Ulacamten: an allosteric cardiac myosin inhibitor derived from a diketopiperazine hit, now in Phase II testing for HFpEF
- Ulacamten was optimized from a diketopiperazine screening hit whose biochemical behavior differed from that of mavacamten and aficamten.
- It acts at a different binding site from those approved cardiac myosin inhibitors and is orally available.
- In healthy and obese ZSF1 rats it lowered left ventricular fractional shortening; human Phase 1 data showed a half-life supporting steady state within about a week.
- It is being tested in the Phase II AMBER-HFpEF trial (NCT06793371).
💡 Points Based on the abstract
Ulacamten's real question is differentiation: if the site really differs from mavacamten and aficamten, does it give a gentler, less steep exposure-to-contractility relationship? HFpEF patients have little systolic reserve, so that window matters more than potency. I'd want ATPase selectivity against skeletal and smooth muscle myosin and a full dose-response of fractional shortening.