The FDA’s Cardiovascular and Renal Drugs Advisory Committee stood against Cytokinetics, Inc., finding that the benefits of its heart failure hopeful didn’t outweigh its risks.
Courtesy of Sarah Silbiger/Getty Images
In an 8-3 decision, the FDA‘s Cardiovascular and Renal Drugs Advisory Committee voted against California-based Cytokinetics, Inc., finding that the benefits of its heart failure hopeful omecamtiv mecarbil (OM) didn’t outweigh its risks.
In a briefing document sent to the panel, an issue was cited with the mixed efficacy results backing OM, muddled further by safety concerns.
The FDA is expected to reach a final decision on OM in the coming months. The PDUFA target action date is on Feb. 28, 2023.
Cytokinetics backed its regulatory bid for OM with one Phase III study: the GALACTIC-HF trial, which, with more than 8,250 patients enrolled, is among the largest trials in heart failure.
The study employed a composite endpoint of cardiovascular death or heart failure events as its primary efficacy measure. Compared with the placebo, OM slashed this risk by 8%, a statistically significant effect with a p-value of 0.025.
Cytokinetics further drew confidence in its heart failure candidate from a pre-specified sub-group analysis. In patients with a left ventricular ejection fraction not exceeding 28%, a typical hallmark of worsening heart failure, OM reduced the likelihood of the primary endpoint by 16%, with a stronger p-value of 0.003.
OM consistently demonstrated higher treatment effects in sicker patients. For instance, the drug cut the risk of the composite endpoint by 17% in those hospitalized in the last three months and 23% in patients with elevated levels of the N-terminal-pro brain natriuretic peptide.
These results are “the most biologically plausible,” given the drug’s mechanism of action of increasing myocardial contractility to boost cardiac function, according to the FDA.
Not Enough Evidence, Risks of Toxicity and an Unapproved Test
Still, the FDA’s advisers said that the evidence supporting OM was too thin. While the drug did satisfy its primary efficacy measure, the overall treatment effect was small, and none of the secondary endpoints were met.
“The small treatment effect, with a p-value that is not very persuasive for a single trial, without established effects on any of the secondary efficacy endpoints, calls into question whether the statutory requirement for substantial evidence of effectiveness has been met,” stated the briefing document.
For the potential efficacy signals in patients with LVEF worse than 28%, the experts wrote that “there is no scientific basis for this differential effect.”
Regarding safety, the advisory committee conceded that the risk of dose-limiting cardiotoxicity due to OM’s mechanism of action was generally contained in GALACTIC-HF.
However, Cytokinetics employed a pharmacokinetic-guided dosing approach in the study, which the company proposed to do away with in the real world.
Without measuring plasma OM concentrations for dose adjustment, patients could be subjected to higher drug exposure levels, which “could increase the potential risk of OM-associated cardiotoxicity,” according to the FDA.
Cytokinetics has subsequently agreed to a guided dosing strategy but has proposed to use a lab-based test not approved by the FDA. The advisory committee also saw this as an issue, pointing out that the agency cannot rely on data from uncleared tests.
If pharmacokinetic-guided dosing is crucial to determine whether OM is safe and effective, then the test “should be cleared or approved contemporaneously with OM,” the expert panel stated.
