Ahead of adcomm, FDA raises uncertainties on benefit-risk profile of Cytokinetics' potential heart drug
The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.
The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.
The FDA on Friday made clear the uncertainties ahead of the adcomm, noting the “small treatment effect” in the pivotal GALACTIC-HF trial and adding, “This uncertainty is based on both efficacy and safety considerations.”
And despite hitting on the primary efficacy, the numbers “were driven by HF events with no trends of improvement on CV mortality. 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,” the agency said.
The agency also questioned why this single trial result “was not accompanied by confirmatory evidence,” adding:
The treatment effect appeared to favor those with a LVEF <28%, but there is no scientific basis for this differential effect. The benefit/risk profile is further tenuous, because only 2 additional major cardiac ischemic events per 100 PY are needed to negate the potential small net benefit observed in the overall GALACTIC-HF population.
Cytokinetics, meanwhile, laid out its case for approval for its cardiac myosin activator, noting that the GALACTIC-HF trial “has the features of a single trial that could provide substantial evidence of effectiveness as the basis for a single-trial approval.”
While acknowledging that the “overall effect size was modest,” this prespecified subgroup of LVEF “had the most statistically significant interaction effect in both univariate and multivariate analyses and is a biologically plausible modifier of the treatment effect in patients with reduced cardiac function given the mechanism of action of omecamtiv mecarbil.”
The outside experts next week will vote once on whether the benefits of omecamtiv mecarbil outweigh its risks for the treatment of heart failure with reduced ejection fraction. If an adcomm member votes yes, the FDA also wants to know if pharmacokinetic-based dosing is essential for the safe and effective use.
On the dosing strategy, the FDA noted that Cytokinetics initially proposed a post-approval dosing strategy based on scheduled, forced dose titration (i.e., all patients will titrate up to the maximum dose of 50 mg 4 weeks after the start of treatment), but then decided to go with a PK-guided dosing strategy, such as what was used in the GALACTIC-HF trial.
But the agency also explained how typically if diagnostic testing, such as PK-guided dosing, is essential for safe and effective use of a therapeutic, the test is developed alongside the therapeutic and brought up for approval simultaneously with the drug.
While a close vote may be in the works, Cytokinetics has been building up commercial operations in case of a potential approval. In its first quarter earnings report, the biotech said it’s hired its first field sales staff and is actively recruiting other positions to help the launch.
Whether the green light comes through or not, investors’ attention has largely turned toward the next pipeline program called aficamten, a myosin inhibitor designed to treat symptomatic obstructive hypertrophic cardiomyopathy.