Rocky regulatory road lies ahead for the cardiac myosin activator

Omecamtiv mecarbil received a thumbs-down from FDA advisors who complained of its inadequate evidence base during a Cardiovascular and Renal Drugs Advisory Committee meeting on Tuesday.

Members voted 8-3 (with no abstentions), stating that the benefits of omecamtiv mecarbil do not outweigh its risks for the treatment of heart failure with reduced ejection fraction (HFrEF), based on data coming largely from a single phase III trial.

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

The drug’s proposed indication of preventing cardiovascular death and heart failure events in HFrEF was “too broad of a claim for the data that we saw,” said Michael Blaha, MD, MPH, a cardiologist at Johns Hopkins University in Baltimore, who provided one of the no votes.

Nevertheless, members acknowledged that omecamtiv mecarbil could fill an unmet need for people with advanced heart failure who are often intolerant to existing therapies on the market. “I said yes on the basis of need,” said C. Noel Bairey Merz, MD, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Medical Center in Los Angeles.

The phase III trial in question, GALACTIC-HFopens in a new tab or window, was the basis of omecamtiv mecarbil’s marketing application and had shown that the 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% with placebo over a median 21.8 months (HR 0.92, 95% CI 0.86-0.99).

Although technically a success, the trial’s modest main result did not reach a level of significance to the FDA’s likingopens in a new tab or window, and there were no benefits on any of the secondary efficacy endpoints, such as cardiovascular death or quality of life.

“I would have been encouraged if there was a quality-of-life benefit … There wasn’t any evidence, despite the 8,000-patient study here, of a quality-of-life benefit and that makes this less attractive,” commented Steven Nissen, MD, a cardiologist at Case Western Reserve University in Cleveland, who voted no on the drug.

Only in a subgroup analysis did a signal emerge that showed that HFrEF patients with the lowest ejection fractions perhaps had a larger treatment effect from omecamtiv mecarbil. FDA advisors did suggest more stringent labeling — limiting use to people with ejection fractions of 25% and below, for instance — if omecamtiv mecarbil were to be approved.

Advisory committee members also recommended including a contraindication for people with atrial fibrillation (Afib) or atrial flutter in omecamtiv mecarbil’s label if it were to be approved, as this subgroup had excess cardiovascular deaths taking the drug in GALACTIC-HF.

Due to safety concerns related to high exposure to omecamtiv mecarbil, its manufacturer, Cytokinetics, has proposed that oral dosing should be guided by plasma concentrations of the drug, albeit as measured by a central laboratory assay that has not won FDA approval or clearance. The advisory committee members agreed that pharmacokinetic-based dosing — similar to what was used in the phase III trial — would be essential for the safe and effective use of the drug.

Cardiologist Christopher O’Connor, MD, of Duke University in Durham, North Carolina, and Inova Heart and Vascular Institute in Falls Church, Virginia, said that omecamtiv mecarbil presents a path, even if it is a narrow one, to proceeding safely to provide benefit to a selected population of high-risk HFrEF patients. He was one of the three committee members who voted yes on the drug.

Nissen highlighted the need for the single trial to be replicated, recommending a future study in a focused population with no Afib and low enough ejection fraction to see clinical benefits.

The FDA is not required to follow the advice of the advisory committee, but it often does.

Source:Medscape