute our products commercially and/or the registration of medical device and/or pharmaceutical sales representatives in the jurisdiction. Many U.S. states have adopted laws similar to the

federal Anti-Kickback Statute and False Claims Act, and may apply to our business practices, including, but not limited to, research, distribution, sales or marketing arrangements and claims involving healthcare items or services reimbursed by non-governmental payors, including private insurers. In addition, some states have passed laws that require manufacturers to implement compliance programs or to comply with the pharmaceutical and medical device industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated by the federal government. Several states also impose other marketing restrictions or require manufacturers to make marketing or price disclosures to the state. State and foreign laws, including, for example, the European Union General Data Protection Regulation, which became effective May 2018, also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts. There are ambiguities as to what is required to comply with these state requirements and if we fail to comply with an applicable state law requirement we could be subject to penalties. Finally, there are state and foreign laws governing the privacy and security of health information, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus complicating compliance efforts.

Violations of fraud and abuse laws, including federal and state anti-kickback and false claims laws, may be punishable by significant criminal and civil sanctions, including fines and civil monetary penalties, the possibility of exclusion from federal healthcare programs (including Medicare and Medicaid), curtailment or restructuring of operations, disgorgement and corporate integrity agreements, which impose, among other things, rigorous operational and monitoring requirements on companies. Similar sanctions and penalties, as well as imprisonment, also can be imposed upon executive officers and employees of such companies.

European Healthcare Laws

Many EU member states have adopted specific anti-gift statutes that further limit commercial practices for medical devices and medicinal products, 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 U.S., on manufacturers. Certain countries also mandate implementation of commercial compliance programs.

Coverage and Reimbursement in the United States

Significant uncertainly exists as to the coverage and reimbursement status of procedures using any product candidates for which we may obtain regulatory approvals. In the U.S., sales of our product candidates, if approved, will depend, in part, on the extent to which governmental authorities, private health insurers and other third-party payors provide coverage for and establish adequate reimbursement levels for the procedures in which our product candidates, if approved, are used. In the U.S., third-party payors include federal and state healthcare programs, private managed care plans, health insurers and other organizations. Adequate coverage and reimbursement from governmental healthcare programs, such as Medicare and Medicaid in the U.S., and commercial payors are critical to new product acceptance.

Our ability to commercialize any products successfully also will depend in part on the extent to which coverage and reimbursement for procedures using our products will be available from government health administration authorities, private insurers and other organizations. In the U.S., the principal decisions about reimbursement for new medicines are typically made by CMS, an agency within the U.S. Department of Health and Human Services. CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare and certain private payors may follow CMS policies. Coverage and reimbursement by governmental and other third-party payors may depend upon a number of factors, including the third-party payor’s determination that use of a product or service and its use for a particular patient is:

a covered benefit under its health plan;

safe, effective and medically necessary;

appropriate for the specific patient;

cost-effective; and

neither experimental nor investigational.

We cannot be sure that coverage and reimbursement will be available for any procedure that uses our product candidate that we commercialize and, if coverage and reimbursement are available, what the level of reimbursement will be. Coverage may also be more limited than the purposes for which a product candidate is approved by the FDA or comparable foreign regulatory authorities. Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of medical devices and medical services, in addition to questioning their safety and efficacy. Obtaining coverage and reimbursement approval of a product from a government or other third-party payor is a time consuming and costly process that could require us to provide to each payor supporting scientific, clinical and cost-effectiveness data for the use of our product on a payor-by-payor basis, with no assurance that coverage and adequate reimbursement will be obtained.

No uniform policy of coverage and reimbursement among payors in the U.S. exists and coverage and reimbursement for procedures can differ significantly from payor to payor. Moreover, the process for determining whether a third-party payor will provide coverage for a product or procedure may be separate from the process for establishing the reimbursement rate that such a payor will pay for the procedure using new medical devices and technology. A payor’s decision to provide coverage for a procedure does not imply that an adequate reimbursement rate will be approved to also cover the cost of our product candidates, if approved. Further, one payor’s determination to provide coverage for a product or procedure does not assure that other payors will also provide coverage for the product or procedure. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to ensure profitability.

Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are challenging the prices charged for medical products. In addition, many pharmaceutical manufacturers must calculate and report certain price reporting metrics to the government, such as average sales price and best price. Penalties may apply in some cases when such metrics are not submitted accurately and timely. Further, these prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs. Payment methodologies may be subject to changes in healthcare legislation and regulatory initiatives. At the state level, legislatures have increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

There has also been increasing legislative and enforcement interest in the U.S. with respect to drug pricing practices. Specifically, 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, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, and review the relationship between pricing and manufacturer patient programs. For example, HHS imposes rebates on many Medicare Part B and Medicare Part D products to penalize price increases that outpace inflation on an annual basis. In addition, HHS has been empowered to negotiate the price of certain single-source biologics that have been on the market for at least eleven (11) years covered under Medicare as part of the Medicare Drug Price Negotiation Program. Each year up to twenty (20) products will be selected by HHS for the Medicare Drug Price Negotiation Program. Products subject to the Medicare Drug Price Negotiation Program are expected to experience a significant reduction in reimbursement from the Medicare program on a per unit basis.

In international markets, reimbursement and healthcare payment systems vary significantly by country, and many countries have instituted price ceilings on specific product lines and procedures. In the EU, member states are facing increased pressure to limit public healthcare spending. There can be no assurance that procedures using our product candidates, once approved, will be covered for a specific indication or will be considered cost-effective by third-party payors, that an adequate level of reimbursement will be available or that the third-party payors’ reimbursement policies will not adversely affect our ability to sell our product candidate profitably, once approved. More and more, local, product specific reimbursement law is applied as an overlay to Medical Devices Regulation, which has provided an additional layer of clearance requirement. Historically, products launched in the EU do not follow the price structures of the Unites States and product prices in the EU have generally been significantly lower as compared to the U.S.

The marketability of any product candidates for which we receive regulatory approval for commercial sale may suffer if the government and third-party payors fail to provide adequate coverage and reimbursement. In addition, emphasis on managed care, the increasing influence of health maintenance organizations, and additional legislative changes in the U.S. has increased, and we expect will continue to increase, the pressure on healthcare pricing. The downward pressure on the rise in

healthcare costs in general, particularly medical devices and surgical procedures and other treatments, has become very intense. Coverage policies and third- party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained for one or more products for which we receive regulatory approval, less favorable coverage policies and reimbursement rates may be implemented in the future.

Healthcare Reform

The U.S. and some foreign jurisdictions are considering or have enacted a number of legislative and regulatory proposals to change the healthcare system in ways that could affect our ability to sell our product candidates profitably, if approved. Among policy makers and payors in the U.S. and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality or expanding access. Current and future legislative proposals and executive actions to further reform healthcare or reduce healthcare costs may limit coverage of or lower reimbursement for the procedures associated with the use of our products, when and if approved. The cost containment measures that payors and providers are instituting and the effect of any healthcare reform initiative implemented in the future could impact our revenue from the sale of our future products.

The implementation of the Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010 (collectively the “ACA”), in the U.S., for example, has changed healthcare financing and delivery by both governmental and private insurers substantially, and affected medical device manufacturers significantly.

Since its enactment, there have been judicial, executive and political challenges to certain aspects of the ACA. For example, on July 4, 2025, the One Big Beautiful Bill Act (the “OBBBA”) was signed into law, which narrowed access to ACA marketplace exchange enrollment and declined to extend the ACA enhanced advanced premium tax credits that expired at the end of 2025, which, among other provisions in the law, are anticipated to reduce the number of Americans with health insurance. The OBBBA also is expected to reduce Medicaid spending and enrollment by implementing work requirements for some beneficiaries, capping state-directed payments, reducing federal funding, and limiting provider taxes used to fund the program. Congress is considering proposed legislation intended to further reduce healthcare costs with alternatives to replace the expired ACA subsidies. It is unclear how any challenge to repeal or replace the ACA will impact our business.

In addition, other legislative changes have been proposed and adopted since the ACA was enacted:

The Budget Control Act of 2011, among other things, reduced Medicare payments to providers by 2% per fiscal year, effective on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through 2032, unless additional Congressional action is taken. Additionally, the American Taxpayer Relief Act of 2012, among other things, further 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 Medicare Access and CHIP Reauthorization Act of 2015 repealed the formula by which Medicare made annual payment adjustments to physicians and replaced the former formula with fixed annual updates and a new system of incentive payments that began in 2019 that are based on various performance measures and physicians’ participation in alternative payment models, such as accountable care organizations.

The American Rescue Plan Act of 2021 eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, beginning January 1, 2024.

The current administration is pursuing policies to reduce regulations and expenditures across government agencies including at HHS, the FDA, CMS and related agencies. These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business. For example, the current administration has announced agreements with pharmaceutical companies that require the drug manufacturers to offer, through a direct-to-consumer platform (TrumpRx), U.S. patients and Medicaid programs prescription drug Most-Favored Nation pricing equal to or lower than those paid in other developed nations, with additional mandates for direct-to-patient discounts and repatriation of foreign revenues. Other recent actions, for example, include (1) directing agencies to reduce agency workforce and cut programs; (2) directing HHS and other agencies to lower prescription drug costs through a variety of initiatives; (3) imposing tariffs on imported pharmaceutical products; and (4) as part of the Make America Healthy Again Commission’s Strategy Report released in September 2025, working across government agencies to increase enforcement on direct-to-consumer pharmaceutical advertising. Additionally, the current

administration recently called on Congress to enact “The Great Healthcare Plan,” to codify and expand Most-Favored Nation pricing, lower government subsidies to private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase, and enact restrictions on pharmacy benefit manager payment methodologies, among other things. These actions and policies may significantly reduce U.S. drug prices, potentially impacting manufacturers’ global pricing strategies and profitability, while increasing their operational costs and compliance risks. In June 2024, in Loper Bright Enterprises v. Raimondo, the U.S. Supreme Court greatly reduced judicial deference to regulatory agencies, which could increase successful legal challenges to federal regulations affecting our operations. Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program.

On December 13, 2021, Regulation No 2021/2282 on Health Technology Assessment (“HTA”), amending Directive 2011/24/EU, was adopted. The Regulation entered into force in January 2022 and has been applicable since January 2025, with phased implementation based on the type of product, i.e., oncology and advanced therapy medicinal products as of 2025, certain high-risk medical devices as of 2026, orphan medicinal products as of 2028, and all other medicinal products by 2030. The Regulation intends to boost cooperation among EU member states in assessing health technologies, including new medicinal products as well as certain high-risk medical devices, and provide the basis for cooperation at the EU level for joint clinical assessments in these areas. It 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 highest 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 technology, and making decisions on pricing and reimbursement.

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 and state governments will pay for healthcare products and services, which could result in reduced demand for our future products or additional pricing pressure.

Data Privacy & Security

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, including clinical trial data, and could apply now or in the future to our operations or the operations of our partners. In the U.S., 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. For example, the European Union’s General Data Protection Regulation (“EU GDPR”), the United Kingdom’s GDPR (“UK GDPR”) (collectively, “GDPR”) imposes strict requirements for processing the personal data of individuals within the European Economic Area and United Kingdom. Companies that must comply with the GDPR face increased compliance obligations and risk, including more robust regulatory enforcement of data protection requirements and potential fines for noncompliance of up to 20 million Euros under the EU GDPR, 17.5 million pounds sterling under the UK GDPR or, in each case, 4% of annual global revenue, whichever is greater; or private litigation related to processing of personal data brought by classes of data subjects or consumer protection organizations authorized at law to represent their interests. 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 may lead to significant civil and/or criminal penalties and restrictions on data processing.

Employees and Human Capital Resources

On January 31, 2025, we announced that pursuant to our Strategic Reprioritization, we streamlined resources, including a workforce reduction impacting 22 employees, or approximately 17% of our workforce. The Strategic Reprioritization was substantially implemented by the second quarter of 2025. As of March 1, 2026, we have 100 full-time employees, 73 of whom are dedicated to research and development, and 14 of whom hold doctorate degrees (i.e., Ph.D., Pharm.D. or M.D.). None of our employees are represented by labor unions or covered by collective bargaining agreements. We consider our relationship with our employees to be good.

We recognize that our continued ability to attract, retain and motivate exceptional employees is vital to ensuring our long-term competitive advantage. Our employees are critical to our long-term success and are essential to helping us meet our goals. Among other things, we support and incentivize our employees in the following ways:

Talent Development, Compensation and Retention. We strive to provide our employees with a rewarding work environment, including the opportunity for growth, success and professional development. We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development programs that enable continued learning and growth and a robust employment package—all designed to attract and retain a skilled and diverse workforce.

Health and Safety. We support the health and safety of our employees by providing health care, retirement planning, paid time off and other additional benefits, which are intended to assist employees to manage their well-being.

Corporate Information

Fractyl Health, Inc. was originally incorporated in Delaware on August 30, 2010 under the name MedCatalyst, Inc. The Company subsequently changed its name to Fractyl Laboratories Inc. on January 10, 2012 and then to Fractyl Health, Inc. on June 9, 2021.

Available Information

We file electronically with the U.S. Securities and Exchange Commission (the “SEC”) our Annual Reports on Form 10‑K, Quarterly Reports on Form 10‑Q, Current Reports on Form 8‑K, proxy statements and other information. Our filings with the SEC are available to the public over the Internet at the SEC’s website at www.sec.gov. We make available on our website at http://ir.fractyl.com, free of charge, copies of these reports as soon as reasonably practicable after filing or furnishing these reports with the SEC. The information on our website is deemed not to be incorporated in this Annual Report on Form 10-K or to be part of this Annual Report on Form 10-K.