NASDAQ: TYRA

We demonstrated initial clinical proof-of-concept results with oral dabogratinib in the SURF301 study, a Phase 1 proof-of-concept study in metastatic urothelial carcinoma (mUC). Oral dabogratinib demonstrated encouraging anti-tumor activity and was generally well-tolerated, with infrequent FGFR2- and FGFR1-associated toxicities. Response, safety, pharmacokinetics (PK) / pharmacodynamics (PD) and circulating tumor DNA (ctDNA) data from this study were leveraged to select doses that have the potential to achieve our target product profile for efficacy and safety in our Phase 2 trials and beyond.

We are currently advancing oral dabogratinib in three Phase 2 trials for three outsized market indications: SURF303, evaluating the treatment of low-grade upper tract urothelial carcinoma (LG-UTUC); SURF302, evaluating the treatment of intermediate risk non-muscle invasive bladder cancer (IR NMIBC); and BEACH301, evaluating the treatment of achondroplasia (ACH) in children. If we are successful with these Phase 2 studies, we expect to advance oral dabogratinib toward three potential registrational trials in LG-UTUC, IR NMIBC and ACH. We are calling this approach our “dabogratinib 3x3” strategy.

SURF303 for LG-UTUC: This open-label Phase 2a/b clinical trial was designed as a potential registrational trial to evaluate the efficacy and safety of oral dabogratinib at doses of 60 mg and 80 mg once daily (QD) in participants with FGFR3-altered low-grade upper tract urothelial carcinoma, where approximately 85% of tumors are driven by FGFR3. Study startup is ongoing and the first patient in this study is anticipated to be dosed in 2026.

SURF302 for IR NMIBC: This open-label Phase 2 clinical trial is evaluating the efficacy and safety of oral dabogratinib at 50 mg and 60 mg QD in participants with FGFR3-altered low-grade, IR NMIBC, where approximately 70% of tumors are driven by FGFR3. We anticipate reporting initial three-month CR data from approximately 10-20 patients per cohort from this study by the end of the first half of 2026.

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BEACH301 for ACH: This study is an open-label, Phase 2 dose-escalation/dose-expansion trial evaluating oral dabogratinib at lower doses (0.125, 0.25, 0.375, 0.50 mg/kg), as compared to the oncology studies, in children ages 3 to 10 with ACH with open growth plates, where approximately 99% of cases are driven by FGFR3. The study is enrolling a safety sentinel cohort of 3 or more participants per dose level in children ages 5 to 10, and a natural history run-in for cohorts 1 and 2 with children ages 3 to 10. Initial results from the safety sentinel cohort, including 6-month average height velocity (AHV) results and interim safety, are on-track and expected to be reported in the second half of 2026.

Our Other Programs

TYRA-430 was designed to be biased for FGFR4 and FGFR3 over the FGFR1 and FGFR2 isoforms specifically to address the FGF19 signaling pathway, while also potentially limiting side effects due to inhibition of FGFR1 and FGFR2, as well as to address acquired resistance mutations that have limited the efficacy of previous FGFR4-specific inhibitors. TYRA-430 is currently being evaluated in SURF431, a global, Phase 1, multicenter, open-label trial, with a focus on achieving clinical proof-of-concept in a cohort of patients with FGF19+ hepatocellular carcinoma (HCC).

TYRA-200 is an FGFR1/2/3 inhibitor designed to be active against nearly all of the clinically identified acquired resistant mutations that arise during treatment with pan-FGFR inhibitors, which we believe is necessary to address the problem of disease progression due to polyclonal resistance. TYRA-200 is currently being evaluated in SURF201, a global, Phase 1, multicenter, open-label trial, with a focus on achieving clinical proof-of-concept in a cohort of FGFR2-driven intrahepatic cholangiocarcinoma (ICC) resistant to previous FGFR inhibitors.

Our Pipeline

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Our Strategy

Our mission is to improve outcomes for patients living with cancer and genetically defined conditions. We are executing on our mission by focusing on advancing our pipeline and building a leading company around FGFR biology. With this strategy, our goal is the discovery, development and commercialization of next-generation precision small molecules against clinically validated targets to treat a wide range of indications currently lacking adequate treatment options.

The elements of our strategy to achieve this goal are to:

1.
Advance our lead product candidate, oral dabogratinib, toward pivotal studies and commercialization in the United States and certain other territories in urothelial cancers and skeletal dysplasia conditions;

2.
Advance our early-stage clinical pipeline and maintain our position as a leader in our focus area of FGFR biology; and

3.
Harness the power of our SNÅP platform to expand our pipeline of next-generation precision medicines for oncology and rare disease indications within FGFR biology and potentially other target areas of interest.

All of our assets have been developed in-house and we retain full development and commercialization rights for our pipeline. We intend to maximize the value of our pipeline by retaining development and commercialization rights to our product candidates, indications and geographies that we believe we can ultimately commercialize successfully on our own if they are approved. We will seek to collaborate on product candidates that we believe have promising utility in disease areas or patient populations that are better served by the resources or specific expertise of larger biopharmaceutical companies.

Our SNÅP Platform

Our proprietary SNÅP platform enables rapid and precise drug design through iterative molecular SNÅPshots that help us design and predict which product candidates will demonstrate the highest potency, selectivity and tolerability in the clinic. Through this approach, we have developed next-generation precision small molecule candidates with novel structures designed to inhibit the target while avoiding off-target toxicities and resistance mutations.

Our SNÅP platform is driven by our ability to generate iterative data rapidly and concurrently from the following three key pillars.

1.
Protein crystallography. We have developed proprietary protein crystallography techniques that enable us to determine the co-crystal structures of newly synthesized compounds in target proteins in as little as three days. This enables weekly generation of detailed structural insights on the precise interactions and conformational changes that occur when our potential product candidates bind to a particular target, creating opportunities to further refine the structural design.

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Cell-based assays. We assess inhibitor potency directly in in vitro target-specific anti-proliferation assays, in addition to enzymatic assays, to enable us to simultaneously understand target potency and cell penetration as well as target-specific cell killing. Our process allows us to generate data on newly synthesized compounds in as little as two days.

3.
In vivo models. Our direct structural insights and in vitro datasets are complemented by in vivo pharmacologic data generated through in-house animal models that provide us with bioavailability, PK data and anti-tumor activity in as little as five days.

Together, these three pillars of our platform provide a molecular SNÅPshot for our compound candidates. At this time, we are able to generate a molecular SNÅPshot for a compound candidate within one week. We believe that a sharp focus on efficiently generating these three key empirical datasets for compound candidates enables us to balance speed with the robust identification of pivotal insights to rapidly and precisely iterate the design of our novel molecular structures.

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Overcoming First Generation FGFR Inhibitor Liabilities

We have initially leveraged our SNÅP approach to develop novel small molecules designed to overcome the toxicity and resistance liabilities of prior generation pan-FGFR inhibitors. Four FGFR targeted therapies have been approved by the U.S. Food and Drug Administration (FDA) for oncology: erdafitinib for bladder cancer that has spread or cannot be removed by surgery, and pemigatinib, infigratinib and futibatinib for ICC with FGFR2-fusions or gene rearrangements (infigratinib was later withdrawn from the market effective March 31, 2023). These inhibitors have demonstrated clinical responses, however, response rates and duration of response are limited and come with toxicities driven by the inhibition of FGFR receptors 1, 2 and 4. FGFR1 is expressed in kidney cells where it regulates phosphate and calcium reabsorption, and consequently, inhibition of FGFR1 results in hyperphosphatemia. Inhibition of FGFR2 can result in toxicities that significantly impact quality of life, such as skin and nail toxicities (e.g., onycholysis and hand-foot syndrome), stomatitis, and ocular toxicities such as keratitis and blurred vision. Inhibition of FGFR4 disrupts bile acid metabolism and can result in diarrhea and elevated liver enzymes (AST and ALT). Hyperphosphatemia was a dose-limiting toxicity (DLT) of erdafitinib and was reported in over 70% of patients in the Phase 3 clinical trial conducted in mUC. Overall, Phase 3 AEs resulted in 72% dose interruptions, 69% dose reductions, and 14% treatment discontinuations. By way of example, we believe the safety and tolerability profile of erdafitinib is a key limitation to its efficacy, as demonstrated by the dosing instructions to start at a daily 8 mg dose, and only increase to 9 mg if hyperphosphatemia is not observed. A similarly high rate of FGFR-related toxicities has been reported in clinical trials of other non-isoform selective FGFR inhibitors including pemigatinib, infigratinib and futibatinib in pivotal studies for ICC. In addition to being limited by toxicity, patients can develop acquired drug resistance, ultimately resulting in disease progression and discontinuation of therapy.

Our FGFR3 Program for Urothelial Carcinoma

Dabogratinib for LG-UTUC and NMIBC

FGFR3 is a protein receptor expressed on the cell surface that stimulates cellular proliferation upon binding of fibroblast growth factor. Uncontrolled activation of FGFR3 has been implicated in oncogenesis across the spectrum of urothelial carcinoma, and most frequently in the earliest stages of the disease.

Dabogratinib was designed to be more selective for FGFR3 over FGFR1, FGFR2, and FGFR4, to minimize side effects resulting from inhibition of these related proteins and achieve greater potency against the FGFR3 driver mutation. Dabogratinib established clinical proof-of-concept in SURF301 in mUC, and is currently being studied in the global Phase 2a/b SURF303 trial in patients with LG-UTUC, as well as the global Phase 2 SURF302 trial in patients with IR NMIBC.

Disease background – urologic cancers

Urothelial carcinoma (UC) is one of the most common malignancies of the genitourinary system. Urothelial carcinoma is classified anatomically, with tumors originating in the ureters and renal pelvis known as upper tract urothelial carcinoma (UTUC) and tumors originating in the lower tract referred to as bladder cancer. Across urothelial carcinoma, tumors are often characterized by histologic grade (low or high) as well as by invasiveness.

UTUC is estimated to account for 5-10% of urothelial cancer cases and is defined as a rare disease. We estimate that approximately 50% of UTUC tumors are diagnosed at the non-invasive stage and that approximately 40% of non-invasive tumors present with low-grade histology.

Lower tract urothelial carcinoma, or bladder cancer, is classified into three broad categories: NMIBC where the cancer is restricted to surface lining of the bladder, muscle invasive bladder cancer (MIBC), which is a cancer that has grown deeper into the bladder wall, and mUC, in which cancer has spread beyond the bladder. NMIBC comprises the largest population of bladder cancer patients, representing 70-75% of cases diagnosed annually in the United States. NMIBC can be categorized as low, intermediate and high risk for recurrence or progression, with a significant proportion categorized as intermediate and high risk.

FGFR3 more commonly drives lower grade and more localized stages of urothelial carcinoma. The

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incidence of activating FGFR3 mutations is estimated to be between 80-90% in LG-UTUC, 60-80% in IR NMIBC and 10-20% in mUC, making FGFR3 an attractive target for development and particularly in early-stage disease.

In 2022, there were over 740,000 people living with bladder cancer and an estimated 50,000 people living with UTUC in the United States alone. We estimate that in 2025, approximately 185,000 US patients were seeking therapy for first-time treatment or to address a recurrence across LG-UTUC and bladder cancer. Applying FGFR3 alteration incidence to these estimates, we believe that approximately 80,000 FGFR3+ patients, including approximately 3,000 LG-UTUC patients and approximately 35,000 IR NMIBC patients, are addressable across bladder cancer in the United States alone annually.

Potential UTUC and bladder cancer patient populations for our FGFR3 inhibitor

Current LG-UTUC treatment landscape and unmet need

Significant unmet need remains in treating patients with LG-UTUC who are at risk of kidney loss and dialysis. The structure of the upper tract, including ureter length, diameter and orientation, and intra-renal anatomy, present challenges with diagnosis and treatment. Repetitive kidney-sparing surgeries are the favored standard of care, but will miss up to 25% of UTUC tumors due to challenging anatomy and frequent multifocality, and comes with the risks of repeat general anesthesia and intra- and post-operative complications. 35–50% of all low grade UTUC tumors will recur within 3 years, with an even higher rate for large tumors. After one or more recurrences, patients often proceed to radical nephroureterectomy, which can result in chronic dialysis and increased cardiovascular morbidity and mortality.

Jelmyto, a mitomycin hydrogel, is the only non-surgical option approved for renal pelvis tumors 5–15mm in size, based on a 71-patient pivotal Phase 2 trial. Uptake has been limited due to modest efficacy (58% CR and 56% 12-month duration of response (DoR), high rates of local AEs (including 58% ureteric obstruction, 34% urinary tract infection (UTI) and 25% renal dysfunction), challenging administration (ureteral catheter with fluoroscopy or nephrostomy tube) and burdensome preparation (more than 40 steps over 45–60 minutes). A few additional locally-administered product candidates are currently in Phase 2 or 3 development for LG-UTUC.

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Current NMIBC treatment landscape and unmet need

NMIBC is one of the most recurrent of all cancers and current standard of care treatment comes with drawbacks. For low grade lesions, Transurethral Resection of Bladder Tumor (TURBT) with or without adjuvant intravesical chemotherapy is the standard of care, whereas high risk lesions should be treated with either adjuvant BCG or radical cystectomy. Repeat TURBT comes with risks and burden to patients, including the need to undergo general anesthesia and potential for AEs such as bladder perforation. Within the first two years of initial standard of care treatment, intermediate risk NMIBC recurrence rates are as high as 40% at two years. Zusduri, an intravesical chemotherapy hydrogel, is the single novel therapy approved for IR NMIBC, with only other intravesical therapies remaining in development.

Phase 2 data for erdafitinib in NMIBC suggest the potential for FGFR inhibitors in this indication. In the final Phase 2 analysis, low dose oral erdafitinib demonstrated an 89% CR rate in IR NMIBC patients and notably, the 12-month DoR for those who remained on study drug was 100%. The safety and tolerability results were generally consistent with that known for erdafitinib, despite using a lower 6 mg daily dose in these studies. TAR-210, an erdafitinib-containing device implanted every three months via the urethra, also demonstrated a 90% CR rate in IR patients and 90% recurrence-free survival (RFS) in high-risk papillary patients as presented at AUA 2024. Johnson & Johnson has initiated a Phase 3 trial for TAR-210 in low grade IR NMIBC patients and has not indicated plans to develop oral erdafitinib further in this setting.

Our solution, oral dabogratinib, in LG-UTUC and NMIBC

We believe an orally administered, highly specific FGFR3-selective inhibitor, with minimal effects from other FGFR-related toxicities, has the potential to be highly efficacious and tolerable and represents a potentially large future market opportunity for patients with LG-UTUC and IR NMIBC.

Designing inhibitors that bind to the ATP-binding site and that can selectively differentiate between FGFR3 and FGFR1 is challenging due to the near-identical amino acid sequence in this site. We utilized the differentiated approach of our SNÅP platform to generate compounds, including oral dabogratinib, that capitalize on subtle conformational differences between FGFR3 and FGFR1 to obtain greater than ten-fold selectivity for FGFR3 versus FGFR1. In comparison, other FGFR inhibitors that are approved or in clinical development such as erdafitinib, pemigatinib, futibatinib and infigratinib, have demonstrated low or no selectivity for FGFR3 over FGFR1 and FGFR2.

Oral dabogratinib clinical data from SURF301 Phase 1 proof-of-concept study

SURF301 was designed as a proof-of-concept clinical study to determine the recommended Phase 2 dose of oral dabogratinib in cancer and skeletal dysplasia conditions. Treatment with oral dabogratinib was evaluated in patients with solid tumors across ten dose levels, ranging from 10 mg-120 mg QD, including 40 mg and 50 mg BID. This study is no longer recruiting new patients.

In October 2024, we reported interim data showing a 50% response rate (5/10) in FGFR3 positive patients who received 90 mg daily of oral dabogratinib, with a 100% disease control rate, and favorable safety results demonstrating infrequent FGFR2 and 1 associated toxicities.

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We believe this data suggests that 90 mg QD is the optimal dose for further evaluation in the mUC setting, however, no further development is planned at this time due to our prioritized focus on what we believe are more attractive market opportunities. We expect to publish final Phase 1 results from SURF301 in a future scientific publication.

At 90 mg QD, improved anti-tumor activity and tolerability were observed with oral dabogratinib as compared to erdafitinib

Notably, at dose levels equal to or lower than 60 mg QD, including target dose levels for NMIBC and skeletal conditions, oral dabogratinib exhibited favorable interim safety results as of the data cutoff date. No hyperphosphatemia, ALT or AST increases, discontinuations or dose reductions were reported at doses equal to or below 60 mg QD.

FGFR-related toxicities were infrequent at lower doses

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In the PK/PD analysis in 50 patients as of the data cutoff of August 15, 2024, oral dabogratinib plasma concentrations indicated adequate FGFR3 IC90 target coverage at ≥90 mg QD, the half maximal inhibitory concentration (IC50) target coverage at 60 mg QD, with 40 mg QD nearly covering IC50.

Exposure at doses ≥90 mg and ≥60 mg exceeded FGFR3 IC90 and IC50 target coverage, respectively

ctDNA analysis published in 18 FGFR3+ mUC patients with positive ctDNA at baseline show strong target engagement at 90 mg QD and activity at doses of 40 mg and 60 mg QD.

ctDNA changes in FGFR3+ mUC patients show activity at >40 mg

The totality of response, safety, PK/PD and ctDNA data from this study, as well as data from pan-FGFR inhibitors, were leveraged to select lower doses that we believe have the potential to achieve our target product profiles designed to optimize for efficacy and minimal FGFR 1 / 2 / 4 toxicity for in our Phase 2 studies and beyond. These data were presented in a poster at the ASCO Genitourinary Cancer Symposium meeting in February 2026.

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Future clinical development plans for oral dabogratinib in LG-UTUC and NMIBC

We believe that the full development potential for oral dabogratinib may cover the entire spectrum of disease in urothelial carcinoma and may represent a large opportunity given the high prevalence of FGFR3 mutations and the potential to treat earlier disease.

In November 2025, we announced that an Investigational New Drug application (IND) was cleared by the FDA to enable SURF303, a global, open-label, multicenter Phase 2a/b clinical study evaluating the efficacy and safety of oral dabogratinib in participants with LG-UTUC. In Part A, up to 25 participants are being randomized initially to treatment with oral dabogratinib at 60 mg QD or treatment with oral dabogratinib at 80 mg QD, respectively. Following a review of available efficacy and safety results within Part A, an additional dosing cohort may be evaluated. The primary endpoint is CR rate within six months in FGFR3+ patients. Secondary endpoints include CR within 6 months in all comers, duration of response, safety and tolerability, and conversion of unresectable to resectable disease. Part B was designed as a potential registrational trial and will recruit up to 100 patients at the recommended Phase 2 dose. The first patient in this study is anticipated to be dosed in 2026.

In August 2025, we announced that the first patient was dosed in SURF302, a global, open-label, multicenter Phase 2 clinical study evaluating the efficacy and safety of oral dabogratinib in participants with FGFR3-altered low-grade, IR NMIBC. Up to 30 participants are being randomized initially to treatment with oral dabogratinib at 50 mg QD or treatment with oral dabogratinib at 60 mg QD, respectively. Following a review of available efficacy and safety results, an additional dosing cohort may be evaluated, if necessary. The primary endpoint is CR rate at three months. Secondary endpoints include time to recurrence, the median duration of response, Recurrence Free Survival (RFS), Progression Free Survival (PFS), safety and tolerability.

Our FGFR3 Program for Skeletal Conditions

Dabogratinib for ACH and Skeletal Conditions

Alterations in FGFR3 are implicated in skeletal conditions due to its role in regulating bone and cartilage formation. We believe that there is a significant opportunity to develop oral dabogratinib to potentially address the long-term complications associated with these skeletal conditions including ACH, hypochondroplasia (HCH), Turner syndrome, Short Stature Homeobox (SHOX) deficiency, other FGFR3-driven genetic syndromes and idiopathic short stature.

Disease background

FGFR3 is expressed in growth plate chondrocytes (cartilage cells) where it functions in signaling pathways to limit growth. The G380R mutation in FGFR3, which causes an estimated 99% of ACH, as well as other activating mutations, increases FGFR3 activity, resulting in excessive limitation of growth in the long bones, vertebral bodies and skull base. In children with ACH, the most common form of dwarfism, these growth differences can result in life-long health complications such as sleep apnea, obesity, recurrent ear infections, and bowed legs. The most serious sequelae include spinal stenosis (narrowing of the spinal canal); up to 20% of infants require surgery to address narrowing at the base of the skull (foramen magnum stenosis), which can be life-threatening; in adults, spinal stenosis of the lower back results in chronic pain, necessitating surgery and long-term pain management.

ACH is an autosomal dominant condition that occurs in approximately 1 in 15,000 to 40,000 newborns worldwide, and it is estimated that there are approximately 3,000 affected individuals under the age of 18 in the United States and approximately 23,000 addressable, affected individuals under the age of 18 worldwide. Approximately 80% of ACH cases arise through a spontaneous mutation of FGFR3, whereas 20% of cases are familial.

FGFR3 is implicated in multiple additional skeletal conditions, including HCH, which is most commonly caused by the N540K mutation (approximately 70-80%) in the FGFR3 gene. SHOX is a transcription factor for FGFR3 and deletion of the SHOX gene in Turner syndrome and SHOX deficiency commonly presents with short stature.

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Current treatment landscape and unmet need

ACH had been managed primarily through surgical and physical therapy intervention until the accelerated approval of Voxzogo (vosoritide) in 2021. Voxzogo is a daily injected C-natriuretic peptide (CNP) analog, which acts downstream of FGFR3. In a pivotal study, children treated with 15 mg/kg of Voxzogo achieved 5.66 cm/year in AHV, a 1.40 cm improvement over 4.26 cm baseline. Children in the Phase 2 trial treated with 15 mg/kg achieved 5.91 cm/year AHV, 1.87 cm improvement over 4.04 cm baseline. Children treated with 30 mg/kg saw a lower change from baseline, suggesting the CNP pathway activity is potentially dose-limited in FGFR3-driven conditions. Yuviwel (TransCon CNP), a prodrug of CNP administered to children with ACH by injection on a weekly basis, showed similar efficacy in Phase 3 and was approved by the FDA in February 2026. BridgeBio is developing infigratinib, a daily oral, low-dose FGFR1/2/3 inhibitor, which achieved 5.96 cm/yr AHV and a 1.74 cm/yr improvement over 4.22 cm/yr baseline in a Phase 3 study. BridgeBio previously published that adult doses above 0.33 mg/kg are limited by hyperphosphatemia and to date they have not exceeded the 0.25 mg/kg dose in clinical studies for pediatric skeletal conditions. BioMarin disclosed that prolonged treatment with Voxzogo could result in a final adult height improvement of 26 cm or more in ACH, potentially 20 cm (approximately 8 inches) less than average height for adult males without ACH, pointing to remaining unmet need. To reach final average male stature, 2.7 cm/yr AHV improvement would be needed over 17 years, and, to our knowledge, no approved or pipeline product candidates have achieved this to-date.

Our solution, oral dabogratinib, in ACH

By engaging FGFR3 selectively at higher, safe doses, oral dabogratinib may have the potential to meaningfully improve height, health and functional outcomes beyond what can be achieved with current therapies in development for children with ACH, HCH, Turner syndrome, SHOX deficiency, other FGFR3-driven genetic syndromes and idiopathic short stature. Based on the population size and potential addressable unmet need, we believe ACH alone represents a large future market opportunity for oral dabogratinib.

In the Imagine Institute’s FGFR3Y367C/+ preclinical model, oral dabogratinib administered daily at a 1.2 mg/kg dose for 15 days, increased body length in mice by 17.9% compared to the vehicle (p<0.0001) and increased the length of the femur (+22.6%), tibia (+33.0%) and L4-L6 (+23.5%) in mice (p<0.0001). 1.2 mg/kg in mice roughly equates to a 0.5 mg/kg dose in children and a 40 mg dose in adults. Oral dabogratinib also demonstrated increases in long bone length in the Imagine Institute’s HCH mouse model.

Development plans for oral dabogratinib in ACH

In August 2025, we announced that the first child was dosed in BEACH301, a global, Phase 2, multi-center, open-label clinical trial of oral dabogratinib for children ages 3 to 10 with ACH with open growth plates. The primary objective of the study is to assess safety and tolerability in children with ACH and evaluate change from baseline in annualized growth velocity to determine the dose(s) for further development. Secondary objectives include evaluating change from baseline in height z-score, proportionality and PK.

The study is initially enrolling a safety sentinel cohort of 3 or more children, ages 5 to 10, per dose level (0.125, 0.25, 0.375, 0.50 mg/kg). The study is also enrolling children who are treatment-naïve (Cohort 1) and those who have received prior growth-accelerating therapy (Cohort 2) ages 3-10 at multiple sites across the globe. Cohorts 1 and 2 are anticipated to initiate treatment after completion of safety sentinel dose escalation and a six-month observation period, with each cohort expecting to enroll up to 10 participants per dose level.

We have cleared the first two doses in the safety sentinel cohort and are currently dosing children at the third safety sentinel dose level of 0.375 mg/kg and we expect to report initial data from the safety sentinel cohort of the BEACH301 study in the second half of 2026.

In July 2023 and January 2024, the FDA granted orphan drug designation and rare pediatric disease designation to oral dabogratinib, respectively, for the treatment of ACH.

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Our FGF19+ Program

TYRA-430 for Hepatocellular Carcinoma

FGF19 is a post-prandial enterohepatic hormone that signals through FGFR4 and its associated co-receptor Beta-Klotho (KLB) to exert its normal cellular functions. In a subset of certain cancers, such as HCC, gastric adenocarcinoma, and squamous esophageal carcinoma, FGF19 is aberrantly expressed due to focal chromosomal amplifications or epigenetic mechanisms, promoting tumor cells to become dependent on the FGFR4/KLB/FGF19 oncogenic axis.

An experiment run by Tao et al (2022) demonstrated a greater dependence of HCC JHH-7 cells on KLB, the common co-receptor for FGFR3 and FGFR4, than on either receptor alone. This is also consistent with the results of the double knock down of FGFR3 and 4 being more deleterious than knock down of either receptor alone, suggesting the need for dual inhibition of FGFR3 or FGFR4.

TYRA-430 is an investigational FGFR4/3 biased inhibitor for FGF19+/FGFR4-driven cancers that is designed to be agnostic to acquired resistance mechanisms originating from the V550 gatekeeper and the C552 mutations.

In April 2025, we commenced our Phase 1 clinical trial of TYRA-430, SURF431, a multi-center, open label study designed to evaluate the safety, tolerability, and PK of TYRA-430 and determine the optimal dose for further development, the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D), as well as evaluate preliminary antitumor activity in advanced HCC and other solid tumors with activating FGF/FGFR pathway aberrations. We believe TYRA-430 has the potential to address a significant unmet need in HCC, where there are no approved biomarker-driven, targeted therapies.

Our FGFR2 Program

TYRA-200 for ICC

FGFR2 is a protein receptor present on the cell surface that promotes cellular proliferation and transformation upon binding of fibroblast growth factor. Activating gene alterations of FGFR2 have been implicated in the tumorigenesis of multiple solid tumor types.

TYRA-200 is an investigational, oral, FGFR1/2/3 inhibitor designed to be active against activating FGFR2 gene alterations, as well as clinically important molecular brake and gatekeeper resistance mutations, and selective for FGFR4. We are focusing initial Phase 1 development of TYRA-200 in FGFR2-driven ICC resistant to treatment with prior FGFR inhibitors.

In December 2023, we commenced our Phase 1 clinical trial of TYRA-200, SURF201, a multi-center, open label study designed to evaluate the safety, tolerability, and PK of TYRA-200 and determine the optimal dose for further development, the MTD and RP2D, as well as evaluate preliminary antitumor activity. SURF201 is currently enrolling ICC patients with acquired kinase domain mutations. Positive data in this setting, where other FGFR inhibitors have not succeeded, would potentially provide confidence in our belief that addressing acquired resistance may prolong the duration of responses, and ultimately PFS, in the FGFR-naive setting.

Beyond FGFR-resistant and FGFR-naive ICC, there is potential for TYRA-200 to extend into metastatic endometrial carcinoma as well as advanced colorectal, breast, ovarian, gastric, and lung cancer.

Our Discovery Engine

We continue to leverage the SNÅP platform in the discovery and development of additional, undisclosed preclinical programs. These efforts are focused in the field of FGFR biology as well as other targets that are important drivers for opportunities across precision oncology and genetically defined conditions.

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Competition

The pharmaceutical and biotechnology industries are characterized by rapidly advancing technologies, intense competition, and a strong emphasis on proprietary products. While we believe that our technology, technical expertise, and drug development experience provide us with competitive advantages, we face increasing competition from many different sources, including pharmaceutical and biotechnology companies, academic institutions, governmental agencies, and public and private research institutions. Product candidates that we successfully develop and commercialize may compete with existing and/or new therapies that may become available in the future.

Many of our competitors, either alone or with their collaborators, have significantly greater financial resources, established presence in the market, expertise in manufacturing, research and development, pre-clinical activities and clinical trial conduct. Additionally, many of our competitors are commercial-stage entities with experience in obtaining regulatory approvals and reimbursement for marketed approved products. These competitors also compete with us in recruiting and retaining qualified scientific and management personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for, our programs. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with larger and/or established companies. Additional mergers and acquisitions may result in even more resources being concentrated in our competitors.

Our commercial potential could be reduced or eliminated if our competitors develop and commercialize products that are more effective, have a more favorable safety profile, and are more convenient or less expensive than products that we may develop. Our competitors also may obtain FDA or other foreign regulatory approval(s) for their products more rapidly than us, which could result in our competitors establishing a strong market position before we are able to enter the market or could otherwise make our development more complicated. We believe the key competitive factors affecting the success of all of our programs are likely to be efficacy, including duration of human response and breadth of coverage, safety and patient convenience.

There are numerous companies developing or marketing treatments for cancer, including many major pharmaceutical and biotechnology companies. These treatments consist of small molecule drug products, biologics, cellular therapies, and traditional chemotherapy.

For oral dabogratinib in LG-UTUC, the only agent commercially available is Urogen’s Jelmyto, a hydrogel reformulation of mitomycin C, which was approved in April of 2020. Additional agents in Phase 2 or 3 development include Steba Biotech’s TOOKAD Vascular Photodynamic Therapy, Ferring’s nadofaragene firadenovec and Sustained Therapeutics’ ST-02.

For oral dabogratinib in IR NMIBC, the only agent commercially available beyond intravesical BCG or chemotherapy is Urogen’s Zusduri, a hydrogel reformulation of mitomycin C, which was approved in June of 2025. Additional agents in Phase 3 development include Janssen Pharmaceutical’s TAR-210, CG Oncology’s crestostimogene grenadenorepvec and Ferring’s nadofaragene firadenovec.

For oral dabogratinib in ACH, BioMarin’s Voxzogo and Ascendis’ Yuviwel (TransCon CNP) are approved for children of any age with open growth plates. BridgeBio’s infigratinib has published topline Phase 3 results. Ascendis published Phase 2 data on TransCon CNP and TransCon Human Growth Hormone and BioMarin is studying BMN-333, a long-acting CNP in Phase 1 development.

For oral dabogratinib in HCH, BioMarin’s vosoritide is in Phase 3 development, BridgeBio’s infigratinib has initiated a Phase 2/3 study and Ascendis has disclosed plans to initiate a clinical study. BioMarin has also initiated a Phase 2 basket trial for vosoritide in children with Turner syndrome, SHOX Deficiency and Noonan Syndrome without sufficient response to human growth hormone, in addition to a Phase 2 study for children with idiopathic short stature.

For TYRA-430 in HCC, several multi-kinase inhibitors have been approved for the treatment of HCC, but there are currently no approved targeted therapies, including FGFR4-specific inhibitors. In the late line setting, approved, non-targeted treatment options include Bayer’s Stivarga, Exelixis’ Cabometyx, Eli Lilly’s Cyramza,

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Merck’s Keytruda and BMS’ Opdivo combined with Yervoy. There are a number of FGFR4 clinical stage programs, with most of the development focused in China, including CStone Pharmaceuticals and Blueprint Medicine’s BLU-554 (fisogatinib), Everest Medicine’s FGF401 and Abbisko Therapeutics’ ABSK-011.

For TYRA-200 in ICC, there are two pan-FGFR inhibitors available in the United States that are indicated for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a FGFR2 fusion or other rearrangement: Incyte Corporation’s Pemazyre and Taiho Oncology’s Lytgobi. Additional inhibitors in development include Elevar’s Lirafugratinib, TransThera’s tinengotinib and Cogent’s CGT-4859.

Intellectual Property

We strive to protect the intellectual property and proprietary technology that we consider important to our business through a variety of methods, including seeking and maintaining patents intended to cover our product candidates and compositions, their methods of use and processes for their manufacture, and any other inventions that are important to our business. We rely on know-how and continuing technological innovation to develop and maintain our proprietary position. We also rely on trade secrets and know-how that may be important to the development of our business. We seek to obtain domestic and international patent protection and endeavor to promptly file patent applications for new commercially valuable inventions to expand our intellectual property portfolio.

We are building a patent portfolio and have substantial confidential know-how relating to our product candidates and SNÅP platform. As of March 1, 2026, our intellectual property portfolio consists of three granted U.S. patents, 11 pending U.S. provisional applications, 10 pending U.S. nonprovisional applications, 100 pending foreign patent applications, five granted foreign patents and 15 patent applications pursuant to the Patent Cooperation Treaty (PCT), all of which are solely owned by us. We do not license any material patent rights from any third party. Collectively, our patent rights relate to various aspects of our product candidates.

We continually assess and refine our intellectual property strategy as we develop new product candidates and improvements to our SNÅP platform. To that end, we are prepared to file additional patent applications in any appropriate fields if our intellectual property strategy requires such filings, or where we seek to adapt to competition or seize business opportunities. Further, we are prepared to file patent applications, as we consider appropriate under the circumstances, relating to the new technologies that we develop.

We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications we may own or license in the future, nor can we be sure that any patents we may own or license in the future will be useful in protecting our technology. Please see the section entitled “Risk Factors—Risks Related to Our Intellectual Property” for additional information on the risks associated with our intellectual property strategy and portfolio.

Intellectual Property Relating to Our FGFR3 Program

With regard to our FGFR3 product candidates, as of March 1, 2026, we own three pending U.S. provisional applications, four pending U.S. nonprovisional applications, three granted U.S. patent, 10 pending PCT patent applications, 53 pending foreign applications and four granted foreign patents. These patent rights relate to the FGFR3 product candidates’ compositions of matter, formulations containing them, methods of manufacturing, and methods of treating diseases, using our FGFR3 product candidates. Specifically, we have two granted U.S. patents, four granted foreign patents and 28 pending foreign patent applications directed to the composition matter of our leading candidate in the FGFR3 program. We expect any patents issued from these applications to expire between 2040 and 2046 without accounting for any patent term adjustment or extension that may be available.

Intellectual Property Relating to Our FGFR2 Program

With regard to our FGFR2 program, as of March 1, 2026, we own three pending U.S. provisional applications, two pending U.S. nonprovisional applications, one pending PCT patent application, one granted

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foreign patent and 16 pending foreign applications. These patent rights relate to the FGFR2 program’s compositions of matter, formulations containing them, methods of manufacturing, and methods of treating diseases. Specifically, we have one pending U.S. nonprovisional and 15 pending foreign patent applications directed to the composition matter of our leading candidate in the FGFR2 program. We expect any patents issued from these applications to expire between 2040 and 2046 without accounting for any patent term extension that may be available.

Intellectual Property Relating to Other Programs

With regard to our other programs, including the FGFR4 program, as of March 1, 2026, we own five pending U.S. provisional patent applications, four pending U.S. nonprovisional applications, four pending PCT patent applications and 32 pending foreign applications. These patent rights relate to these other programs’ compositions of matter, formulations containing them, methods of manufacturing, and methods of treating diseases. We expect any patents issued from these applications to expire between 2042 and 2046 without accounting for any patent term extension that may be available.

Scope and Duration of Intellectual Property Protection

The term of individual patents depends upon the laws of the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the earliest date of filing of a non-provisional patent application. However, the term of United States patents may be extended for delays incurred due to compliance with the FDA requirements or by delays encountered during prosecution that are caused by the USPTO. For example, for drugs that are regulated by the FDA under the Hatch-Waxman Act, the FDA is permitted to extend the term of a patent that covers such drug for up to five years beyond the normal expiration date of the patent, provided that the extended patent term may not exceed fourteen years after the date of approval of the marketing application. In the future, if and when our product candidates receive FDA approval, we expect to apply for patent term extensions on any issued U.S. patents covering those product candidates. We intend to seek patent term extensions for our current and future issued patents in jurisdictions where these are available; however, there is no guarantee that the applicable authorities, including the USPTO and FDA, will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions. Our issued patent and any patents issuing from our pending patent applications are expected to expire on dates ranging from 2040 to 2046, without accounting for potentially available patent term extensions or patent term adjustments.

However, the actual protection afforded by a patent varies on a product-by-product basis, from country-to-country, and depends upon many factors, including the type of patent, the scope of its coverage, the availability of regulatory-related extensions, the availability of legal remedies in a particular country and the validity and enforceability of the patent.

The patent positions of companies like ours are generally uncertain and involve complex legal and factual questions. No consistent policy regarding the scope of claims allowable in patents in the field of oncology therapy has emerged in the United States. The patent situation outside of the United States is even more uncertain. Changes in the patent laws and rules, either by legislation, judicial decisions, or regulatory interpretation in the United States and other countries may diminish our ability to protect our inventions and enforce our intellectual property rights, and more generally could affect the value of our intellectual property. In particular, our ability to stop third parties from making, using, selling, offering to sell, importing or otherwise commercializing any of our patented inventions, either directly or indirectly, will depend in part on our success in obtaining, defending and enforcing patent claims that cover our technology, inventions, and improvements. We cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our current or future patents will be commercially useful in protecting our product candidates and the methods used to manufacture them. Moreover, our current or future patents may not guarantee us the right to practice our technology in relation to the commercialization of our product candidates.

The area of patent and other intellectual property rights in biotechnology is an evolving one with many risks and uncertainties, and third parties may have blocking patents that could be used to prevent us from commercializing our product candidates and practicing our proprietary technology. Our current or future patents may be challenged, narrowed, circumvented or invalidated, which could limit our ability to stop competitors from

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marketing related product candidates or limit the length of the term of patent protection that we may have for our product candidates. In addition, the rights granted under our current or future issued patents may not provide us with protection or competitive advantages against competitors with similar technology. Furthermore, our competitors may independently develop similar technologies. For these and other reasons, we may have competition for our product candidates. Moreover, because of the extensive time required for development, testing and regulatory review of a potential product, it is possible that before any product candidate can be commercialized, any related patent may expire or remain in force for only a short period following commercialization, thereby reducing any protection afforded by the patent. For this and other risks related to our proprietary technology, inventions, improvements, SNÅP platform and product candidates, please see the section entitled “Risk Factors—Risks Related to Our Intellectual Property.”

We have filed applications for trademark registrations in connection with our product candidates in various jurisdictions, including the United States. We have filed for trademark protection of the TYRA, TYRA BIOSCIENCES and HEALTH BEYOND HEIGHT marks with the United States Patent and Trademark Office and certain foreign patent and trademark organizations. We have registered trademarks in the United States and other jurisdictions.

We also rely on trade secret protection for our confidential and proprietary information. Although we take steps to protect our confidential and proprietary information as trade secrets, including through contractual means with our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors, third parties may independently develop substantially equivalent proprietary information and techniques or otherwise gain access to our trade secrets or disclose our technology. Thus, we may not be able to meaningfully protect our trade secrets. It is our policy to require our employees, consultants, outside scientific collaborators, sponsored researchers and other advisors to execute confidentiality agreements under the commencement of employment or consulting relationships with us. These agreements provide that all confidential information concerning our business or financial affairs developed or made known to the individual during the individual’s relationship with us is to be kept confidential and not disclosed to third parties except in specific circumstances. In the case of employees, the agreements provide that all inventions conceived by the individual, and which are related to our current or planned business or research and development or made during normal working hours, on our premises or using our equipment or proprietary information, are our exclusive property. In many cases our confidentiality and other agreements with consultants, outside scientific collaborators, sponsored researchers and other advisors require them to assign or grant us licenses to inventions they invent as a result of the work or services they render under such agreements or grant us an option to negotiate a license to use such inventions. Despite these efforts, we cannot provide any assurances that all such agreements have been duly executed, and any of these parties may breach the agreements and disclose our proprietary information, and we may not be able to obtain adequate remedies for such breaches.

We also seek to preserve the integrity and confidentiality of our proprietary technology and processes by maintaining physical security of our premises and physical and electronic security of our information technology systems. Although we have confidence in these individuals, organizations and systems, agreements or security measures may be breached, and we may not have adequate remedies for any breach. To the extent that our employees, contractors, consultants, collaborators and advisors use intellectual property owned by others in their work for us, disputes may arise as to the rights in relation to the resulting know-how or inventions. For more information, please see the section entitled “Risk Factors—Risks Related to Our Intellectual Property.”

Commercialization

We intend to retain significant development and commercial rights to our product candidates and, if marketing approval is obtained, to commercialize our product candidates on our own, or potentially with a partner, in the United States and other regions. We currently have no sales, marketing or commercial product distribution capabilities. We intend to build the necessary infrastructure and capabilities over time for the United States, and potentially other regions, following further advancement of our product candidates. Clinical data, the size of the addressable patient population, the size of the commercial infrastructure and manufacturing needs may all influence or alter our commercialization plans.

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Manufacturing

We do not have any manufacturing facilities or personnel. We currently rely, and expect to continue to rely, on third parties for the manufacture of our product candidates undergoing preclinical testing, as well as for subsequent clinical testing and commercial manufacture if our product candidates receive marketing approval. We believe this strategy allows us to focus our expertise and resources on the development of our product candidates by eliminating the need for us to invest in our own manufacturing facilities, equipment and personnel.

We plan to put agreements in place with contract manufacturing organizations for the necessary quantities of active pharmaceutical ingredients (API) and drug product for each of our product candidates, on a project-by-project basis, based on our development needs.

As we advance our product candidates through development, we will explore adding backup suppliers for the API and drug product for each of our product candidates to protect against any potential supply disruptions.

Government Regulation

Government authorities in the United States, at the federal, state and local level, and other countries extensively regulate, among other things, the research, development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, marketing and export and import of drug products. A new drug must be approved by the FDA through the New Drug Application (NDA) process before it may be legally marketed in the United States. We, along with any third-party contractors, will be required to navigate the various preclinical, clinical and commercial approval requirements of the governing regulatory agencies of the countries in which we wish to conduct studies or seek approval of our products and product candidates. The process of obtaining regulatory approvals and the subsequent compliance with applicable federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

U.S. Drug Development Process

In the United States, the FDA regulates drugs under the federal Food, Drug, and Cosmetic Act (the FDCA) and its implementing regulations. The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources. The process required by the FDA before a drug may be marketed in the United States generally involves the following:

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completion of certain preclinical laboratory tests, animal studies and formulation studies in accordance with FDA’s Good Laboratory Practice (GLP) requirements and other applicable regulations;

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

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approval by an independent Institutional Review Board (IRB) or ethics committee at each clinical site before each trial may be initiated;

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performance of adequate and well-controlled human clinical trials in accordance with good clinical practices (GCPs) to establish the safety and efficacy of the proposed drug for its intended use;

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preparation of and submission to the FDA of an NDA after completion of all pivotal trials;

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

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

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satisfactory completion of an FDA inspection of the manufacturing facility or facilities at which the drug is produced to assess compliance with current Good Manufacturing Practice (cGMP) or similar

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foreign requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

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satisfactory completion of potential FDA audit of select clinical trial sites to assure compliance with GCP; and

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FDA review and approval of the NDA to permit commercial marketing of the product for particular indications for use in the United States.

Prior to beginning the first clinical trial with a product candidate in the United States, a sponsor must submit an IND to the FDA. An IND is a request for allowance from the FDA to administer an investigational drug product to humans. 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, PK, pharmacology, and PD characteristics of the product; chemistry, manufacturing, and controls information; and any available human data or literature to support the use of the investigational product. 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 allowance to begin a clinical trial.

Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators 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 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. 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.

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. 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. Depending on its charter, this group may determine whether a trial may move forward at designated check points based on access to certain data from the trial. The FDA or the sponsor may suspend a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients. There are also requirements governing the reporting of ongoing clinical studies and clinical study results to public registries.

Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

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Phase 1: The product candidate 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.

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Phase 2: The product candidate 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.

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Phase 3: The product candidate is administered to an expanded patient population to further evaluate dosage, to provide statistically significant 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. These clinical trials, sometimes referred to as Phase 4 studies, may be used to gain additional experience from the treatment of patients in the intended therapeutic indication. In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug and finalize a process for manufacturing the product in commercial quantities in accordance with cGMP or similar foreign requirements. The manufacturing process must be capable of consistently producing quality batches of the product candidate and, among other things, the manufacturer must develop methods for testing the identity, strength, quality and purity of the final drug. In addition, 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.

U.S. Review and Approval Process

Assuming successful completion of all required testing in accordance with all applicable regulatory requirements, the results of product development, including results from preclinical and other non-clinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product. Data can come from company-sponsored clinical studies intended to test the safety and effectiveness of the use of the product, or from a number of alternative sources, including studies initiated by independent investigators. The submission of an NDA is subject to the payment of substantial user fees; a waiver of such fees may be obtained under certain limited circumstances. Additionally, no user fees are assessed on NDAs for products designated as orphan drugs, unless the product also includes a non-orphan indication.

The FDA conducts a preliminary review of an NDA within the first 60 days after submission, before accepting it for filing, to determine whether it is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept an NDA for filing. In this event, the NDA must be resubmitted with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. Once filed, the FDA reviews an NDA to determine, among other things, whether a product is safe and effective for its intended use and whether its manufacturing is cGMP-compliant to assure and preserve the product’s identity, strength, quality and purity. Under the Prescription Drug User Fee Act guidelines that are currently in effect, the FDA has a goal of ten months from the filing date to complete a standard review of an NDA for a drug that is a new molecular entity. This review typically takes twelve months from the date the NDA is submitted to the FDA because the FDA has approximately two months to make a “filing” decision after the application is submitted.

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

Before approving an NDA, the FDA 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

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specifications. Additionally, before approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCPs.

After the FDA evaluates an NDA and conducts any necessary 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 indicates that the review cycle of the application is complete, and the application will not be approved in its present form. A CRL usually describes all of the deficiencies that the FDA has identified and may require additional clinical data, such as an additional clinical trial or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing. When 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 and/or reviewing proposed labeling. If a CRL is issued, the sponsor must resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application. Even if such data and information are submitted, the FDA may decide that the NDA does not satisfy the criteria for approval.

If regulatory approval of a product is granted, such approval will be granted for particular indications and may entail limitations on the indicated uses for which such product may be marketed. For example, the FDA may approve the NDA with a Risk Evaluation and Mitigation Strategy (REMS) to ensure the benefits of the product outweigh its risks. A REMS is a safety strategy to manage a known or potential serious risk associated with a medicine 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. The FDA may also require one or more post-market studies and surveillance to further assess and monitor the product’s safety and effectiveness after commercialization, and may limit further marketing of the product based on the results of these post-marketing studies.

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, original NDAs and 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 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.

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 reviewing new 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 product candidate has opportunities for more frequent interactions with the applicable FDA review team during product development and, once an NDA is submitted, the application may be eligible for priority review. An NDA for a Fast Track product candidate may also be eligible for rolling review, where the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

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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.

Any marketing application for a drug submitted to the FDA for approval, including a product candidate with a Fast Track 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. An NDA 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 new-molecular-entity NDAs, 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.

Additionally, depending on the design of the applicable clinical trials, 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 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, and may require that such confirmatory studies be underway prior to granting any accelerated approval. Products receiving accelerated approval may be subject to expedited withdrawal procedures if the sponsor fails to conduct the required confirmatory studies in a timely manner or if such studies fail to verify the predicted clinical benefit. In addition, the FDA requires pre-approval of promotional materials as a condition of accelerated approval, which could adversely impact the timing of the commercial launch of the product.

Fast Track designation, Breakthrough Therapy 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.

Orphan Drug Designation and Exclusivity

Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, defined as a disease or condition with a patient population of fewer than 200,000 individuals in the United States, or a patient population greater than 200,000 individuals in the United States and when there is no reasonable expectation that the cost of developing and making available the drug in the United States will be recovered from sales in the United States for that drug. Orphan drug designation must be requested before submitting an NDA. After the FDA grants orphan drug designation, the generic identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

If a product that has orphan drug designation subsequently receives the first FDA approval for the drug and disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications, to market the same drug for the approved indication or use within such disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity in the relevant indication or if the FDA finds that the holder of the orphan drug exclusivity has not shown that it can assure the availability of sufficient quantities of the orphan drug to meet the needs relating to the approved indication or use of patients with the disease or condition for which the drug was designated. Orphan drug exclusivity does not prevent the FDA from approving a different drug for the same indication or use, or the same drug for a different indication or use. Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA application user fee.

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A designated orphan drug may not receive orphan drug exclusivity if it is approved for a use that is broader than the disease or condition for which it received orphan designation. In addition, orphan drug exclusive marketing rights in the United States may be lost if the FDA later determines that the request for designation was materially defective or, as noted above, if a second applicant demonstrates that its product is clinically superior to the approved product with orphan exclusivity in the relevant indication or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs relating to the approved indication or use of patients with the rare disease or condition.

Rare Pediatric Disease Priority Review Voucher Program

In 2012, the U.S. Congress authorized the FDA to award priority review vouchers to Sponsors of certain rare pediatric disease product applications. This program is designed to encourage development of new drug and biological products for prevention and treatment of certain rare pediatric diseases. Specifically, under this program, a sponsor who receives an approval for a drug or biologic for a “rare pediatric disease” may qualify for a voucher that can be redeemed to receive priority review of a subsequent marketing application for a different product. The Sponsor of a rare pediatric disease drug product receiving a priority review voucher may transfer (including by sale) the voucher to another sponsor. The voucher may be further transferred any number of times before the voucher is used, as long as the Sponsor making the transfer has not yet submitted the application. The FDA may also revoke any priority review voucher if the rare pediatric disease drug for which the voucher was awarded is not marketed in the U.S. within one year following the date of approval.

For purposes of this program, a “rare pediatric disease” is a (a) serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth to 18 years, including age groups often called neonates, infants, children, and adolescents; and (b) rare diseases or conditions within the meaning of the Orphan Drug Act. Congress has only authorized the Rare Pediatric Disease Priority Review Voucher program until September 30, 2029. Consequently, unless Congress reauthorizes the program, the sponsor of the marketing application for a drug that receives Rare Pediatric Disease Designation will only be eligible to receive a voucher if the FDA grants the designation on or before September 30, 2029.

Post-approval Requirements

Drug products manufactured or distributed pursuant to FDA approvals 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. Drug 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 NDA holders and product manufacturers. 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 labeling 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 program. Other potential consequences include, among other things:

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

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fines, warning letters, or untitled letters;

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clinical holds on clinical studies;

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

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

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

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

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

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injunctions or the imposition of civil or criminal penalties.

The FDA closely regulates the marketing, labeling, advertising and promotion of drug products. A company can make only those claims relating to safety and efficacy, purity and potency that are approved by the FDA and in accordance with the provisions of the approved label. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses. Failure to comply with these requirements can result in, among other things, adverse publicity, warning letters, corrective advertising and potential civil and criminal penalties. Physicians may prescribe, in their independent professional medical judgment, legally available products for uses that are not described in the product’s labeling and that differ from those tested by us and approved by the FDA. Physicians may believe that such off-label uses are the best treatment for many patients in varied circumstances. The FDA does not regulate the behavior of physicians in their choice of treatments. The FDA does, however, restrict manufacturer’s communications on the subject of off-label use of their products. However, companies may share truthful and not misleading information that is otherwise consistent with a product’s FDA-approved labelling.

Marketing Exclusivity

Non-patent regulatory exclusivity provisions authorized under the FDCA can delay the submission or the approval of certain marketing applications. The FDCA provides a five-year period of non-patent data exclusivity within the United States to the first applicant to obtain approval of an NDA for a new chemical entity. A drug is a new chemical entity if the FDA has not previously approved any other new drug containing the same active moiety, which is the molecule or ion responsible for the action of the drug substance. During the exclusivity period, the FDA may not approve or even accept for review an abbreviated new drug application (ANDA) or an NDA submitted under Section 505(b)(2) (505(b)(2) NDA) submitted by another company for another drug containing the same active moiety, regardless of whether the drug is intended for the same indication as the original innovative drug or for another indication, where the applicant does not own or have a legal right of reference to all the data required for approval. However, an application may be submitted after four years if it contains a certification of patent invalidity or non-infringement to one of the patents listed with the FDA by the innovator NDA holder.

The FDCA alternatively provides three years of non-patent exclusivity for an NDA, or supplement to an existing NDA if new clinical investigations, other than bioavailability studies, that were conducted or sponsored by the applicant are deemed by the FDA to be essential to the approval of the application, for example new indications, dosages or strengths of an existing drug. This three-year exclusivity covers only the modification for which the drug received approval on the basis of the new clinical investigations and does not prohibit the FDA from approving ANDAs or 505(b)(2) NDAs for drugs containing the active agent for the original indication or condition of use. Five-year and three-year exclusivity will not delay the submission or approval of a full NDA. However, an applicant submitting a full NDA would be required to conduct or obtain a right of reference to any preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

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Pediatric exclusivity is another type of marketing exclusivity available in the United States. Pediatric exclusivity provides for an additional six months of marketing exclusivity attached to another period of regulatory exclusivity or existing patent term if a sponsor conducts clinical trials in children in response to a written request from the FDA and meets other conditions. The issuance of a written request does not require the sponsor to undertake the described clinical trials. In addition, orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity, except in certain circumstances.

FDA Regulation of Companion Diagnostics

If safe and effective use of a drug depends on an in vitro diagnostic, then the FDA may require approval or clearance of that diagnostic, known as a companion diagnostic, at the same time that the FDA approves the therapeutic product. In August 2014, the FDA issued final guidance clarifying the requirements that will apply to approval of therapeutic products and in vitro companion diagnostics. According to the guidance, if FDA determines that a companion diagnostic device is essential to the safe and effective use of a novel therapeutic product or indication, FDA may will not approve the drug or new indication if the companion diagnostic device is not also approved or cleared for that indication. Approval or clearance of the companion diagnostic device will ensure that the device has been adequately evaluated and has adequate performance characteristics in the intended population. The review of in vitro companion diagnostics in conjunction with the review of our product candidates will, therefore, likely involve coordination of review by the FDA’s Center for Drug Evaluation and Research and the FDA’s Center for Devices and Radiological Health Office of In Vitro Diagnostics and Radiological Health.

Under the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices. In the United States, the FDCA and its implementing regulations, and other federal and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing, manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post-market surveillance.

Unless an exemption applies, each medical device commercially distributed in the United States generally requires either FDA clearance of a 510(k) premarket notification, or approval of a premarket approval (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. While most Class I devices—devices that generally pose a low risk to users—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. Devices deemed by the FDA to pose the greatest risks, or devices that have a new intended use, or use advanced technology that is not substantially equivalent to that of a legally marketed device, are automatically placed in Class III, requiring approval of a PMA unless down-classified in accordance with the “de novo” 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.

To obtain 510(k) clearance, a manufacturer must submit to the FDA a premarket notification demonstrating that the proposed device is “substantially equivalent” to a predicate device already on the market. 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. 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 request down-classification of the device through the “de novo” process.

The PMA process is more demanding than the 510(k) premarket notification process, and can take several years or longer. It involves a rigorous premarket review during which the applicant must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and information about the device and its components regarding, among other things, device design, manufacturing and labeling. PMA applications are

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subject to an application fee. In addition, PMAs for certain devices must generally include the results from extensive preclinical and adequate and well-controlled clinical trials to establish the safety and effectiveness of the device for each indication for which FDA approval is sought. As part of the PMA review, the FDA will typically inspect the manufacturer’s facilities for compliance with the Quality Management System Regulation (QMSR), which imposes elaborate testing, control, documentation and other quality assurance requirements.

If the FDA’s evaluation of the PMA application is favorable, the FDA typically issues an approvable letter requiring the applicant’s agreement to specific conditions, such as changes in labeling, or specific additional information, such as submission of final labeling, in order to secure final approval of the PMA. If the FDA’s evaluation of the PMA or manufacturing facilities is not favorable, the FDA will deny approval of the PMA or issue a not approvable letter. A not approvable letter will outline the deficiencies in the application and, where practical, will identify what is necessary to make the PMA approvable. The FDA may also determine that additional clinical trials are necessary, in which case the PMA approval may be delayed for several months or years while the trials are conducted and then the data submitted in an amendment to the PMA. If the FDA concludes that the applicable criteria have been met, the FDA will issue a PMA for the approved indications, which can be more limited than those originally sought by the applicant. The PMA can include post-approval conditions that the FDA believes necessary to ensure the safety and effectiveness of the device, including, among other things, restrictions on labeling, promotion, sale and distribution. Once granted, PMA approval may be withdrawn by the FDA if compliance with post-approval requirements, conditions of approval or other regulatory standards are not maintained or problems are identified following initial marketing.

After a device is placed on the market, it remains subject to significant regulatory requirements. Medical devices may be marketed only for the uses and indications for which they are cleared or approved. Device manufacturers must also establish registration and device listings with the FDA. A medical device manufacturer’s manufacturing processes and those of its suppliers are required to comply with the applicable portions of the QMSR, which currently cover the methods and documentation of the design, testing, production, processes, controls, quality assurance, labeling, packaging and shipping of medical devices. Domestic facility records and manufacturing processes are subject to periodic unscheduled inspections by the FDA. The FDA also may inspect foreign facilities that export products to the United States.

Other U.S. Healthcare Laws

Pharmaceutical companies like us are subject to additional healthcare regulation and enforcement by the federal government and by authorities in the states and foreign jurisdictions in which they conduct their business. Such regulation and enforcement may constrain the financial arrangements and relationships through which we research, develop, and ultimately, sell, market and distribute any products for which we obtain marketing approval. Such laws include, without limitation, federal and state anti-kickback, fraud and abuse, and false claims laws, such as the federal Anti-Kickback Statute and the federal civil False Claims Act, as well as federal and state transparency laws and regulations with respect to drug pricing and payments and other transfers of value made by pharmaceutical manufacturers to physicians and other health care providers, such as the federal Physician Payments Sunshine Act.

Violation of any of such laws or any other governmental regulations that apply may result in significant criminal, civil and administrative penalties including damages, fines, imprisonment, disgorgement, additional reporting requirements and oversight if we become subject to a Corporate Integrity Agreement or similar agreement to resolve allegations of non-compliance with these laws, contractual damages, reputational harm, diminished profits and future earnings, disgorgement, exclusion from participation in government healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.

U.S. Coverage and Reimbursement

Significant uncertainty exists as to the coverage and reimbursement status of any product candidate for which we may seek regulatory approval. Sales in the United States will depend, in part, on the availability of sufficient coverage and adequate reimbursement from third-party payors, which include government health programs such as Medicare, Medicaid, TRICARE and the Veterans Administration, as well as managed care organizations and private health insurers. Prices at which we or our customers seek reimbursement for our product candidates can be subject to challenge, reduction or denial by third-party payors. For products administered under

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the supervision of a physician, obtaining coverage and adequate reimbursement may be particularly difficult because of the higher prices often associated with such drugs.

The process for determining whether a third-party payor will provide coverage for a product is typically separate from the process for setting the reimbursement rate that the payor will pay for the product. In the United States, there is no uniform policy among payors for coverage or reimbursement. Decisions regarding whether to cover any of a product, the extent of coverage and amount of reimbursement to be provided are made on a plan-by-plan basis. Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own coverage and reimbursement policies, but also have their own methods and approval processes. Therefore, coverage and reimbursement for products can differ significantly from payor to payor. As a result, the coverage determination process is often a time-consuming and costly process that can require manufacturers to provide scientific and clinical support for the use of a product to each payor separately, with no assurance that coverage and adequate reimbursement will be applied consistently or obtained in the first instance.

Third-party payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products and services, in addition to their safety and efficacy. Adoption of price controls and cost-containment measures, and adoption of more restrictive policies in jurisdictions with existing controls and measures, could further limit sales of any product that receives approval. Third-party payors may not consider our product candidates to be medically necessary or cost-effective compared to other available therapies, or the rebate percentages required to secure favorable coverage may not yield an adequate margin over cost or may not enable us to maintain price levels sufficient to realize an appropriate return on our investment in drug development. Additionally, decreases in third-party reimbursement for any product or a decision by a third-party payor not to cover a product could reduce physician usage and patient demand for the product.

Moreover, as a condition of participating in, and having products covered under, certain federal healthcare programs, such as Medicare and Medicaid, if we market a product that is approved, we may become subject to federal laws and regulations that require pharmaceutical manufacturers to calculate and report certain pricing metrics to the government, including the Average Manufacturer Price (AMP) and Best Price under the Medicaid Drug Rebate Program, the Medicare Average Sales Price, the 340B Ceiling Price, and Non-Federal AMP reported to the Department of Veteran Affairs, and with respect to Medicaid, pay statutory rebates on utilization of manufacturers’ products by Medicaid beneficiaries. Compliance with these laws and regulations will require significant resources and may have a material adverse effect on our revenues.

U.S. Healthcare Reform

In the United States, there has been, and continues to be, several legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities, and affect the profitable sale of product candidates.

Among policy makers and payors in the United States, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United States, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected by major legislative initiatives. For example, the Affordable Care Act (ACA) was enacted in the United States in 2010. Among the provisions of the ACA of importance to our potential product candidates, the ACA: established an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents; extended manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care organizations; expanded the entities eligible for discounts under the 340B drug pricing program; increased the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program; and established a Center for Medicare and Medicaid Innovation at CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending. Since its enactment, there have been judicial and Congressional challenges to certain aspects of the ACA. On June 17, 2021, the U.S. Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without specifically ruling on the constitutionality of the ACA.

In addition, other legislative changes have been adopted since the ACA was enacted. The Budget Control Act of 2011, among other things, reduced Medicare payments to providers, which went into effect on April 1, 2013

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and will remain in effect until 2032, unless additional Congressional action is taken. The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers, including hospitals, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

Moreover, there has recently been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed products. This has resulted in several Congressional inquiries and proposed and enacted federal and state regulations designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for pharmaceutical products. The Inflation Reduction Act of 2022 (IRA) was enacted in 2022. The IRA marks the most significant action by Congress with respect to the pharmaceutical industry since adoption of the ACA in 2010. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare, with prices that can be negotiated subject to a cap; imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023); redesigns the Medicare Part D benefit (beginning in 2024); and replaces the Part D coverage gap discount program with a new manufacturer discount program (beginning in 2025). The Centers for Medicare & Medicaid Services has published the negotiated prices for the initial ten drugs, which went into effect in January 2026, and the subsequent 15 drugs, which will first be effective in 2027. The Centers for Medicare & Medicaid Services has also published the next set of 15 drugs that will be subject to negotiation. The IRA permits the Secretary of the Department of Health and Human Services (HHS) to implement many of these provisions through guidance, as opposed to regulation, for the initial years. HHS has and will continue to issue and update guidance as these programs are implemented, although the Medicare drug price negotiation program is currently subject to legal challenges. The impact of the IRA on us and the pharmaceutical industry cannot yet be fully determined but is likely to be significant.

More recently, the One Big Beautiful Bill Act, which was enacted in July 2025, imposes significant reductions in the funding of the Medicaid program. Such reductions are expected to decrease the number of persons enrolled in Medicaid and reduce the services covered by Medicaid, which could adversely affect our sales of any product candidate that we commercialize.

The Trump administration is pursuing a two-fold strategy to reduce drug costs in the United States. While it is unclear whether and how the Trump proposals will be implemented, the Trump policies are likely to have a negative impact on the pharmaceutical industry and on our ability to receive adequate revenues for any product candidate that we commercialize. On the one hand, President Trump has threatened to impose significant tariffs on pharmaceutical manufacturers that do not adopt pricing policies such as most favored nation pricing, which would tie the price for drugs in the United States to the lowest price in a group of other countries. In response, multiple manufacturers have entered into confidential pricing agreements with the federal government. On the other hand, the Trump administration is pursuing traditional regulatory pathways to impose drug pricing policies and published two proposed regulations in December 2025, referred to as Globe and Guard. If finalized, these regulations would implement mandatory payment models under which manufacturers of eligible drugs would be required to pay rebates to the federal government on a portion of the units of their drugs that are reimbursed by Medicare, with the rebate amount based on most favored nation pricing. Imposing a rebate in the United States that is based on drug prices outside the United States would mark a drastic and unprecedented shift in the U.S. pharmaceutical market, and while the impact of the Globe and Guard proposed regulations, if finalized, cannot yet be determined, it is likely to be significant. Even regulatory proposals or executive actions that are ultimately deemed unlawful could negatively impact the U.S. pharmaceutical sector and our business.

Individual states in the United States have also become increasingly active in implementing regulations designed to control pharmaceutical 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. Some states have enacted legislation creating so-called prescription drug affordability boards with the goal of imposing price limits on certain drugs in these states, and at least one state board is imposing an upper payment limit. States are also seeking to implement general, across the board price caps for pharmaceuticals, or are seeking to regulate drug distribution. Some measures are designed to encourage importation from other countries. In addition, regional healthcare authorities and

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individual hospitals are increasingly using bidding procedures to determine which drugs and suppliers will be included in their healthcare programs. Furthermore, there has been increased interest by third party payors and governmental authorities in reference pricing systems and publication of discounts and list prices.

We expect that additional state and federal healthcare reform measures will 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 products once approved or additional pricing pressures. The implementation of cost containment measures or other healthcare reforms may prevent us from being able to generate revenue, attain profitability or commercialize our product candidates.

Foreign Regulation

To market any product outside of the United States, we would need to comply with numerous and varying regulatory requirements of other countries regarding safety and efficacy and governing, among other things, clinical trials, marketing authorization (MA), commercial sales and distribution of our products. The foreign regulatory approval process includes all of the risks associated with FDA approval set forth above, as well as additional country-specific regulation.

Whether or not we obtain FDA approval for a product, we must obtain approval of a product by the comparable regulatory authorities of foreign countries before we can commence clinical trials or marketing of the product in those countries. Approval by one regulatory authority does not ensure approval by regulatory authorities in other jurisdictions. The approval process varies from country to country, can involve additional testing beyond that required by FDA, and may be longer or shorter than that required for FDA approval. The requirements governing the conduct of clinical trials, product licensing, pricing, promotion, and reimbursement vary greatly from country to country.

Non-clinical Studies and Clinical Trials in the EU

Similarly to the United States, the various phases of non-clinical and clinical research in the European Union (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). In particular, non-clinical studies, both in vitro and in vivo, must be planned, performed, monitored, recorded, reported and archived in accordance with the GLP principles, which define a set of rules and criteria for a quality system for the organizational process and the conditions for non-clinical studies. These GLP standards reflect the Organization for Economic Co-operation and Development requirements.

Clinical trials of medicinal products in the EU must be conducted in accordance with EU and national regulations and the International Council for 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. 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.

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While the EU Clinical Trials Directive required a separate clinical trial application (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 Good Manufacturing Practice (GMP). Other national and EU-wide regulatory requirements may also apply.

Marketing Authorization in the EU

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

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“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 are valid throughout the EU. The centralized procedure is compulsory for certain types of medicinal products such as (i) medicinal products derived from biotechnological processes, (ii) designated orphan medicinal products, (iii) advanced therapy medicinal products (ATMPs) (such as gene therapy, somatic cell therapy and tissue engineered products) and (iv) medicinal products containing a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases or autoimmune diseases and other immune dysfunctions, and viral diseases. The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU.

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

Under the centralized procedure the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops. Under the above described procedures, in order to grant the MA, the EMA or the competent authorities of the EU member states make an assessment of the risk benefit balance of the product on the basis of scientific criteria concerning its quality, safety and efficacy. MAs have an initial duration of five years. After these five years, the authorization may be renewed on the basis of a reevaluation of the risk-benefit balance.

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Data and Marketing Exclusivity in the EU

In the EU, new products authorized for marketing (i.e., reference products) generally receive eight years of data exclusivity and an additional two years of market exclusivity upon MA. If granted, the data exclusivity period prevents generic and 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 ten years have elapsed from the initial MA of the reference product in the EU. The overall ten-year market exclusivity period can be extended to a maximum of eleven years if, during the first eight years of those ten 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 or biological entity, and products may not qualify for data exclusivity.

Orphan Medicinal Products in the EU

The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States. A medicinal product can be designated as an orphan if its sponsor can establish that: (1) the product is intended for the diagnosis, prevention or treatment of a life threatening or chronically debilitating condition (2) either (a) such condition affects not more than five in 10,000 persons in the EU when the application is made, or (b) the product, without the benefits derived from the orphan status, would not generate sufficient return in the EU to justify the necessary investment; and (3) there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been authorized for marketing in the EU or, if such method exists, the product will be of significant benefit to those affected by that condition.

Orphan designation must be requested before submitting an MAA. An EU orphan medicinal product designation entitles a party to incentives such as reduction of fees or fee waivers, protocol assistance, and access to the centralized procedure. Upon grant of a MA, orphan medicinal products are entitled to ten years of market exclusivity for the approved indication, which means that the competent authorities cannot accept another MAA, or grant a MA, or accept an application to extend a MA for a similar medicinal product for the same indication for a period of ten years. The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed pediatric investigation plan (PIP). No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for orphan indications. Orphan medicinal product designation does not convey any advantage in, or shorten the duration of, the regulatory review and approval process.

The orphan exclusivity period may be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for which it received orphan designation, including where it is shown that the product is sufficiently profitable not to justify maintenance of market exclusivity or where the prevalence of the condition has increased above the threshold. Additionally, MA may be granted to a similar product for the same indication at any time if (i) the second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically superior; (ii) the applicant consents to a second orphan medicinal product application; or (iii) the applicant cannot supply enough orphan medicinal product.

Pediatric Development

In the EU, MAAs for new medicinal products have to include the results of studies conducted in the pediatric population, in compliance with a PIP agreed with the EMA’s Pediatric Committee (PDCO). The PIP sets out the timing and measures proposed to generate data to support a pediatric indication of the product candidate for which MA is being sought. The PDCO can grant a deferral of the obligation to implement some or all of the measures of the PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults. Further, the obligation to provide pediatric clinical trial data can be waived by the PDCO when these data is not needed or appropriate because the product is likely to be ineffective or unsafe in children, the disease or condition for which the product is intended occurs only in adult populations, or when the product does not represent a significant therapeutic benefit over existing treatments for pediatric patients. Once the MA is obtained in all the EU

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member states and study results are included in the product information, even when negative, the product is eligible for six months’ supplementary protection certificate extension (if any is in effect at the time of approval) or, in the case of orphan medicinal products, a two year extension of the orphan market exclusivity is granted.

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.

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.

Regulation of Companion Diagnostics in the EU

In the EU, in vitro diagnostic medical devices (IVD MDs), were regulated by the EU Directive on in vitro diagnostic medical devices (Directive No. 98/79/EC, as amended) (IVDD), which regulated the placing on the market, the European Conformity (CE) marking, the essential requirements, the conformity assessment procedures, the registration obligations for manufacturers and devices as well as the vigilance procedure. IVD MDs had to comply with the requirements provided for in the IVDD, and with further requirements implemented at national level (as the case may be).

The regulation of companion diagnostics is subject to further requirements since Regulation (EU) No 2017/746 (IVDR) became applicable on May 26, 2022. Following subsequent legislative changes, European institutions adopted a “progressive” roll-out of the IVDR to prevent disruption in the supply of in vitro diagnostic medical devices. Therefore, the IVDR applies since May 26, 2022, but there is a tiered system extending the grace period for many devices (depending on their risk classification) before they have to be fully compliant with the regulation. The IVDR introduced a new classification system for companion diagnostics which are now specifically defined as diagnostic tests that support the safe and effective use of a specific medicinal product, by identifying patients that are suitable or unsuitable for treatment. Companion diagnostics will have to undergo a conformity assessment by a notified body. Before it can issue an EU certificate, the notified body must seek a scientific opinion from the EMA on the suitability of the companion diagnostic to the medicinal product concerned if the medicinal product falls exclusively within the scope of the centralized procedure for the authorization of medicines, or the medicinal product is already authorized through the centralized procedure, or a MAA for the medicinal product has been submitted through the centralized procedure. For other substances, the notified body can seek the opinion from national competent authorities or the EMA.

The aforementioned EU rules are generally applicable in the EEA.

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

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Human Capital

As of February 25, 2026, we had 87 full-time employees, including a total of 21 employees with M.D. or Ph.D. degrees. Of these full-time employees, 67 employees are engaged in research and development.

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.

Our human capital resources objectives include, as applicable, identifying, recruiting, retaining, incentivizing and integrating our existing and additional employees. The principal purposes of our equity incentive plans are to attract, retain and motivate selected employees, consultants and directors through the granting of stock-based compensation awards. We value our employees and regularly benchmark total rewards we provide, such as short and long-term compensation, 401(k) plan participation, health, welfare and quality of life benefits, paid time off and personal leave, against our industry peers to ensure we remain competitive and attractive to potential new hires.

Available Information

Our internet address is www.tyra.bio. Our investor relations website is located at https://tyrabio.investorroom.com. We make available free of charge on our investor relations website under “SEC Filings” our annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K, our directors’ and officers’ Section 16 reports and any amendments to those reports as soon as reasonably practicable after filing or furnishing such materials to the SEC. They are also available for free on the SEC’s website at www.sec.gov.

We use our investor relations website as a means of disclosing material non-public information and for complying with our disclosure obligations under Regulation FD. Investors should monitor such website, in addition to following our press releases, SEC filings and public conference calls and webcasts. Information relating to our corporate governance is also included on our investor relations website The information in or accessible through the SEC and our website are not incorporated into, and are not considered part of, this filing.