AbbVie begins its Steap1 climb

Targeting Steap1 has previously fallen flat, but AbbVie clearly hasn’t been dissuaded by others’ misfortunes. The group’s ABBV-969, an ADC hitting both Steap1 and PSMA, has just gone into human trials, according to recently unveiled clinicaltrials.gov listings.

AbbVie will hope to fare better than Roche, which discontinued development of its anti-Steap1 ADC vandortuzumab vedotin after struggling to find a therapeutic window. Meanwhile, Haisco is moving forward with a USP1 inhibitor, a mechanism that has seen other recent interest, and the Chinese groups HC Biopharma and Avistone are breaking new ground with an anti-PD-1 x CTLA-4 x VEGF MAb and a type II c-MET inhibitor respectively.

Steap1 x PSMA

AbbVie unveiled ABBV-969 last November when it acquired ImmunoGen, although the asset was developed in house. The ADC is being tested in metastatic castration-resistant prostate cancer, a disease in which a PSMA-targeted radiopharmaceutical, Novartis’s Pluvicto, is already approved.

Steap1 is another antigen that’s highly expressed in prostate cancer, and the most advanced project here is Amgen’s bispecific T-cell engager xaluritamig (AMG 509). This produced promising early results in prostate cancer at last year’s ESMO meeting – with the caveat that toxicity was relatively high. Amgen is planning a phase 3 trial. 

ABBV-969 is the only project targeting Steap1 and PSMA in the same molecule, according to OncologyPipeline. The related antigen Steap2 is also being investigated in prostate cancer, but AstraZeneca’s Car-T candidate AZD0754 appears to be the only active project here. 

Common USP

In USP1 inhibition Haisco Pharmaceutical has now joined the likes of Roche and Exelixis, which last year both struck deals over projects with this target.

USP1 is said to regulate DNA damage response in a manner distinct from other synthetic lethality approaches, including PARP inhibition. Indeed, several players are combining USP1 and PARP blockers.

Meanwhile, two anti-CD20 approaches entered the clinic within the past week: Legend’s Car-T LUCAR-20SP and Sinocelltech’s T-cell engager SCTB35. However, these projects look late in a field where the likes of Genmab/AbbVie’s Epkinly and Roche’s Columvi are already established.

Oncolytic viruses have so far disappointed, but this hasn’t stopped Johnson & Johnson joining the fray with JNJ-87704916, being tested in solid tumours as monotherapy and in combination with the company’s PD-1 inhibitor cetrelimab. J&J gained the oncolytic virus project through its $140m takeout of BeneVir in 2018. 

While various groups are looking at PD-1 x CTLA-4 and PD-1 x VEGF bispecific antibodies, China’s HC Biopharma looks unique in combining all three targets in HC010, another recent entrant to the clinic. However, toxicity will surely be closely watched given the issues with CTLA-4 and VEGF inhibition in particular.

Another trailblazer is Avistone Pharmaceuticals with the type II c-MET inhibitor ANS014004. According to the company, this project could address MET mutations beyond exon 14 skipping, for which type I c-MET inhibitors such as Novartis's Tabrecta are already approved. Although Avistone is based in China, it has bagged funding from western investors including Vivo Capital and Bain Capital, suggesting global interest in this approach.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 13 and 19 March 2024. IST=investigator-sponsored trial.