Insilico still feels the need for TEAD

Targeting the Hippo/Yap/TEAD pathway hasn’t worked well for Ikena, but this hasn’t stopped other groups from getting involved. The latest to take a punt on this mechanism, according to newly revealed listings on the clinicaltrials.gov registry, is Insilico Medicine.

Meanwhile, Servier is persevering with CD74, a target that has claimed the likes of Gilead and Sutro. Possibly more promising is MAT2A, where Ideaya recently produced intriguing results; here, CSPC Pharmaceutical will soon take its contender into the clinic.

And Pierre Fabre and Scorpion are joining the ranks of those hoping to go better than Tagrisso with fourth-generation projects designed to hit mutations not addressable by the AstraZeneca drug. However, it’s notable that many of the leaders here have shifted focus to newer assets, highlighting the fast-moving nature of this space.

Hippo flop

Ikena was the lead proponent of inhibiting the Hippo/Yap/TEAD pathway, until it ditched its contender IK-930 in May, following disappointing early data last year.

The most advanced contender now is Vivace’s pan-TEAD inhibitor VT3989, which is in a phase 1/2 solid tumour trial. Early results showed 7 responses among 69 patients; most of these were in mesothelioma patients.

Ikena’s flop doesn’t seem to have put other companies off; as well as Insilico’s ISM6331, which is set to start human trials in October, other recent clinical entrants include Springworks with SW-682, and BridGene with BGC515. Novartis is also active here, with a Yap-TEAD interaction inhibitor, IAG933, in phase 1 with a focus on mesothelioma.

CD74 concerns

Another target that has so far left much to be desired is CD74. Sutro quietly discontinued its ADC this year, while Gilead has tried its luck with both a monoclonal antibody and an ADC, to no avail.

There are reasons to be cautious about Servier’s contender, S227928: as a payload this uses an MCL1 inhibitor, an untested class. Indeed, Amgen terminated a phase 1 study of its MCL1 inhibitor tapotoclax (AMG 176) due to lack of clinical efficacy; the project is still listed in Amgen’s pipeline.

There might be fundamental issues with the target, too. Researchers have noted that, while CD74 is highly expressed on the surface of malignant B cells, it is also found in circulating blood or vascular tissue, and have suggested that this “antigen sink” must be overcome if efforts against this target are to succeed.

A search of OncologyPipeline shows S227928 to be the only active CD74-targeting asset in development.

MAT2A mania

CSPC might have picked more wisely with MAT2A, where there are so far only a handful of players. Notably, GSK left this space when it decided not to opt in to Ideaya’s IDE397 in 2022; last month that project yielded promising early data that could spur more interest in this target.

Next into the clinic will be China’s CSPC, with a domestic phase 1 trial in solid tumours. Other MAT2A contenders include Servier, which is on its second attempt with S95035, and Insilico, which took ISM3412 into the clinic this year.

HDAC selectivity

HDAC inhibition is more crowded, with nearly 30 assets in clinical development, according to OncologyPipeline. A couple of products have FDA approval in lymphoma subtypes, but things haven’t always gone smoothly, with Bristol Myers Squibb withdrawing Istodax from the US in peripheral T-cell lymphoma after the failure of its confirmatory trial.

There appears to be only one selective HDAC1/2/3 inhibitor in development, Junshi and Wigen’s JS125, and this is set to hit the clinic in China in October. The partners will have to hope that being selective will make the difference.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 21 and 26 Aug 2024.