BridgeBio enters the pan-KRAS game

BridgeBio's cancer spin-out, BridgeBio Oncology, is adding a pan-KRAS inhibitor to its clinical offering, which already included a KRAS G12C inhibitor and an unusual PI3Kα:RAS breaker. A first-in-human study of the first molecule, BBO-11818, has just appeared on the clinicaltrials.gov registry.

Recently disclosed listings also show the first phase 1 trials of another FGFR subtype-specific approach from Tyra Biosciences, and an mRNA-based personalised neoantigen immunotherapy from China's Akeso. Not only does the latter present a possible challenge to the leaders in this field, Moderna and BioNTech, its trial includes a combination with the high-profile bispecific ivonescimab.

Ivonescimab, an anti-VEGF x PD-1 MAb, is in the spotlight having been licensed to Summit, but the new phase 1 trial is an Akeso-sponsored effort. This concerns adjuvant pancreatic ductal adenocarcinoma, and will test either the mRNA therapy AK154 on its own or in combination with cadonilimab or ivonescimab. Cadonilimab is notable for being the world's first approved anti-PD-1 x CTLA-4 bispecific.

It's not immediately obvious how similar AK154 is to Moderna's Merck & Co-partnered mRNA-4157 and BioNTech's Roche-partnered autogene cevumeran, but presumably all three involve the on-demand generation of an mRNA therapeutic encoding several neoantigens specific to a patient’s tumour. 

It's evident that companies see the best way forward for these therapies in early settings and as part of combinations. Moderna/Merck are pushing mRNA-4157 forward together with Keytruda, while BioNTech/Roche are testing autogene cevumeran combos with Keytruda, Tecentriq or Opdivo, as well as – interestingly, given the Akeso trial's design – hinting at future use with BioNTech's own PD-L1 x VEGF bispecific, BNT327.

Bridge to KRAS

BridgeBio first revealed plans to spin out its cancer division a year ago, but it's only recently that BridgeBio Oncology has moved to gain a public listing – not via IPO but, controversially, by reversing into a Spac (special-purpose acquisition company).

While the Spac deal has yet to be completed, the company is moving ahead with its stated "best-in-RAS" mission through the projects BBO-8520, BBO-10203, and now BBO-11818. The last was earlier this month dosed to the first patient in its Konquer-101 study, and its new clinicaltrials.gov entry reveals enrolment of subjects with numerous KRAS G12 mutations, as well as KRAS amplification.

It won't go unnoticed that pan-KRAS blockade has, along with G12C and G12D approaches, become a crowded area, with Revolution's daraxonrasib ahead of efforts from Lilly (LY4066434), Pfizer (PF-07934040), BeiGene (BGB-53038) and others. However, BridgeBio claims that BBO-11818 is a "dual inhibitor", targeting both the on and off states of KRAS.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 4 and 8 Apr 2025.

Meanwhile, the FGFR subtype-specific inhibitor field is still awaiting survival data from Amgen's Five Prime-derived anti-FGFR2b MAb bemarituzumab, its promise being the potential avoidance of toxicities associated with broad FGFR blockade.

Tyra's entire investment case centres on this, and the company's lead project, TYRA-300, is an FGFR3-specific inhibitor in phase 2. An anti-FGFR1/2/3 asset, TYRA-200, is in phase 1, and these are now being joined by TYRA-430, which targets FGFR3/4. TYRA-430's Surf-431 study, in solid cancers with FGF/FGFR pathway aberrations, starts this month.