TYRA-300 Advanced Drug Monograph

TYRA-300: A Selective FGFR3 Inhibitor in Clinical Development for Oncological and Skeletal Dysplasia Indications – A Comprehensive Review

1. Abstract

TYRA-300 is an investigational, orally bioavailable, selective inhibitor of Fibroblast Growth Factor Receptor 3 (FGFR3) currently under development by Tyra Biosciences. This agent is being evaluated in dual therapeutic pathways: oncology, for the treatment of metastatic urothelial carcinoma (mUC) and non–muscle-invasive bladder cancer (NMIBC) harboring FGFR3 alterations; and for achondroplasia, the most common form of dwarfism, which is predominantly driven by activating FGFR3 mutations. Preclinical studies have demonstrated TYRA-300's potent anti-tumor activity and its ability to promote bone growth in models of achondroplasia by modulating chondrocyte activity. A key design feature of TYRA-300 is its high selectivity for FGFR3 over other FGFR isoforms (FGFR1, FGFR2, FGFR4), which translates to a potentially more favorable tolerability profile compared to pan-FGFR inhibitors. Early clinical data from the SURF301 trial in patients with FGFR3-altered mUC have shown encouraging response rates and a manageable safety profile, with notably fewer off-target toxicities typically associated with broader FGFR inhibition. For achondroplasia, TYRA-300 has received Orphan Drug Designation and Rare Pediatric Disease Designation from the U.S. Food and Drug Administration (FDA), and the BEACH301 Phase 2 trial in children is underway. The FDA has also cleared Investigational New Drug (IND) applications for Phase 2 studies in NMIBC (SURF302) and pediatric achondroplasia (BEACH301), underscoring its therapeutic potential in addressing significant unmet medical needs in these distinct patient populations.

2. Introduction to TYRA-300

2.1. Overview of Fibroblast Growth Factor Receptors (FGFRs) and FGFR3

The Fibroblast Growth Factor Receptor (FGFR) family comprises four highly conserved transmembrane receptor tyrosine kinases (FGFR1, FGFR2, FGFR3, and FGFR4) that play crucial roles in a multitude of cellular processes, including proliferation, differentiation, migration, and angiogenesis. Ligand binding (fibroblast growth factors, FGFs) to the extracellular domain of FGFRs induces receptor dimerization and autophosphorylation of intracellular tyrosine kinase domains, thereby activating downstream signaling pathways such as RAS-MAPK, PI3K-AKT, PLCγ, and STAT. Dysregulation of FGFR signaling, through mechanisms including gene amplification, activating mutations, or chromosomal translocations leading to fusion proteins, is implicated in the pathogenesis of various human diseases. In oncology, aberrant FGFR signaling can drive tumor growth, survival, and resistance to therapy in a range of malignancies, notably urothelial carcinoma. Specifically, activating alterations in FGFR3 are frequently observed in bladder cancer, particularly in non-muscle invasive forms.1

In skeletal development, FGFR3 is a critical negative regulator of endochondral ossification. Gain-of-function mutations in FGFR3 lead to its constitutive activation, which inhibits chondrocyte proliferation and differentiation in the growth plates, resulting in impaired bone growth and conditions known as skeletal dysplasias, the most common of which is achondroplasia.1

2.2. TYRA-300: A Novel Investigational Agent

TYRA-300 is an investigational, orally active, small molecule inhibitor designed to selectively target FGFR3.3 It is being developed by Tyra Biosciences, Inc. (Nasdaq: TYRA), a clinical-stage biotechnology company focused on next-generation precision medicines targeting FGFR biology.2

A cornerstone of Tyra Biosciences' drug discovery approach is its proprietary SNÅP (Structure-based NÅPshot) platform. This platform facilitates rapid and precise drug design through iterative molecular "SNÅPshots," which are used to predict genetic alterations most likely to cause acquired resistance to existing therapies and to engineer novel compounds with desired selectivity and potency profiles.2 The development of TYRA-300 has been significantly informed by this platform, alongside structural insights derived from hundreds of internally solved FGFR co-crystal structures.1 This meticulous, structure-based design process represents a deliberate strategy to achieve high selectivity for FGFR3. The intention is not merely to inhibit FGFR3 but to do so while minimizing interactions with other FGFR isoforms and, consequently, mitigating the off-target toxicities commonly associated with less selective, or "pan-FGFR," inhibitors.6 This proactive approach to drug design, aiming for an improved therapeutic index by enhancing target specificity, is a distinguishing feature of the TYRA-300 program.

2.3. Rationale for Development

The development of TYRA-300 addresses distinct unmet medical needs in both oncology and rare genetic conditions. In FGFR3-driven cancers, such as metastatic urothelial carcinoma, existing targeted therapies like pan-FGFR inhibitors can be limited by significant toxicities or the emergence of resistance mutations.1 TYRA-300 aims to provide a more tolerable and durably effective option for these patients.

For achondroplasia, which is caused by specific gain-of-function mutations in FGFR3 in over 99% of cases, current management is largely supportive, and there is a significant need for therapies that can address the underlying pathophysiology of the condition.1 TYRA-300 offers the potential for a targeted oral therapy to normalize skeletal development and improve outcomes for individuals with achondroplasia and potentially other FGFR3-related skeletal dysplasias like hypochondroplasia.2

3. Pharmacological Profile

3.1. Chemical Characteristics and Formulation

TYRA-300 is an orally active small molecule.3 Its key physicochemical properties are summarized in Table 1.

Table 1: Physicochemical Properties of TYRA-300

Property	Value	Reference(s)
Molecular Formula	C25​H24​Cl2​N6​O3​S	4
Molecular Weight	559.47 g/mol	4
CAS Number	2800223-30-5	4
Appearance	Solid, white to off-white	4
SMILES	O=S(N(C1)CC1(C2)CN2C(N=C3)=CC=C3C4=NNC5=CC=C(OC@HC6=C(Cl)C=NC=C6Cl)C=C54)(C)=O	4
Key Solubility Notes	Soluble in DMSO (e.g., 100 mg/mL with sonication and warming)	4
Storage (Powder)	-20°C for 3 years; 4°C for 2 years	4
Storage (In Solvent)	-80°C for 6 months; -20°C for 1 month (DMSO)	4

TYRA-300 is formulated for oral administration.[3] Specific details regarding its clinical formulation are proprietary; however, preclinical solubility protocols involve solvents like DMSO, PEG300, Tween-80, and saline or corn oil for in vivo studies.[4] Proper storage is crucial, with powder recommended at -20°C for long-term stability.[4]

3.2. Mechanism of Action and Selectivity

TYRA-300 functions as a selective inhibitor of the FGFR3 tyrosine kinase.3 By binding to the ATP-binding pocket of FGFR3, it blocks the receptor's autophosphorylation and subsequent activation of downstream oncogenic signaling pathways.7 This inhibition is intended to counter the effects of activating FGFR3 gene alterations (mutations or fusions) that drive cell proliferation and survival in cancer, or aberrant chondrocyte regulation in skeletal dysplasias.

A critical aspect of TYRA-300's design is its selectivity for FGFR3 over other FGFR isoforms. The reported half-maximal inhibitory concentrations (IC50) are as follows [4]:

• FGFR3: 11 nM
• FGFR2: 157 nM
• FGFR1: 278 nM
• FGFR4: 4045 nM

These values, summarized in Table 2, quantitatively demonstrate TYRA-300's preferential inhibition of FGFR3. It is approximately 14-fold more selective for FGFR3 over FGFR2, 25-fold over FGFR1, and a substantial 367-fold over FGFR4. This high degree of selectivity is the molecular foundation for its anticipated improved safety and tolerability profile. Pan-FGFR inhibitors, which target FGFR1-4 more broadly, are associated with mechanism-based, off-target toxicities such as hyperphosphatemia (FGFR1 inhibition), stomatitis, and ocular or skin toxicities.[7] By preferentially inhibiting FGFR3 and largely sparing FGFR1, FGFR2, and FGFR4 at therapeutic concentrations, TYRA-300 is designed to minimize these adverse events.[6] This enhanced selectivity is a direct outcome of the structure-based drug design process and is anticipated to allow for more sustained dosing regimens and potentially facilitate combination therapies, ultimately improving the therapeutic window.

Table 2: FGFR Isoform Selectivity of TYRA-300

FGFR Isoform	IC50 (nM)	Fold Selectivity vs. FGFR3 (approx.)	Reference(s)
FGFR1	278	25x	4
FGFR2	157	14x	4
FGFR3	11	1x	4
FGFR4	4045	367x	4

Furthermore, TYRA-300 has been engineered to be effective against known FGFR3 gatekeeper mutations, such as V555M/L, which can emerge during treatment with other FGFR inhibitors and confer resistance.[1] This feature is critical for achieving durable clinical responses in oncology settings.

4. Preclinical Rationale and Findings

4.1. Activity in Oncology Models

Preclinical studies have established the anti-tumor efficacy of TYRA-300 in various models of urothelial cancer and other solid tumors harboring FGFR3 alterations.4 The initial discovery and characterization of TYRA-300, detailing its potent and selective FGFR3 inhibitory activity, were reported by Hudkins RL, et al., in the Journal of Medicinal Chemistry in 2024.4 These foundational studies provided the basis for its advancement into clinical trials for oncological indications.

4.2. Efficacy in Models of Skeletal Dysplasia (Achondroplasia and Hypochondroplasia)

TYRA-300 has demonstrated significant promise in preclinical models of FGFR3-related skeletal dysplasias, particularly achondroplasia and hypochondroplasia.2 In mouse models of achondroplasia (e.g., Fgfr3^Y367C/+ mice), which carry a mutation analogous to that found in human achondroplasia, TYRA-300 treatment has been shown to increase bone growth and address several skeletal abnormalities.13

The mechanism of action in these models involves the normalization of chondrocyte activity within the growth plate. Histological analyses revealed that TYRA-300 mechanistically increases both the proliferation (evidenced by increased Proliferating Cell Nuclear Antigen, PCNA, staining) and differentiation of chondrocytes (indicated by changes in Collagen type X staining and hypertrophic chondrocyte morphology).[13] This leads to a partial restoration of the disproportionality of long bones and a more organized growth plate architecture, with better-defined proliferative and hypertrophic zones.[13] Treatment also resulted in an increased size of the secondary ossification center (SOC), accompanied by enhanced angiogenesis and bone matrix deposition within the SOC.[13]

Beyond linear bone growth, TYRA-300 treatment in these models led to improvements in bone quality, as evidenced by increased bone mineral density (BMD) and bone volume-to-tissue volume ratio (BV/TV) in the femurs.[13] These findings suggest that TYRA-300's benefits extend beyond simply increasing bone length to encompass broader skeletal health. Critically, treatment positively impacted skull dimensions (increased length and width) and significantly increased the size of the foramen magnum (transverse diameter, sagittal diameter, and area by +25.17%).[13] This is of particular importance as foramen magnum stenosis is a serious potential complication of achondroplasia that can lead to neurological compromise.[2] Additionally, TYRA-300 treatment improved the morphology of synchondroses at the base of the skull, potentially preventing their premature fusion, and increased lumbar vertebrae segment length (by +23.49%) and vertebral body height, while also normalizing the shape of intervertebral discs towards that of wild-type mice.[13] These comprehensive skeletal effects observed preclinically suggest that TYRA-300 may offer more than just an increase in stature; it has the potential to mitigate some of the serious medical complications associated with the underlying FGFR3 dysregulation in achondroplasia, thereby significantly broadening its therapeutic impact.

Importantly, TYRA-300 was found to be equally active against the common achondroplasia-causing FGFR3 G380R mutant receptor and wild-type FGFR3 in in vitro binding assays, confirming its relevance for this genetic condition.[14]

5. Clinical Development in Oncological Indications

TYRA-300 is being investigated in multiple clinical trials for oncological indications, primarily focusing on cancers driven by FGFR3 alterations. An overview of these key trials is provided in Table 3.

Table 3: Overview of Key Clinical Trials for TYRA-300

Trial ID (NCT)	Official Title	Phase	Target Indication(s)	Key Objectives	Primary Endpoint(s)	Current Status (as of early 2025)	Key Reference(s)
NCT05544552	A Multicenter, Open-Label Phase 1/2 Study of TYRA-300 in Advanced Urothelial Carcinoma and Other Solid Tumors with Activating FGFR3 Alterations (SURF301)	1/2	Advanced/metastatic Urothelial Carcinoma (mUC), other solid tumors with FGFR3 alterations	Evaluate safety, tolerability, PK, preliminary antitumor activity, identify Recommended Phase 2 Dose (RP2D)	Safety, RP2D (Phase 1); ORR (Phase 2)	Recruiting	8
SURF302	A Phase 2 Trial of TYRA-300 in Patients with FGFR3-Altered Low-Grade, Intermediate-Risk Non–Muscle-Invasive Bladder Cancer	2	Low-grade, intermediate-risk Non–Muscle-Invasive Bladder Cancer (NMIBC) with FGFR3 alterations	Assess efficacy and safety	Complete Response (CR) rate at 3 months	IND Cleared; Dosing Q2 2025	2

5.1. TYRA-300 in Metastatic Urothelial Carcinoma (mUC) and Other Solid Tumors: The SURF301 Trial (NCT05544552)

5.1.1. Study Rationale, Design, Objectives, and Patient Population

The SURF301 trial is founded on the rationale of addressing the significant unmet need for effective and better-tolerated therapies for patients with advanced or metastatic urothelial carcinoma (mUC) harboring activating FGFR3 gene alterations, which are present in up to 20% of such cases.8 Many of these patients have progressed on prior systemic therapies, including chemotherapy and immunotherapy, and may have also been treated with other FGFR inhibitors.7

SURF301 is a first-in-human, multicenter, open-label, global Phase 1/2 study that commenced enrollment in November 2022 and is active in countries including Australia, the United States, France, and Spain.[8] The study is designed in multiple parts:

• Phase 1, Part A (Dose Escalation): Enrolls participants with advanced malignancies, with or without FGFR3 alterations, to determine initial safety and tolerability across escalating dose levels of TYRA-300.
• Phase 1, Part B (Dose Expansion): Focuses on participants with confirmed FGFR3-activating mutations or fusions to further evaluate safety, pharmacokinetics (PK), and preliminary anti-tumor activity at selected dose levels.
• Phase 2 (Tumor Expansion): Will enroll participants in specific cohorts, including FGFR3+ mUC and potentially other tumor types, to further explore the anti-tumor activity and safety of TYRA-300 at the Recommended Phase 2 Dose (RP2D). The primary objectives of the Phase 1 portion are to evaluate the safety, tolerability, and PK of TYRA-300, and to identify the RP2D for subsequent Phase 2 investigation.[8] Preliminary antitumor activity is also a key objective.

5.1.2. Efficacy Outcomes (Interim Data)

Interim data from the SURF301 trial, primarily from the dose escalation and expansion cohorts in patients with FGFR3-altered mUC, were presented by Professor Ben Tran at the EORTC-NCI-AACR (ENA) Symposium in October 2024.11

In patients with FGFR3-altered mUC treated with TYRA-300 at doses of at least 90 mg per day (n=11), the following efficacy was observed 3:

• Partial Response (PR) Rate: 54.5% (6 out of 11 patients).
• Objective Response Rate (ORR): Approximately 50% was reported for the 90 mg daily dose level.[11]
• Disease Control Rate (DCR): 100% (all 11 patients achieved at least stable disease).[3] Notably, three of the six responses were ongoing as of the data cutoff date of August 15, 2024.[3] Responses have also been observed in patients treated at the 120 mg daily dose level, and dose escalation is continuing to identify the optimal dose for further development.[11]

These early efficacy signals are particularly noteworthy. The patient population in SURF301 is often heavily pretreated [7], representing a group with limited therapeutic options and a generally poor prognosis. For context, erdafitinib, an approved pan-FGFR inhibitor, demonstrated an ORR of 40% in its pivotal BLC2001 trial in a similar patient population.[16] The interim ORR of approximately 50-54.5% observed with TYRA-300 is numerically encouraging in this challenging setting. Furthermore, a 100% DCR suggests broad initial activity in preventing disease progression. This level of activity, especially if coupled with the drug's potential to overcome known resistance mutations [1], indicates that TYRA-300 could offer a substantial clinical benefit and warrants its continued and focused development.

Table 4: Summary of Efficacy Results from the SURF301 Trial in mUC (Interim Data, as of Oct 2024)

Dose Level(s) Evaluated	Number of Evaluable Patients (FGFR3-altered mUC)	Overall Response Rate (ORR) (approx.)	Partial Response (PR) Rate	Disease Control Rate (DCR)	Notes	Reference(s)
≥90 mg daily	11	~50-54.5%	54.5% (6/11)	100% (11/11)	3 of 6 PRs ongoing at data cutoff (Aug 15, 2024). Responses also seen at 120 mg.	3

5.1.3. Safety and Tolerability Profile (Interim Data)

Preliminary safety data from SURF301 suggest that TYRA-300 is generally well-tolerated, with a toxicity profile that appears favorable when compared to the pan-FGFR inhibitor erdafitinib.3 Specifically, the typical adverse events (AEs) associated with broader FGFR1 and FGFR2 inhibition, such as hyperphosphatemia, stomatitis, and severe ocular, skin, or nail toxicities, have not been frequently observed with TYRA-300.3

The most commonly reported AE has been diarrhea, which was low-grade in most patients.[11] However, one patient experienced Grade 3 diarrhea, which was considered a dose-limiting toxicity (DLT), at the 90 mg dose level.[3] Some instances of increased transaminase levels (transaminitis) have also been noted.[11] Across all dose ranges evaluated (10 mg to 120 mg daily), serious treatment-related AEs were reported in 10% of patients. This included one case of Grade 3 elevated alanine aminotransferase (ALT) that led to treatment discontinuation.[3]

While the overall safety profile of TYRA-300 appears advantageous due to its selectivity, the observation of Grade 3 AEs and a DLT underscores the critical importance of the ongoing dose escalation and optimization phases within the SURF301 trial. The primary goal of this phase is to identify an RP2D that maximizes the therapeutic index—balancing robust efficacy with acceptable tolerability. The selection of 50 mg and 60 mg daily doses for the SURF302 trial in NMIBC may reflect early learnings from SURF301 regarding the optimal balance for different indications or patient populations, aiming to harness the benefits of FGFR3 selectivity while carefully managing any on-target or specific TYRA-300-related toxicities.

Table 5: Summary of Key Adverse Events in the SURF301 Trial (Interim Data, as of Oct 2024)

Dose Range Evaluated	Most Common Adverse Event	Key Grade ≥3 Adverse Events Reported	Dose-Limiting Toxicities (DLTs)	Serious Treatment-Related AEs (Overall)	Notes on Pan-FGFR AEs	Reference(s)
10 mg - 120 mg daily	Diarrhea (mostly low-grade)	Grade 3 Diarrhea (1 case at 90mg), Grade 3 elevated ALT (1 case, led to D/C)	Grade 3 Diarrhea (1 case)	10%	Typical pan-FGFR AEs not frequently seen (e.g., hyperphosphatemia, stomatitis)	3

5.2. TYRA-300 in Non–Muscle-Invasive Bladder Cancer (NMIBC): The SURF302 Trial

5.2.1. Rationale, Study Design, and Endpoints

The development of TYRA-300 for NMIBC is driven by the high prevalence of activating FGFR3 mutations in this form of bladder cancer, estimated to be as high as 75% in NMIBC overall, particularly in low-grade tumors.1 There is a clear unmet need for better tolerated and effective oral therapeutic options for patients with low-grade, intermediate-risk NMIBC, a population that often faces recurrent disease and burdensome intravesical treatments.3

The FDA cleared the IND application for TYRA-300 in this indication on January 10, 2025, paving the way for the SURF302 trial.[1] SURF302 is an open-label, Phase 2 clinical study designed to evaluate the efficacy and safety of TYRA-300 in patients with FGFR3-altered, low-grade, intermediate-risk NMIBC.[3] The trial plans to enroll up to 90 participants across multiple sites, primarily located in the United States. Enrolled patients will be randomized to receive TYRA-300 orally at either 50 mg once daily (Cohort 1) or 60 mg once daily (Cohort 2). An additional dosing cohort may be explored based on emerging efficacy and safety data from these initial cohorts.[3]

The primary endpoint of the SURF302 trial is the complete response (CR) rate at 3 months post-treatment initiation.[3] Secondary endpoints include time to recurrence, median duration of response, recurrence-free survival (RFS), progression-free survival (PFS), as well as overall safety and tolerability.[3]

The initiation of the SURF302 trial for NMIBC represents a significant strategic expansion for the TYRA-300 program. This move positions the drug in earlier stages of bladder cancer, where FGFR3 alterations are considerably more common than in mUC. An orally available, well-tolerated agent like TYRA-300, if proven effective, could substantially alter current treatment paradigms for intermediate-risk NMIBC. It could offer a less invasive, systemic targeted therapy option, potentially reducing the reliance on repeated transurethral resections and intravesical therapies (such as BCG or mitomycin) for a subset of patients, thereby improving convenience and quality of life while managing disease recurrence in a larger patient segment.

5.2.2. Current Status and Anticipated Milestones

The SURF302 trial is poised to begin, with the first patient expected to be dosed in the second quarter of 2025.2 To spearhead these efforts, Tyra Biosciences has appointed Erik Goluboff, M.D., a urologic oncologist, as Senior Vice President of Clinical Development.2

6. Clinical Development in Achondroplasia: The BEACH301 Trial (NCT06842355 / TYR300-201)

6.1. Pathophysiological Basis and Therapeutic Rationale

Achondroplasia is the most common form of human dwarfism, an autosomal dominant genetic disorder resulting from gain-of-function mutations in the FGFR3 gene.1 Over 99% of cases are caused by a specific point mutation (G380R) in FGFR3.1 This mutation leads to constitutive activation of the FGFR3 receptor, which in turn excessively inhibits chondrocyte proliferation and differentiation within the growth plates of long bones. This impaired endochondral ossification results in characteristic disproportionate short stature and a range of other skeletal abnormalities.13 Individuals with achondroplasia may experience serious medical complications, including foramen magnum stenosis (which can cause compression of the brainstem and spinal cord), spinal stenosis, sleep apnea, and hydrocephalus.2

The therapeutic rationale for TYRA-300 in achondroplasia is to directly target the underlying genetic cause by selectively inhibiting the overactive FGFR3 receptor.[2] By normalizing FGFR3 signaling in chondrocytes, TYRA-300 aims to restore more typical patterns of chondrocyte proliferation and differentiation, thereby promoting longitudinal bone growth and potentially ameliorating other skeletal dysmorphisms. The ultimate goal is to achieve functional improvements and enhance the quality of life for affected individuals.[2]

6.2. Study Design, Eligibility Criteria, and Outcome Measures

The FDA cleared the IND application for TYRA-300 for the treatment of pediatric achondroplasia on October 28, 2024, allowing the BEACH301 trial to proceed.1

BEACH301 (NCT06842355; also TYR300-201) is a Phase 2, multicenter, open-label, dose-escalation and dose-expansion study designed to evaluate TYRA-300 in children with achondroplasia.2 The study plans to enroll approximately 92 participants aged 3 to 10 years (inclusive) who have a molecular diagnosis of achondroplasia (FGFR3 G380R) and radiographically confirmed open growth plates.2

Participants will receive oral TYRA-300 once daily at escalating dose levels, such as 0.125 mg/kg, 0.25 mg/kg, 0.375 mg/kg, and 0.50 mg/kg, for a treatment duration of up to 12 months in the initial phase.[2] The study includes distinct cohorts to assess TYRA-300 in different patient groups [2]:

• Sentinel Safety Cohort: Children aged 5 to 10 years, treatment-naïve.
• Cohort 1: Children aged 3 to 10 years who are naïve to prior growth-accelerating therapy.
• Cohort 2: Children aged 3 to 10 years who have received prior growth-accelerating therapy.

The primary objectives of the BEACH301 study are to assess the safety and tolerability of TYRA-300 in children with achondroplasia and to evaluate the change from baseline in annualized growth velocity (AGV) to identify potentially effective dose(s) for further development.[2] Secondary objectives include evaluating changes from baseline in height Z-score, body proportionality, and pharmacokinetic (PK) parameters of TYRA-300.[2] The study also plans exploratory assessments of functional improvements (e.g., reach, gait), changes in spinal morphology, and quality of life measures.[2]

Key eligibility criteria are summarized in Table 6.

Table 6: Key Eligibility Criteria for the BEACH301 Trial (NCT06842355) in Achondroplasia

Category	Criteria	Reference(s)
Inclusion	Aged 3 to 10 years (inclusive) at consent	17
	Molecular diagnosis of achondroplasia (FGFR3 G380R)	17
	Radiographically confirmed open growth plates at Screening	17
	Able to stand and ambulate independently	17
	Able to take oral medication	17
	Sentinel Safety Cohort: aged 5 to 10 years (inclusive)	17
	Cohort 1: aged 3 to 10 years (inclusive) and naïve to prior growth-accelerating therapy	17
	Cohort 2: aged 3 to 10 years (inclusive) and have received prior growth-accelerating therapy	17
Exclusion	Presence or history of any concurrent disease or condition that would interfere with study participation, safety evaluations, or any uncontrolled or untreated condition that could impact pediatric growth	17
	Diagnosis of endocrine condition that alters calcium/phosphate homeostasis	17
	Prior limb lengthening surgery or planned/expected limb lengthening surgery while enrolled	17
	Taking medications that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4	17
	History or current evidence of corneal or retinal disorder/keratopathy	17
	Presence of guided growth hardware/8 plates; planned or anticipated orthopedic surgeries	17

The design of the BEACH301 trial reflects a meticulous and thoughtful approach to investigating a novel therapy in a vulnerable pediatric population with a rare genetic disorder. The inclusion of both treatment-naïve and previously treated children allows for a broader assessment of TYRA-300's potential applicability. The dose-escalation strategy, starting with very low (mg/kg) doses compared to those used in oncology trials (e.g., 0.125 mg/kg vs. 50-120 mg absolute daily doses), highlights the distinct therapeutic windows and safety considerations inherent in developing a chronic therapy for a pediatric condition.[2] Furthermore, the comprehensive set of endpoints, extending beyond AGV to include measures of proportionality, functional outcomes, and quality of life, indicates an ambition to establish TYRA-300 as a therapy that provides clinically meaningful improvements in the overall well-being of children with achondroplasia, leveraging its selectivity for a potentially favorable long-term safety profile.

6.3. Current Status and Anticipated Milestones

The BEACH301 study is currently active and recruiting participants.17 The clinical trial listing was last updated on March 25, 2025.17 Tyra Biosciences has indicated that the first child with achondroplasia was expected to be dosed in the first or second quarter of 2025 1, with the Q2 2025 projection being the most recent update from March 2025 financial reports.15 The estimated primary completion date for the study is June 30, 2030.17

7. Regulatory Status and Designations

TYRA-300 has achieved several important regulatory milestones, facilitating its clinical development across its targeted indications.

7.1. Investigational New Drug (IND) Clearances by FDA:

• SURF301 (mUC and other solid tumors): An IND was presumably cleared prior to the study's initiation in November 2022.[8]
• SURF302 (NMIBC): The FDA cleared the IND application for TYRA-300 for use in low-grade, intermediate-risk NMIBC. This was announced on January 10, 2025.[1]
• BEACH301 (Achondroplasia): The FDA cleared the IND application to proceed with the Phase 2 study of TYRA-300 in pediatric achondroplasia. This was announced on October 28, 2024.[1]

7.2. Special Designations for Achondroplasia:

Reflecting the significant unmet medical need in achondroplasia, TYRA-300 has received two important designations from the FDA:

• Orphan Drug Designation (ODD): Granted in July 2023.[2]
• Rare Pediatric Disease Designation (RPD): Granted in January 2024.[2]

These special designations (ODD and RPD) are conferred by the FDA to encourage the development of drugs for rare diseases and conditions, particularly those affecting children. They provide significant regulatory and commercial incentives, which can include market exclusivity for a period post-approval (seven years for ODD), tax credits for qualified clinical testing, waiver of Prescription Drug User Fee Act (PDUFA) fees, and eligibility for a priority review voucher upon approval if the RPD criteria are met. The granting of these designations for TYRA-300 in achondroplasia not only highlights the recognized unmet need but also signals regulatory support for its development. From a commercial perspective, these designations, if TYRA-300 is ultimately successful, could provide a substantial period of market protection, thereby enhancing the drug's value proposition for Tyra Biosciences and ensuring continued investment in this important therapeutic area.

8. Comparative Landscape and Therapeutic Potential

8.1. TYRA-300 in Relation to Pan-FGFR Inhibitors (e.g., Erdafitinib) in Oncology

The current standard-of-care targeted therapy for mUC with susceptible FGFR3 or FGFR2 genetic alterations is erdafitinib (Balversa®), a pan-FGFR inhibitor approved by the FDA.8 While erdafitinib has demonstrated clinical benefit, its utility can be limited by a range of adverse events stemming from its inhibition of all four FGFR isoforms (FGFR1-4).3 Common toxicities include hyperphosphatemia (reported in 78.5% of patients in the THOR study), diarrhea (55.5%), stomatitis (52.8%), and various ocular, skin, and nail issues; adverse events led to treatment discontinuation in 19.4% of patients treated with erdafitinib.19

TYRA-300 was specifically designed to overcome these limitations through its high selectivity for FGFR3, thereby minimizing off-target inhibition of FGFR1, FGFR2, and FGFR4.[3] Preliminary data from the SURF301 trial support this hypothesis, indicating a more favorable tolerability profile with fewer of the characteristic pan-FGFR inhibitor-associated AEs.[3] Furthermore, TYRA-300 is engineered to maintain activity against common FGFR3 resistance mutations, such as the V555 gatekeeper mutation, which can limit the efficacy of other FGFR inhibitors.[1]

A comparative summary is presented in Table 7.

Table 7: Comparative Profile: TYRA-300 vs. Erdafitinib in Metastatic Urothelial Carcinoma

Feature	TYRA-300 (Investigational)	Erdafitinib (Approved)	Reference(s) (TYRA-300 / Erdafitinib)
FGFR Selectivity	Highly selective for FGFR3	Pan-FGFR inhibitor (targets FGFR1, 2, 3, 4)	4 / 8
Activity vs. Gatekeeper Mutations	Designed to be active against V555M/L	Susceptible to resistance via gatekeeper mutations	1 / 16
Reported ORR in mUC	~50-54.5% (interim, ≥90mg dose)	40% (BLC2001 pivotal trial)	3 / 16
Key Tolerability Differences	Fewer reports of hyperphosphatemia, stomatitis; Diarrhea most common.	Common: hyperphosphatemia, stomatitis, diarrhea, skin/nail/ocular toxicities.	3 / 19
Administration Route	Oral	Oral	3 / 19
Developer/Marketer	Tyra Biosciences, Inc.	Janssen (Johnson & Johnson)	2 / 9

If TYRA-300 continues to demonstrate comparable or potentially superior efficacy to erdafitinib in larger, more definitive studies, while consistently maintaining its more favorable safety and tolerability profile and its activity against key resistance mutations, it possesses the attributes to become a "best-in-class" agent and the preferred FGFR3-targeted therapy in urothelial cancers. Such a profile would offer a more favorable risk-benefit balance, a critical factor for clinical adoption and improving patient outcomes.

8.2. Potential Role of TYRA-300 in Achondroplasia Management

Current management strategies for achondroplasia are largely symptomatic and focus on addressing complications as they arise.10 Vosoritide, a C-type natriuretic peptide (CNP) analogue administered via daily subcutaneous injection, is an approved therapy that has been shown to increase linear growth in children with achondroplasia by stimulating endochondral bone growth through a pathway parallel to, and downstream of, FGFR3 signaling.21

TYRA-300 offers a distinct and direct mechanism of action by inhibiting the overactive FGFR3 receptor itself, thereby targeting the primary genetic defect in achondroplasia.[13] The preclinical data for TYRA-300 are compelling, suggesting the potential for comprehensive skeletal benefits that extend beyond simply increasing linear growth. These include improvements in bone quality, normalization of skull and foramen magnum dimensions (which could address critical neurological risks), and positive effects on vertebral development and intervertebral disc morphology.[13] Such broad effects, if translated to humans, could lead to a more profound disease-modifying impact, potentially mitigating some of the most serious long-term medical complications associated with achondroplasia. Furthermore, the oral route of administration for TYRA-300 offers a significant convenience advantage over daily injectable therapies like vosoritide, which could improve treatment adherence and quality of life for children and their families.

Thus, TYRA-300 holds the potential to become a transformative, disease-modifying oral therapy for achondroplasia. By directly addressing the overactive FGFR3 receptor, it may offer a more fundamental correction of the underlying pathophysiology. If the breadth of skeletal benefits observed in preclinical studies is confirmed in clinical trials, TYRA-300 could significantly improve long-term skeletal health, reduce the burden of complications, and enhance the overall quality of life for individuals with achondroplasia, potentially complementing or providing a valuable alternative to existing and emerging therapies.

9. Overall Safety Profile Summary (Consolidated)

Across the available data, primarily from the SURF301 oncology trial, TYRA-300 has demonstrated a generally well-tolerated safety profile.3 This is largely attributed to its high selectivity for FGFR3, which minimizes the off-target effects commonly seen with pan-FGFR inhibitors, such as hyperphosphatemia, stomatitis, and severe ocular or skin toxicities.3

The most frequently reported adverse event in the SURF301 trial has been diarrhea, which was predominantly low-grade.11 However, a case of Grade 3 diarrhea was reported as a DLT at the 90 mg dose, and a Grade 3 elevation in ALT led to treatment discontinuation in another patient.3 Overall, serious treatment-related AEs were reported in 10% of patients across a wide dose range (10 mg to 120 mg daily) in the SURF301 study.3

Ongoing dose optimization efforts in SURF301, and the selection of lower doses (50 mg and 60 mg) for the SURF302 NMIBC trial, aim to maximize the therapeutic window by balancing efficacy with tolerability.3 It is noteworthy that achieving a favorable safety profile suitable for chronic administration in pediatric populations was a key objective in the design and development of TYRA-300, particularly for the achondroplasia indication.6 This focus suggests an anticipation of good tolerability at the lower doses planned for the BEACH301 trial.

10. Future Perspectives and Conclusion

TYRA-300 has emerged as a promising investigational agent with significant therapeutic potential across distinct medical fields. Its development is characterized by a strong foundation in structure-based drug design, leading to a highly selective FGFR3 inhibitor. Key achievements to date include the successful clearance of multiple INDs by the FDA for Phase 2 trials in mUC (implicit via SURF301 progression), NMIBC (SURF302), and pediatric achondroplasia (BEACH301), encouraging early clinical data in mUC, and the attainment of Orphan Drug and Rare Pediatric Disease designations for achondroplasia.1

Upcoming milestones are anticipated to further define TYRA-300's clinical utility. These include the selection of an RP2D and advancement into broader Phase 2 evaluation in mUC from the SURF301 trial [1], and initial efficacy and safety data readouts from the SURF302 trial in NMIBC and the BEACH301 trial in achondroplasia. There is also potential for TYRA-300 to be explored in other FGFR3-driven malignancies or other FGFR3-related skeletal dysplasias, such as hypochondroplasia, which has been mentioned as an area of interest.[2]

In oncology, TYRA-300 holds the promise of becoming a more tolerable and potentially more effective targeted therapy for patients with FGFR3-altered urothelial cancers. Its activity against known resistance mutations could offer more durable responses compared to existing options. In achondroplasia, TYRA-300 represents a potential breakthrough as an oral, disease-modifying treatment that may address multiple skeletal aspects of the condition, leading to significant improvements in growth, function, and overall quality of life.

The successful clinical progression and differentiated profile of TYRA-300 also serve as an important validation for Tyra Biosciences' SNÅP drug discovery platform.[2] The ability of this platform to yield a highly selective and clinically active molecule like TYRA-300 may de-risk other candidates in the company's pipeline, such as TYRA-200 (an FGFR1/2/3 inhibitor) and TYRA-430 (an FGFR4/3 inhibitor), which are also focused on precision targeting within the FGFR family.[1] This suggests that the learnings and technological advancements from the TYRA-300 program could be leveraged to accelerate the development of other novel kinase inhibitors, reinforcing the company's strategic focus on FGFR biology.

In conclusion, TYRA-300 is a compelling example of precision medicine in action. Its development underscores the impact of advanced structure-based drug design in creating selective kinase inhibitors that can address significant unmet medical needs with potentially improved efficacy and safety profiles. The ongoing and planned clinical investigations will be crucial in fully elucidating its role in the treatment of FGFR3-driven cancers and achondroplasia.

11. References

3 Targeted Oncology. (Date of article: N/A, based on content likely late 2024/early 2025). FDA Clears NMIBC Agent TYRA-300 for Phase 2 Trial.

4 MedChemExpress. (Date of webpage: N/A). TYRA-300.

13 PMC NCBI. (Date of article: N/A, refers to TYRA-300 increasing bone growth). TYRA-300, an FGFR3-selective kinase inhibitor, increases bone growth in mouse models of achondroplasia and hypochondroplasia.

7 1104health.com. (Date of webpage: N/A). Phase 1/2 Study of TYRA-300 in Advanced Urothelial Carcinoma (SURF301).

1 Tyra Biosciences. (Date of webpage: N/A, reflects ongoing development). Pipeline.

12 PatSnap Synapse. (Date of data: Journal article Sep 26, 2024). Tyra Biosciences TYRA-300 pipeline.

8 ASCO Publications. (Date of article: Feb 15, 2025, for JCO supplement). A multicenter, open-label phase 1/2 study of TYRA-300 in advanced urothelial carcinoma and other solid tumors with activating FGFR3 alterations (SURF301).

11 Urology Times. (Date of article: Mar 5, 2025). Gopa Iyer, MD, highlights SURF301 trial of TYRA-300 in mUC.

17 CenterWatch. (Date of webpage: Last updated March 25, 2025). A Study of TYRA-300 in Children With Achondroplasia: BEACH301.

2 Tyra Biosciences Investor Relations. (Date of press release: October 28, 2024). Tyra Biosciences Receives IND Clearance from FDA to Proceed with Phase 2 Study of TYRA-300 in Pediatric Achondroplasia (BEACH301).

9 AACR Journals Cancer Discovery News. (Date of article: February 28, 2025). FGFR3-Specific Inhibitor Makes a Strong Debut.

6 Drug Hunter. (Date of article: December 16, 2024). TYRA-300.

19 Johnson & Johnson Innovative Medicine. (Date of article: May 12, 2025). SMC approval of BALVERSA® (erdafitinib) helps pave the way for first licensed bladder cancer therapy that specifically targets fibroblast growth factor receptor (FGFR3) alterations.

16 PMC NCBI. (Date of article: July 09, 2024, for PMC full text). Clinical and genomic landscape of FGFR3-altered urothelial carcinoma and treatment outcomes with erdafitinib: a real-world experience.

10 Cleveland Clinic. (Date of webpage: N/A, general information). Achondroplasia: Symptoms, Treatment, Causes & Diagnosis.

20 Mayo Clinic. (Date of webpage: N/A, general information). Dwarfism - Diagnosis and treatment.

5 Morningstar. (Date of press release: May 12, 2025). Tyra Biosciences to Participate at Upcoming Investor Conferences.

17 CenterWatch. (Date of webpage: Last updated March 25, 2025). A Study of TYRA-300 in Children With Achondroplasia: BEACH301.17

18 DrugBank. (Date of webpage: N/A, shows NCT06842355 as recruiting). Condition: Achondroplasia.

11 Urology Times. (Date of article: Mar 5, 2025). Gopa Iyer, MD, highlights SURF301 trial of TYRA-300 in mUC.11

14 Beyond Achondroplasia. (Date of article: N/A, refers to IND submission in 2024). TYRA-300 Heading to Clinical Trial in 2024.

3 Targeted Oncology. (Date of article: N/A, likely late 2024/early 2025). FDA Clears NMIBC Agent TYRA-300 for Phase 2 Trial.3

21 Oxford Academic / JCEM. (Date of article: January 15, 2025). Approach to the Patient with Achondroplasia—New Considerations for Diagnosis, Management, and Treatment.

15 Tyra Biosciences Investor Relations. (Date of press release: March 27, 2025). Tyra Biosciences Reports Fourth Quarter and Full Year 2024 Financial Results and Highlights.

11 Urology Times. (Date of article: March 5, 2025). Gopa Iyer, MD, highlights SURF301 trial of TYRA-300 in mUC..11

1 Tyra Biosciences. (Date of webpage: 2025). Pipeline..1

4 MedChemExpress. (Date of webpage: N/A). TYRA-300..4

13 PMC NCBI. (Date of article: May 08, 2025). TYRA-300, an FGFR3-selective inhibitor, promotes bone growth in two FGFR3-driven models of chondrodysplasia. (Detailed preclinical mechanism for achondroplasia).

2 Tyra Biosciences Investor Relations. (Date of press release: October 28, 2024 / May 8, 2025 / Jan 10, 2025). Tyra Biosciences Receives IND Clearance from FDA to Proceed with Phase 2 Study of TYRA-300 in Pediatric Achondroplasia (BEACH301) and other news releases.

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