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If omecamtiv mecarbil is to gain a heart failure indication, sponsor Cytokinetics has a lot of convincing to do when the FDA Cardiovascular and Renal Drugs Advisory Committee convenes on Tuesday.

FDA advisors will spend the day discussing uncertainties regarding the efficacy and safety of omecamtiv mecarbil based mostly on just one trial, GALACTIC-HF. While that trial met its primary endpoint in people with heart failure with reduced ejection fraction (HFrEF) already taking standard medications, the modest magnitude of benefit disappointed many.

In the double-blind, randomized phase III trial, the investigational cardiac contractility drug reduced the combined rate of cardiovascular death and hospitalization or other urgent treatment for heart failure to 37.0% compared with 39.1% in the placebo group over a median 21.8 months (HR 0.92, 95% CI 0.86-0.99).

"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 FDA wrote in a ahead of the meeting.

Moreover, anticipating that omecamtiv mecarbil's sponsor will try to argue that there is a greater, more persuasive, treatment effect in people with the lowest ejection fractions, the FDA brief called into question the scientific rigor of such a secondary analysis.

The agency also asked the advisory committee to discuss safety issues, including omecamtiv mecarbil's association with troponin I increases and excess cardiovascular deaths in people with atrial fibrillation or atrial flutter at baseline.

Cytokinetics has argued that the drug is relatively safe because it does not interfere with other commonly used heart failure medications, and because it does not adversely affect blood pressure, heart rate, potassium concentrations, or renal function. In addition, there was no increase in cardiac ischemic or ventricular arrhythmic events in GALACTIC-HF.

Omecamtiv mecarbil is a first-in-class cardiac myosin activator that boosts cardiac contractility by increasing the number of myosin heads that can bind to the actin filament and initiate a power stroke at the start of systole.

Even if agency advisors vote that the drug's benefits do outweigh its risks, favoring FDA approval, there is still the question of whether a cumbersome pharmacokinetic-based dosing strategy, similar to what was employed in the phase III trial, should be required for safe and effective use in the real world.

Oral dosing would be guided by plasma concentrations of omecamtiv mecarbil as assessed by a central laboratory assay that the FDA briefing documents pointed to as lacking the agency's approval or clearance.

"The question here is whether the currently proposed [pharmacokinetic]-dosing strategy is sufficient, thus potentially accepting an unapproved central lab result as the basis of dose titration, or critical, thus requiring a [companion diagnostic device], to maximize risk mitigation," FDA reviewers wrote.

Based on GALACTIC-HF, clinicians have predicted a limited role for omecamtiv mecarbil, given the presence of heart failure drugs already on the market that do have proven survival benefits.

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