KRAS and conjugates remain hot
The latest clinical study listings reveal KRAS-targeting projects, ADCs and others starting phase 1.
The latest clinical study listings reveal KRAS-targeting projects, ADCs and others starting phase 1.
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*
Project | Mechanism | Company | Trial | Scheduled start |
---|---|---|---|---|
BH3120 | Anti-PD-L1 x 4-1BB MAb | Hanmi | Solid tumours | 18 Dec 2023 |
FT825/ONO-8250 | Allogeneic (iPSC) HER2 Car-T | Fate/Ono | MonoRx/combo in solid tumours | 5 Jan 2024 |
OKI-219 | PI3Kα H1047R inhibitor | OnKure | Pikture-01, solid tumours incl breast cancer | 22 Jan 2024 |
PTT-936 | ALPK1 activator | Pyrotech Therapeutics | Solid tumours | 31 Jan 2024 |
CUSP06 | Anti-CDH6 ADC | OnCusp (ex Multitude) | Ovarian & other solid cancers | 1 Feb 2024 |
LY4101174 | Anti-Nectin-4 ADC | Lilly (ex Emergence) | Solid tumours | 29 Feb 2024 |
GENA-104A16 | Anti-CNTN4 MAb | Genome & Company | Solid tumours | Feb 2024 |
AT-1965 | CMTR2 inhibitor | Alyssum Therapeutics | Solid tumours | Feb 2024 |
NPX887 | Anti-B7-H7 MAb | NextPoint Therapeutics | B7-H7+ve solid tumours | Feb 2024 |
LPM6690176 | Undisclosed small molecule | Yantai Chuanghe Biotechnology | Solid tumours | Feb 2024 |
MGC026 | Undisclosed ADC | MacroGenics | Solid tumours | Feb 2024 |
ZG2001 | KRAS:SOS1 inhibitor | Zelgen | KRAS-mutated solid tumours | Feb 2024 |
FMC-376 | KRAS G12C inhibitor | Frontier Medicines | Prosper, KRAS G12C-mutated solid tumours | Feb 2024 |
HYP-2090PTSA | KRAS G12C inhibitor | Sichuan Huiyu | KRAS-mutated solid tumours | Feb 2024 |
ACR246 | Anti-5T4 ADC | Adcoris Biopharma | Solid tumours | 1 Mar 2024 |
BG-C9074 | Anti-B7-H4 ADC | DualityBio/ BeiGene | +/- tislelizumab in solid tumours | 6 May 2024 |
MDX2001 | Undisclosed x CD3 x CD28 MAb | Opko Health | Solid tumours | May 2024 |
ASD141 | Anti-CD11b MAb | Ascendo Biotechnology | Solid tumours | Jun 2024 |
KSQ-001EX | Crispr/Cas9 engineered TILs | KSQ Therapeutics | Solid tumours | 31 Jul 2024 |
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.
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