TYRA-430: A Novel FGFR4/3-Biased Inhibitor for FGF/FGFR Pathway-Aberrant Cancers

1. Introduction to TYRA-430 and the FGF/FGFR Pathway in Cancer

1.1. Overview of TYRA-430

TYRA-430 is an investigational, orally administered, reversible, small-molecule inhibitor with a biased specificity for Fibroblast Growth Factor Receptor 4 (FGFR4) and Fibroblast Growth Factor Receptor 3 (FGFR3).[1] Developed by Tyra Biosciences, Inc., TYRA-430 is engineered as a next-generation precision medicine aimed at addressing cancers driven by aberrations in the FGF/FGFR signaling pathway, particularly advanced hepatocellular carcinoma (HCC) and other solid tumors.[4] Its development leverages the company's proprietary SNÅP (Structure-based NÅnobodies and Panel) platform, which facilitates rapid and precise drug design to overcome challenges such as acquired drug resistance.[1] The key characteristics of TYRA-430 are summarized in Table 1.

Table 1: TYRA-430 - Key Drug Characteristics

Characteristic	Description	Source(s)
Drug Name (Synonyms)	TYRA-430	General
Developer	Tyra Biosciences, Inc.	4
Drug Type	Small molecule, oral, reversible, FGFR4/3-biased inhibitor	1
Primary Targets	Fibroblast Growth Factor Receptor 4 (FGFR4), Fibroblast Growth Factor Receptor 3 (FGFR3)	2
Key Mechanism of Action	Inhibition of FGFR4 and FGFR3 kinase activity, particularly in the context of FGF19-driven signaling	2
Therapeutic Areas	Oncology (Neoplasms), Digestive System Disorders (specifically HCC)	5
Lead Indications	Advanced Hepatocellular Carcinoma (HCC) with FGF19 overexpression or other activating FGF/FGFR pathway aberrations; other advanced solid tumors with similar activating FGF/FGFR pathway aberrations	1

1.2. The FGF/FGFR Signaling Pathway in Oncology

The Fibroblast Growth Factor (FGF) and FGF Receptor (FGFR) signaling pathway is a critical regulator of numerous cellular processes essential for normal development and tissue homeostasis, including cell proliferation, differentiation, migration, survival, and angiogenesis.[14] This pathway comprises a family of FGF ligands and four transmembrane tyrosine kinase receptors (FGFR1-4). Ligand binding to FGFRs, often facilitated by co-receptors such as heparan sulfate proteoglycans or Klotho family members, triggers receptor dimerization and autophosphorylation, initiating downstream signaling cascades like RAS/MAPK, PI3K/AKT, and PLCγ/PKC.[14]

Dysregulation of the FGF/FGFR pathway is a well-established oncogenic driver in a diverse range of human malignancies.[2] Aberrant pathway activation can occur through various genetic alterations, including FGFR gene amplifications, activating mutations, chromosomal translocations leading to fusion proteins, or overexpression of FGF ligands.[2] In the context of hepatocellular carcinoma (HCC), the FGF19-FGFR4-Klotho β (KLB) axis has emerged as a particularly important therapeutic target. FGF19, an endocrine FGF primarily produced in the ileum, signals through FGFR4, and in some contexts FGFR3, in complex with the co-receptor KLB, which is abundantly expressed in the liver.[2] Overexpression of FGF19, observed in approximately 20-30% of HCC cases, leads to constitutive activation of this signaling pathway, promoting uncontrolled hepatocyte proliferation and contributing to tumor development and progression.[2] The identification of this specific axis as a driver in a subset of HCC patients has paved the way for the development of targeted therapies aimed at inhibiting FGFR4 and associated pathways.

1.3. Unmet Medical Needs and Limitations of Existing FGFR-Targeted Therapies in HCC

Hepatocellular carcinoma (HCC) represents a significant global health burden, characterized by its aggressive nature and often poor prognosis, particularly in advanced stages. It is among the leading causes of cancer-related mortality worldwide, with projections indicating a continued rise in its impact.[2] For patients with advanced HCC, systemic therapy options have historically been limited. While multi-kinase inhibitors such as sorafenib and lenvatinib have been approved and provide some survival benefit, their efficacy is often modest, and they are associated with significant toxicities.[14] Consequently, a substantial unmet medical need persists for more effective and better-tolerated treatments for advanced HCC.

The discovery of the role of the FGF19-FGFR4 pathway in a subset of HCC patients led to the development of FGFR4-selective inhibitors. Several such agents, including fisogatinib (BLU-554), roblitinib (FGF401), and INCB062079, have been evaluated in clinical trials.[2] However, these highly selective FGFR4 inhibitors have generally demonstrated limited clinical efficacy, with low objective response rates and short durations of response in patients with FGF19-driven HCC.[2]

The suboptimal performance of these selective FGFR4 inhibitors is attributed to several factors. A key mechanism of de novo resistance is the redundant signaling capacity of other FGFRs, particularly FGFR3. Preclinical evidence, including data from CRISPR screens, has shown that FGFR3 can compensate for FGFR4 inhibition in FGF19-positive HCC cells, thereby maintaining downstream oncogenic signaling and limiting the efficacy of FGFR4-selective agents.[2] The prevalent co-expression of FGFR3 with FGFR4 and KLB in FGF19-positive HCC tumors further supports this redundancy as a clinically relevant resistance mechanism.[15]

In addition to de novo resistance, acquired resistance is another major challenge. Tumors can develop mutations in the FGFR4 kinase domain, such as gatekeeper mutations (e.g., V550L/M, C552S), which reduce the binding affinity or efficacy of the inhibitor, leading to treatment failure.[2] These limitations underscore the need for novel therapeutic strategies that can overcome both pathway redundancy and acquired resistance mutations to provide more meaningful and durable clinical benefits for patients with FGF/FGFR pathway-aberrant HCC. The development of TYRA-430, with its dual FGFR4/3 inhibitory profile and activity against known resistance mutations, is a direct attempt to address these shortcomings.

1.4. Tyra Biosciences and the SNÅP Platform

Tyra Biosciences, Inc. is a clinical-stage biotechnology company with a strategic focus on the discovery and development of next-generation precision medicines. The company's primary area of expertise lies in targeting the Fibroblast Growth Factor Receptor (FGFR) family of kinases, which are implicated in a variety of cancers and genetically defined conditions.[1]

Central to Tyra Biosciences' drug discovery engine is its proprietary SNÅP (Structure-based NÅnobodies and Panel) platform.[1] This platform is engineered to enable rapid and precise drug design through an iterative process. A key feature of the SNÅP platform is the generation of "molecular SNÅPshots," which involves obtaining detailed structural information about how potential drug candidates interact with their target proteins. This is achieved, in part, through proprietary protein crystallography techniques that allow for the rapid determination of co-crystal structures of newly synthesized compounds bound to their target kinases, reportedly in as little as three days.[10]

These structural insights are then used to predict genetic alterations within the target protein that are most likely to confer acquired resistance to existing therapies. Armed with this predictive capability, the SNÅP platform guides the design and chemical synthesis of novel compound candidates with innovative structures. These structures are specifically engineered to inhibit the target kinase effectively while also overcoming or avoiding these predicted resistance mutations.[1] This iterative cycle of structural analysis, prediction, and rational design aims to generate product candidates with improved potency, selectivity, and durability of response. Tyra Biosciences' pipeline, which includes TYRA-430 (FGFR4/3-biased inhibitor), TYRA-300 (FGFR3-selective inhibitor), and TYRA-200 (FGFR1/2/3 inhibitor), has been developed utilizing this SNÅP methodology.[1] The company's approach underscores a commitment to addressing the significant challenge of acquired drug resistance in targeted oncology from the earliest stages of drug discovery.

The development of TYRA-430 as an FGFR4/3-biased inhibitor, rather than a pan-FGFR inhibitor or a highly selective FGFR4 inhibitor, represents a nuanced strategy. This approach appears to be informed by the clinical and preclinical experiences with previous generations of FGFR inhibitors. Pan-FGFR inhibitors, while potentially addressing pathway redundancy, often carry a burden of toxicity due to the inhibition of FGFR1 and FGFR2, which are involved in various physiological processes (e.g., phosphate homeostasis by FGFR1). Conversely, highly selective FGFR4 inhibitors have demonstrated limited efficacy, largely attributed to compensatory signaling through FGFR3 in FGF19-driven HCC.[2] TYRA-430's "FGFR4/3-biased" design suggests an attempt to achieve a therapeutic sweet spot: potently inhibiting the key oncogenic drivers (FGFR4 and its redundant partner FGFR3) in the context of FGF19 overexpression, while potentially minimizing the off-target effects associated with broader FGFR1/2 inhibition, thereby aiming for an improved therapeutic window. This strategic positioning, born from an understanding of prior limitations, highlights an evolution in the design of FGFR-targeted therapies.

Furthermore, the SNÅP platform's emphasis on proactively "predicting" and "designing against" acquired resistance mechanisms [1] represents a significant departure from more reactive drug development strategies. For many targeted therapies, resistance mechanisms are often identified only after the drug is in clinical use or late-stage development, necessitating the subsequent development of next-generation inhibitors. By integrating structural biology and predictive modeling to anticipate common resistance mutations (such as the FGFR gatekeeper mutations that TYRA-430 is designed to overcome [2]), the SNÅP platform aims to build durability into its drug candidates from the outset. This proactive approach, if clinically validated, could lead to therapies with more sustained efficacy and a longer period of benefit for patients. The focus on FGF19-driven HCC, which accounts for a 20-30% subset of HCC patients [2], also aligns with the broader paradigm of precision oncology, where treatments are tailored to specific molecular alterations driving individual cancers. Success in this biomarker-defined population could not only provide a much-needed therapeutic option for these patients but also further validate the utility of biomarker-driven strategies in historically challenging malignancies like HCC.

2. TYRA-430: Mechanism of Action and Preclinical Rationale

2.1. Dual Inhibition of FGFR4 and FGFR3

TYRA-430 is a first-in-class, orally bioavailable, reversible small-molecule inhibitor specifically engineered to exhibit biased inhibitory activity against both FGFR4 and FGFR3.[1] This dual specificity is central to its therapeutic hypothesis. The FGF19 ligand, when overexpressed in certain cancers like HCC, exerts its oncogenic effects by binding to and activating its cognate receptors, primarily FGFR4, but also FGFR3, in complex with the essential co-receptor Klotho β (KLB).[2] By potently inhibiting the kinase activity of both these receptors, TYRA-430 aims to achieve a more comprehensive blockade of the FGF19-driven signaling cascade compared to agents that target FGFR4 alone. The "biased" nature of its inhibition suggests a degree of selectivity for FGFR4 and FGFR3 over other members of the FGFR family (FGFR1 and FGFR2), a characteristic that may be crucial for optimizing the therapeutic index by minimizing off-target toxicities associated with pan-FGFR inhibition.

2.2. Rationale for Dual Inhibition: Overcoming Pathway Redundancy and De Novo Resistance

The development of TYRA-430 as a dual FGFR4/3 inhibitor is directly rooted in the observed limitations of FGFR4-selective inhibitors in clinical trials for FGF19-driven HCC.[2] These earlier agents, despite effectively inhibiting FGFR4, often resulted in suboptimal clinical responses, including low objective response rates and limited duration of benefit. A key reason for this lack of durable efficacy is the phenomenon of pathway redundancy, where FGFR3 can compensate for the loss of FGFR4 signaling.[2]

Preclinical investigations, including sophisticated genome-wide CRISPR loss-of-function screens, have provided compelling evidence that FGFR3 expression can indeed restrict the pro-apoptotic and anti-proliferative effects of FGFR4-selective inhibitors in HCC cell models.[15] In cells where both FGFR3 and FGFR4 are expressed along with KLB, FGF19 can continue to drive oncogenic signaling through FGFR3 even when FGFR4 is effectively blocked. This functional redundancy serves as a mechanism of de novo, or intrinsic, resistance. The clinical relevance of this observation is underscored by data from The Cancer Genome Atlas (TCGA) and other studies indicating that FGFR3 is frequently co-expressed with FGFR4 and KLB in FGF19-positive HCC tumors.[15] Therefore, by concurrently inhibiting both FGFR4 and FGFR3, TYRA-430 is designed to cut off this escape route, potentially leading to more profound and sustained tumor inhibition in FGF19-driven cancers.

2.3. Activity Against Acquired FGFR4 Resistance Mutations

Beyond addressing de novo resistance due to pathway redundancy, TYRA-430 has been engineered to counteract acquired resistance, a common challenge with targeted kinase inhibitors. Acquired resistance often arises from the selection and outgrowth of tumor cells harboring mutations in the target kinase that reduce drug binding or efficacy. In the context of FGFR4 inhibition, specific "gatekeeper" mutations in the kinase domain, such as those at residues Val550 (e.g., V550L, V550M) and Cys552 (e.g., C552S), have been identified as mechanisms that can confer resistance to FGFR4 inhibitors, including covalent inhibitors.[2]

Preclinical studies have demonstrated that TYRA-430 maintains potent inhibitory activity against these known FGFR4 gatekeeper resistance mutations.[2] This activity is a critical aspect of its profile, suggesting that TYRA-430 could be effective in patients whose tumors have developed resistance to prior FGFR4-targeted therapies or, if used as an earlier line of treatment, could potentially delay or prevent the emergence of such resistant clones, leading to more durable clinical responses. This capability differentiates TYRA-430 from some earlier-generation FGFR4 inhibitors that are susceptible to these resistance mechanisms.

2.4. Reversible, Non-Covalent Inhibition

TYRA-430 functions as a reversible, non-covalent inhibitor of its target kinases, FGFR4 and FGFR3.[2] This mode of binding contrasts with that of irreversible (covalent) inhibitors, which form a permanent chemical bond with their target. The choice of a reversible binding mechanism can have several implications for a drug's pharmacological profile. Reversible inhibitors typically have different pharmacokinetic/pharmacodynamic (PK/PD) relationships, potentially allowing for more flexible dosing and management of target-related toxicities. Furthermore, the types of resistance mutations that emerge against reversible inhibitors can differ from those selected by covalent inhibitors. While covalent inhibitors can offer advantages in terms of prolonged target engagement and potency against wild-type targets, they can also be susceptible to specific resistance mutations that alter the targeted covalent binding site or lead to off-target liabilities if the covalent warhead is reactive. TYRA-430's reversible mechanism, coupled with its demonstrated activity against resistance mutations that affect covalent inhibitors, suggests a strategic design aimed at providing a distinct and potentially more advantageous therapeutic profile in the landscape of FGFR-targeted therapies.

The design of TYRA-430 as a reversible dual FGFR4/3 inhibitor appears to be a carefully considered strategy. The limitations of first-generation FGFR4-selective covalent inhibitors, such as fisogatinib (BLU-554), included the emergence of resistance via gatekeeper mutations (e.g., FGFR4 V550M).[17] By adopting a reversible binding mode and optimizing the chemical scaffold through the SNÅP platform, Tyra Biosciences aims for TYRA-430 to effectively inhibit both wild-type and common mutant forms of FGFR4, as well as FGFR3, thereby addressing multiple layers of potential drug resistance. This multi-pronged approach to overcoming resistance—targeting pathway redundancy and specific kinase domain mutations—underpins the therapeutic rationale for TYRA-430. The "FGFR4/3-biased" nature of the inhibitor further refines this strategy, suggesting an effort to achieve potent inhibition of the primary oncogenic drivers (FGFR4 and FGFR3 in the context of FGF19-driven HCC) while potentially minimizing interactions with FGFR1 and FGFR2. Such selectivity is critical because off-target inhibition of FGFR1 can lead to hyperphosphatemia, a common dose-limiting toxicity for many pan-FGFR inhibitors, and FGFR2 inhibition has been linked to other adverse events. Thus, the specific inhibitory profile of TYRA-430 seeks to optimize the balance between efficacy and tolerability.

3. Preclinical Efficacy and Safety Profile

3.1. In Vitro Potency and Comparative Efficacy

The preclinical evaluation of TYRA-430 has yielded promising results regarding its potency and selectivity. In engineered Ba/F3 cellular assays, where cell survival and proliferation are dependent on specific FGFR signaling, TYRA-430 demonstrated potent inhibition of cells driven by wild-type FGFR3 and wild-type FGFR4.[2] A critical finding from these in vitro studies is the retained potency of TYRA-430 against Ba/F3 cells expressing known FGFR4 gatekeeper resistance mutations, including variants at Cys552 and Val550.[2] This activity against clinically relevant resistance mechanisms is a key differentiating feature.

Furthermore, in HCC cell lines characterized by activation of the KLB/FGF19/FGFR3/4 signaling pathway (such as Hep3B, HuH-7, and JHH-7), TYRA-430 consistently displayed superior potency in reducing cell viability when compared directly with several other agents. These comparators included:

• Standard-of-care multi-kinase inhibitors: Sorafenib and lenvatinib, which are approved for advanced HCC but have broad kinase inhibitory profiles and associated toxicities.[2]
• Investigational covalent FGFR4-selective inhibitors: Fisogatinib (BLU-554) and roblitinib (FGF401), which represent earlier attempts to specifically target the FGFR4 pathway.[2] The superior in vitro potency of TYRA-430 over these agents in relevant HCC cellular models provides a strong preclinical basis for its potential clinical advantage.

3.2. In Vivo Anti-Tumor Efficacy in Xenograft Models

The promising in vitro activity of TYRA-430 translated into significant anti-tumor efficacy in in vivo animal models.

• Hepatocellular Carcinoma (HCC) Xenograft Model: In a human HuH-7 HCC cell line-derived xenograft model in immunodeficient nu/nu mice, oral administration of TYRA-430 resulted in a substantial 96% tumor growth inhibition (TGI).[2] This effect was markedly superior to that of lenvatinib (75% TGI) and the covalent FGFR4 inhibitor roblitinib (FGF401, 86% TGI) when evaluated in the same model system.[2]
• Gastric Cancer Patient-Derived Xenograft (PDX) Model: To further assess its efficacy in a model that may better recapitulate human tumor biology, TYRA-430 was tested in the GA180 gastric cancer PDX model, which is characterized by FGF19-driven signaling. In this model, TYRA-430 again demonstrated superior anti-tumor activity, achieving 93% TGI. This was significantly more effective than roblitinib, which achieved 56% TGI in the same PDX model.[2]

The robust TGI observed in these distinct in vivo models, particularly the outperformance of both standard-of-care and other investigational FGFR inhibitors, underscores the preclinical therapeutic potential of TYRA-430. The efficacy in an FGF19-driven gastric cancer PDX model also suggests that the utility of TYRA-430 might extend beyond HCC to other solid tumors dependent on this signaling pathway.

3.3. Preclinical Safety and Pharmacokinetics Overview

While the provided research summaries focus heavily on the efficacy of TYRA-430, detailed preclinical toxicology studies and comprehensive pharmacokinetic (PK) data are not extensively elaborated. TYRA-430 is administered orally, a feature that generally offers patient convenience.[1] The core design principle of TYRA-430 as an "FGFR4/3-biased" inhibitor, as opposed to a pan-FGFR inhibitor, inherently aims to improve the therapeutic window by potentially avoiding or reducing toxicities associated with the inhibition of FGFR1 and FGFR2. For instance, FGFR1 inhibition is often linked to hyperphosphatemia, while FGFR2 inhibition has been associated with other class-specific adverse events such as nail and skin toxicities or ocular adverse events. Tyra Biosciences' development of TYRA-300, a highly selective FGFR3 inhibitor, explicitly mentions the goal of avoiding toxicities related to FGFR1, FGFR2, and FGFR4 inhibition [1], suggesting a company-wide strategy focused on optimizing selectivity to enhance tolerability.

The first-in-human clinical trial, SURF431, will be instrumental in defining the human safety, tolerability, and PK profile of TYRA-430.[6] Standard safety assessments in such trials will meticulously monitor for class-specific toxicities typical of tyrosine kinase inhibitors (TKIs) and FGFR inhibitors, which can include gastrointestinal disturbances (diarrhea, nausea), fatigue, dermatologic reactions, and effects on liver function, in addition to more specific FGFR-related effects like hyperphosphatemia and ocular changes.[25]

Table 2: Summary of Key Preclinical Efficacy Data for TYRA-430

Assay Type	Model System	Key Genetic Drivers/Context	TYRA-430 Activity/Potency	Comparator(s) & Activity	Resistance Mutation Coverage	Source(s)
In vitro cell viability	Ba/F3-FGFR3 WT	Engineered FGFR3 dependence	Potent inhibition	N/A	N/A	2
In vitro cell viability	Ba/F3-FGFR4 WT	Engineered FGFR4 dependence	Potent inhibition	N/A	N/A	2
In vitro cell viability	Ba/F3-FGFR4 Cys552 mutant	Engineered FGFR4 Cys552 resistance mutation	Potent inhibition	Implied superior to covalent FGFR4 inhibitors	Yes (Cys552)	2
In vitro cell viability	Ba/F3-FGFR4 Val550 mutant	Engineered FGFR4 Val550 resistance mutation	Potent inhibition	Implied superior to covalent FGFR4 inhibitors	Yes (Val550)	2
In vitro cell viability	Hep3B, HuH-7, JHH-7 HCC cell lines	Endogenous KLB/FGF19/FGFR3/4 pathway activation	Superior potency	Sorafenib, Lenvatinib, Fisogatinib (BLU-554), Roblitinib (FGF401) (all show lesser potency)	N/A	2
In vivo Tumor Growth Inhibition (TGI)	HuH-7 HCC xenograft (nu/nu mice)	Endogenous FGF19/FGFR4 pathway	96% TGI	Lenvatinib (75% TGI), FGF401 (86% TGI)	N/A	2
In vivo Tumor Growth Inhibition (TGI)	GA180 Gastric Cancer PDX model	FGF19-driven	93% TGI	Roblitinib (FGF401) (56% TGI)	N/A	2

The compelling preclinical efficacy of TYRA-430, particularly its consistent outperformance against both standard-of-care multi-kinase inhibitors (sorafenib, lenvatinib) and earlier-generation selective FGFR4 inhibitors (fisogatinib, roblitinib) across various HCC models, provides a strong rationale for its clinical development.[2] This superiority suggests that TYRA-430 may offer an improved therapeutic window or greater depth of response if these preclinical advantages translate to human patients.

Furthermore, the demonstration of significant anti-tumor activity in an FGF19-driven gastric cancer PDX model (GA180) [2] is noteworthy. While HCC is the primary focus, this finding hints at a broader therapeutic potential for TYRA-430 in other malignancies characterized by aberrant FGF19/FGFR4/3 signaling. This aligns with the design of the SURF431 clinical trial, which includes a cohort for "other advanced solid tumors" with relevant FGF/FGFR pathway alterations, allowing for an early exploration of TYRA-430's activity beyond HCC.[1]

A particularly crucial aspect of TYRA-430's preclinical profile is its potent activity against known FGFR4 gatekeeper resistance mutations, such as Cys552 and Val550 variants.[2] Acquired resistance through such mutations has been a documented mechanism of clinical failure for some FGFR4 inhibitors, for instance, fisogatinib (BLU-554).[17] By effectively inhibiting these resistant forms of FGFR4, TYRA-430 offers the potential to treat patients who have progressed on prior FGFR4-targeted therapies or to provide a more durable response by preventing or delaying the emergence of these common resistance mechanisms. This characteristic is a direct output of Tyra Biosciences' SNÅP platform, which is geared towards designing therapies that can overcome acquired drug resistance. The successful translation of this preclinical resistance-breaking activity into clinical benefit would represent a significant advance in the field of FGFR-targeted therapy.

4. Clinical Development Program: The SURF431 Study (NCT06915753)

4.1. Regulatory Status and Study Initiation

Tyra Biosciences has successfully navigated the initial regulatory steps for TYRA-430. The U.S. Food and Drug Administration (FDA) granted Investigational New Drug (IND) clearance for TYRA-430, permitting the initiation of its clinical development program.[1] Following this clearance, the first-in-human Phase 1 clinical trial, designated SURF431 (also known by protocol ID TYR430-101), commenced, with the first patient reported as dosed in the second quarter of 2025.[1] One source specified the trial initiation date as April 1, 2025.[27]

4.2. Study Design and Objectives (SURF431 - NCT06915753)

The SURF431 trial is a Phase 1, multi-center, open-label, global study designed to evaluate TYRA-430 in patients with advanced cancers harboring FGF/FGFR pathway aberrations.[6] The study is structured in two main parts:

• Part A (Dose Escalation): This part will enroll patients with locally advanced unresectable/metastatic HCC or other advanced solid tumors with documented FGF/FGFR pathway alterations. TYRA-430 will be administered as an oral monotherapy at various dose levels using a sequential assignment approach. The primary goal of Part A is to assess the safety and tolerability of TYRA-430, identify any dose-limiting toxicities (DLTs), and determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D).[23]
• Part B (Dose Expansion): Once the MTD/RP2D is established in Part A, Part B will enroll patients into specific cohorts to further evaluate the safety, tolerability, and preliminary anti-tumor activity of TYRA-430 at the selected dose(s).
• Cohort 1: This cohort will focus on patients with advanced HCC. Eligibility will require FGF19 immunohistochemistry (IHC) testing on archival tumor tissue.[23]
• Cohort 2: This cohort will include patients with other advanced solid tumors (excluding FGFR3-altered urothelial carcinoma and primary central nervous system tumors) that have an eligible activating gain-of-function alteration in the FGFR3 or FGFR4 gene, or focal amplifications of FGF19.[23]

The primary objectives of the SURF431 study are to evaluate the safety and tolerability of TYRA-430 and to establish the MTD and/or RP2D.6

Secondary and exploratory objectives include characterization of the pharmacokinetic (PK) profile of TYRA-430, assessment of pharmacodynamic (PD) markers of target engagement and biological activity, and evaluation of preliminary anti-tumor efficacy (e.g., Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR)).6 The study is sponsored by Tyra Biosciences, Inc. 23 and is currently recruiting participants, with an estimated total enrollment of approximately 100 patients.23

4.3. Target Patient Population and Key Eligibility Criteria

The SURF431 trial targets adult patients (≥ 18 years) with histologically confirmed, locally advanced/metastatic HCC or other advanced solid tumors that are not amenable to curative therapy and possess activating FGF/FGFR pathway aberrations.[23] Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and adequate organ function.

Key Inclusion Criteria for Part A (Dose Escalation):

• Histologically confirmed locally advanced unresectable/metastatic HCC (BCLC stage B not eligible for locoregional therapy, or stage C; Child-Pugh Class A) OR histologically confirmed advanced solid tumor with documented FGF/FGFR pathway alterations.
• Prior standard-of-care therapy appropriate for tumor type; any number of prior therapies, including FGFR inhibitors, are permitted.[23]
• Availability of archival tumor tissue (if available, collected ≤2 years prior to enrollment) is requested, but a new biopsy is not mandatory if archival tissue is unavailable.[23]

Key Inclusion Criteria for Part B, Cohort 1 (HCC Dose Expansion):

• Histologically confirmed locally advanced/metastatic HCC, BCLC stage B (not eligible for locoregional therapy) or stage C, Child-Pugh Class A.
• Prior standard-of-care therapy.
• Availability of an archival FFPE tumor tissue specimen (≤2 years old) for central FGF19 IHC testing is mandatory.[23]
• At least one measurable lesion per RECIST v1.1.[23]

Key Inclusion Criteria for Part B, Cohort 2 (Other Solid Tumors Dose Expansion):

• Histologically confirmed advanced solid tumor (excluding FGFR3-altered urothelial carcinoma and primary CNS tumors).
• Must have an eligible activating gain-of-function alteration in the FGFR3 or FGFR4 gene, or focal amplifications of FGF19, as determined by a local laboratory.[23]
• Prior standard-of-care therapy.
• At least one measurable lesion per RECIST v1.1.[24]

Key Exclusion Criteria (Applicable to various parts/cohorts):

• Disease suitable for local therapy with curative intent.
• Inadequate recovery from prior anticancer therapy toxicities.
• Receipt of specified anticancer therapies (immunotherapy, TKIs, other systemic therapy) within defined washout periods prior to the first dose of TYRA-430.[23]
• Prior discontinuation of an anti-FGFR therapy due to significant toxicity (defined as hepatotoxicity ≥Grade 3 or any Grade 4 toxicity).[23]
• Serum phosphorus level > ULN at screening that remains elevated despite medical management.
• History of or current uncontrolled cardiovascular disease.
• Active, symptomatic, or untreated brain metastases, or diagnosis of primary CNS malignancies.
• Gastrointestinal disorders significantly affecting oral drug administration or absorption.
• For Part B, Cohort 1 (HCC): Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC. Critically, prior treatment with pan-FGFR inhibitors or FGFR4-selective inhibitors is an exclusion criterion for this specific cohort, ensuring a population naïve to this class of agents for a clearer efficacy signal in FGF19-driven HCC.[23]
• For Part B, Cohort 2 (Other Solid Tumors): Histologically confirmed HCC or urothelial cancer are excluded from this cohort as they are covered elsewhere or have distinct FGFR therapeutic landscapes.[23]

4.4. Study Timelines and Locations

The SURF431 trial (NCT06915753) officially commenced on April 1, 2025.[27] The first patient was dosed in the second quarter of 2025, aligning with the company's projections.[1] The estimated primary completion date for the study is January 1, 2028.[27] The trial is being conducted at multiple centers globally, with initial sites identified in the United States and Canada. These include prominent academic institutions such as Johns Hopkins University, Stanford Cancer Institute, University of California San Francisco (UCSF), Massachusetts General Hospital Cancer Center, and the University Health Network Princess Margaret Cancer Center in Toronto.[23]

Table 3: Overview of the SURF431 (NCT06915753) Phase 1 Clinical Trial

Parameter	Details	Source(s)
Trial Identifier	NCT06915753; TYR430-101	6
Phase	1	1
Title	A Multicenter, Open-label, First-in-Human Study of TYRA-430 in Advanced Hepatocellular Carcinoma and Other Solid Tumors With Activating FGF/FGFR Pathway Aberrations	23
Status	Recruiting (First patient dosed Q2 2025)	5
Sponsor	Tyra Biosciences, Inc.	23
Primary Objectives	Evaluate safety, tolerability, MTD, and RP2D of TYRA-430.	6
Secondary Objectives	Evaluate PK, PD, and preliminary antitumor activity of TYRA-430.	6
Target Population	Adults (≥18 years) with locally advanced/metastatic HCC or other advanced solid tumors with activating FGF/FGFR pathway aberrations, who have received prior standard of care.	23
Intervention	TYRA-430 monotherapy administered orally. Part A: Dose Escalation. Part B: Dose Expansion (Cohort 1: Advanced HCC with FGF19 overexpression; Cohort 2: Other advanced solid tumors with FGF/FGFR aberrations).	23
Key Inclusion Criteria	Documented FGF/FGFR pathway alteration (FGF19 amplification or FGFR3/4 activating alteration for relevant cohorts), ECOG PS 0-1, adequate organ function. For HCC: BCLC stage B/C, Child-Pugh A.	23
Key Exclusion Criteria	Prior discontinuation of anti-FGFR therapy due to significant toxicity (for Part A, some prior FGFRi allowed; for Part B HCC cohort, no prior FGFR4i/pan-FGFRi), uncontrolled cardiovascular disease, active brain metastases.	23
Estimated Enrollment	~100 patients.	23
Locations	Multiple sites in US and Canada (e.g., Johns Hopkins, Stanford, UCSF, MGH, Princess Margaret).	23

The design of the SURF431 trial, particularly its two-part structure with distinct dose expansion cohorts, reflects a well-considered clinical development strategy. Part A, the dose escalation phase, will establish the fundamental safety and PK profile of TYRA-430. The subsequent Part B expansion cohorts allow for a more focused investigation in specific patient populations. Cohort 1, dedicated to FGF19-driven HCC (requiring central FGF19 IHC confirmation), will provide critical data in the primary target indication. The exclusion of patients with prior FGFR4 or pan-FGFR inhibitor treatment in this HCC cohort is a key design choice aimed at obtaining a cleaner efficacy signal in a population naïve to this specific class of agents, which is important for establishing baseline activity.[23]

Cohort 2, which enrolls patients with other advanced solid tumors harboring FGFR3/4 activating alterations or FGF19 amplifications, serves an important exploratory purpose.[23] This "basket" component allows Tyra Biosciences to efficiently screen for signals of activity across a range of tumor types that share the relevant molecular drivers. Positive signals from this cohort could open avenues for future development in indications beyond HCC, broadening the potential impact of TYRA-430. The allowance of prior FGFR inhibitor treatment in the dose-escalation phase (Part A) [23] is also strategically significant. It provides an early opportunity to assess whether TYRA-430 can indeed overcome resistance mechanisms that may have led to failure of previous FGFR-targeted therapies, a core tenet of its design rationale stemming from the SNÅP platform. The initiation of dosing in Q2 2025 marks a critical milestone, moving TYRA-430 from the preclinical realm into human testing, where its therapeutic hypothesis will be rigorously evaluated.

5. Emerging Clinical Data and Future Directions

As the SURF431 Phase 1 trial for TYRA-430 is in its early stages, with the first patient dosed in Q2 2025 [1], comprehensive clinical data on efficacy and safety are not yet available. However, the study is designed to systematically gather this information.

5.1. Pharmacokinetics and Pharmacodynamics (PK/PD)

A key objective of the SURF431 trial is to thoroughly characterize the pharmacokinetic profile of TYRA-430 in humans. This will involve collecting data on its absorption, distribution, metabolism, and excretion (ADME) following oral administration.6 Understanding these parameters is crucial for determining appropriate dosing schedules and identifying potential drug-drug interactions.

Pharmacodynamic assessments will also be integral to the study. These will likely involve the analysis of biomarkers to confirm target engagement (i.e., inhibition of FGFR4 and FGFR3) and to measure the downstream effects on relevant signaling pathways within tumor tissue and/or surrogate tissues. Such PD data will help to correlate drug exposure with biological activity and guide dose optimization.

5.2. Preliminary Safety and Tolerability

The initial dose escalation phase (Part A) of SURF431 will provide the first insights into the safety and tolerability profile of TYRA-430 in cancer patients.[6] Close monitoring for adverse events (AEs) will be conducted, with particular attention paid to potential class-specific toxicities associated with FGFR inhibitors. These can include, but are not limited to, hyperphosphatemia (often linked to FGFR1 inhibition, which TYRA-430 aims to minimize through its biased profile), gastrointestinal toxicities (such as diarrhea and stomatitis), dermatologic toxicities (e.g., hand-foot syndrome, dry skin), ocular adverse events (e.g., dry eye, retinal pigment epithelial detachments), and potential effects on liver function.[25] The identification of the MTD and RP2D will be based on the observed safety and tolerability across different dose levels. A favorable safety profile, particularly if it demonstrates an improvement over less selective FGFR inhibitors, would be a significant advantage for TYRA-430.

5.3. Early Signals of Anti-Tumor Activity

Preliminary evidence of anti-tumor activity will be a critical early readout from the SURF431 trial, initially from the dose escalation cohorts and more definitively from the dose expansion cohorts.6 Efficacy will be assessed using standard oncologic criteria, such as Response Evaluation Criteria in Solid Tumors (RECIST v1.1), to determine objective response rates (ORR), disease control rates (DCR), and duration of response (DOR).23

Particular attention will be paid to responses in patients with FGF19-driven HCC (Cohort 1 of Part B) and in patients with other solid tumors harboring the specified FGFR3/4 alterations or FGF19 amplifications (Cohort 2 of Part B). Early signs of durable responses, especially in heavily pre-treated patients or those whose tumors possess known resistance mutations to other FGFR inhibitors, would provide strong validation for TYRA-430's mechanism of action and therapeutic potential.

5.4. Future Development and Therapeutic Potential

The data emerging from the SURF431 Phase 1 trial will be pivotal in shaping the future clinical development strategy for TYRA-430. If the trial successfully demonstrates a manageable safety profile and encouraging preliminary anti-tumor activity, particularly in biomarker-defined patient populations, it would pave the way for subsequent Phase 2 and potentially Phase 3 studies. These later-stage trials would aim to confirm efficacy in larger, more defined patient cohorts, potentially in comparison to standard-of-care treatments.

TYRA-430 holds the potential to address a significant unmet medical need, especially in advanced FGF19-driven HCC, where there are currently no approved biomarker-driven targeted therapies that specifically address the FGFR4/3 axis and associated resistance mechanisms.[1] Its ability to overcome resistance mutations observed with prior FGFR4 inhibitors could position it as a valuable option for patients who have progressed on other treatments or as a more durable therapy in earlier lines.

Future development might also explore TYRA-430 in combination with other anticancer agents. Given the complex tumor microenvironment and the interplay of multiple signaling pathways in cancer, combination strategies often yield synergistic effects. Potential partners could include immunotherapies (e.g., checkpoint inhibitors) or other targeted agents, depending on the evolving understanding of resistance mechanisms and synergistic interactions in specific tumor types. The broader applicability of TYRA-430 in other FGF19-driven or FGFR3/4-altered solid tumors, as suggested by preclinical data in gastric cancer models and the design of the SURF431 Cohort 2, also represents an important avenue for future expansion.

The definition of an optimal RP2D from the SURF431 study will be a critical step. This dose must achieve a delicate balance: providing sufficient target engagement of both FGFR4 and FGFR3 to elicit a robust anti-tumor response, while maintaining a safety and tolerability profile that is manageable for patients, particularly in the context of advanced cancer. The "FGFR4/3-biased" design of TYRA-430 is intended to facilitate this balance by minimizing inhibition of FGFR1 and FGFR2, thereby potentially avoiding some of the more challenging class-related toxicities of pan-FGFR inhibitors, such as severe hyperphosphatemia or certain dermatological and ocular side effects. Early clinical data demonstrating this favorable therapeutic index will be crucial for the drug's continued development and ultimate clinical utility. Furthermore, any early efficacy signals observed in patients who have previously progressed on other FGFR inhibitors, or those harboring known resistance mutations, would strongly validate the core hypothesis behind TYRA-430's design and the capabilities of the SNÅP platform.

6. Conclusion and Expert Perspective

6.1. Summary of TYRA-430's Profile and Development

TYRA-430 is an orally bioavailable, reversible, small-molecule inhibitor characterized by its biased targeting of both FGFR4 and FGFR3. Developed by Tyra Biosciences using their proprietary SNÅP platform, TYRA-430 is engineered to address the limitations of previous FGFR-targeted therapies in FGF19-driven hepatocellular carcinoma and other solid tumors with specific FGF/FGFR pathway aberrations. The core rationale for its development lies in overcoming de novo resistance mediated by FGFR3 signaling redundancy and acquired resistance driven by FGFR4 kinase domain mutations. Preclinical studies have demonstrated superior potency and efficacy of TYRA-430 compared to existing multi-kinase inhibitors and earlier-generation FGFR4-selective agents, including activity against known resistance mutations. TYRA-430 has entered clinical development with the initiation of the SURF431 Phase 1 trial (NCT06915753), which is currently enrolling patients to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity.

6.2. Potential Advantages and Challenges

TYRA-430 presents several potential advantages that could position it favorably in the therapeutic landscape:

• Dual FGFR4/3 Inhibition: Addresses the clinically relevant mechanism of FGFR3 pathway redundancy that limits the efficacy of FGFR4-selective inhibitors in FGF19-driven HCC.
• Activity Against Resistance Mutations: Preclinical data suggest potency against known FGFR4 gatekeeper mutations, offering potential benefit in patients resistant to prior FGFR therapies or a more durable response.
• Oral Bioavailability: Offers patient convenience and facilitates chronic dosing regimens.
• Reversible Inhibition: Provides a distinct pharmacological profile compared to covalent inhibitors, which may influence its safety and resistance spectrum.
• FGFR4/3-Biased Selectivity: Aims to optimize the therapeutic index by focusing inhibition on key oncogenic drivers while potentially sparing FGFR1 and FGFR2, thereby mitigating certain class-associated toxicities like severe hyperphosphatemia.
• Precision Medicine Approach: Targets a biomarker-defined patient population (FGF19 overexpression or specific FGFR3/4 alterations), aligning with the paradigm of personalized oncology.

Despite these potential advantages, the development of TYRA-430 faces inherent challenges:

• Clinical Translation of Preclinical Efficacy: The robust preclinical efficacy must translate into meaningful and durable clinical benefit in human patients.
• Safety and Tolerability: While the biased selectivity aims to improve tolerability, on-target toxicities related to FGFR4/3 inhibition and potential off-target effects must be carefully managed. The overall safety profile will be critical for its competitiveness.
• Biomarker Development and Validation: Accurate and reliable companion diagnostics or biomarker assays will be essential for identifying the appropriate patient populations most likely to benefit from TYRA-430.
• Competitive Landscape: The field of targeted therapy for HCC and other solid tumors is dynamic. TYRA-430 will need to demonstrate a clear clinical advantage (in terms of efficacy, safety, or patient-reported outcomes) over existing treatments and other investigational agents targeting similar pathways or indications.[14]
• Heterogeneity of FGFR Aberrations: The diverse nature of FGF/FGFR alterations across different tumor types may necessitate tailored development strategies and could impact response rates.

6.3. Outlook for TYRA-430 in Precision Oncology

TYRA-430 embodies a rational, next-generation approach to FGFR-targeted therapy, informed by the lessons learned from previous inhibitors and leveraging advanced drug design principles. Its development is a testament to the increasing sophistication in targeting oncogenic driver pathways and proactively addressing mechanisms of drug resistance.

The ongoing SURF431 Phase 1 trial represents a critical juncture for TYRA-430. The initial data on safety, tolerability, PK/PD, and preliminary efficacy will be instrumental in determining its future trajectory. If the promising preclinical profile, particularly its dual FGFR4/3 inhibition and activity against resistance mutations, translates into a favorable therapeutic index in patients, TYRA-430 could emerge as a significant new treatment option.

Specifically for FGF19-driven HCC, a disease with a clear unmet need and no currently approved biomarker-driven therapies targeting this precise axis, TYRA-430 has the potential to establish a new standard of care for a defined patient subset. Success in this indication would not only benefit patients but also validate the scientific rationale behind its design and the capabilities of Tyra Biosciences' SNÅP platform.[1] The inclusion of a cohort for other solid tumors with FGF/FGFR aberrations in the Phase 1 study also provides an opportunity to explore broader applications, potentially expanding its impact across the oncology landscape.

The journey of TYRA-430 through clinical development will be closely watched by the oncology community. Its progress will offer valuable insights into the therapeutic utility of dual FGFR4/3 inhibition and the ongoing efforts to develop more precise and durable targeted therapies for patients with FGF/FGFR pathway-driven cancers. The success of TYRA-430, alongside other pipeline candidates like TYRA-300 and TYRA-200, will ultimately reflect the strength of Tyra Biosciences' innovative drug discovery platform in tackling complex oncological challenges.

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