FDA turns down Cytokinetics' once-promising heart failure drug omecamtiv

With an innovative approach to treating heart failure, Cytokinetics touted a game-changing medicine that could someday become available for an elusive condition that effects more than 6 million in the U.S.

But that hope is flickering. In a complete response letter (CRL) to Cytokinetics on Tuesday, the FDA rejected the application for approval of heart failure candidate omecamtiv mecarbil.

The thumbs down was not a surprise. In December, the FDA’s Cardiovascular and Renal Drug Advisory Committee voted 8-3 against recommending omecamtiv for approval for patients with heart failure with reduced ejection fraction (HFrEF).

The FDA told the company that a new trial will be needed showing that the benefits of omecemtiv outweigh the risks. South San Francisco-based Cytokinetics has “no plans” to conduct an additional trial and will instead shift focus to another of treatment in phase 3 testing, aficamten.

While omecemtiv is a cardiac myosin activator, which helps the heart contract and boost its ability to pump oxygen-rich blood to the body, aficamten is a cardiac myosin inhibitor. It restricts the pumping action of an overactive heart.

A year ago, Cytokinetics kicked off a phase 3 trial of aficamten for symptomatic obstructive hypertrophic cardiomyopathy (HCM). The condition causes a thickening of the heart muscle and restricts blood flow. Aficamten showed its potential in a phase 2 trial.

“We’re a company that’s always worked to develop new drugs, new mechanisms and not pivot on any success or failure of any one particular program,” Cytokinetics’ R&D chief Fady Malik said in an interview with Fierce Pharma last week. “That’s sort of a franchise approach, meaning when we started building the cardiovascular part of our company, we wanted to have multiple shots on goal.”

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While sounding resigned last week to a rejection for omecemtiv, Malik also voiced great optimism about the prospects of aficamten. It’s a feeling shared by investors who boosted the price of shares in reaction to the adcom vote in December, believing it signaled to Cytokinetics that it was time to move on to the more promising Plan B.

The company has yet to gain an FDA approval in its 26 years in business. Aficamten would not be the first-in-class drug for HCM, but it’s close behind. Bristol Myers Squibb launched Camzyos last year to treat the condition.

“We think there’s some advantages to aficamten that will make it more successful down the road,” Malik said.

Tuesday’s FDA rejection was based on a trial of more than 8,200 patients, which achieved its primary objective to reduce heart failure events and hospitalization. The magnitude of effect was not convincing, however, and the FDA was looking for more.

Sealing the fate of omecamtiv was that it failed to reduce the risk of death. Nor did it move the needle on other secondary measures such as time to first hospitalization, death from any cause and change from baseline on the Kansas City Cardiomyopathy Questionnaire. The survey measures how patients perceive their health status, including their heart failure symptoms and how they affect quality of life.

In late 2020, the results of the trial convinced Amgen to end its 14-year partnership with Cytokinetics on the drug.

In its submission, the company asked the FDA to consider an approval based on a subgroup analysis that showed omecamtiv was more effective in those who had a more severe form of heart failure. Cytokinetics specified that group as those with lower left ventricular ejection fraction of less than 28%.  

“As soon as you do any sort of scientific journey, you learn things along  the way,” Malik said. “This is a patient population where the risks are the highest and the use of our existing drugs are the hardest. And it’s where we have the largest benefit. So, we think there’s a real strong rationale for its approval.”

RELATED: FDA puts Merck's heart failure drug on priority review track

The FDA had other problems with Cytokinetics’ submission. Although the trial was huge, it was the only one conducted for omecamtiv. Another issue was dosing. During the trial, it was calculated using diagnostic testing that helped set the correct dose for patients who might be at higher risk for over-exposure. Using that method would have also required approval of the diagnostic tool used during the trial.