AstraZeneca is following some of its big pharma peers into KRAS, paying Jacobio $100m up front for ex-China rights to the pan-KRAS inhibitor JAB-23E73. The molecule is reasonably well advanced, featuring in two separate phase 1/2 studies together seeking to enrol over 600 patients with KRAS-mutated cancers.
Astra already has an in-house presence in KRAS G12D, but companies like Pfizer, Lilly, Amgen, Roche and BeOne had already moved into pan-KRAS coverage, and the Jacobio deal will to an extent allow it to catch up. However, the leader here is Revolution, and its phase 3 molecule daraxonrasib is a pan-RAS(on) inhibitor, a feature JAB-23E73 cannot boast.
That said, Jacobio investors expressed concern that their company had let JAB-23E73 go for just $100m. Jacobio’s shares on the Hong Kong stock exchange were down 14% on Monday, the first day of trading after the deal was announced.
Jacobio describes JAB-23E73 as a pan-KRAS(on/off) with high selectivity to spare HRAS and NRAS inhibition. It sees future development in pancreatic, lung and colorectal cancers, but so far doesn’t appear to have released any clinical data with it; an AACR poster in 2023 described JAB-23425, an earlier molecule from Jacobio’s pan-KRAS series, as being tolerable and combinable with Erbitux.
Crowded
If $100m seems an undemanding sum to pay for one of the more advanced projects in this space, perhaps this is explained by the number of similarly acting projects in development, where supply is perhaps starting to outstrip demand.
OncologyPipeline reveals no fewer than 11 clinical-stage pan-KRAS inhibitors, in addition to a pan-KRAS degrader from Astellas (ASP5834), and six more clinical assets with pan-RAS activity. Also worthy of mention is preclinical pan-KRAS work at Boehringer Ingelheim (BI-2493 and BI-2865) and at Kumquat (KQB726); the latter recently attracted Bayer as a partner for its KRAS G12D-selective inhibitor.
Clinical-stage projects with pan-KRAS activity
If Revolution's pan-RAS approach is the one to follow then it’s possible that pan-KRAS molecules are already on shaky ground. Perhaps the most important pan-RAS projects after daraxonrasib are GenFleet’s GFH276, which recently went into a phase 1 trial, and Erasca’s ERAS-0015, a pan-RAS “molecular glue”.
Erasca secured ERAS-0015, along with the pan-KRAS inhibitor ERAS-4001, from China’s Joyo Pharmatec in a May 2024 deal that cost it just $12.5m up front. At the same time Erasca canned its in-house preclinical pan-KRAS programme, and a year later it discontinued a pan-RAF inhibitor licensed from Novartis to focus on the two Joyo-derived assets.
For its part, Astra is separately developing AZD0240, an engineered T-cell receptor therapy that targets KRAS G12D and is restricted to patients with the HLA-A*11:01 haplotype, in phase 1. However, a small-molecule KRAS G12D inhibitor, AZD0022, was discontinued last month, barely a year after starting its phase 1 trial.
