FDA advisers elected to not recommend Cytokinetics' heart failure med, voting eight to three that the risks of omecamtiv mecarbil outweigh its potential benefits.
The decision pours cold water on a mixed bag of data accrued in the second-largest clinical trial of heart failure patients, which the company argued support the use of the drug among patients with worse heart function. Now faced with a February 2023 decision deadline, the FDA will have to decide whether to follow the panel's vote or whether to approve the medicine.
The vote followed a lengthy but consistently focused meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee on Tuesday, in which a range of issues varying from study design to safety caused concern among a majority of the committee members. In all, the convened experts concluded that the data at their disposal were murky and too muddled to validate a positive risk-benefit profile.
In the company’s phase 3 trial, dubbed GALACTIC-HF, omecamtiv mecarbil was found to reduce the amount of heart failure events, the trial’s primary endpoint, but failed to reduce cardiovascular deaths. The results were better among a subset of the sickest patients, which was the focal point of the company’s argument supporting approval.
“[W]e’re recognizing that this is an add-on therapy,” said CEO Robert Blum in an interview ahead of the meeting. “This is not a potential medicine that should be used in all heart failure patients."
Blum said in a release following the vote that his conviction remains and that Cytokinetics plans to "engage constructively" with the FDA.
The company by and large stuck to a similar script in the meeting, emphasizing that left ventricle ejection fraction (LFEV) was the key to unlocking therapeutic benefits for the drug. The company also delineated results based on whether enrolled patients had atrial fibrillation or atrial flutter, pointing to data showing that patients without such conditions faired significantly better. But LVEF levels were the most critical trait, specifically patients with ejection fraction less than 28%, with the company saying that no matter how they sliced it, patients with lower fraction rates had better outcomes.
“When we look at LVEF as a continuous measure in GALACTIC, it is evident no matter how we model this, that the treatment effect is truly greatest in those patients with lowest ejection fraction, with a continuous improvement in benefit as LVEF declines,” said Scott Solomon, M.D., a professor of medicine at Harvard and a member of the executive committee for Cytokinetics’ GALACTIC-HF phase 3 trial.
But FDA staffers raised a number of flags, namely that the company showed a “narrow” therapeutic window and that the dosing titration strategy in the trial required an unapproved test.
The company used a unique immunoassay during its registrational trial to assess patients’ plasma levels, a gauge that could identify those at risk of over-exposure. But as part of its discussions with regulators, Cytokinetics proposed a more simplified dosing staircase using an already validated test.
Cytokinetics also proposed to regulators that it could approve the specific companion diagnostic from the trial, although that would delay the launch of omecamtiv mecarbil by at least one year.
Beyond concerns about the test, the FDA and advisers questioned whether there was a wide enough therapeutic window before the drug increased the risk of cardiac toxicity.
“In a recent exploratory analysis that we did, I do have the concern that the optimal therapeutic range [sic] could be lower or narrower than the sponsor originally determined,” said FDA clinical reviewer Tzu-Yun McDowell, Ph.D.
The issues raised regarding the assay and related toxicity concerns were a microcosm of the larger discussions: There was no one issue that plagued Cytokinetics' prospects, but it was a multitude of factors that chipped away at confidence.
The lack of a flagrant issue dogged advisers when it came time to vote, including Debra Dunn, a patient representative who said she switched her vote from no to yes, even though she raised concerns with the number of women recruited. Chris O’Connor, M.D., a professor of medicine at Duke University, similarly voted yes, arguing that the committee would have been more open to accepting subset data had it been debating a prospective cancer medication. David Moliterno, M.D., disagreed, saying he’d have still voted no in that hypothetical event.
Included among the no votes was Csaba P. Kovesdy, M.D., who said the available evidence just didn’t support a positive benefit-risk profile. Julia Lewis, M.D., added that the lack of strong evidence given the size of the trial actually deterred her support given the number of patients and the amount of data. And Daniel Gillen, Ph.D., was not completely sold on the subgroup analysis.
“I do have issues with the subgroup analysis if that's pointed to as the primary reason for approval … and going forward, I do believe that that subgroup should be validated in a future trial,” he said.