With an innovative approach to treating heart failure, Cytokinetics promoted a groundbreaking medicine that could potentially address a condition affecting more than 6 million people in the U.S. However, that hope is now dimming.
On Tuesday, the FDA issued a complete response letter (CRL) rejecting the application for approval of the heart failure candidate omecamtiv mecarbil.
This decision was anticipated; 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 informed the company that a new trial would be necessary to demonstrate that the benefits of omecamtiv outweigh the risks.
Cytokinetics, based in South San Francisco, has “no plans” to conduct an additional trial and will instead shift its focus to another treatment in phase 3 testing, aficamten.
Unlike omecamtiv, which is a cardiac myosin activator that helps the heart contract and pump oxygen-rich blood, aficamten is a cardiac myosin inhibitor that restrains the pumping action of an overactive heart.
A year ago, Cytokinetics initiated a phase 3 trial of aficamten for symptomatic obstructive hypertrophic cardiomyopathy (HCM), a condition that thickens the heart muscle and restricts blood flow. Aficamten showed promise 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.”
While anticipating a rejection for omecamtiv last week, Malik also expressed great optimism about aficamten’s prospects.
This sentiment is shared by investors, who increased the stock price following the advisory committee vote in December, interpreting it as a signal for Cytokinetics to proceed with the more promising Plan B.
The company has yet to gain FDA approval in its 26 years of operation. Aficamten would not be the first-in-class drug for HCM, but it is close behind. Bristol Myers Squibb launched Camzyos last year to treat the condition.
“We think there are 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 met its primary objective of reducing heart failure events and hospitalizations. However, the effect’s magnitude was not convincing, and the FDA sought more compelling evidence.
Omecamtiv’s fate was sealed by its failure to reduce the risk of death or impact other secondary measures, such as time to first hospitalization, death from any cause, and changes from baseline on the Kansas City Cardiomyopathy Questionnaire.
This survey measures patients’ perceived health status, including heart failure symptoms and their impact on quality of life.
In late 2020, trial results led Amgen to end its 14-year partnership with Cytokinetics on the drug.
In its submission, Cytokinetics requested that the FDA consider approval based on a subgroup analysis indicating omecamtiv was more effective in patients with a more severe form of heart failure, specifically those with a left ventricular ejection fraction of less than 28%.
“As soon as you go on 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 is the most challenging. And it’s where we have the largest benefit. So, we think there’s a strong rationale for its approval.”
The FDA had additional concerns with Cytokinetics’ submission. Despite the large trial size, it was the only one conducted for omecamtiv. Another issue was dosing.
During the trial, dosing was calculated using diagnostic testing to set the correct dose for patients at higher risk of over-exposure. Approval of this method would have also required approval of the diagnostic tool used during the trial.
