MAT2A inhibition gets another endorsement

Unlike GSK, Gilead appears to have recognised the potential of MAT2A inhibition, and that's good news for the handful of other companies developing inhibitors of this enzyme. That includes Ideaya, though the irony of Gilead deciding against buying into Ideaya's own IDE397, in spite of having had a look at that asset through a clinical trial collaboration, won't go unnoticed.

Ideaya has continued to work solo on IDE397 since GSK handed back rights to this MAT2A inhibitor in 2022, and that work has included a trial collaboration focusing on a combination with Gilead's Trodelvy. However, rather than formally licensing IDE397, Gilead last week paid $80m up front for Genhouse's much earlier-stage MAT2A inhibitor, GH31.

GSK already looked foolish for giving up on IDE397 when two years after its exit Ideaya posted phase 1 data that largely endorsed the promise of MAT2A inhibition. Not long afterwards BeiGene (now known as BeOne) gave the mechanism another vote of confidence when it paid $150m up front for rights to CSPC Pharmaceutical's BG-89894.

As such, Gilead's decision to opt for Genhouse's molecule looked surprising, but one explanation is that the company liked what it saw in IDE397, but couldn't negotiate an acceptable price with Ideaya so went to the Chinese company instead. GH31, which has yet to enter US trials and only recently began clinical testing in China, has only cost Gilead $80m.

Urothelial carcinoma

The timing of the latest deal followed early data with the IDE397/Trodelvy combo in urothelial carcinoma, an indication where Trodelvy previously struggled. The TROP2-targeting ADC achieved a 23% response rate in Tropics-04, a confirmatory trial whose failure for OS forced the withdrawal of its accelerated approval in the third-line setting.

IDE397 plus Trodelvy, meanwhile, produced six confirmed partial responses among 16 heavily pretreated urothelial carcinoma patients. Three of those responses were seen among seven patients receiving the recommended phase 2 dose of IDE397 30mg plus Trodelvy 7.5mg/kg, giving an ORR of 43%. Notably, one third of the total patients had previously received Padcev.

While this finding is still early and based on a small sample, the signal appears stronger than historical monotherapy results, and Gilead will likely seek to pair its newly acquired MAT2A inhibitor with Trodelvy, and to embark on a similar development strategy.

TROP2 ADCs

Even against other anti-TROP2 ADCs, such a combination looks competitive. Merck & Co/Kelun reported a 46% response rate for sacituzumab tirumotecan among 11 second-line post-chemo patients at last year’s ASCO-GU meeting, though pivotal testing has yet to begin.

Daiichi Sankyo, by contrast, has already advanced Datroway into phase 3, but early data from Tropion-Pantumor01 showed a response rate of 25% in 40 urothelial cancer patients, most of whom had received prior Padcev.

Beyond Ideaya, the rest of the MAT2A inhibitors in the clinic remain in early stages of development, with companies such as Servier, BeOne and Insilico Medicines running first-in-human trials for their programmes.

Selected MAT2A inhibitors

Note: *China only. Source: OncologyPipeline.