No SOS for Bayer's SOS1

Bayer is persisting in trying to add SOS1 inhibition to activity on KRAS G12C: the latest first-in-human study listings on the clinicaltrials.gov registry show the group next month starting phase 1 with the SOS1 inhibitor BAY 3498264, with or without Amgen’s Lumakras.

SOS1 plus KRAS activity was once seen as an important combo strategy, but one of its leading exponents, Boehringer Ingelheim, has given up on it with the discontinuations of BI 1701963 and BI 1823911. Also notable in phase 1 trial initiations is another struggling German company, Merck KGaA, which is taking an anti-GD2 ADC, M3554, into a study in soft tissue sarcoma and glioblastoma.

GD2 is perhaps best known for being the target of United Therapeutics' Unituxin and Y-Mabs' Danyelza, both of which are US-approved for paediatric neuroblastoma. Rather than being an ADC, however, both drugs are naked MAbs, and their prescribing information carries boxed warnings of serious infusion reactions and neurotoxicity.

Danyelza is approved on an accelerated basis. OncologyPipeline reveals several other GD2-targeting projects in clinical development across biopharma, but many of these, including Autolus's AUTO6, are Car-T therapies; Merck KGaA's M3554 is the only one using an ADC modality (it comprises a topoisomerase 1 inhibitor payload and cleavable linker), at any stage of development.

KRAS in and out

Meanwhile, plenty of work is still ongoing in SOS1 inhibition, though beyond Bayer’s BAY 3498264 most of this is preclinical.

Bristol Myers Squibb’s MRTX0902, derived from the $4.8bn Mirati takeover, is in phase 1/2 with or without Krazati in KRAS-mutated cancers, a trial that broadly mirrors Bayer's. As well as the Boehringer assets, SOS1 inhibitor discontinuations include Erasca's preclinical ERAS-9, as that company too has shifted its KRAS strategy in and out of various projects.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between 15 and 29 Oct 2024; FDC=fixed-dose combination.

Investors will also note the entry into phase 1 of another molecule from the private German biotech Tubulis, which is notable for being an ADC player that has attracted significant amounts of venture capital, most recently closing an upsized €128m series B round in March.

Going into the clinic now is TUB-030, an ADC targeting the 5T4 antigen. Numerous companies have worked on 5T4 in the past, and despite successes being hard to come by there has been a recent uptick in activity with assets using the ADC modality, perhaps most notably from Exelixis, which has taken XB010 into clinical trials.

OncologyPipeline also reveals clinical-stage anti-5T4 ADCs from Adcoris Biopharmaceutical, Kirilys Therapeutics and Byondis. While Tubulis lists TUB-030 as its pipeline lead, it already has one other clinical-stage ADC, namely TUB-040, which targets NaPi2b, and which began the Napistar1-01 study in June.

Among other recent phase 1 starts clinicaltrials.gov lists the Johnson & Johnson molecules JNJ-89402638 and JNJ-90189892. However, that company hasn't revealed these projects' targets, and the studies' enrolment criteria give no hints as to what these might be.