AstraZeneca doubles down on GPC3

GPC3 has become a high-profile target thanks to AstraZeneca and AbelZeta’s Car-T efforts, and the UK company is upping its bet on this target with a newly clinical-stage T-cell engager, AZD9793. However, Roche and Sanofi have just left the GPC3 T-cell engager arena, suggesting that Astra might have its work cut out.

Other projects going into human testing, according to the latest listings on clinicaltrials.gov, include Genhouse Bio’s PRMT5 inhibitor GH56,

GPC3 

During its full-year earnings last week Roche disclosed the discontinuation of its anti-GPC3 T-cell engager ERY974, although the group apparently still has a naked MAb against this target, codrituzumab.

On the same day Sanofi binned its similarly acting contender SAR444200, which had yielded phase 1 safety and biomarker data at ESMO 2023. The company didn’t give a reason for its decision, but it’s notable that it had added a new dose level with a slower lead-in, to mitigate cytokine release syndrome.

AstraZeneca’s AZD9793 differs from these projects in that it’s designed to recruit CD8+ T cells specifically, and minimise CD4+ T-cell activation, with the aim of limiting cytokine release. It could soon become clear whether this is achievable, and if it makes a difference in humans.

While there are 50 GPC3-targeting projects in the clinic, according to OncologyPipeline, only two other T-cell engagers are in active development, from Keymed and Zhejiang Shimai Pharmaceutical – both being trialled in China.

PRMT5 & USP1

PRMT5 has also seen its fair share of disappointment, with missteps from Amgen and Tango Therapeutics. But this hasn’t stopped Genhouse Bio from taking its hopeful, GH56, into a Chinese phase 1 study in MTAP-deleted solid tumours.

Amgen and Tango are still active here (the latter with a next-generation asset, TNG462); other contenders include Bristol Myers Squibb, with the Mirati-originated BMS-986504 (previously known as MRTX1719), AstraZeneca and BeiGene.

Another troubled target, USP1, is seeing some first-in-human action with the entrance of Asieris Pharmaceutical’s ASN-3186. However, Roche’s similarly acting RO7623066 (now known as RG6614) disappointed at last year’s ASCO.

Other USP1 inhibitors in development include Exelixis/Insilico’s XL309, in phase 1, and Debiopharm’s Debio 0432, in preclinical trials.

More KRAS, less CHD6

Meanwhile, companies have been piling into KRAS, with G12D a popular target despite producing mixed data so far. The jury is still out on KRAS G12D degradation in particular, following disappointing results with Astellas’s contender ASP3082.

PAQ Therapeutics’ new clinical entrant PT0253 looks likely to share this mechanism: the project’s phase 1 trial is enrolling patients with G12D-mutated solid tumours, and the private US company specialises in autophagy, which it describes as a mechanism for “natural cellular degradation”.

Although G12D inhibition is popular, there are only a few other G12D degraders in the clinic, according to OncologyPipeline: as well as ASP3082, which is still in play, Astellas has a similarly acting asset, ASP4396, which entered human trials last year. Ranok Therapeutics’ RNK08954 just went into phase 1/2, while Arvinas hopes to hit the clinic with its unnamed KRAS G12D degrader this year.

Less crowded is CDH6, although there has been big pharma interest here, with Merck licensing Daiichi’s raludotatug deruxtecan as part of its 2023 ADC mega-deal.

Jiangsu Simcere is the latest to enter this arena with its ADC hopeful SIM0505 joining another Chinese group, Hansoh, and the private US company OnCusp in the clinic.

And OMA1 is even less crowded: OncologyPipeline lists Bantam’s BTM-3566 as the only asset hitting this target.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 22 and 28 Jan 2025.