BridgeBio’s oncology spinout must stand out from the crowd

A new kid on the oncology block emerged last week, with the spinout of BridgeBio’s oncology unit. Formerly known as TheRas, and now named BridgeBio Oncology, the private group has $200m of new money in the bank and a pipeline of three early-stage projects. 

With the new group's focus on KRAS inhibition and the PI3Kα/AKT pathway, investors must be convinced that these projects are differentiated. The former space is very crowded while the latter has been tarred by serious toxicity concerns.  

BridgeBio Oncology’s most advanced agent is targeting KRAS G12C; BBO-8520 entered the clinic in April. The developer claims that this it is differentiated by virtue of being a dual inhibitor, modifying both GTP-bound (active) and GDP-bound (inactive) forms of KRAS G12C, also known as its "on" and "off" states. 

The two approved KRAS agents, Amgen's Lumakras and Bristol Myers Squibb's Krazati, target the inactive form of KRAS G12C and leave room for improvement, although plenty of developers are already working here. 

The group’s second KRAS asset, BBO-11818, is a pan-KRAS inhibitor. This approach is being spearheaded by Revolution; that biotech plans to take its pan-KRAS project, RM-6236, into phase 3 later this year. BBO-11818 targets both active and inactive forms, whereas RM-6236 claims active targeting only. 

BridgeBio plans to file an IND for its pan-KRAS project in 2025, by which time it will likely be jostling for attention among several similar projects. A wave of pan-KRAS inhibiting assets, including both degraders and inhibitors, are lining up to enter the clinic, according to a recent analysis of OncologyPipeline data. 

Seeking alpha

A third project will also have competition when it enters the clinic, possibly by the end of this year. BBO-10203, described as a PI3Kα:RAS breaker, is claimed to be a novel approach to PI3Kα/AKT inhibition, in an attempt to avoid hyperglycaemia, a toxicity that has derailed much work in this field. An IND will be filed in the coming weeks. 

This project follows well-worn pathways. AstraZeneca’s Truqap became the first AKT inhibitor to be approved last year, a notable win considering that numerous similar agents have fallen by the wayside, for example Roche’s ipatasertib. 

When it comes to PI3K inhibition, many developers are pursuing projects against the alpha isoform, specificity for which is needed to avoid the unacceptable toxicity that contributed to several withdrawals from the market of less targeted agents. Roche is way ahead here with inavolisib, which has been filed for approval in breast cancer, with a verdict due later this year. 

But others are also active here, and OncologyPipeline reveals several assets in early clinical trials. Relay and Scorpion, both of which have allosteric inhibitors of PI3Ka, are due to release data later this year. 

PI3Kα inhibitors in clinical development 

Source: OncologyPipeline.