The Food and Drug Administration’s (FDA) Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 8 to 3 that the benefits of omecamtiv mecarbil do not outweigh its potential risks in the treatment of heart failure with reduced ejection failure (HFrEF).

Omecamtiv mecarbil is a selective small molecule cardiac myosin activator designed to increase contractility without increasing intracellular calcium in cardiac myocytes or myocardial oxygen consumption. The New Drug Application included data from the phase 3 GALACTIC-HF trial (ClinicalTrials.gov Identifier: NCT02929329), which assessed the efficacy and safety of omecamtiv mecarbil in 8256 adults who were either hospitalized at the time of enrollment for a primary reason of heart failure or had a hospitalization or admission to an emergency room for heart failure within 1 year prior to screening. 

Results showed that treatment with omecamtiv mecarbil met the primary composite endpoint demonstrating a statistically significant reduction in cardiovascular (CV) death or heart failure events compared with placebo. A greater treatment effect of omecamtiv mecarbil was observed in patients with lower left ventricular ejection fraction (LVEF). However, no reduction in the secondary endpoint of time to CV death was observed.

While the trial did meet its prespecified primary endpoint, the panel noted in the briefing document that “the small observed treatment effect was not considered clinically and statistically persuasive, in the absence of a favorable trend for CV death, significant key secondary endpoints, nor clinically meaningful improvement in patient symptoms.”

Results from the phase 2b COSMIC-HF study (ClinicalTrials.gov Identifier: NCT01786512), which were expected to serve as confirmation of benefit, showed improvements in several hemodynamic parameters with omecamtiv mecarbil though the benefits associated with these changes remained unclear, according to the committee.

The benefit-risk assessment was further complicated by different outcomes for patients based on baseline LVEF and atrial fibrillation/flutter. Subgroup analysis showed an increased risk of CV death in patients with atrial fibrillation/flutter treated with omecamtiv mecarbil.

Additional concerns included the potential for drug-related cardiotoxicity, with evidence suggesting that excessive exposure to omecamtiv mecarbil increased the risk of myocardial ischemia/infarction.

“We are disappointed there was not a greater consensus amongst Committee members relating to the benefit-risk of omecamtiv mecarbil, and we maintain our conviction in the strength of evidence supporting its potential benefit for patients suffering from HFrEF,” said Robert I. Blum, Cytokinetics’ President and CEO. “We continue to believe omecamtiv mecarbil can be a valuable add-on therapy for patients with worsening heart failure who remain at high risk for heart failure events and hospitalization despite treatment with available guideline-directed medical therapy. We plan to engage constructively with FDA as it completes its review of the application for omecamtiv mecarbil.”

Although not bound by the committee’s recommendations, the FDA does take them into consideration when making decisions on approval. A Prescription Drug User Fee Act target date of February 28, 2023 has been set for the application.

References

  1. Cytokinetics announces outcome of FDA advisory committee vote on omecamtiv mecarbil. News release. Cytokinetics. Accessed December 14, 2022. https://www.globenewswire.com/news-release/2022/12/13/2573263/35409/en/Cytokinetics-Announces-Outcome-of-FDA-Advisory-Committee-Vote-On-Omecamtiv-Mecarbil.html.
  2. FDA Briefing Document. NDA# 216401: Omecamtiv Mecarbil. Accessed December 14, 2022. https://www.fda.gov/media/163821/download.