FDA panel declines to support approval of omecamtiv mecarbil
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An FDA advisory committee voted 8-3 against supporting the approval of the HF drug omecamtiv mecarbil, with panelists citing a small observed benefit for a limited group of patients.
In discussion after the vote, members of the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) noted that although the pivotal trial, GALACTIC-HF, met its primary endpoint, the observed benefit in adults with HF with reduced ejection fraction was small, did not include a CV mortality benefit and was seen only in patients with a very low EF. Additionally, panelists were concerned with an observed increased risk for myocardial ischemia and worsening HF in patients with baseline atrial fibrillation or flutter, as well as no improvement in quality of life measures and a modest effect on HF hospitalization.
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“The benefits here were small, and if you remove the less severe [HF] events — that is urgent outpatient visits — [the finding is] no longer statistically significant,” Cardiology Today Editorial Board Member Steven E. Nissen, MD, MACC, chief academic officer of the Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute and the Lewis and Patricia Dickey Chair in Cardiovascular Medicine at Cleveland Clinic, said after his “no” vote. “This is really insufficient for a single trial. I would have been encouraged if there was a quality of life benefit. Why do patients want to take medications? They want to feel better. There wasn’t any evidence, despite 8,000 patients studied, of a meaningful quality of life benefit. That makes this less attractive.”
“This is a novel mechanism but an old-fashioned contractility drug, which are known to have narrow benefit-to-toxicity ratios,” Cardiology Today Editorial Board Member C. Noel Bairey Merz, MD, FACC, FAHA, professor of medicine (cardiology) and director of the Barbra Streisand Women’s Heart Center at the Smidt Heart Institute, Cedars-Sinai, said after voting in support of approving the drug. “I say ‘yes’ on the basis of need and my personal experience ... Up to half of severe HF patients are intolerant to [guideline-directed medical therapy]. I also suggest there be assays required to keep this as safe as the clinical trial. I anticipate [if approved] this drug will likely be used in a small subset by advanced HF cardiologists, offering at least a little bit more safety.”
Significant but small treatment effect
As Healio previously reported, data from GALACTIC-HF demonstrated that omecamtiv mecarbil (Cytokinetics), a novel selective cardiac myosin activator, was associated with an 8% reduction in CV death or first HF events in patients with HFrEF. In the study, patients with an EF of 28% (the median of the cohort) or lower benefited more from omecamtiv mecarbil than patients with EF greater than 28%. In the group with EF at or below the median, omecamtiv mecarbil reduced the primary endpoint by 16% (HR = 0.84; 95% CI, 0.77-0.92), but the group with EF above the median, omecamtiv mecarbil had no impact on the primary endpoint (HR = 1.04; 95% CI, 0.94-1.16; P for interaction = .003).
The trial implemented a pharmacokinetic-guided posology to optimize dosing and ensure safety by minimizing the risk due to excessive exposure to omecamtiv mecarbil.
In briefing documents, the FDA stated that the results of GALACTIC-HF showed a statistically significant but small treatment effect for the primary efficacy endpoint. “Although the results were driven by HF events, the treatment effect on HF events did not show statistically significant improvement for subjects on omecamtiv mecarbil compared to placebo,” the FDA wrote. “There were no differences between the arms of the trial for CV death or for all key secondary endpoints that otherwise may have supported the persuasiveness of a single trial. Phase 2 trials focused only on echocardiographic parameters.”
Increased risk with AF/flutter
During a presentation, the FDA cited two principal safety concerns for omecamtiv mecarbil related to dosing and safety. The FDA cited data showing excessive exposure to omecamtiv mecarbil increased risk for myocardial ischemia and HF, particularly in participants with AF or flutter, and noted an optimal therapeutic dosing range “has not been well established.”
“With the efficacy and the safety issues discussed in this presentation, the FDA review team is not certain whether the benefit of omecamtiv mecarbil outweighs the risk,” Tzu-Yun McDowell, PhD, clinical reviewer in the division of cardiology and nephrology in the Office of New Drugs at the FDA, said during the presentation. “On the benefit side, there was a small treatment effect from the single pivotal trial. The results were not statistically persuasive and may not provide an adequate basis for concluding the benefits.”
On the risk side, McDowell said, there was concern regarding drug-associated cardiotoxicity with the drug, and that risk could vary depending on whether — or how well — a pharmacokinetic dosing strategy was followed in a real-world setting.
The FDA noted that, under a pharmacokinetic-guided dosing strategy, the risk profile of omecamtiv mecarbil is generally acceptable except for patients with AF or flutter, who were at greater risk for CV death due to worsening HF when assigned the drug vs. placebo.
‘Compelling’ addition for the neediest patients
Speaking on behalf of Cytokinetics, Scott D. Solomon, MD, professor of medicine at Harvard Medical School, senior physician and director of noninvasive cardiology at Brigham and Women’s Hospital, said the greatest benefit on patient outcomes was seen in those with worse HF and the highest event rates, adding that the characteristics of omecamtiv mecarbil allow for its use where current standard of care can be challenging.
“The benefits of omecamtiv mecarbil outweigh its risks and make it a compelling addition to therapies we have available to treat our neediest patients with HFrEF,” Solomon said.
Commenting after the vote, Thomas J. Wang, MD, the Donald W. Seldin Distinguished Chair in Internal Medicine at UT Southwestern Medical Center in Dallas, agreed that there could be a role for omecamtiv mecarbil for patients not currently served by existing therapies. However, the data show the reduction in HF hospitalizations was modest, he said.
“The issue is whether there is enough here to move ahead on the basis of what we have seen from the single clinical trial,” Wang said. “Given the modest potential benefit and the residual uncertainties, I am not sure that is justified yet. There would be value in a true confirmatory trial, likely targeted at patients with very low EF.”
Panelists who voted against recommending approval suggested the sponsor conduct a smaller study with an enriched population of participants who have a lower EF without AF or flutter, using pharmacokinetic-based dosing along with a parallel validation process for assessing drug exposure.
The advisory panel’s recommendations are nonbinding, although the FDA often follows its suggestions.
References:
- Cytokinetics briefing information. fda.gov/media/163822/download. Accessed Dec. 12, 2022.
- FDA briefing information. fda.gov/media/163821/download. Accessed Dec. 12, 2022.
Perspective
Back to TopI am not surprised the panel declined to support approval. This was a group of symptomatic HF patients in a large study and a very novel mechanism of action to study in HF, which was a big undertaking. Certainly, even though the composite endpoint was positive, which was that there was a significant reduction in the composite endpoint of HF events or death, when you separated those out, there was no difference in death between groups. There was possibly a signal of benefit in people with low EF.
Even though the background medical therapy was very good in both arms, there was a very small percentage of SGLT2 inhibitor use, which is now a cornerstone of therapy for HF. If everyone was maximized on guideline-directed medical therapy, would the effect have been diminished even more?
I wonder if a different study, looking at a sicker population, may show benefit. Then, we could determine if there is a role for this type of drug in the symptomatic patients.
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