The U.S. FDA has issued Cytokinetics Inc. a complete response letter (CRL) for omecamtiv mecarbil, branding the clinical evidence behind it is as not “persuasive” enough to establish its effectiveness for reducing the risk of heart failure events and cardiovascular death.

The company is developing the drug as an add-on therapy for patients with worsening heart failure who remain at high risk for heart failure events and hospitalization.  

The FDA wants to see results from an additional clinical trial to establish sufficient evidence of effectiveness with benefits that outweigh the risks. Although Cytokinetics plans to request a meeting with the agency to find out what may be required to support potential approval of the drug, it does not plan to resource further studies.

The FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted against the drug, a first-in-class selective cardiac myosin activator that’s been in development since 2005 and which is designed to target the pumping mechanisms of the heart, on Dec. 13, 2022. 

Just three of the CRDAC members argued that omecamtiv’s benefits outweigh its risks for the treatment of HF in patients with reduced ejection fraction (HFrEF), with the other eight panelists casting negative votes, some of whom pointed their fingers at the mixed nature of the available data so far. 

Some CRDAC members said that in a trial as large as Galactic-HF (it was the second largest global heart disease clinical trial ever, enrolling more than 8,000 patients in over 30 countries), the phase III study that was used to support Cytokinetics’ application, a stronger benefit should have been seen. The drug performed fairly well, meeting the primary efficacy endpoint: the time to a first heart failure event or cardiovascular death.  

But the 8% treatment effect, though statistically significant, was small, with a 0.0252 p-value, and driven by reduction in hospitalizations rather than cardiac death. No differences were observed between the Galactic-HF arms for cardiac death, quality of life or other key secondary endpoints. 

In an interview with BioWorld that took place a day before the FDA made its decision, CEO of Cytokinetics Robert Blum admitted the single-digit treatment effect was “modest,” but he said the neutral effect on cardiovascular death should still be deemed “quite meaningful.” 

“Heart failure is the number one reason why patients … are hospitalized, especially over the age of 65. These hospitalizations are contributing very significantly to the economic burden as well as the morbidity of the disease,” he said. 

Blum was keen to highlight that a subgroup of patients in the trial who were at higher risk of heart failure (those who had recently been hospitalized; had higher levels of a biomarker known as BMP, which indicates cardiac wall stress; had more compromised kidney function; and those with higher blood pressure) experienced “a doubling or more of the effect,” and said that the company had been “asserting and advocating” use of the drug in this particular patient population, though he conceded that the “single digit ranges” of these effects were not statistically significant.

Despite the FDA’s ruling on omecamtiv mecarbil, Blum said that the company would still be pursuing “potential approvals in other international markets”, but it could be the end of the road for the drug in the U.S. at least.

Spotlight on aficamten 

With the CRL setback, Cytokinetics plans to “double down” on the remaining two late-stage clinical candidates in its pipeline, and especially with its second cardiovascular offering aficamten.

“It is our intention to substantially dial up our commitment to aficamten, approximately two-thirds of our R&D spending this year is going to a broadening of the development pipeline for aficamten, under every scenario,” Blum told BioWorld.

Aficamten is a cardiac myosin inhibitor oral medication which is being evaluated in patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM) in a phase III study and in a phase II trial for non-obstructive HCM. The company plans to report data on this study later in 2023. 

Cytokinetics is also developing reldesemtiv, an investigational fast skeletal muscle troponin activator, currently the subject of COURAGE-ALS, a phase III clinical trial in patients with amyotrophic lateral sclerosis. The company expects to complete enrollment in the first half of this year, but appears cautious as to potential negative outcomes, with Blum admitting that an upcoming “second interim analysis” would dictate whether the study needs to be halted “were it to be deemed futile” or, alternatively, upsized “if that may be appropriate for added statistical power.” 

“Both of those are possible outcomes, more probably, perhaps, is the fact that the study will just complete its enrollment as was originally intended. We’ll look forward to what could be data from what may be a first muscle-directed therapy for ALS in 2024,” he said.