Tyra Biosciences Inc

Overview

We are a clinical-stage biotechnology company focused on developing next-generation precision medicines that target large opportunities in Fibroblast Growth Factor Receptor (FGFR) biology. Our in-house precision medicine platform, SNÅP, enables rapid and precise drug design through iterative molecular SNÅPshots that help predict genetic alterations most likely to cause acquired resistance to existing therapies. Our initial focus is on applying our accelerated small molecule drug discovery engine to develop therapies in targeted oncology and genetically defined conditions.

In oncology, the widespread availability of approved targeted treatments, such as kinase inhibitors, has transformed the cancer treatment landscape. Despite the therapeutic benefit that targeted oncology treatments have created for some patients, the response rate and duration of efficacy is often limited by acquired drug resistance, off-target toxicities and other shortcomings of existing therapies. We are using our proprietary SNÅP platform in order to generate novel product candidates that are specifically designed to limit off-target toxicities and address acquired drug resistance to provide next-generation treatment options.

Our lead product candidate, TYRA-300, is an investigational, oral, FGFR3-selective inhibitor currently being evaluated in an international, multi-center, open label Phase 1 clinical study, SURF301 (Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors). SURF301 (NCT05544552) was designed to determine the optimal and maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300. SURF301 is currently enrolling adults with locally advanced or metastatic urothelial carcinoma (mUC) and other advanced solid tumors with FGFR3 gene alterations. As of March 2024, the Part A, Phase 1 portion of SURF301 has completed dose escalation without determining an MTD, and the current expansion cohorts in Part B are evaluating potentially therapeutic once daily and twice daily doses. We expect to submit initial results from the SURF301 Phase 1 portion for presentation at a scientific congress in the second half of 2024.

Beyond oncology, FGFR3 is implicated in many genetically-defined conditions, such as achondroplasia (ACH) and other skeletal dysplasias, due to its role in regulating bone and cartilage formation. In March 2023, we announced we were expanding development of TYRA-300 into ACH based on positive preclinical results demonstrated in a study performed in collaboration with the Imagine Institute in Paris, France. Data from the study showed that TYRA-300 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) (with n=8 for TYRA-300, after excluding two mice from dataset when molecular analysis showed chimeric incorporation of mutation, and n=10 for vehicle, after excluding one vehicle mouse from dataset when molecular analysis showed chimeric incorporation of mutation). Achondroplasia, the most common form of dwarfism, is a skeletal dysplasia in which growth plate cartilage is affected, resulting in decreased growth of the long bones, vertebral bodies and skull base. These growth differences can result in health complications such as foramen magnum and spinal stenosis, hydrocephalus, genu varum (bowed legs), and sleep apnea. A specific DNA mutation in FGFR3 causes an estimated 99% of ACH.

We believe that the design of TYRA-300 may have a meaningful impact on ACH and potentially other skeletal dysplasias. We are conducting additional Investigational New Drug Application (IND)-enabling studies and plan to submit an Investigational New Drug (IND) application to the FDA in the second half of 2024 for the initiation of a Phase 2 clinical trial testing multiple doses of TYRA-300 to support children with ACH. We expect that the primary objective of this study will be to assess safety and tolerability in children with ACH and determine the dose(s) for further development. We expect that secondary objectives will include evaluating change in growth velocity, growth proportionality and pharmacokinetics (PK). We are also planning exploratory assessments of clinical outcomes and quality of life measures, and an evaluation of biomarkers to determine dose-response relationships to TYRA-300. Our current expectation is that the study will initially evaluate treatment naïve children ages 5-12 to determine optimal dose ranges, and will also include a separate cohort and analysis of children ages 5-12 with ACH who have received and did not tolerate or respond to a prior growth accelerating therapy. In July 2023 and January 2024, the FDA granted Orphan Drug Designation (ODD) and Rare Pediatric Disease (RPD) Designation to TYRA-300, respectively, for the treatment of ACH.

Our second oncology product candidate, TYRA-200, is an investigational, oral, FGFR1/2/3 inhibitor with potency against activating FGFR2 gene alterations, as well as clinically important molecular brake and gatekeeper resistance mutations. TYRA-200 is currently being evaluated in a multi-center, open label Phase 1 clinical study, SURF201 (Study in Previo Usly treated and Resistant FGFR2+ Cholangiocarcinoma and Other Advanced Solid Tumors) (NCT06160752) that is designed to evaluate the safety, tolerability, and PK of TYRA-200 and determine the optimal dose for further development and the MTD and RP2D, as well as evaluate preliminary antitumor activity.

Our SNÅP Platform

We developed our proprietary SNÅP platform to efficiently identify and selectively target vulnerabilities in the mutant proteins where genetic alterations have eliminated or reduced the effectiveness of targeted therapies. Through the rapid generation of precise molecular SNÅPshots, we continually gain deeper insights into the structure of inhibitor binding sites and how commonly occurring genetic alterations lead to acquired drug resistance to existing therapies. Leveraging these insights, we aim to predict the genetic alterations most likely to cause resistance to specific existing therapies and develop compound candidates with innovative structures that are designed to inhibit the target while avoiding those mutations. Furthermore, we have developed this platform as a tool to fine-tune selectivity of candidates where we seek to minimize the activity of one target over another. Each SNÅPshot enables us to see protein and compound interactions on an angstrom scale, with an aim to build in selectivity for a target even among a family of proteins that share a very similar sequence identity. Through this process, we identify product candidates that may have the potency and selectivity to, if approved, be used as important treatment options to address critical unmet needs.

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

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.

Cell-based assays. We assess inhibitor potency directly inin 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.

In vivo models. Our direct structural insights andin vitro datasets are complemented byin 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.

SNÅP platform

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.

Our Programs

Below is an overview of our programs.

Our FGFR3 Programs—TYRA-300

In oncology, we are developing our lead product candidate, TYRA-300, an investigational, oral, selective inhibitor of FGFR3, for the treatment of patients with locally advanced or metastatic mUC and other advanced solid tumors with activating mutations in FGFR3. One common mechanism of acquired drug resistance in kinases such as FGFR3 is the emergence of gatekeeper mutations. For example, the V555M and V555L gatekeeper mutations have been shown to block access to a portion of the binding pocket accessed by first generation pan-FGFR inhibitors, such as Balversa (erdafitinib), the only currently FDA approved FGFR-targeted therapy for mUC, as well as Pemazyre (pemigatinib) and Lytgobi (futibatinib), which are pan-FGFR inhibitors approved for intrahepatic cholangiocarcinoma with activating FGFR2 fusions or other rearrangements. Because we believe the gatekeeper mutation represents a key limitation to the efficacy and durability of first generation FGFR inhibitors, we have designed TYRA-300 to avoid interactions with the gatekeeper region of the FGFR binding site. In cell-based assays and preclinical xenograft models, we observed that TYRA-300 had similar potency against cells harboring the wild-type or the gatekeeper mutations.

In addition to addressing the gatekeeper resistance mutations, we have designed TYRA-300 to be more selective for FGFR3 over FGFR1, FGFR2, and FGFR4 to minimize off-target side effects, providing potential clinical advantages over less selective first-generation compounds. The product labels of first-generation inhibitors report high discontinuation and dose reduction rates, ranging from 23% for pemigatinib to 75% for infigratinib. Each approved inhibitor reports hyperphosphatemia (60%+), which is a well-characterized adverse event, due to FGFR1 inhibition. Hyperphosphatemia is an electrolyte disorder characterized by an elevated level of phosphate in the blood. Hyperphosphatemia is commonly observed in patients treated with these inhibitors, and is the dose-limiting toxicity for erdafitinib, which may potentially limit its efficacy. This is particularly important in the mUC population, where more than half of patients are ineligible for cisplatin therapy due to underlying renal dysfunction, making hyperphosphatemia resulting from pan-FGFR inhibitors more difficult to manage. FGFR2 drives potentially debilitating oral, nail, ocular, and skin toxicities, and FGFR4 drives gastrointestinal-related toxicities such as diarrhea and increases in liver enzymes (aspartate aminotransferase and alanine transaminase).

In addition, we believe that if we are able to establish a differentiated tolerability profile for TYRA-300, we will have the potential to pursue additional indications, including a large population of patients with non-muscle invasive bladder cancer (NMIBC) as well as other FGFR3-driven conditions, where pan-FGFR inhibitors may see limited use due to toxicity from inhibition of FGFR1, FGFR2, and FGFR4. It is estimated that a majority of the approximately 80,000 annual cases of urothelial cancer in the United States are initially diagnosed as NMIBC, where up to 80% may harbor FGFR3 activating mutations. This is a large potential future market opportunity for our product candidate with approximately 50,000+ addressable patients with intermediate to high risk, FGFR3+ NMIBC seeking new treatment annually in the United States. This patient population represents a potential outsized opportunity in oncology relative to most other targeted therapies.

The risk of recurrence of NMIBC, or progression to muscle-invasive bladder cancer (MIBC), results in long term urologic follow up and treatment, which may ultimately lead to surgical removal of the bladder (cystectomy). Janssen Pharmaceutical’s Balversa (erdafitinib), a pan-FGFR inhibitor, received full approval for adult patients with locally advanced or metastatic UC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. In addition, Janssen has reported preliminary clinical data regarding erdafitinib’s potential anti-tumor activity in patients with NMIBC. In 2023, erdafitinib administered orally demonstrated a 75% complete response (CR) rate in intermediate risk patients (data presented at the 2023 ASCO Genitourinary (GU) Symposium) and a 73% 6 months’ CR rate in high-risk carcinoma in situ (CIS) patients (data presented at the 2023 Society of Urologic Oncology (SUO)). Further, in a randomized setting versus intravesical chemotherapy, erdafitinib prolonged relapse-free survival (RFS) compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after bacillus Calmette-Guérin (BCG) therapy and refused or were ineligible for radical cystectomy. However, the safety and tolerability profile displayed in these studies was generally consistent with that known for oral erdafitinib, despite using a lower 6 mg daily dose, leading to tolerability issues. Janssen has reported it is now pursuing locally administered erdafitinib with TAR-210, an erdafitinib-eluting intravesical device that demonstrated an 87% CR rate in intermediate risk patients and 82% RFS in high-risk papillary patients in preliminary datasets (presented at the European Society for Medical Oncology (ESMO) conference in 2023). Based on these findings targeting FGFR3, we believe an orally administered selective FGFR3 inhibitor, with minimal effects from other FGFR-related toxicities, could address patients in an area with a high unmet need.

Our FGFR3 Achondroplasia and Skeletal Dysplasia Program

Beyond oncology, mutations in FGFR3 are implicated in a family of skeletal conditions due to its role in regulating bone and cartilage formation. We believe that there is an opportunity to develop TYRA-300 to potentially address the long-term complications associated with these rare skeletal conditions including achondroplasia, hypochondroplasia, thanatophoric dysplasia, and other FGFR3-driven genetic syndromes. Our structural insights into FGFR3-selective chemistry from TYRA-300 may provide an opportunity to develop an oral therapy that provides significant benefit to these children.

In March 2023, we announced we were expanding development of TYRA-300 into achondroplasia based on positive preclinical results demonstrated in a study performed in collaboration with the Imagine Institute in Paris, France. In the study, TYRA-300 was evaluated in FGFR3 wild-type and mutant preclinical models to measure increases in growth and bone length, compared to vehicle-treated mice. In an FGFR3 Y367C/+ model, TYRA-300 was administered daily at a 1.2 mg/kg dose for 15 days. TYRA-300 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). We are conducting additional IND-enabling studies and plan to submit an IND to the FDA in the second half of 2024 to enable a Phase 2 study in pediatric achondroplasia.

Our FGFR2 Program

Our second product candidate, TYRA-200, is an FGFR1/2/3 inhibitor with potency against activating FGFR2 gene alterations, as well as clinically important molecular brake and gatekeeper resistance mutations. We are studying TYRA-200 initially in FGFR2-driven Intrahepatic cholangiocarcinoma (ICC) resistant to previous FGFR inhibitors. TYRA-200 is currently being evaluated in a multi-center, open label Phase 1 clinical study, SURF201 (Study in Previo Usly treated and Resistant FGFR2+ Cholangiocarcinoma and Other Advanced Solid Tumors) (NCT06160752) that is designed to evaluate the safety, tolerability, and PK of TYRA-200 and determine the optimal dose for further development and the MTD and RP2D, as well as evaluate preliminary antitumor activity. Acquired resistance mutations, such as gatekeeper and molecular brake mutations, have been observed in patients treated with Pemazyre (pemigatinib) and Lytgobi (futibatinib), two FDA approved pan-FGFR inhibitors for ICC. Newer agents in the clinic, such as lirafugatinib (RLY-4008), thus far have shown limited activity against some of these key resistance mutations, indicating that acquired resistance remains an area of high unmet need. We have designed TYRA-200 to be active against nearly all of the clinically identified acquired resistant mutations that arise during treatment with other FGFR inhibitors, which we believe is necessary to address the problem of disease progression due to polyclonal resistance.

Our FGF19+ Program

We are also progressing TYRA-430, a molecule designed to address unmet needs in cancers driven by the FGF19/FGFR4 oncogenic axis. Our FGF19+ program is initially focused on hepatocellular carcinoma (HCC), where FGF19 overexpression has been shown to be an important driver in a subpopulation of HCC. Recent insights into FGF/FGFR signaling in HCC indicates the potential for TYRA-430 to address an important bypass mechanism by also inhibiting FGFR3, as well as acquired resistance mutations that have limited the efficacy of previous FGFR4-specific inhibitors. In addition, we are exploring a novel mitigation strategy that may address dose-limiting FGFR4-specific toxicity seen with previous inhibitors.

Our Strategy

At Tyra, we do not accept that cancer patients with acquired drug resistance should be left with the devastating reality of limited or no treatment options or that people with genetically defined conditions should not have treatment options providing meaningful medical benefit. Our vision is to become a leading biotechnology company utilizing our unique approach to designing and developing next-generation precision medicines that target large opportunities in FGFR biology. Key elements of our strategy to achieve our vision are as follows:

Advance next-generation precision medicines through clinical development and regulatory approval. We are developing our oncology product candidates with a goal of overcoming acquired resistance and off-target toxicities that result in reduction of the therapeutic effects of less selective pan-FGFR inhibitors. We are initially developing TYRA-300 for patients with mUC, where a more selective, gate keeper agnostic, inhibitor may be more potent, better tolerated, and result in higher response rates and longer duration of responses. While TYRA-300 is being evaluated initially in mUC, we believe that a better tolerated, highly selective molecule can address earlier NMIBC disease, where a balance of efficacy and tolerability are important factors for patient adherence and acceptance. In November 2022, we commenced our Phase 1 clinical trial of TYRA-300, SURF301 (Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors), an international multi-center, open label study designed to determine the optimal and MTD and the RP2D of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300. In July 2023 and January 2024, the FDA granted ODD and RPD Designation to TYRA-300, respectively, for the treatment of ACH.

In March 2023, we announced we were expanding development of TYRA-300 into ACH based on positive preclinical results demonstrated in a study performed in collaboration with the Imagine Institute in Paris, France. We are conducting additional IND-enabling studies and plan to submit an IND to the FDA in the second half of 2024 to support the initiation of a Phase 2 clinical trial testing multiple doses of TYRA-300 to support children with ACH. We expect that the primary objective of this study will be to assess safety and tolerability in children with ACH and determine the dose(s) for further development. We also expect that secondary objectives will include evaluating change in growth velocity, growth proportionality and pharmacokinetics. We are also planning exploratory assessments of clinical outcomes and quality of life measures, and an evaluation of biomarkers to determine dose-response relationships to TYRA-300.

Our second product candidate, TYRA-200, is an FGFR1/2/3 inhibitor that is specifically designed to retain potency against all of the known resistance mutations that arise in ICC patients who are treated with other FGFR inhibitors. No other FGFR inhibitors retain potency across all of these mutations to the same degree as TYRA-200 in vitro. We hypothesize that each FGFR inhibitor will select for resistance mutations for which they have the least potency, resulting in disease progression and treatment failure. We believe the ability to address the breadth of mutations with TYRA-200 fills an important unmet need in this population of ICC patients and could drive longer duration of response compared to other FGFR inhibitors. In December 2023, we commenced our Phase 1 clinical trial of TYRA-200, SURF201 (Study in previo Usly treated and Resistant FGFR2+ Cholangiocarcinoma and Other Advanced Solid Tumors), a multi-center, open label study designed to evaluate the safety, tolerability, and PK of TYRA-200 and determine the optimal dose for further evaluation and the MTD and RP2D, as well as evaluate preliminary antitumor activity. This study will initially focus on demonstrating whether TYRA-200 can provide clinical benefit to patients who had an initial response and then progressed on a prior FGFR inhibitor due to acquired resistance mutations.

Harness the strength of our SNÅP platform to rapidly develop additional next-generation precision therapies. We believe our SNÅP platform has disrupted the conventional process used to discover differentiated product candidates, resulting in what we believe is a significantly condensed time frame. Although our initial focus has been on a specific set of drug targets, our SNÅP platform can be extended to multiple gene families and therapeutic areas. We plan to leverage our SNÅP platform to expand our pipeline with additional oncology and genetically-defined conditions where there is high unmet need.

Leverage the recent advances in the precision medicine landscape to potentially expedite our product candidates’ development. There have been multiple recent accelerated approvals by the FDA of targeted therapies based on compelling clinical outcomes from single-arm dose expansion cohort clinical trials. Recent accelerated approvals have been conditionally granted in as little as three years from initial clinical testing. Our clinical programs are designed to address important unmet medical needs, which may allow us to leverage these precedents used by recently approved precision oncology and rare disease drugs to seek expedited regulatory review(s) and approval(s) if we successfully develop one or more of our product candidates. However, we have not discussed accelerated approval with the FDA for any of our programs, and as a result, there is no assurance that an accelerated pathway will be available to us or that it will lead to a faster development process or a faster regulatory review. While an accelerated pathway may potentially expedite development or the approval process, it does not change the FDA’s standards of approval or increase the likelihood that a product candidate will receive approval.

In addition, advances in next-generation genomic sequencing, particularly blood-based assays (liquid biopsy), continue to expand access to information that helps patients and their physicians identify potential personalized therapies that address tumor and germline mutations. We believe increasing access to liquid biopsy in our clinical trials may assist us in identifying and enrolling patients, thereby allowing us to accelerate the development timeline of our product candidates.

Maximize the value of our product candidates across multiple therapeutic areas through accelerated development and potential partnerships. We believe that our ability to generate product candidates with improved selectivity for the target of interest enables the possibility of designing and developing product candidates for indications outside of oncology. Specifically, we believe we can apply our SNÅP platform to targets, such as FGFR3, that have data validating their role in the pathogenesis of genetic conditions, including achondroplasia and other skeletal dysplasias. We currently retain worldwide rights to all of our product candidates. We will consider entering into compound, target or geographic specific strategic partnerships on an opportunistic basis if we believe that such a partnership can accelerate the development and/or maximize the market potential of a product candidate.

Background

Protein kinase inhibitors in cancer and the challenge posed by acquired drug resistance

Receptor tyrosine kinases (RTKs) are a family of proteins that respond to external growth factors affecting cell proliferation. In cancer, RTKs can be constitutively activated though gain-of-function mutations or gene rearrangements, driving tumor growth. Protein kinase inhibitors are a class of targeted therapies that can effectively block protein kinase signaling and cause tumor regression. These targeted therapies have delivered profound therapeutic benefits in the treatment of cancer. Despite the success of these drugs, they have been susceptible to acquired drug resistance and reduction of effect, leaving patients with limited or no treatment options. In particular, these current or first-generation kinase inhibitors lose potency in response to mutations that prevent the drug from binding to the target protein, allowing the kinase to continue to function resulting in continued tumor growth. This mutation, and resulting loss of potency from these kinase inhibitors, results in the patient’s cancer becoming refractory to treatment and the patient regressing.

Overview of RTK activating mutations and acquired drug resistance mutations

Development of acquired drug resistance to kinase inhibitors is common among protein kinases. Acquired on-target resistance has emerged in nearly every validated target, including FGFR, RET, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KIT, neurotrophic tropomyosin receptor kinase (NTRK), ROS1 and mesenchymal epithelial transition factor (MET). These key resistance mutations can be generally grouped into four classes:

Gatekeeper. Mutations such as BCR-ABL T315I and EGFR T790M are known as gatekeeper mutations because they are found at a key location at the entrance to a hydrophobic pocket in the back of the adenosine triphosphate (ATP) binding site that many kinase inhibitors access to increase potency and obtain specificity.

Molecular brake. Activating mutations in the kinase domain of RTKs are associated with the development of many forms of cancer. A number of these mutations cluster in a hinge region of the kinase structure, resulting in kinase activation by disengaging a highly conserved region referred to as a molecular brake.

Cys mutant. Irreversible kinase inhibitors, such as Tagrisso (osimertinib), typically covalently attach to cysteine residues in the kinase active site. EGFR C797S and corresponding mutations in cysteine residues of other kinases prevent binding and block the activity of these inhibitors.

Solvent front. Certain kinase inhibitors obtain their specificity by interacting with amino acid residues located at the opening of the ATP binding site to solvent. Mutations in these residues that lead to drug resistance are referred to as solvent front mutations.

The rapid rise of mutations that enable tumors to become resistant to previous generations of kinase inhibitors poses a challenge to drug developers, one that we believe will demand innovation for a long time to come.

Commercial success of next-generation kinase inhibitors

Osimertinib is an example of how a next-generation kinase inhibitor can not only overcome the limitations of acquired drug resistance to first generation therapies, but also demonstrate broader applicability across different lines of therapies. While first generation EGFR inhibitors, such as Iressa (gefitinib) and Tarceva (erlotinib), led to significant improvements in tolerability compared to standard of care chemotherapy, on average, tumor responses last only six to twelve months before disease progression. About 50% of treated patients developed drug resistance due to a gatekeeper mutation at T790M. Osimertinib’s ability to overcome this key gatekeeper mutation, which limited the duration of efficacy of first generation EGFR inhibitors, has contributed to osimertinib realizing 2022 sales of $5.4 billion, more than double the amount of the peak sales achieved by the two first generation inhibitors in 2013. In addition to its ability to overcome the gatekeeper mutation, osimertinib also displayed higher mutant selectivity and other performance enhancements resulting in greater tolerability, safety and efficacy. When used earlier in treatment, osimertinib nearly doubled progression-free survival compared to gefitinib or erlotinib with a better overall safety profile.

Illustration of osimertinib overcoming gatekeeper mutations

FGFR gene alterations in cancer and skeletal dysplasias

The FGFR family consists of four highly conserved RTKs, FGFR1-4. These receptors regulate a variety of cellular functions, including proliferation, differentiation, and survival. These genomic alterations, many of which lead to increased FGFR activity, have been found in cancers throughout the body, as shown in the figure below. The highest FGFR alteration frequencies are seen in urothelial cancer, ICC, hepatocellular carcinoma, endometrial cancer, lung cancers, breast cancer and cervical cancer. FGFR3’s critical role in chondrogenesis presents multiple sizeable opportunities outside of oncology. Alterations in FGFR3 have been found to drive around 99% of achondroplasia cases and additional FGFR3-related skeletal dysplasias, with a total addressable prevalence exceeding 40,000 children per year.

Alterations in FGFR drive many cancers and skeletal dysplasias

Four FGFR targeted therapies have been approved by the FDA for oncology: erdafitinib for locally advanced or metastatic urothelial carcinoma, or bladder cancer, 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. While patients may initially respond to FGFR targeted therapies, many develop acquired drug resistance, ultimately resulting in disease progression and discontinuation of therapy. Decreased activity of erdafitinib and pemigatinib due to resistance mutations that alter their ability to bind to the active site, such as gatekeeper mutations, has been observed. Gatekeeper mutations have also been seen in patients in a clinical trial treated with infigratinib while acquired-resistance molecular brake mutations have been seen in patients in clinical trials of pemigatinib, infigratinib and futibatinib. Off-target toxicities driven by FGFR1, 2, and 4 selectivity have also driven high rates of dose reductions and discontinuations, limiting treatment duration and potential efficacy for patients.

Beyond oncology, the FGFR3 pathway has been clinically validated in achondroplasia. In 2021, BioMarin Pharmaceutical’s Voxzogo, a once daily injectable C-natriuretic peptide (CNP) analog was granted accelerated approval in the United States for children with achondroplasia who are 5 years of age and older. CNP acts as a positive regulator of the signaling pathway downstream of FGFR3 to promote endochondral bone growth. Voxzogo approval was based on a 1.57cm/year mean annual height velocity improvement versus placebo. While the approval of Voxzogo is an important milestone in the treatment of children with achondroplasia, the long-term therapeutic benefit of increasing growth velocity is not yet known and the daily injection regimen for Voxzogo is also challenging for children and their parents. BridgeBio Pharma, Inc. (BridgeBio) is developing low dose infigratinib, an oral FGFR 1/2/3 inhibitor for achondroplasia, and in 2023 announced preliminary data for 12 subjects (Cohort 5, 0.25 mg/kg once daily) demonstrating a mean annual height velocity improvement of 3.38cm/year over baseline growth velocity. We believe TYRA-300, a once-daily oral FGFR3 selective inhibitor, may have a meaningful impact for children with achondroplasia and potentially other skeletal dysplasias.

Our Approach and Solution

Our SNÅP platform

We developed our proprietary SNÅP platform to efficiently identify and selectively target vulnerabilities in the mutant proteins where genetic alterations have eliminated or reduced the effectiveness of current targeted therapies. Our SNÅP platform is driven by our ability to generate iterative data rapidly and concurrently from three key pillars. Rapid generation of crystallographic data, use of custom cell-based assays andin vivo models comprise the three pillars of our platform. We leverage our platform to identify and develop product candidates that may have the potency and selectivity to address the liabilities that acquired drug resistance has created for other therapies. Collectively, our efforts to optimize and integrate these three pillars in parallel have enabled us to condense our design cycles and more quickly develop high quality, differentiated product candidates.

Rapid generation of crystallographic data

We have streamlined the use of protein crystallography to visualize the interaction of our potential product candidates with binding pockets of protein kinases. Through our proprietary methods, we can rapidly induce crystal formation and enhance crystal durability. Together, this reduces the time required to generate new crystal structures. We routinely generate co-crystal structures on newly synthesized compounds in as little as three days, a pace that allows us to continually refresh and, we believe, improve our insights into the features and structures that enable us to discover compounds that are potent and selective inhibitors of our targets. The rapid and iterative nature of our proprietary approach also allows us to address known mutations and potentially avoid future mutations.

While conventional discovery approaches prioritize computational simulations based on a small number of structures or structural models, we believe the ability to generate a large amount of empirical data obtained from many protein crystal structures is more informative and allows us to better design our product candidates. We are able to sustain rapid crystallography throughput, enabling the generation of graphical images of protein structures with and without bound inhibitors that, when combined with enzyme, cell andin vivo assays, comprise molecular SNÅPshots. These structures show the exact binding conformation of small molecules to our protein targets as well as the variations in protein structure that they induce at a resolution down to a single tenth of an angstrom (Å). We iterate rapidly between the wet lab and the crystallography lab and believe that the resulting datasets provide us with robust empirical data more quickly relative to conventional approaches as we seek innovative compounds that can potentially improve the selectivity and acquired drug resistance activity seen with other kinase inhibitors.

We capture variations in ligand-protein interactions by generating molecular SNÅPshots of many ligands

This figure shows several structures of the same protein which has been co-crystallized with different inhibitors. Certain regions of the protein, shown as dark gray loops, assume different conformations in the presence of different ligands. The plasticity of the protein revealed by these structures informs our drug design.

Custom cell-based assays

Determining the potency, selectively and cytotoxicity of our compounds early through custom cell-based assays allows us to rapidly evaluate, design and optimize our potential product candidates. The cell-based assays we use are a combination of cell lines derived from naturally occurring tumors and treatment-resistant tumors as well as engineered cell lines in which specific kinases or kinase mutations are introduced to create panels of isogenic cells. By providing direct evidence of cell penetration and target engagement, we believe these assays yield more meaningful information about the potential of our compounds compared to the artificial system of purified proteins used in standard enzymological screens. While we also assess the potency and selectivity of our compounds using enzyme assays, these assays primarily serve to provide concordance to the validity of our cell-based assays. As a result, these cellular systems are our primary screening tools to progress our potential product candidates. We are able to run newly synthesized compounds through these cell-based assays in as little as two days, helping to drive a rapid, iterative drug design cycle.

In vivo models

The ability to rapidly assess the potential of our compounds throughin vivo models to determine their PK/pharmacodynamic (PD) parameters in addition to their target-specific antitumor activity is paramount. We establish and validate the majority of our models in-house, which allows us to rapidly test new compounds and to collect actionable data in as little as five days. We feed this information back into our design cycle, allowing us to condense the traditional drug discovery timeline, prior to commencing clinical development.

A tight compound design, synthesis and testing loop

Our philosophy is to execute activities such as obtaining crystal structures, assaying for cellular activity and generatingin vivo data not as a set of sequential steps, but rather in concurrence in order to save time. Whereas more traditional drug discovery efforts may rely upon the availability of crystallographic andin vivo model data at monthly intervals, we strive to generate this data on a weekly basis. We do not wait to determine if a compound passes a potency test in a cell-based assay before evaluating it in other assays, with the explicit understanding that there is key knowledge to be gained from compounds that are not as potent as expected.

Our synchronized and compressed data generation cycle time allows us to accelerate drug discovery by allowing the execution of more drug design cycles in a fixed amount of time

Our ever-growing understanding of protein and inhibitor interactions, deepened by the crystal structures we continue to generate, provides insights that we leverage in product candidate engineering. We combine these potency and selectivity predictions with metabolic stability, bioavailability and PK data to design small molecules with the chemical properties required to become potential product candidates. In a single weekly drug discovery cycle, we profile newly synthesized compounds as follows.

Generating a crystal structure with a target protein in as little as three days.

Evaluating activity in ‘on-target’ and ‘off-target’ cell-based assays in as little as two days.

Measuring, efficacy, or tumor growth inhibition (TGI), of newly synthesized compounds in as little as five days.

Taken together, the high-resolution structural data and preclinical experiments inform new chemistry designs that are rapidly synthesized for evaluation in our next weekly drug discovery cycle. This process, enabled by trade-secrets and proprietary engineered assays, comprises our SNÅP platform. Our highly experienced team of medicinal chemists efficiently utilizes our platform to rapidly synthesize compounds designed to further optimize potency and selectivity, among other properties, while avoiding interactions with mutations which are known to induce drug resistance to other kinase inhibitors.

SNÅP platform

Targeted Oncology

Targeted oncology therapies approved by the FDA since 2018 have received their initial approvals in as little as three years after their first-in-human dosing began. FDA guidance indicates that the agency may accept overall response rate data from single-arm clinical trials as evidence of substantial clinical benefit that is sufficient for accelerated approval in settings with an unmet medical need. The nature of our clinical programs address areas of high unmet medical need, and based on these precedents, we believe that our product candidates may be eligible for accelerated approval should they demonstrate appropriate safety and efficacy in our clinical trials. However, we have not yet discussed criteria for accelerated approval with the FDA for any of our programs, and as a result, there can be no assurance that an accelerated pathway will be available for us or that it will lead to a faster development process or a faster regulatory review. While an accelerated pathway may potentially expedite development or the approval process, it does not change the FDA’s standards of approval or increase the likelihood that a product candidate will receive approval. In fact, recent guidance from FDA has indicated greater scrutiny of the accelerated approval process, particularly with regard to enrollment and readout of confirmatory trials needed for full approval.

Our FGFR3 Programs—TYRA-300 for Oncology

We are developing TYRA-300, an investigational, oral, selective inhibitor of FGFR3, for the treatment of patients with locally advanced or metastatic mUC and other advanced solid tumors with activating mutations in FGFR3. Resistance to approved and investigational pan-FGFR inhibitors has been shown to arise due to mutations in the gatekeeper region of FGFR3. We have designed TYRA-300 to avoid this region of FGFR3 and, in preclinical models to date, TYRA-300 has demonstrated similar potency against both wild-type and resistant FGFR3 targets. In addition, we have designed TYRA-300 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. We believe this differentiation will enable us to expand into multiple cohorts of FGFR3-driven cancer including mUC patients naïve to prior FGFR therapy, tumor agnostic populations, as well as patients with intermediate- and high-risk NMIBC. Although no head-to-head clinical trials have been conducted, we believe the use of comparative in vitro and in vivo data from pre-clinical studies provides meaningful insight into the potential for our product candidates to improve on certain characteristics of approved and investigational FGFR inhibitors and helps inform potential future clinical development of our product candidates.

Market Opportunity

Urothelial cancer disease background

Urothelial cancer (UC) is one of the most common malignancies of the genitourinary system and can involve the bladder or the upper urinary tract. Patients with UC classically present with painless blood in the urine. However, because this symptom is similar to those of benign disorders, such as urinary tract infections, cystitis, prostatitis and the passage of kidney stones, diagnosis of UC is often delayed as these other, more common, conditions are ruled out. Delays in diagnosis can lead to worse outcomes due to the presence of more advanced stage disease by the time a diagnosis of UC is made. We refer to bladder cancer, NMIBC and MIBC when describing localized disease, and UC and mUC when describing a population that includes both bladder and upper urinary tract cancers.

An estimated 82,290 new cases of bladder cancer and 16,710 deaths are projected for 2023 in the United States and over 725,000 people were living with bladder cancer in the United States in 2020. Globally, bladder cancer accounts for approximately 600,000 new cases and 200,000 deaths each year. Bladder cancer itself is classified into two broad categories: NMIBC where the cancer is restricted to surface lining of the bladder; and MIBC, which is a cancer that has grown deeper into the bladder wall and has a higher potential metastatic spread. Approximately 25-30% of newly diagnosed cases of bladder cancer are MIBC. Of the remaining 70-75% of new diagnoses of bladder cancer that are NMIBC cases, an estimated 10 to 15% progress to MIBC. Whereas the five-year survival for early stage NMIBC is 96.7%, it falls to 8.3% for metastatic MIBC.

FGFR3 is a protein receptor expressed on the cell surface that stimulates cellular proliferation upon binding of a fibroblast growth factor. Uncontrolled activation of FGFR3 has been implicated in the oncogenesis of multiple solid tumor types. The incidence of activating FGFR3 mutations in bladder cancer has been estimated to be as high as 80% in NMIBCs and up to 20% of mUC, making FGFR3 an attractive target for development.

Clarivate Analytics estimated that in 2022, across NIMBC, MIBC and mUC, approximately 160,000 patients were seeking therapy for first-time treatment or to address a recurrence. Applying FGFR3 alteration incidence to Clarivate Analytics’ estimates, we believe that approximately 60,000 FGFR3+ patients are addressable across intermediate and high risk NMIBC, MIBC and mUC in the United States alone. Additionally, studies indicate that approximately 0.7% of solid tumors outside of bladder cancer are driven by FGFR3 alterations.

Potential patient populations for our FGFR3 inhibitor

Standard of care and current limitations for the treatment of locally advanced or metastatic UC

Patients diagnosed with locally advanced or metastatic UC have newer treatment options with recent practice changing results reported in the first-line treatment setting. As reported at ESMO 2023, the combination of the antibody-drug conjugate Padcev (enfortumab vedotin) with the PD-1 inhibitor Keytruda (pembrolizumab) demonstrated a significant clinical benefit over standard platinum-based combination chemotherapy. In the EV-302/Keynote-A39 Phase III study, overall survival was improved from a median of 16.5 months for chemotherapy (95%CI 13.9-18.3) to 31.5 months for Padcev-Keytruda (95% CI, 25.4-not reached; HR 0.47; 95% CI, 0.38-0.58; P < .00001). However, the overall survival benefit was paired with significant systemic toxicities, such as peripheral neuropathy, hyperglycemia, increased liver enzymes, increased creatinine, diarrhea, skin rash, immune-related complications, and bone marrow suppression. Based on these data, in December 2023, the FDA granted full approval for the Padcev-Keytruda combination for the treatment of mUC in the frontline setting. Another Phase 3 study (Checkmate 901) for the combination of Opdivo (nivolumab) with cisplatin and gemcitabine in the frontline setting demonstrated an overall survival benefit of 21.7 months (95% CI, 18.6-26.4) compared to 18.9 months for chemotherapy alone (95% CI, 14.7-22.4). Prior to these studies, the standard treatment for patients was platinum-based chemotherapy with cisplatin or carboplatin in combination with gemcitabine. The median overall survival for patients treated with chemotherapy is only 12.7 months. Following chemotherapy, patients may receive immunotherapies, such as Bavencio (avelumab) as maintenance therapy or Keytruda (pembrolizumab) after progression on chemotherapy.

The approval of Padcev in combination with Keytruda has the potential to significantly shift the mUC treatment landscape. Both Keytruda and Padcev were approved as monotherapies in the second-line setting, but are now anticipated to largely be used in the first-line as the new standard of care. For FGFR3+ mUC patients who have received Padcev-Keytruda in the frontline setting, erdafitinib may become the second-line treatment of choice based on the results of the Phase 3 THOR study comparing erdafitinib to investigator's choice chemotherapy that was presented at ASCO 2023. The interim analysis demonstrated an overall survival benefit of 12.1 months for erdafitinib versus 7.8 months for investigator-choice chemotherapy. The safety profiles were consistent with the known profiles of erdafitinib and chemotherapy. Serious treatment-related adverse events were observed in 13.3% and 24.1% of patients with erdafitinib and chemotherapy, respectively, and grade 3/4 treatment-related adverse events were observed in 45.9% and 46.4% of patients with erdafitinib and chemotherapy, respectively. More treatment-related adverse events leading to dose reduction were observed with erdafitinib (66%) versus chemotherapy (21%), and 8% and 13% of patients had treatment-related adverse events leading to discontinuation of erdafitinib and chemotherapy, respectively. Central serous retinopathy occurred in 23 patients (17%) with erdafitinib (grade 1-2, 20 patients). In January 2024, the FDA granted full approval for erdafitinib for the treatment of patients with locally advanced or metastatic UC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Erdafitinib is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-L1 inhibitor therapy. Other approved options for treatment of mUC include Trodelvy (sacituzumab govitecan-hziy), another antibody-drug conjugate targeting the Trop-2 receptor, which was granted accelerated approval for mUC following treatment with platinum-containing chemotherapy and a checkpoint inhibitor based upon an overall response rate of 33.3%. Despite these recent advances with combination regimens and targeted agents, there continues to be a high unmet need for less toxic alternative first-line regimens as well as improvements in both efficacy and toxicity in subsequent lines of therapy.

Standard of care and current limitations for the treatment of localized MIBC

Patients suffering from localized MIBC are potentially curable with surgery, which may include trans-urethral resection (TURBT) partial cystectomy (partial removal of the bladder), or radical cystectomy (complete removal of the bladder and nearby lymph nodes) depending on the stage of the tumor. For those who are not physically able or willing to undergo surgery, localized radiation to the bladder is an option, but local recurrence rates are high, survival rates are no better than surgery, and few contemporary randomized studies have been performed comparing radiation and surgery in the same population of patients. TURBT and partial cystectomy are reserved for highly selected patients with earlier stage tumors, often combined with neoadjuvant chemoradiotherapy for those who are willing and able to tolerate such aggressive therapy. Despite these strict criteria, recurrence rates are high (as high as 60% in some series). For the majority of patients who can have surgery, complete removal of the bladder and lymph nodes remains the only potentially curative treatment option. However, despite such a life altering operation, recurrence of metastatic disease is estimated to be 50%, highlighting the need for effective adjuvant therapies that can decrease the risk of recurrence. Nivolumab was recently approved for the adjuvant treatment of patients at high risk for recurrence following surgery for bladder cancer. While there are currently no approved targeted therapies available for MIBC, a number of tyrosine kinase inhibitors are being studied in this setting. We believe that effective oral therapies that can reduce the rate of recurrence following surgery remains a high unmet need.

Standard of care and current limitations for the treatment of NMIBC

NMIBC comprises the largest population of bladder cancer patients, representing 70-75% of cases diagnosed annually in the United States. Initial evaluation consists of local resection to confirm the diagnosis and establish the grade and stage of the tumor. NMIBC can be categorized as low, intermediate and high risk. Low grade lesions are confined to the lining of the bladder. However, a significant proportion are considered intermediate and high risk for recurrence. Treatment of NMIBC is directed at reducing recurrences and preventing progression to a more advanced stage. For low grade lesions, local resection with or without adjuvant intravesical chemotherapy or Bacillus Calmette-Guerin (BCG), and close follow up are usually successful in curing the disease, whereas high risk lesions should be treated with either adjuvant BCG or radical cystectomy. Recurrence overall for NMIBC is 30-70%, but for high-risk patients, 5-year recurrence rates are as high as 80%, with progression to muscle invasive disease in up to 50% of patients. An additional 10-15% will recur with metastatic disease. Following recurrence of NMIBC, few bladder-sparing options are available to prevent future recurrences and disease progression. Those with NMIBC that recurs following BCG and are unable or refuse surgery may be treated with pembrolizumab, which was approved for patients with carcinoma in situ (CIS) based on a complete response rate of 41% and a median duration of response of 16.2 months, or Adstiladrin, a non-replicating adenoviral vector-based gene therapy that was approved in 2022 for patients with Papillary or CIS BCG-unresponsive NMIBC based on a 51% response rate and median duration of response of 9.7 months. Data has been submitted to the FDA in support of an NDA for N-803, an antibody cytokine fusion protein, showing a 71% response rate and 26.6 month duration of response for patients with BCG-unresponsive NMIBC, but only in the CIS subset, highlighting the need to provide the majority of patients with additional treatment options. In May 2023, the FDA issued a complete response letter in relation to the biologics license application (BLA) submitted for N-803 and in October of 2023 the FDA accepted a BLA resubmission. The PDUFA date for a decision on the resubmission is noted to be April 23, 2024.

FGFR Inhibitors

Patients with somatic alterations in FGFR3 can be treated with FGFR inhibitors. Currently, the only FDA approved FGFR inhibitor for locally advanced or metastatic UC is erdafitinib. In urothelial carcinoma patients with susceptible FGFR3 genetic alterations that progressed after at least one line of PD-(L)1 containing therapy, erdafitinib demonstrated a 35.3% overall response rate and a median progression free survival of 5.6 months and overall survival of 12.1 months, outperforming standard of care chemotherapy. We believe one of the key limitations to erdafitinib’s duration of response is the emergence of resistance mutations in the gatekeeper domain. This same mutation may limit the efficacy of other first generation FGFR inhibitors such as infigratinib, pemigatinib and futibatinib in mUC. In a study of infigratinib and other FGFR inhibitors, the mutation that has been described in patients is the valine to methionine gatekeeper mutation at the V555 position of FGFR3, which results in a significant shift in potency of all of the first generation FGFR inhibitors. Once patients progress due to acquired drug resistance, there are very few options available, representing a significant unmet need in this patient population.

FGFR gatekeeper mutations block binding, resulting in a loss of potency in first generation FGFR inhibitors such as erdafitinib

Erdafitinib and TAR-210 have established PoC for FGFR3 inhibition across bladder cancer; however, unmet needs remain

Erdafitinib is a pan-FGFR inhibitor and due to its lack of selectivity, there are toxicities associated with the inhibition of FGFR receptors 1, 2 and 4. FGFR1 is expressed in kidney cells where it regulates phosphate and calcium reabsorption, and inhibition of FGFR1 results in hyperphosphatemia. Inhibition of FGFR2 can result in toxicities that significantly impact quality of life, such as dry mouth and stomatitis, skin, ocular and nail toxicities (e.g., onycholysis and hand-foot syndrome), and ocular toxicities such as keratitis and blurred vision. Inhibition of FGFR4 disrupts bile acid metabolism, and can result in diarrhea and liver toxicity. Hyperphosphatemia was a dose-limiting toxicity of erdafitinib and was reported in over 70% of patients in the Phase 3 clinical trial. Overall, adverse events resulted in 72% dose interruptions, 69% dose reductions, and 14% treatment discontinuations. We believe the safety and tolerability profile of erdafitinib is a key limitation of 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.

Approximately 40-80% of NMIBC has been shown to carry FGFR3 gene alterations, the majority of which are activating point mutations. There are currently no approved targeted therapies for FGFR3-driven NMIBC patients. We believe that FGFR inhibitors have the potential to be highly efficacious in NMIBC, as suggested by oral erdafitinib’s preliminary 75% CR rate in intermediate risk patients presented at ASCO GU 2023, 77% RFS in high-risk papillary patients presented at ESMO 2023 and 73% 6 months’ CR rate in high-risk CIS patients presented at SUO 2023. The safety and tolerability results were generally consistent with that known for erdafitinib, despite using a lower 6mg daily dose in this study. TAR-210, an erdafitinib-containing device administered via the urethra, also demonstrated an 87% CR rate in intermediate risk patients and 82% RFS in high-risk papillary patients as presented at ESMO 2023. We believe an orally administered highly specific FGFR3-directed inhibitor, with minimal effects from other FGFR-related toxicities, has the potential to be highly efficacious and tolerable and represent a potentially large future market opportunity for our product candidate in the approximately 50,000+ addressable patients with intermediate to high risk, FGFR3+ NMIBC seeking new treatment annually in the United States.

We believe the limitations of current standard of care therapies, as well as the liabilities of first generation FGFR inhibitors, necessitates a solution that can address this unmet need and improve patient outcomes.

Our solution, TYRA-300

In November 2022, we initiated our Phase 1 clinical trial of TYRA-300, SURF301 (Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors), an international, multi-center, open label study designed to determine the optimal and MTD and the RP2D of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300.

SURF301 is currently enrolling adults with locally advanced or metastatic UC and other advanced solid tumors with FGFR3 gene alterations. As of March 2024, the Part A Phase 1 portion of SURF301 has completed dose escalation without determining an MTD, and the current expansion cohorts in Part B are evaluating potentially therapeutic once daily and twice daily doses. We expect to submit initial results from the SURF301 Phase 1 dose escalation and expansion portions for presentation at a scientific congress in 2024.

Preclinical data for TYRA-300 suggests the potential for a differentiated profile versus erdafitinib, including potency observed against the gatekeeper mutation and selectivity for FGFR3. Although no head-to-head clinical studies have been conducted, we believe that these pre-clinical studies assist with the characterization of our product candidates and inform future clinical development.

TYRA-300 is active in a bladder cancer xenograft model

UM-UC-14 is a human bladder cancer cell line which contains an FGFR3 S249C activating mutation. TYRA-300 was tested in a preclinical mouse xenograft model using this cell line, as seen in the figure below. TYRA-300 given either once daily (QD) at a dose of 18 mg/kg or twice daily (BID) at a dose of 9 mg/kg led to substantial inhibition of tumor growth in this model. We observed 90% tumor growth inhibition (TGI) at the 9 mg/kg BID dose and 96% TGI at the 18 mg/kg QD dose. We observed 91% TGI with erdafitinib using a 12.5 mg/kg BID dose in this study.

TYRA-300 tumor growth inhibition in a UM-UC-14 xenograft model

Antitumor activity in the FGFR3 S249C activating mutant UM-UC-14 bladder cancer xenograft model in nu/nu mice of various doses of TYRA-300 (3, 6, and 9 mg/kg BID, upper left; and 6, 12, and 18 mg/kg QD, lower left) and erdafitinib (12.5 mg/kg BID) shown in both the upper and lower left. Body weight averages for the dose groups depicted in the upper and lower left are shown in the upper and lower right, respectively. All doses were by oral administration. No TGI was observed for TYRA-300 at 3 mg/kg BID. TGI observed for the other TYRA-300 doses is shown in parentheses; 6 mg/kg BID (53%), 9 mg/kg BID ( 90%), 6 mg/kg QD (46%), 12 mg/kg QD (80%), and 18 mg/kg QD (96%). We observed 91% TGI for 12.5 mg/kg BID erdafitinib. Data points represent mean tumor volume (n=6 per group except 6 mg/kg BID TYRA-300 dosing group where one animal was found dead at day 7 of treatment where n=5) and error bars represent standard error of the mean.

In this model, we used a salt form of TYRA-300, and the vehicle is 30% hydroxypropyl beta cyclodextrin (HP-ß-CD) for both the erdafitinib and TYRA-300 groups. Based on the results of this study, we expect to use a salt form of TYRA-300 for future TYRA-300 development. The salt form/cyclodextrin formulation used here replaces the polyethylene glycol 400 formulation we used in the bladder cancer xenograft model utilizing the RT112/84 +/- V555M immortalized cancer cell line, as described further below.

Potent inhibition of FGFR3 mutants including gatekeeper mutations

We utilized our SNÅP platform to design TYRA-300 to avoid any interactions with the gatekeeper region of FGFR3, which most other FGFR kinase inhibitors rely on for potency. In a bladder cancer xenograft model, we observed that we could obtain FGFR3 potency roughly equivalent to that of erdafitinib, by targeting other parts of the kinase active site. Although no head-to-head clinical studies have been conducted, this design strategy provides what we believe is a key advantage in that FGFR3 proteins containing gatekeeper mutations, such as V555M, were inhibited by TYRA-300 with very similar potency to wild-type FGFR3. Other FGFR inhibitors were at least 30-fold less potent versus FGFR3 V555M.

TYRA-300 retained potency against multiple potential acquired drug resistance mutations in FGFR3

TYRA-300 retained potency in a V555M CRISPR mutated RT112/84 immortalized cancer cell line

The ability of TYRA-300 to maintain potency against the V555M gatekeeper mutation, as observed inin vitro assays conducted to date, was tested in a preclinical xenograft model containing an FGFR3 fusion, as seen in the figure below. TYRA-300, at a dose of 12.5 mg/kg twice daily, led to significant inhibition of tumor growth in this model. We also observed inhibition of tumor growth by erdafitinib at a dose of 12.5 mg/kg twice daily in this model. We engineered a gatekeeper mutation into the cell line used for this model. We observed 77% inhibition of tumor growth by TYRA-300 in xenografts using the cell line containing the gatekeeper mutation, while we observed 12% tumor growth inhibition in the gatekeeper xenograft treated with erdafitinib.

TYRA-300 tumor growth inhibition was maintained in the presence of the FGFR3 V555M gatekeeper mutation in a RT112/84 xenograft model

Anti-tumor activity of TYRA-300 (95% TGI, upper left) and erdafitinib (73% TGI, lower left) dosed BID by oral administration in the FGFR3::TACC3 fusion activating RT112/84 bladder cancer xenograft model in Balb/c nude mice. Data points represent mean tumor volume (n=8 per group on left, n=6 per group on right) and error bars represent standard error of the mean. To test the effect of the gatekeeper mutation on tumor growth inhibition, we introduced the V555M mutation into the FGFR3::TACC3 fusion gene in the RT112/84 cell line using CRISPR. Anti-tumor activity in this isogenic gatekeeper containing model was evaluated using TYRA-300 (77% TGI, upper right) and erdafitinib (12% TGI, lower right) dosed BID by oral administration. The erdafitinib delivery vehicle in this experiment is 20% hydroxypropyl beta cyclodextrin and the TYRA-300 delivery vehicle is polyethylene glycol 400.

High selectivity for FGFR3

Designing inhibitors that bind to the ATP-binding site and 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 TYRA-300, 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. The high FGFR3-specificity that we observed to date for our potential product candidates for FGFR3 also extended to the broader family of protein kinases, where we showed that very few kinases were inhibited by our potential product candidates. Although we have not conducted any head-to-head clinical studies, we believe that TYRA-300’s relative selectivity for FGFR3 observed in pre-clinical studies may address dose limiting toxicities of the first-generation compounds, enabling higher dosing and potentially better efficacy.

TYRA-300 was highly selective for FGFR3 over other FGFR isoforms in a Ba/F3 cell-based assay

Beyond selectivity for FGFR3 relative to FGFR1, FGFR2 and FGFR4, TYRA-300 avoided off-target inhibition of other kinases when profiled in a scanMAX (KINOMEscan) screen.

TYRA-300 was highly selective for FGFR3 over other protein kinases

Phosphate levels in vivo

In a xenograft model using a bladder cancer-derived cell line RT112/84 shown above, treatment with TYRA-300 led to tumor regression at a dose of 12.5 mg/kg delivered twice a day. Treatment with erdafitinib also resulted in tumor volume reduction at the same dose in this model. Because the human dosing of erdafitinib is limited by hyperphosphatemia we measured the plasma phosphate levels in male Sprague Dawley rats 24 hours after dosing. Plasma phosphate levels in TYRA-300 treated rats were not substantially elevated at 10 mg/kg, 30 mg/kg, or 60 mg/kg doses, unlike the erdafitinib doses, as seen in the figure below. We believe TYRA-300 may be able to sustain higher doses without inducing hyperphosphatemia.

TYRA-300 did not elevate phosphate relative to erdafitinib

Effect of a single oral dose (10, 30 or 60 mg/kg) of TYRA-300 or erdafitinib on plasma phosphate levels 24 hours after dosing in male Sprague Dawley rats. Each data point represents the plasma phosphate measurement from the pooled sample of all 4 rats per dose group. Plasma phosphate levels were observed to be lower in the TYRA-300 treated groups than in the erdafitinib treated groups.

Clinical development plans for TYRA-300 in oncology

In November 2022, we initiated our Phase 1 clinical trial of TYRA-300, SURF301 (Study in Untreated and Resistant FGFR3+ Advanced Solid Tumors), an international, multi-center, open label study designed to determine the optimal and MTD and the RP2D of TYRA-300, as well as to evaluate the preliminary antitumor activity of TYRA-300. SURF301 is currently enrolling adults with advanced urothelial carcinoma and other solid tumors with FGFR3 gene alterations.

We previously conducted IND-enabling studies for TYRA-300. In a completed 10-day non-GLP toxicology study in rats, TYRA-300 was well tolerated at dose levels up to 20 mg/kg in both males and females. We also conducted GLP toxicology studies in animals of TYRA-300 using the salt form/cyclodextrin formulation as part of our IND-enabling activities. TYRA‑300 was well tolerated at dose levels up to 5 mg/kg daily in rats and doses up to 2 mg/kg daily in dogs for 28 days.

The Phase 1 portion of our SURF301 study has been designed as an accelerated dose escalation study and the primary objectives of the Phase 1 portion is evaluation of the safety and tolerability of TYRA-300, and to determine the optimal and maximum tolerated dose and the recommended Phase 2 dose (RP2D). In addition, we plan to characterize the PK/PD relationship for TYRA-300 as well as conduct early validation studies of a liquid biopsy companion diagnostic test to assist us in identifying appropriate patients for our product candidates. As of March 2024, the Part A Phase 1 portion of SURF301 has completed dose escalation without determining an MTD, and the current expansion cohorts in Part B are evaluating potentially therapeutic once daily and twice daily doses. We expect to submit initial results from the SURF301 Phase 1 dose escalation and expansion portions for presentation at a scientific congress in the second half of 2024.

The Phase 2 portion of our trial will be generally consistent with the well-established precedent of clinical trials of approved targeted therapies. If we believe the data from any or all of these predefined patient populations are sufficient to support marketing authorization, we expect to seek feedback from the FDA in order to evaluate our ability to pursue and receive accelerated approval in the United States. We have not discussed any plans to pursue accelerated approval with the FDA, and there can be no assurance that after evaluation of the clinical trial results and/or feedback from the FDA, that we will decide to pursue accelerated approval or any other form of expedited development, review, or approval. We initially plan to evaluate TYRA-300 in the following three populations of FGFR3-positive tumors.

Metastatic UC patients who have received an FGFR inhibitor previously and have developed resistance to that inhibitor due to an FGFR3 mutation, such as the gatekeeper V555M.

Metastatic UC patients who have not yet received an FGFR inhibitor where we believe a reduction in toxicities and side effects, as well as the avoidance of the selection for the V555M gatekeeper mutations, have the potential to lead to improved tolerability, higher dosing and increasing the duration of responses.

Any solid tumors containing known activating FGFR3 gene alterations.

Our future plans include potential combination studies with a PD-1/PD-L1, ADC's, or other novel agents in 1L and 2L mUC, where the risk of overlapping toxicities may be diminished when combined with TYRA-300. If our clinical data for TYRA-300 suggests differentiated safety and efficacy results, we will evaluate pursuing TYRA-300 potentially as treatment in earlier bladder cancer settings (NMIBC), where minimizing side effects is a significant consideration for treatment choice and patient adherence. We believe that the full development potential for TYRA-300 may cover the entire spectrum of disease in urothelial cancer, and may represent a large opportunity relative to other drug targets given the high prevalence of FGFR3 mutations and the potential to treat earlier disease settings.

Our FGFR3 Program—TYRA-300 for Skeletal Dysplasias

Beyond oncology, mutations in FGFR3 are implicated in a family of skeletal conditions due to its role in regulating bone and cartilage formation. We believe that there is an opportunity to develop TYRA-300 to potentially address the long-term complications associated with these rare skeletal conditions including achondroplasia, hypochondroplasia, thanatophoric dysplasia, and other FGFR3-driven genetic syndromes.

Achondroplasia background

Achondroplasia, the most common form of dwarfism, is a skeletal dysplasia in which growth plate cartilage is affected, resulting in decreased growth of the long bones, vertebral bodies and skull base. These growth differences can result in health complications such as cranial and spinal stenosis, hydrocephalus, genu varum (bowed legs), and sleep apnea. A specific DNA mutation in FGFR3 causes an estimated 99% of achondroplasia. FGFR3 is expressed in growth plate chondrocytes (cartilage cells) where it functions in signaling pathways to limit growth. The G380R mutation, as well as other activating mutations, increase the activity of the FGFR3 protein, resulting in excessive limitation of growth causing these bones to be shorter than normal.

Achondroplasia 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 250,000 affected individuals worldwide and 3,000 affected individuals under the age of 18 in the United States. Approximately 80% of achondroplasia cases arise through a spontaneous mutation of FGFR3, whereas 20% of cases are familial. While the heterozygous FGFR3 mutation is rarely fatal, achondroplasia results 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.

Current treatment for achondroplasia

In 2021, Voxzogo (vosoritide), a C-natriuretic peptide analog that is a once daily injectable, was approved in the United States to increase linear growth in children with achondroplasia who are 5 years of age and older with open growth plates. In Europe, Voxzogo is approved to treat children with achondroplasia aged 2 and older with open growth plates. The pivotal study enrolled 120 children 5 to 15 years of age with genetically-confirmed achondroplasia. They were randomized to receive either 15mcg/kg daily injections of Voxzogo or placebo for 52 weeks, followed by an open label extension study in which all children received Voxzogo. At the end of the 52 week treatment period, the children who received Voxzogo had an average linear growth velocity of 4.26cm/yr, translating to an increase from baseline of 1.57cm/yr greater than placebo. In a 10-person cohort in the Phase 2 study, 15mg/kg daily injection of Voxzogo achieved a mean growth velocity of 6.06cm/yr and a 2.01cm/yr change from baseline.

In October 2023, the FDA approved Voxzogo for children under the age of 5 based on phase 2 data showing that children over the age of 2 treated with Voxzogo over four years demonstrated mean height Z-score improvement of 1.1 to 1.4 standard deviations and a mean height gain of 6.3 to 7.8 centimeters when compared to an untreated children population with ACH. Additionally, children under the age of 2 years treated with VOXZOGO for three years, had a mean height Z-score improvement of 0.8 to 1.0 standard deviations and a height gain between 3.5 and 3.9 cm.

In 2022 and 2023, BridgeBio established clinical proof of concept for infigratinib, a daily oral FGFR1/2/3 inhibitor with phase 2 data in achondroplasia. In cohort 5 of the Phase 2 study, 12 evaluable children receiving a daily dose of 0.25 mg/kg achieved 6.9 cm/yr average linear growth velocity and a 3.38 cm/yr improvement over baseline. Based on this phase 2 data, BridgeBio has initiated the run-in portion of a phase 3 study.

In 2022 and 2023, Ascendis established clinical proof of concept for TransCon CNP, a prodrug of CNP administered to children with ACH by injection on a weekly basis. Phase 2 data presented in 2022 showed children treated with 100 μg/kg/week dose demonstrated AHV of 5.42 cm compared to 4.35 cm for children treated with placebo. 12-month data presented at the JP Morgan conference in 2024 aligned with these figures.

Unmet need in achondroplasia and skeletal dysplasias

There is a strong need for an oral therapy selective for FGFR3 in Achondroplasia

While the approval of Voxzogo is an important milestone in the treatment of children with achondroplasia, the long-term therapeutic benefit of increasing growth velocity is not yet known. There are no long-term follow up data for Voxzogo to determine whether any of the health complications facing people with achondroplasia are alleviated. The daily delivery of Voxzogo can also be challenging for children and their parents. Voxzogo is supplied as a lyophilized powder that must be reconstituted in sterile water and injected daily into the skin. Injection site reactions, including swelling and redness, occurred in 85% of children; other complications include a risk of low blood pressure following injection. In addition, 35% of children developed anti-drug antibodies. While there was no association in the clinical trial with a decrease in linear growth velocity, it is not known if these antibodies might decrease the effectiveness of this treatment over longer periods of time.

There are other short-term and life-long complications such as cranial or spinal stenosis, hydrocephalus, cardiovascular events and sleep apnea associated with these skeletal dysplasia syndromes. Individuals may need to undergo surgery to correct spine or bone abnormalities and to reduce the pressure inside the brain in cases of hydrocephaly due to a narrow foramen magnum.

In rarer FGFR3-driven genetic syndromes such as thanatophoric dysplasia, another FGFR3-related skeletal condition, children often die in the neonatal period due to the severity of the skeletal abnormalities. As such, there remains a high unmet need for additional therapies that have the potential to address these conditions.

Opportunity for FGFR3 inhibitor in skeletal dysplasias

We believe that an oral, highly selective inhibitor of mutant FGFR3 may be highly desirable in pediatric achondroplasia because it could enable more convenient dosing and may have the potential to address long-term complications in affected individuals, including cranial or spinal stenosis, hydrocephalus and sleep apnea, alleviating the need for multiple painful surgeries and improving quality of life for this population. Additionally, a highly selective FGFR3 may have the ability to serve unmet needs of children with hypochondroplasia, thanatophoric dysplasia, other FGFR3-driven genetic syndromes and genetic short stature.

Our solution, TYRA-300

In March 2023, we announced we were expanding development of TYRA-300 into achondroplasia based on positive preclinical results demonstrated in a study performed in collaboration with the Imagine Institute in Paris, France.

TYRA-300 has demonstrated selectivity for FGFR3 in preclinical models, as well as statistically significant increases in growth and bone length in the Imagine Institute FGFR3 Y367C/+ preclinical model. Although no head-to-head clinical studies have been conducted, we believe that these pre-clinical studies assist with the characterization of our product candidates and inform future clinical development.

TYRA-300 was active in a FGFR3 Y367C/+ preclinical model

TYRA-300 was studied in the Imagine Institute’s FGFR3 Y367C/+ preclinical model. In the study, TYRA-300 was evaluated in FGFR3 wild-type and mutant preclinical models to measure increases in growth and bone length, compared to vehicle-treated mice. In an FGFR3 Y367C/+ model, TYRA-300 was administered daily at a 1.2 mg/kg dose for 15 days. TYRA-300 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).

TYRA-300 increased bone growth in an FGFR3 Y367C/+model

Development plans for TYRA-300 in Achondroplasia

We are conducting additional IND-enabling studies and plan to submit an IND to the FDA in the second half of 2024 to support the initiation of a Phase 2 clinical trial testing multiple doses of TYRA-300 to support children with ACH. Additionally, we plan to evaluate development opportunities in hypochondroplasia, thanatophoric dysplasia, other FGFR3-driven genetic syndromes and genetic short stature.

In July 2023 and January 2024, the FDA granted ODD and RPD Designation to TYRA-300, respectively, for the treatment of ACH.

Our FGFR2 program—TYRA-200

Our second product candidate, TYRA-200, is an investigational, oral, FGFR1/2/3 inhibitor with potency against activating FGFR2 gene alterations, as well as clinically important molecular brake and gatekeeper resistance mutations. Similar to therapies designed for the treatment of FGFR3-driven cancers, resistance to both approved and investigational FGFR inhibitors has been shown to arise due to gene alterations in FGFR2. We have designed

TYRA-200 to be active against multiple acquired resistant mutations that arise during treatment with other FGFR2 inhibitors. Although no head-to-head clinical trials have been conducted, we believe the use of comparativein vitro data from pre-clinical studies provides meaningful insight into the potential for TYRA-200 to improve on certain characteristics of approved and investigational FGFR inhibitors, and helps inform potential future clinical development of TYRA-200. We are studying TYRA-200 initially in FGFR2-driven ICC resistant to previous FGFR inhibitors. In December 2023, we commenced our Phase 1 clinical trial of TYRA-200, SURF201 (Study in Previo Usly treated and Resistant FGFR2+ Cholangiocarcinoma and Other Advanced Solid Tumors), 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 and the MTD and RP2D, as well as evaluate preliminary antitumor activity.

ICC disease background

Potential patient populations for our FGFR2 inhibitor

ICC is a form of cancer that originates in the bile ducts, which are a series of thin vessels that transport bile from liver cells to the small intestine. Diagnosis of ICC is often difficult as it is not associated with any specific symptoms other than dull abdominal pain, weight loss, and elevated liver enzymes. ICC is a rare tumor, accounting for an estimated 10-20% of intrahepatobiliary cancers and an estimated ~11% of cancers of unknown primary origin. The median overall survival for all patients diagnosed with ICC is reported to be 16.1 months. The median overall survival for patients diagnosed with late-stage disease is less than one year.

FGFR2 is a protein receptor present on the cell surface that promotes cellular proliferation and transformation upon binding of fibroblast growth factor. Similar to FGFR3, activating gene alterations of FGFR2 have been implicated in the tumorigenesis of multiple solid tumor types. Approximately 15-20% of patients with ICC have genetic alterations in FGFR2, which are primarily gene rearrangements and activating mutations. In addition to ICC, FGFR2 drives and estimated ~7% of endometrial cancers and 0.8% of other solid tumors.

Standard of care and current limitations for the treatment of Advanced ICC

Acquired resistance is a key unmet need in FGFR2+ ICC

Currently, surgical recession is the only curative option available to ICC patients. However, only up to one-third of patients are eligible for surgery at diagnosis and up to 70% of patients experience a recurrence largely within the first two years following surgery. Patients with unresectable tumors are typically treated with systemic therapies. The previously recommended frontline regimen was a combination of gemcitabine and cisplatin, which offered a median overall survival benefit of 11.7 months. A Phase 3 study demonstrating statistically significant median overall survival benefit for the combination of durvalumab with gemcitabine and cisplatin vs gemcitabine plus cisplatin (12.8 months [95% CI 11.1, 14] vs 11.5 months [95% CI 10.1, 12.5]) led to an approval in previously untreated unresectable or metastatic biliary tract cancer in September 2022. A second Phase 3 study comparing pembrolizumab plus gemcitabine and cisplatin vs gemcitabine and cisplatin also reported a statistically significant overall survival benefit (12.7 months [95% CI 11.5, 13.6] vs 10.9 months [95% CI 9.9, 11.1]). The results from these two studies firmly establish a role for immunotherapy in combination with cisplatin-based chemotherapy as a new standard of care in 1L cholangiocarcinoma. Upon disease progression, patients with actionable mutations, such as IDH1/IDH2 and FGFR2 alterations, are eligible to receive targeted therapies.

FGFR inhibitors

Patients with somatic alternations in FGFR2 are eligible to be treated with Pemazyre (pemigatinib), a pan-FGFR inhibitor that received accelerated approval in the United States in 2020 for treatment following chemotherapy. In the Phase 2 clinical trial of pemigatinib for the treatment of ICC, the overall response rate was 36% (95% CI 27, 45) with a median duration of response of 9.1 months (95% CI 6.0, 14.5). A second pan-FGFR inhibitor, Truseltiq (infigratinib), received accelerated approval in the United States in 2021 based on an overall response rate of 23% (95% CI 16, 32) and a median duration response of 5.0 months (95% CI 3.7, 9.3). It was subsequently announced that as of March 31, 2023, infigratinib would be withdrawn from the market and no longer be developed in oncology indications. A third pan-FGFR inhibitor, futibatinib, received accelerated approval for ICC with FGFR2 gene fusions or rearrangements in September 2022 on the basis of a single arm study that showed an ORR of 42% (95%CI 32, 52) and a median duration of response of 9.7 months (95% CI 7.6, 17.1). The investigational FGFR2-specific inhibitor lirafugratinib has reported ~80% response rates in a small dataset of patients who have not received an FGFR inhibitor previously, though lirafugratinib, KIN-3248, and the multi-kinase inhibitor tinengotinib have shown limited activity in patients whose tumors have developed these acquired resistance mutations.

We believe the critical unmet need for patients with FGFR2 fusion or FGFR2-altered ICC is balancing the potency for the wild type and the numerous on-target resistance mutations that emerge in patients treated with currently approved and investigational FGFR inhibitors. The most frequently occurring acquired drug resistance mutations are active site mutations such as the gatekeeper and amino acids comprising the molecular brake. These mutations, as well as allosteric gain-of-function mutations, have been observed clinically to confer resistance to the currently approved FGFR inhibitors. We believe maintaining potency against all of these clinically important mutations as well as wild-type FGFR2 could potentially improve efficacy and duration of response.

Acquired drug resistance is common in patients with ICC treated with FGFR inhibitors

Our solution, TYRA-200

In preclinical models to date, TYRA-200 has demonstrated potency against gatekeeper, molecular brake, and A-loop activator mutations and selectivity for FGFR1-3 over FGFR4. Although no head-to-head clinical studies have been conducted, we believe that these pre-clinical studies assist with the characterization of TYRA-200 and inform future clinical development.

TYRA-200 is active in an FGFR2 driven endometrial cancer xenograft model

AN3CA is a human endometrial cancer cell line which contains an FGFR2 N550K activating mutation. TYRA-200 was tested in a preclinical mouse xenograft model using this cell line, as seen in the figure below. TYRA-200 given BID at a dose of 10 mg/kg or 15 mg/kg BID led to substantial inhibition of tumor growth in this model. We observed TGI with futibatinib using a 15 mg/kg QD dose in this study.

TYRA-200 tumor growth inhibition in a AN3CA xenograft model

Antitumor activity in the FGFR2 N550K, K311R mutant AN3CA endometrial cancer xenograft model in nu/nu mice of various doses of TYRA-200 (10 and 15 mg/kg BID, left) and futibatinib (15 mg/kg QD, right). All doses were by oral administration. Regression, calculated as % Regression (for ∆T<0) = 100*(∆T/T 0,), observed for TYRA-200 10 mg/kg BID is 14%, and for 15 mg/kg BID is 56%. We observed 5% regression with 15 mg/kg QD futibatinib. The vehicle for TYRA-200 is 30% hydroxypropyl beta cyclodextrin, and the vehicle for futibatinib is 0.5% hydroxypropyl methylcellulose with 0.2% tween 80. Data points represent mean tumor volume (n=6 per group) and error bars represent standard error of the mean.

Potent inhibition of FGFR2 mutants including gatekeeper, molecular brake, and A-loop activator mutations

We utilized our SNÅP platform to design TYRA-200 to retain potency for a variety of acquired resistance mutations that alter FGFR2 protein structure and consequently can affect inhibitor potency. In preclinical models conducted to date, TYRA-200 has demonstrated similar potency in FGFR2-driven Ba/F3 cells to erdafitinib, pemigatinib, futibatinib or infigratinib, while reducing or eliminating the decrease in potency observed with N550K/H/D and E566A molecular brake, V565F/L/I gatekeeper, and K660E/N A-loop activator resistance mutations.

Acquired resistance mutations alter FGFR2 protein structure

TYRA-200 retained potency against multiple potential acquired drug resistance mutations in FGFR2

The potential of TYRA-200 to maintain potency against the V565F gatekeeper mutation, a key liability of pemigatinib, infigratinib, futibatinib, and erdafitinib as observed inin vitro assays conducted to date, was tested in a preclinical allograft model of an FGFR2-driven Ba/F3 cell line with the V565F gatekeeper mutation as seen in the figure below. We observed 96% and 98% inhibition of tumor growth by TYRA-200 in the allograft, while we observed 62% tumor growth inhibition in the allograft treated with futibatinib.

TYRA-200 tumor growth inhibition was maintained in the presence of the FGFR2 V565F gatekeeper mutation in a Ba/F3 FGFR2 allograft model

Antitumor activity in the Ba/F3-FGFR2 V565F gatekeeper mutant model in nu/nu mice of various doses of TYRA-200 (10 and 15 mg/kg BID, left) and futibatinib (15 mg/kg QD, right). All doses were by oral administration. TGI observed for TYRA-200 10 mg/kg BID is 96%, and for 15 mg/kg BID is 98%. We observed 62% TGI for 15 mg/kg QD futibatinib. The vehicle for TYRA-200 is 30% hydroxypropyl beta cyclodextrin, and the vehicle for futibatinib is

0.5% hydroxypropyl methylcellulose with 0.2% tween 80. Data points represent mean tumor volume (n=6 per group) and error bars represent standard error of the mean.

Selectivity for FGFR1/2/3 vs FGFR4

Designing covalent inhibitors that bind to the ATP-binding site and selectively differentiate between FGFR2 and other isoforms 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 TYRA-200, that capitalize on subtle conformational differences between FGFR4 and the other isoforms to obtain greater selectivity for FGFR1-3 versus FGFR4. In comparison, the covalent FGFR inhibitor futibatinib has demonstrated lower selectivity for FGFR4, which may point to a potential to be dose limited by FGFR4-related toxicities such as diarrhea and liver toxicity. In clinical studies of futibatinib, the dose limiting toxicity in Phase 1 was Grade 3 elevation of liver function tests in 3 of 9 patients at 24mg. In the Phase 2 registration study in ICC, Grade 3 liver enzyme abnormalities were observed in 7 to 13% of patients and 39% of patients experienced diarrhea of any grade at a dose of 20mg daily. The selectivity for FGFR1-3 vs FGFR4 that we observed for TYRA-200 also extended to the broader family of protein kinases, where we observed that very few kinases were inhibited. Although we have not conducted any head-to-head clinical studies, we believe that TYRA-200’s relative selectivity for FGFR1-3 relative to FGFR4 observed in pre-clinical studies may result in improved tolerability with respect to futibatinib.

TYRA-200 was selective for FGFR1-3 over FGFR4 in a Ba/F3 cell-based assay

Beyond selectivity over FGFR4, TYRA-300 avoided off-target inhibition of other kinases when profiled in a scanMAX (KINOMEscan) screen.

TYRA-200 was highly selective for FGFR2 over other protein kinases

Development plans for TYRA-200

In December 2023, we commenced our Phase 1 clinical trial of TYRA-200, SURF201 (Study in Previo Usly treated and Resistant FGFR2+ Cholangiocarcinoma and Other Advanced Solid Tumors), 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 and the MTD and RP2D, as well as evaluate preliminary antitumor activity. SURF201 is currently enrolling adults with advanced solid tumors that contain FGF/FGFR pathway alterations, as well as participants with intrahepatic cholangiocarcinoma with acquired kinase domain mutations. The currently approved pan-FGFR inhibitors as well as several investigational agents are not active against the entire spectrum of clinically important acquired resistance mutations that develop in response to FGFR inhibition. Polyclonal resistance (multiple resistance mutations that occur in the same patient) is a common feature in this patient population, and the ability to demonstrate clinically beneficial activity in this setting will provide proof of concept and validate the design principles behind TYRA-200. These data would provide confidence in our belief that addressing acquired resistance may prolong the duration of responses, and ultimately PFS, in the FGFR-naive setting, and confirm our belief that TYRA-200 is highly differentiated in the competitive landscape of FGFR inhibitors. Beyond FGFR-resistant and FGFR-naive ICC, there is potential for TYRA-200 to extend into metastatic endometrial carcinoma, where up to 7-16% of patients have FGFR2 mutations, of which 25% are N549 molecular brake activating mutations. Additional FGFR2-driven patient populations in advanced colorectal, breast, ovarian, gastric, and lung cancer will also be evaluated in a tumor agnostic fashion.

Our FGF19+ discovery program

FGFR4 is expressed broadly in normal tissues, including lung, liver, and the GI tract. FGFR4 as an oncology target has been primarily studied in hepatocellular carcinoma, where, in association with the co-receptorb-klotho, it is the cell surface receptor for FGF19. Approximately 30% of HCC cases are thought to be dependent on FGFR4 signaling due to amplification or overexpression of FGF19. Several FGFR4-selective inhibitors have been developed and evaluated in the clinic with limited success, potentially due to an FGFR3-mediated bypass mechanism.

Role of FGFR4/FGF19 in cancer

FGFR4 is involved in the transduction of key signals essential for cellular proliferation and survival. Aberrant activation of the FGFR4 pathway is observed in multiple malignancies, most notably in hepatocellular carcinoma (~30% of cases). It is also implicated as a driver in approximately 7.5% of pediatric rhabdomyosarcomas, in breast cancer cases, and less commonly in other select solid tumors.

The role of FGFR4 in cancer has been best described in hepatocellular carcinoma. In normal hepatocytes, FGFR4 regulates bile acid synthesis and hepatocyte proliferation in response to fibroblast growth factor 19 (FGF19). FGF19 is a post-prandial enterohepatic hormone that signals through FGFR4 and its associated co-receptor Klotho-b (KLB) to exert its normal cellular functions. In certain cancers, such as HCC, gastric adenocarcinoma, squamous esophageal carcinoma, and breast cancer, 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.

There are currently no approved therapies that selectively target the FGFR4-FGF19 axis. A successful approach would represent the introduction of a first-in-class targeted therapy in HCC.

Pan FGFR inhibitors have been previously studied in FGFR4-driven malignancies, such as HCC. Development of erdafitinib was initiated in HCC and subsequently discontinued, while futibatinib is currently being studied in combination with immunotherapy in a FGF19-selected population in HCC. However, these approaches have been constrained in other indications by the dose-limiting toxicities elicited by off-target inhibition of FGFR1 and FGFR2.

Previous attempts to selectively target FGFR4 resulted in sub-optimal responses with short durations. Clinical studies with the FGFR4-selective inhibitors fisogatinib and roblitinib demonstrated the potential of targeting FGFR4 in HCC patients whose tumors expressed FGF19. While the overall response rates of 17% and 21%, respectively, provided clinical proof-of-concept, the durability was short and acquired drug resistance was observed in some cases.

Results from the fisogatinib study led to the identification of FGFR4 mutations known to interfere with drug activity. These mutations included V550 gatekeeper mutations and C552 mutations, both of which were found to cause a loss of fisogatinib potency of more than 1,000-fold.

Our FGF19+ Program

Our FGFR4 drug discovery efforts are driven by our deep structural understanding of the FGFR family including over 70 co-crystal structures of FGFR4 itself. TYRA-430 is designed to be agnostic to acquired resistance mechanisms originating from the V550 gatekeeper and the C552 mutations, as well as other potential FGFR-driven compensatory mechanisms. We anticipate that TYRA-430 will also have potential for antitumor activity in patients with spontaneous FGFR4 activating mutations at the gatekeeper (V550), as well as in rare FGFR4 fusions, while addressing the FGFR3 bypass mechanism.

Potential patient populations for our TYRA-430

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, R&D, 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. Janssen Pharmaceutical’s Balversa (erdafitinib) received full approval for adult patients with locally advanced or mUC with susceptible FGFR3 genetic alterations whose disease has progressed on or after at least one line of prior systemic therapy. Erdafitinib is not recommended for the treatment of patients who are eligible for and have not received prior PD-1 or PD-L1 inhibitor therapy.

Janssen has reported preliminary clinical data regarding the potential efficacy of erdafitinib, a pan-FGFR inhibitor, in patients with NMIBC. In 2023, erdafitinib administered orally demonstrated a 75% complete response (CR) rate in intermediate risk patients (data presented at the 2023 ASCO Genitourinary (GU) Symposium) and a 73% 6 months’ CR rate in high-risk carcinoma in situ (CIS) patients (data presented at the 2023 Society of Urologic Oncology (SUO)). Further, in a randomized setting versus intravesical chemotherapy, erdafitinib prolonged relapse-free survival (RFS) compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after bacillus Calmette-Guérin (BCG) therapy and refused or were ineligible for radical cystectomy. However, the safety and tolerability profile displayed was generally consistent with that known for oral erdafitinib, despite using a lower 6mg daily dose, leading to tolerability issues. Janssen has reported it is now pursuing locally administered erdafitinib with TAR-210, an erdafitinib-eluting intravesical device that also demonstrated an 87% CR rate in intermediate risk patients and 82% RFS in high-risk papillary patients in preliminary datasets (presented at ESMO 2023). Based on these findings targeting FGFR3, we believe an orally administered selective FGFR3 inhibitor, with minimal effects from other FGFR-related toxicities, could successfully address patients in an area with a high unmet need.

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 (pemigatinib) and Taiho Oncology’s Lytgobi (futibatinib). These indications are approved in the United States under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Incyte Corporation is currently conducting a confirmatory Phase 3 clinical study in treatment-naïve, metastatic unresectable cholangiocarcinoma (NCT03656536). Taiho has an active randomized study in frontline cholangiocarcinoma (NCT04093362) that is no longer recruiting, as well as a separate confirmatory trial testing two doses of futibatinib in patients with previously-treated, locally advanced or metastatic unresectable cholangiocarcinoma (NCT05727176). In addition, TransThera has initiated a global Phase 3 study of tinengotinib versus investigator's choice chemotherapy (FOLFOX or FOLFIRI) in FGFR-altered cholangiocarcinoma patients who are relapsed/refractory to chemotherapy and have not been treated with more than one prior FGFR inhibitor.

There are a number of FGFR-isoform selective inhibitors in development for oncology as well. Kinnate Biopharma Inc.’s product candidate KIN-3248, an FGFR2/3 inhibitor was being developed for ICC and UC (NCT05242822) and in November 2023 the company announced it was exploring strategic alternatives for the program after disclosing 2 responses of 31 treated patients in phase 1. Relay Therapeutics, Inc.’s FGFR2-specific inhibitor lirfugratinib is currently in Phase 2 with stated plans to develop their candidate in a tumor agnostic setting (NCT04526106). Lilly’s Loxo Oncology recently initiated a Phase 1 study in mUC for LOXO-435 (LOX-24350), an isoform-selective FGFR3 inhibitor compound (NCT05614739).

In 2021, BioMarin Pharmaceutical’s Voxzogo, a once daily injectable C-natriuretic peptide (CNP) analog was granted accelerated approval in the United States for children with achondroplasia who are 5 years of age and older and confirmatory study commitments are ongoing. Approval was based on a 1.57cm/year mean annual height velocity improvement versus placebo. In 2022, BioMarin announced positive Phase 2 results for vosoritide in infants and young children up to five years of age with achondroplasia and, in the second half of 2023 was approved in the U.S. for children under the age of five in Europe for children over the age of four months. In 2023, BridgeBio announced preliminary data for Cohort 5 of the infigratinib PROPEL study (NCT04265651) demonstrating that 12 evaluable children dosed with 0.25mg/kg daily demonstrated a mean annual height velocity of 6.9cm/year and an improvement of 3.38cm/year over baseline growth velocity. In 2022 Ascendis also announced positive Phase 2 data for once-weekly TransCon CNP, a prodrug that slowly releases CNP (NCT04085523). Phase 2 data showed children treated with 100 μg/kg/week dose demonstrated AHV of 5.42cm compared to 4.35cm for children treated with placebo. 12 month data presented at the JP Morgan conference in 2024 aligned with these figures.

Several multi-kinase inhibitors have been approved for the treatment of HCC, but there are currently no approved FGFR4-specific inhibitors approved. There are a number of FGFR4 clinical stage programs, with most of the development focused in China. CStone Pharmaceuticals and Blueprint Medicine completed a Phase 1/2 study of BLU-554 (fisogatinib) in HCC in combination with a checkpoint inhibitor (NCT04194801). H3 Biomedicines has recruited a Phase 1/2 study of H3B-6527 in HCC (NCT02834780), but no further details are publicly available. Novartis completed a Phase 1/2 study of FGF401 alone and in combination with a checkpoint inhibitor in HCC (NCT02325739), and a similar study with FGF401 is now being conducted by Everest Medicines in combination with pembrolizumab in China. Abbisko Therapeutics is conducting a Phase 1 study (NCT04906434) to assess the tolerability and preliminary anti-tumor activity of its FGFR4-selective inhibitor ABSK-011, but development has been limited to China.

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 15, 2024, our intellectual property portfolio consisted of six pending U.S. provisional applications, five pending U.S. nonprovisional applications, 46 pending foreign patent applications, and six patent applications pursuant to the Patent Cooperation Treaty (PCT) all of which are solely owned by us. At this time, we do not own any issued patents in the U.S, and 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 15, 2024, we owned three pending U.S. provisional applications, two pending U.S. nonprovisional applications, three pending PCT patent applications and 30 pending foreign applications. 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 one pending U.S. nonprovisional and 29 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 2045 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 15, 2024, we owned two pending U.S. provisional applications, two pending U.S. nonprovisional application, 14 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 13 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 2042 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 15, 2024, we owned one pending U.S. provisional patent application, one pending U.S. nonprovisional application, three pending PCT patent applications and two Taiwanese pending 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 patent issued from this application to expire between 2042 and 2044 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 to any of our 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. If patents are issued on our pending patent applications, the resulting patents are expected to expire on dates ranging from 2040 to 2045, unless we receive patent term extension or patent term adjustment, or both.

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. With respect to both licensed and company-owned intellectual property, 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 patents that may be granted to us in the future will be commercially useful in protecting our product candidates and the methods used to manufacture them. Moreover, those patents that may issue in the future 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 patents that may issue in the future may be challenged, narrowed, circumvented or invalidated, which could limit our ability to stop competitors from 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 any 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 intend to file 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 and TYRA BIOSCIENCES marks with the United States Patent and Trademark Office and certain foreign patent and trademark organizations.

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.

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 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 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 so-called 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.

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

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 a 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 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 pivotal Phase 3 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. In issuing the CRL, the FDA may recommend actions that the applicant might take to place the NDA in condition for approval, including requests for additional information or clarification. 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.

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 currently requires as a condition for accelerated approval pre-approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.

Fast Track designation, Breakthrough Therapy designation, 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 same disease or condition for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with orphan drug exclusivity 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 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 disease or condition, or the same drug for a different disease or condition. Among the other benefits of orphan drug designation are tax credits for certain research and a waiver of the NDA application user fee.

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 or the manufacturer of the approved product is unable to assure sufficient quantities of the product to meet the needs 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. On December 27, 2020, the Rare Pediatric Disease Priority Review Voucher Program was extended. Under the current statutory sunset provisions, after September 30, 2024, FDA may only award a voucher for an approved rare pediatric disease product application if the Sponsor has rare pediatric disease designation for the drug, and that designation was granted by September 30, 2024. After September 30, 2026, FDA may not award any Rare Pediatric Disease Priority Review Voucher.

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

Market 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 marketing 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), or 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.

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 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 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 QSR, 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 QSR, 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 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, 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. In March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, collectively referred to as the ACA, was passed, which substantially changed the way healthcare is financed by both governmental and private insurers, and significantly affected the pharmaceutical industry. Among other changes, the ACA increased the minimum level of Medicaid rebates payable by manufacturers of brand name drugs from 15.1% to 23.1%; required collection of rebates for drugs paid by Medicaid managed care organizations; required manufacturers to participate in a coverage gap discount program, in which manufacturers must agree to offer point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D; imposed a non-deductible annual fee on pharmaceutical manufacturers or importers who sell certain “branded prescription drugs” to specified federal government programs; implemented a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted, or injected; expanded eligibility criteria for Medicaid programs; created a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research, along with funding for such research; and established a Center for Medicare and Medicaid Innovation at the CMS to test innovative payment and service delivery models to lower Medicare and Medicaid spending, potentially including prescription drug spending. Since its enactment, there have been judicial and political 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. Most recently, in March 2021, Congress enacted the American Rescue Plan Act of 2021, which, among other things, eliminated the statutory cap on drug manufacturers’ Medicaid Drug Rebate Program rebate liability, effective January 1, 2024. Drug manufacturers’ Medicaid Drug Rebate Program rebate liability was previously capped at 100% of the average manufacturer price for a covered outpatient drug. Other changes included aggregate reductions to Medicare payments to providers, which went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect into 2032, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022, unless additional Congressional action is taken. On January 2, 2013, the American Taxpayer Relief Act of 2012 was signed into law, which, among other things, reduced Medicare payments to several providers, including hospitals, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

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. On August 16, 2022, the Inflation Reduction Act of 2022 (IRA) came into law. Among other things, the IRA requires manufacturers of certain drugs to engage in price negotiations with Medicare (beginning in 2026), imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation (first due in 2023), and replaces the Part D coverage gap discount program with a new discounting program (beginning in 2025). The IRA permits the Secretary of the Department of Health and Human Services to implement many of these provisions through guidance, as opposed to regulation, for the initial years. On August 29, 2023, HHS announced the list of the first ten drugs that will be subject to price negotiations, although the Medicare drug price negotiation program is currently subject to legal challenges. For that and other reasons, it is currently unclear how the IRA will be effectuated.

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. In addition, regional healthcare authorities and 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 good laboratory practice (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.

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 foresees a three-year transition period. The extent to which ongoing and new clinical trials will be governed by the CTR varies. Clinical trials for which an application was submitted (i) prior to January 31, 2022 under the EU Clinical Trials Directive, or (ii) between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the EU Clinical Trials Directive remain governed by said Directive until January 31, 2025. After this date, all clinical trials (including those which are ongoing) will become 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.

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 drug destination, 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 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 pharmaceutical 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 onin vitro diagnostic medical devices (Directive No. 98/79/EC, as amended) (IVDD), which regulated the placing on the market, the 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 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 a 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.

Human Capital

As of March 18, 2024, we had 49 full-time employees, including a total of 16 employees with M.D. or Ph.D. degrees. Of these full-time employees, 37 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.