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KRAS and conjugates remain hot

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*

ProjectMechanismCompanyTrialScheduled start
BH3120Anti-PD-L1 x 4-1BB MAbHanmiSolid tumours18 Dec 2023
FT825/ONO-8250Allogeneic (iPSC) HER2 Car-TFate/OnoMonoRx/combo in solid tumours5 Jan 2024
OKI-219PI3Kα H1047R inhibitorOnKurePikture-01, solid tumours incl breast cancer22 Jan 2024
PTT-936ALPK1 activatorPyrotech TherapeuticsSolid tumours31 Jan 2024
CUSP06Anti-CDH6 ADCOnCusp (ex Multitude)Ovarian & other solid cancers1 Feb 2024
LY4101174Anti-Nectin-4 ADCLilly (ex Emergence)Solid tumours29 Feb 2024
GENA-104A16Anti-CNTN4 MAbGenome & CompanySolid tumoursFeb 2024
AT-1965CMTR2 inhibitorAlyssum TherapeuticsSolid tumoursFeb 2024
NPX887Anti-B7-H7 MAbNextPoint TherapeuticsB7-H7+ve solid tumoursFeb 2024
LPM6690176Undisclosed small moleculeYantai Chuanghe BiotechnologySolid tumoursFeb 2024
MGC026Undisclosed ADCMacroGenicsSolid tumoursFeb 2024
ZG2001KRAS:SOS1 inhibitorZelgenKRAS-mutated solid tumoursFeb 2024
FMC-376KRAS G12C inhibitorFrontier MedicinesProsper, KRAS G12C-mutated solid tumoursFeb 2024
HYP-2090PTSAKRAS G12C inhibitorSichuan HuiyuKRAS-mutated solid tumoursFeb 2024
ACR246Anti-5T4 ADCAdcoris BiopharmaSolid tumours1 Mar 2024
BG-C9074Anti-B7-H4 ADCDualityBio/ BeiGene+/- tislelizumab in solid tumours6 May 2024
MDX2001Undisclosed x CD3 x CD28 MAbOpko HealthSolid tumoursMay 2024
ASD141Anti-CD11b MAbAscendo BiotechnologySolid tumoursJun 2024
KSQ-001EXCrispr/Cas9 engineered TILsKSQ TherapeuticsSolid tumours31 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.