KRAS and conjugates remain hot

As if the KRAS inhibitor field wasn’t crowded enough, three more companies are now muscling their way in: Zelgen’s ZG2001, Frontier Medicines’ FMC-376 and Sichuan Huiyu’s HYP-2090PTSA are all entering first-in-human studies this month, the latest clinicaltrials.gov listings reveal.

The newly disclosed entries also show a number of antibody-drug conjugates starting phase 1, and these also target antigens that have recently been growing in popularity: Nectin-4, CDH6 and B7-H4. Elsewhere, OnKure is taking a novel approach to PI3K inhibition, while Adcoris is targeting an antigen that will ring bells with long-time UK biotech investors.

In KRAS the G12C mutation has resulted in two approved drugs so far – Amgen’s Lumakras and Bristol Myers Squibb’s Krazati. Interest is increasingly falling on a separate sub-mutation, G12D, but it’s G12C that is the focus for this month’s new entrants, though only HYP-2090PTSA appears to be a conventional KRAS G12C inhibitor. 

Zelgen’s ZG2001 is said to be a pan-KRAS inhibitor that binds to the catalytic region of SOS1, a separate modality that some companies have tried to target in combinations. And Frontier, a private US biotech, describes FMC-376 as a “direct dual” inhibitor, targeting active and inactive states of KRAS G12C; preclinical data claiming activity in NSCLC, pancreatic and colorectal cancers were presented at last year’s AACR.

Another private US biotech, OnKure, is also focused on targeted oncology, and raised $54m in a series C last May. Its OKI-219 is said to be selective for H1047R, the most common mutation in PI3Kα, being found in 15% of breast cancer and 4% of cancers overall. Targeting this mutation with over 100-fold selectivity could avoid on-target toxicities, the group claims.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 31 Jan and 6 Feb 2024.

It’s clear that ADCs remain hot, with deals continuing to be struck this year. One 2023 transaction, Lilly’s takeover of Emergence, brought with it the Nectin-4 targeting project LY4101174, which is now entering phase 1.

Pfizer’s Padcev has validated the Nectin-4 target, spurring interest from others, and just last month Corbus threw its hat into the ring. B7-H4 is another hot ADC antigen, judging by GSK’s interest in Hansoh Pharma, and Pfizer’s ongoing commitment after its Seagen takeout, and the clinical pipeline now includes BeiGene’s BG-C9074.

Daiichi Sankyo’s huge ADC deal with Merck & Co last year was partly driven by the CDH6-targeting raludotatug deruxtecan, which then put up impressive data at ESMO. Earlier Multitude Therapeutics licensed to OnCusp the ex-China rights to CUSP06, described as a “highly differentiated CDH6-targeting ADC”, and CUSP06’s phase 1 study has just begun.

Finally in the ADC space China’s Adcoris Biopharma is advancing the 5T4-targeting ACR246 into the clinic. 5T4 is an antigen in which the UK’s Oxford Biomedica had a major presence until the blow-up of its phase 3 renal cancer trial of Trovax, a 5T4-targeting immunotherapy, in 2008.

Some work on 5T4 has quietly continued, and four years ago AbbVie tied up with Genmab over a T-cell engager, GEN1044, with this mechanism. A year later GEN1044 was discontinued after hitting toxicity in phase 1.