Tyra Biosciences (TYRA) Study Update summary

Background and Rationale

• Up to 20% of advanced/metastatic urothelial cancers have activating FGFR3 alterations, but current FGFR inhibitors lack isoform specificity, leading to off-target toxicities such as hyperphosphatemia, ocular, skin, and GI side effects.

• TYRA-300 was designed for high selectivity against FGFR3 and to overcome resistance from FGFR3 gatekeeper mutations, aiming to minimize off-target effects.

Study Design and Methods

• SURF301 is a Phase I/II, multi-center, open-label study evaluating TYRA-300, an oral FGFR3-selective inhibitor, in adults with advanced solid tumors, focusing on those with FGFR3 alterations, including metastatic urothelial cancer.

• Dose escalation (10–120 mg QD) included any FGF/FGFR pathway alteration; dose expansion (40–90 mg QD) required FGFR3 alterations.

• Key endpoints include optimal dose, safety, pharmacokinetics, pharmacodynamics, and preliminary anti-tumor activity.

• Pharmacodynamic and ctDNA analyses were performed on plasma samples at multiple timepoints.

Interim Efficacy Results

• At doses ≥90 mg QD, 6 of 11 (54.5%) FGFR3+ mUC patients achieved confirmed partial responses, with a 100% disease control rate and ongoing responses in some cases.

• TYRA-300 demonstrated dose-dependent anti-tumor activity and was generally well-tolerated, with infrequent FGFR2 and FGFR1-associated toxicities.

• The study population was heavily pretreated, with a median age of 66 and 76% having received three or more prior therapies.

• TYRA-300 showed greater selectivity for FGFR3 over FGFR1/2/4 compared to approved FGFR inhibitors, with 63x selectivity over FGFR1 and 55x over FGFR4.

• Decreases in ctDNA fractions (>50%) were observed in participants with FGF/FGFR3-altered tumors treated at 90 mg QD, indicating molecular response.