Astellas makes its KRAS degrader choice

Astellas has narrowed its bet in the KRAS G12D degrader space, discontinuing one of the two assets it had advanced into the clinic. Somewhat surprisingly, it has bet on the original asset it had taken forward, deciding to end development of the follow-on.

The two molecules differed in only one element: the E3 ligase they used to achieve target degradation. The Japanese company has decided to discontinue ASP4396, which used a cereblon E3 ligase, while the surviving asset, setidegrasib, uses a Von Hippel-Lindau (VHL) E3 ligase.

According to comments made during the company’s third-quarter fiscal year earnings call, Astellas decided to drop ASP4396 after determining that its data were no better than those it reported for setidegrasib. The company did not disclose detailed numbers, but said results would be shared once they were ready.

Setidegrasib improvement

That leaves the company focused on setidegrasib, a programme that initially raised questions following early readouts, but which has since shown improving clinical performance with two pivotal trials announced in lung and pancreatic cancers.

At the Triple (EORTC-NCI-AACR) symposium the company disclosed data from relapsed NSCLC patients showing a higher confirmed response rate with the go-forward dose of 600mg weekly than what Revolution presented at AACR for zoldonrasib.

More recently, at ASCO-GI, Astellas reported a 42% response rate in 12 patients with front-line KRAS G12D-mutant pancreatic ductal adenocarcinoma.

However, as with other KRAS-targeted approaches, toxicity remains a concern. In the latest ASCO-GI dataset setidegrasib showed a 59% rate of grade 3 or higher adverse events.

Even so, Astellas continues as the leading company in the KRAS G12D degrader field, with only two other biotechs managing to push their assets into the clinic so far: Arvinas and PAQ Therapeutics.

Arvinas is running a phase 1/2 trial in solid tumours, and in 2025 said it expected data as early as this year. Meanwhile, PAQ Therapeutics is running a phase 1 trial in solid tumours, with results expected by the end of 2026.

Beyond KRAS G12D, Astellas is also expanding its KRAS strategy, with a pan-KRAS degrader already in the clinic.

Selected KRAS G12D degraders 

Source: OncologyPipeline.