Triple meeting 2024 – Tyra’s targeted FGFR3 push

Johnson & Johnson’s Balversa, first approved in 2019, brought a targeted treatment for bladder cancer, specifically for disease driven by FGFR3 mutations. Now things might get even more precise, with Tyra Biosciences presenting the first clinical data on TYRA-300, a molecule it reckons is far more specific for FGFR3 than Balversa.

The issue is important because Balversa’s pan-FGFR inhibition results in toxicities thought to be associated with activity at FGFR1 and FGFR2. Meanwhile, TYRA-300 has shown some evidence that it’s safer, a late-breaking plenary at the Triple (EORTC-NCI-AACR) symposium has shown, in addition to yielding a 55% response rate among 11 bladder cancer patients.

A lot is riding on the data; Tyra raised $173m in a Nasdaq flotation in September 2021, at a time when it was still a preclinical company. Not only are the TYRA-300 clinical data its first, with its lead pipeline project, the company is now capitalised at $1.5bn, having seen its shares climb 102% since the start of this year.

Triple data

Presenting the Triple data, from the phase 1/2 Surf301 study, Peter McCallum Cancer Centre’s Professor Ben Tran called TYRA-300 a first-in-class FGFR3-specific inhibitor. 

OncologyPipeline bears this out: the only other FGFR3-specific small-molecule inhibitor in clinical trials is Lilly’s LOXO-435/LY3866288. That started a phase 1 study in January 2023 in FGFR3-mutated cancers, with or without Keytruda, but has yet to yield any human data.

Surf301 has fairly broad enrolment criteria, allowing patients to have received prior FGFR inhibitors. The presence of an FGFR3 mutation wasn’t a criterion for dose escalation, but was required for dose expansion. Balversa is approved for FGFR3-mutated bladder cancer after failure on at least one line (now typically Padcev plus Keytruda), so Surf301 represents a relatively late-line setting.

Against this background a 55% ORR seems impressive. Specifically this related to TYRA-300 doses of 90mg/day or higher, and amounted to six confirmed partial responses among 11 FGFR3-positive bladder cancer patients. FGFR3 target coverage is achieved with 90mg/day, Tran told a Triple media briefing, and Surf301 has tested TYRA-300 up to 120mg/day.

At 90mg/day there was a dose-limiting toxicity of grade 3 diarrhoea, and (more worryingly) a treatment discontinuation due to grade 3 ALT elevation. Across 41 patients evaluable for safety the rates of grade 3 ALT and AST increase were 5% and 2% respectively, but there were no grade 4 or higher treatment-related adverse events.

FGFR1/2 toxicities

Especially promising was the apparent absence of significant retinopathy or hyperphosphataemia; both are listed on the Balversa label’s warnings section, and appear to be associated with the J&J drug’s inhibition of FGFR2 and FGFR1 respectively.

The ability to hit FGFR3 is important because 10-20% of bladder cancers are thought to be driven by FGFR3 mutations. TYRA-300’s affinity for FGFR3 is similar to Balversa’s, Tran said, while being 63 times higher than for FGFR1, and 19 times higher than for FGFR2. FGFR1/2-related toxicities with Tyra’s molecule are very infrequent, he added.

Tyra is separately developing a pan-FGFR1/2/3 inhibitor, TYRA-200, in a first-in-human cholangiocarcinoma trial (Surf201). Investors will now decide whether its approach is targeted enough to justify a $1.5bn valuation.

Industry projects with activity specifically at FGFR3

Source: OncologyPipeline.