Kyowa joins GSK in Tim-3

GSK is now the only big pharma standing in Tim-3 blockade, but another contender has entered the fray, with Kyowa Kirin taking its ADC KK2845 into the clinic, according to the latest listings on clinicaltrials.gov.

Other new entrants include a third shot at PRMT5 inhibition from Tango, which discontinued its first-generation asset last year, and Yangli’s selective PARP1 inhibitor – a field that has drawn interest from AstraZeneca, Gilead and Merck KGaA.

Tim-3 & PRMT5

AstraZeneca and Bristol Myers Squibb both recently exited the Tim-3 space, which has also seen disappointments from the likes of Novartis, Roche and Lilly. The big hope here now is GSK’s monoclonal antibody cobolimab, which is facing readout of the phase 3 Costar Lung study this half. The only other clinical-stage project from a large biopharma is BeiGene’s surzebiclimab, in phase 1/2.

Still, Kyowa might hope to do better with KK2845, the sole Tim-3-targeting ADC in development, according to OncologyPipeline. The project, developed using Synaffix technology, is in a phase 1 Japanese study in relapsed/refractory AML that began in October.

Tango Therapeutics is one of the leading proponents of PRMT5 inhibition, despite recently discontinuing its lead project, TNG908, following lacklustre data in glioblastoma. The company already has a second, non-brain-penetrant project, TNG462, in the clinic, and now it’s also taking a brain-penetrant asset, TNG456, into a phase 1/2 study in MTAP-deleted solid tumours including glioblastoma. 

The trial will include both monotherapy and a combination with Lilly’s CDK4/6 inhibitor Verzenio. Meanwhile TNG462, which Tango is developing in lung and pancreatic cancers, is due to yield phase 1/2 data this year, with pivotal trials planned for 2026 if all goes well.

Amgen’s PRMT5 contender, AMG 193, produced disappointing results at last year's ESMO, but this doesn’t appear to have put others off: other contenders include Bristol Myers Squibb, with the Mirati-originated BMS-986504 (previously known as MRTX1719), AstraZeneca and, most recently, Genhouse Bio.

PARP1 & EGFR

It’s hoped that selectively hitting PARP1 could be less toxic than broad PARP inhibition, and the latest group to take a punt on this mechanism is Shenzhen Yangli, which last year began a Chinese phase 1/2 trial of its contender, VB15010.

AstraZeneca is the most advanced player here, with saruparib in pivotal trials in breast and prostate cancer. The UK group also has another shot with the brain-penetrant asset AZD9574, while Gilead has also bought into this arena with the 2023 acquisition of Xinthera, and Merck KGaA licensed Jiangsu Hengrui’s HRS-1167 (also known as M9466).

Dizal’s DZD6008, meanwhile, appears to be a fourth-generation EGFR inhibitor. Here, the company could go up against Black Diamond: both are targeting C797 mutations, which are linked with resistance to third-generation drugs like AstraZeneca’s Tagrisso.

Black Diamond’s BDTX-1535 has shown activity in C797S-mutant NSCLC, while Dizal’s phase 1 Tian-Shan2 trial is enrolling patients with C797X mutations, among others. The Chinese study began in June 2024 but has only just been listed on clinicaltrials.gov.

KRAS G12D?

One mystery asset among the latest clutch of clinical trial initiations is Incyte’s INCB186748; this could be a KRAS G12D inhibitor, as the study requires patients to have a G12D mutation.

If this is indeed the case, it’s unclear what it means for Incyte’s existing clinical-stage KRAS G12D project, INCB161734; the company is promising proof-of-concept data this year. Incyte hadn’t responded to questions from ApexOnco about INCB186748’s identity at the time of publication.

There are plenty of others vying for a piece of the G12D space, and the project to beat currently is Revolution Medicines’ RMC-9805, which produced promising early data at last year’s Triple meeting.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between 5 and 11 Feb 2025.