Cytokinetics will finally get the chance to make the case for its heart failure drug to the FDA’s advisory committee next week. But it seems the agency is uneasy about the single study used to support the application and whether that phase 3 test covered some of the company’s asks.
Omecamtiv mecarbil is under review to reduce the risk of cardiovascular death and heart failure events in patients with chronic and symptomatic heart failure with reduced ejection fraction. The phase 3 trial called GALACTIC-HF was used to support the application.
The company found that omecamtiv mecarbil reduced heart failure events and kept patients out of the hospital, which was the main goal of the study. But a key secondary endpoint looking at cardiovascular death was not met, meaning the therapy was not found to extend patients’ lives.
The FDA is now asking the Cardiovascular and Renal Drugs Advisory Committee to consider some key questions about omecamtiv mecarbil. In fact, calling this panel to assess Cytokinetics’ application is an extra layer of review that wasn’t originally the plan. When accepting the application, the FDA declined to convene the committee but later reversed its decision.
The committee will meet Tuesday to consider three questions that the FDA posed in its briefing documents released today:
- Do the results of the GALACTIC-HF trial meet the statutory requirements for substantial evidence of effectiveness? And, if so, does the evidence support Cytokinetics’ request to focus the approval on a subgroup of the sickest patients?
- Patients who had atrial fibrillation or atrial flutter did not see any improvement in heart failure events and were at increased risk of cardiovascular death compared to placebo during the GALACTIC-HF trial. The committee is being asked to discuss the benefits and risks of omecamtiv mecarbil in these patients.
- Whether a dosing strategy that uses diagnostic testing is necessary for safe and effective use of omecamtiv mecarbil to ensure its benefits outweigh the risks.
The FDA briefing documents said the study “showed a statistically significant but small treatment effect” on the main endpoint of reducing the events, but the secondary goals were a miss.
“There were no differences between the arms of the trial for [cardiovascular] death or for all key secondary endpoints that otherwise may have supported the persuasiveness of a single trial,” the FDA explained.
A single trial can be used to support a regulatory approval; however, the FDA seems to be arguing here that Cytokinetics did not tick off enough boxes on the secondary endpoints to support a nod. The agency said the small treatment effect on the main endpoint had “a p-value that is not very persuasive for a single trial.”
The FDA is therefore wondering whether Cytokinetics has met the requirements for establishing effectiveness.
After discussion with the FDA about the efficacy data, the documents say Cytokinetics raised the potential for targeting the approval toward a subgroup population. The company believes patients who went into the trial with lower left ventricular ejection fraction less than 28% may see greater benefit than the overall studied population in GALACTIC-HF. This is a measure of how much blood the heart is able to push out to the body. A lower number would mean a patient whose heart is less able to keep up with what the body needs.
But the FDA is concerned that there is no evidence to support efficacy in this population and that the subgroup analysis was not sufficiently controlled.
“The division has concerns about the reliance on the subgroup finding for an efficacy claim, especially in the setting where the trial may not have met the statutory requirements for substantial evidence of effectiveness,” the documents say.
If Cytokinetics can overcome the evidence concerns, omecamtiv mecarbil is still not in the clear. The company initially proposed for approval a simplified dosing strategy that was not used in the trial. The new method would see all patients work up to the maximum 50-mg dose four weeks after the start of treatment. But during the trial, dosing was calculated using diagnostic testing that helped set the correct dose for patients who might be at higher risk for over-exposure.
Omecamtiv mecarbil has been associated with adverse events such as myocardial ischemia, or reduced blood flow to the heart, and heart failure. Cytokinetics’ proposal could lead to over-exposure and increase the risk of cardiotoxicity, the FDA said.
While the company agreed after discussions to abandon the new dosing plan and revert to something more in line with what was studied, the agency now wonders if a companion diagnostic would be required to go along with the therapy to determine the correct dose for patients and ensure safe and effective use.
The diagnostic requirements would need to be included in omecamtiv mecarbil’s instructions for use. Moreover, these types of tests are ideally developed “contemporaneously” with the therapeutic using data from the same clinical trial used to establish clinical performance.