KAT6 catalysts to kick off 2025

Given the early clinical promise of KAT6 inhibition in breast cancer it might come as a surprise how little industry work is ongoing concerning this target. True, Ideaya recently entered this field, and Olema has made much of its ongoing efforts, which should see phase 1 work begin this year, but OncologyPipeline shows that just two molecules are in clinical trials at present.

Pfizer was first to present human data with a KAT6 inhibitor, PF-07248144, at ASCO 2023, and the promise appeared to hold up at last month's San Antonio Breast Cancer symposium. That molecule is to enter pivotal trials imminently, but one question is how KAT6 inhibitors might combine with SERDs in breast cancer, given their seemingly modest monotherapy activity.

Pfizer's SABCS update said nothing about PF-07248144 monotherapy, which was the first data the group revealed 18 months ago. Notably, since then Pfizer appears to have turned towards combining PF-07248144 with Faslodex, and monotherapy data were last reported at ASCO 2024, showing an 11% ORR.

The good news is that the subsequent development of fresh responses to the Faslodex combo, hinted at during ASCO, appears to have materialised: among 23 second-line and 20 third-line HER2-negative breast cancer patients given PF-07248144 plus Faslodex, ORRs rose respectively from 22% and 40% at ASCO to 30% and 45% at SABCS.

Safety?

However, the SABCS update was also notable for how little was said about safety. This is despite the abstract revealing the death of a patient from pneumonitis, and the fact that dose-limiting toxicities (mostly neutropenia) had earlier been disclosed as occurring from even the lowest monotherapy dose tested.

In a recent podcast Evercore ISI analysts questioned the absence of updates on these safety points at SABCS, but said that at least the toxicities seemed not to overlap with those of SERDs, a fact that should bode well for combinations. 

Any investors awaiting updates from KAT6 inhibitor competitors will similarly have to pay close attention not only to efficacy, but also to side effects. These competitors include Menarini, whose MEN2312, licensed from InSilico Medicine for $12m up front a year ago, is still the only other KAT6 inhibitor in clinical development, having started a phase 1 Orserdu combo trial last October.

Olema, meanwhile, has been talking up its contender, OP-3136, which it licensed from Dr Reddy's for $8m up front in June 2022, as having preclinical efficacy both as monotherapy and in combination with its CERAN/SERD palazestrant. Last month the FDA cleared an IND, and the molecule is expected to enter phase 1 early this year.

Apart from these projects the only other contenders appear to be IDE251, which Ideaya nominated as a development candidate three weeks ago, and an unnamed KAT6A project generated by the French drug discovery company Qubit Pharmaceuticals. Qubit is seeking a partner to take its project forward.

It's not yet clear whether a focus on KAT6A might offer advantages versus hitting KAT6 more broadly. Olema's OP-3136 has previously been described as a KAT6A/6B inhibitor, as has PF-9363, a molecule Pfizer has worked on preclinically.

Also relatively untested is the value of hitting KAT7, as Ideaya wants to with IDE251. In nominating IDE251 Ideaya said this molecule had monotherapy promise in breast and lung cancers with 8p11 amplification – an apparently unique approach versus the rest of the KAT6 inhibitor pack.

KAT6 inhibitors in development

Source: OncologyPipieline.

The table in this story has been updated to include Isosterix's IST-477.