SPOTLIGHT –
The advisory committee voted 3-8 against the benefit-risk profile of omecamtiv mecarbil for heart failure with reduced ejection fraction.
US Food and Drug Administration (FDA)
4:30 PM: The CRDAC recommended against the benefit-risk profile of omecamtiv mecarbil for the treatment of HFrEF in a 3 – 8 vote.
Committee members answered the question "Do the benefits of omecamtiv mecarvil outweigh its risks for the treatment of heart failure with reduced ejection fraction?"
Those in favor of omecamtiv mecarbil often noted that while the overall trial showed a small benefit of the therapy and similar risk profile to placebo, the unmet need still remains.
“My personal experience is that up to half of severe heart failure patients are intolerant of guideline-directed therapy,” C. Noel Bairey Merz, MD, Barbra Streisand Women’s Heart Center, Cedars-Sinai Medical Center. “I anticipate that given the barriers, it will likely be used in a small subset of advanced heart failure cardiologists, offering to me at least a bit more safety.”
Others emphasized that unmet need in a high risk heart failure patient population, likening the issue as the same for very ill cancer patients. A path forward with this therapy may be possible and be both effective and safe for this patient population.
Those who voted against the therapy called to mind the lack of quality of life improvements and no effect on CV death. Some criticisms of the trial included the large population, including small numbers of women and lack of positive effect observed, as well as the subgroup analysis.
“I do have issues with subgroup analysis if that is pointed to as the primary reason for approval and lack of precisification in terms of a hypothesis in this subgroup,” Gillen said. “I do believe the subgroup should be validated in a future trial. If it were to be done, I would exclude the AFF population given the potential harm we have seen.”
4:00 PM: In the committee discussion, Steve Nissen, MD, Chief Academic Officer, Heart, Vascular & Thoracic Institute, Cleveland Clinic, remained hesitant on the benefit of omecamtiv mecarbil.
“The proposed benefits are small and it appears to me that they are driven in large part by the urgent outpatient visits, not by hospitalization or death,” Nissen said. “If you look at the heart endpoints, it does not appear that there is much of a benefit.”
He added that other issues were the lack of quality of life benefits, particularly no improvement in KCCQ. As well, he noted his surprise with an EF up to a year old being used to qualify patients instead of more approximate to the trial, ultimately weakening the argument made in the post-hoc analysis of the potential benefits of omecamtiv mecarbil.
Daniel Gillen, MD, Chancellor’s Professor and Chair, Department of Statistics, University of California, Irvine, was additionally in agreement that the evidence was not confirmatory.
“With respect to the way I am judging the evidence in the overall population where we have a modest effect and no effect on survival, I am dubious,” Gillen said. “With regards to the phase 2 study, the phase 3 study was only performed because the therapy showed promise. I can take it as supportive evidence, but I can not take it as evidence of independent evidence.”
The committee members added that the population is very important, but the concerns are on the first in-class drug trial. Two concerns addressed with a consensus noted the phase 2 trial does not provide sufficient evidence and the proposed benefit is still small.
Then, if the therapy were to be approved, the committee members discussed what the labeling should say about use as a function of LVEF.
“If this were approved I think I would advocate a LVEF equal to or less than 25% which is much more user friendly in practice and helps prevent against the variability that one might have that could reach over the 28% boundary,” said Christopher O’Connor, MD, Professor of Medicine, Duke University.
Mcihael Blaha, MD, Director of Clinical Research Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, agreed that the only way he could see an indication being supported based on the single trial presented is to have severely reduced LVEF, such as that less than 25%, is supported by the analysis. He noted the therapy should really be used in those patients with severely reduced ejection fraction.
“One could argue the labels say it was potentially only at benefit at low ejection fraction and shouldn’t be used in patients with a higher ejection fraction for reasons others have stated,” said Julia B. Lewis, MD, Professor of Medicine, Vanderbilt Medical Center.
The next discussion addressed the label in regards to the use of omecamtiv mecarbil in patients with AFF.
“We view mortality not only in efficacy, but in safety and I think the FDA provided a nice analysis on a worrisome signal of cardiovascular death,” O’Connor said. Since it is easy to obtain rhythm status at time of drug initiation, I think it should say normal sinus rhythm.”
All committee members agreed that the label should include some comment about the potential harm in patients with AFF. With the benefit side of this drug being limited by the quality of life data, they should remain on the safe side about warning a patient in AFF and potentially requiring them to be in normal sinus.
Then, the members discussed whether the therapy is safe enough to support its proposed use and consider its safety with and without pharmacokinetic-based dosing. The members were divided, but generally agreed that pharmacokinetic-dosing would be an important component of the therapy. Some brought up concerns on drug-drug interactions, while others believed an 8,000 person study would have had interactions.
2:55 PM: In the open public hearing, opinions on the approval for omecamtiv mecarbil were mixed.
Nina Zeldes, PhD, Public Citizen’s Health Research Group strongly opposed FDA approval of omecamtiv mecarbil, noting that the minimal benefits demonstrated in the GALACTIC-HF trial did not outweigh the significant risks and the evidence of omecamtiv mecarbil’s benefit was not accompanied by confirmatory evidence.
They added the efficacy and safety of this drug are based on only one trial without adequate, reliable confirmatory evidence. The limitations of the post-hoc analysis make it impossible to evaluate the potential benefit of omecamtiv mecarbil for patients whose LVEF at baseline was lower than 28% and the increased risk seen in AFF patients, particularly in those treated with digoxin. Zeldes urged the committee to vote no on the voting question and strongly recommended the FDA did not approve omecamtiv mecarbil.
“We agree with the FDA that ‘given the limitations inherent in post hoc analyses, one cannot be certain about differential risk in patient subgroups, thus impacting regulatory decision-making,’” Zeldes said.
Others, including Gregory Lewis, MD, Section Head of Heart Failure, Massachusetts General Hospital, indicated that omecamtiv mecarbil works well in patients with severe forms of heart failure. He described two patients of his who underwent treatment in a clinical trial with LVEF below 20%.
For the patients, the medication had a dramatic beneficial effect and they experienced marketed improvement in their cardiac function. Since learning they were on active study medication, his patients continue to ask if they will be able to resume taking their medication, serving as the reason Lewis chose to join the advisory committee meeting discussion.
Jacob Abraham, MD, Division Chief of Advanced Heart Failure, Providence Heart Institute, urged the committee to approve the therapy for the vulnerable population with heart failure, suggesting its benefit observed in GALACTIC-HF could ultimately have an important effect on these patients.
12:30PM: The FDA presented a review on the efficacy and safety of omecamtiv mecarbil. They aimed to discuss the benefits of the therapy and if there is adequate evidence for these benefits. They additionally questioned the label, if approved, and what it would say about use as a function of LVEF and use in patients with atrial fibrillation and flutter (AFF), as well as its overall safety.
The FDA noted that using baseline LVEF to determine the subjects who may benefit has limitations of the pos-hoc model used to describe the relationship. The vagueness of “benefits are increasing evidence the lower the LVEF” is not clearly actionable for health care providers. It additionally does not account for uncertainty in the LVEF measurement.
Over the course of its development, the FDA expressed concern about cardiovascular safety in association with dosing of omecamtiv mecarbil. Prior to submission of the NDA, Cytokinetics, Inc. informed that the immunoassay used in the GALACTIC-HF study for PK-guided dose titration would not be commercialized. They then submitted the NDA proposing scheduled, forced dose titration without the need for PK guidance.
A subgroup analysis indicated an increased risk of CV death in patients with AFF compared to placebo. There is an unclear mechanism, but the analysis noted patients with AFF could be more susceptible to potential cardiotoxicity related to omecamtiv mecarbil. Some subsets of AFF patients, including those with digoxin use and LVEF ≥28%, had worse results for CV death. it is unclear whether AFF patients at risk could be prospectively identified.
The FDA noted the principal safety concern of omecamtiv mecarbil is the potential risk of dose-limiting cardiotoxicity in the context of a narrow therapeutic window. The company identified the risk of myocardial ischemia due to excessive exposure in early studies and proposed a safety threshold of 1,000 ng/mL.
The FDA has a concern that exposure to omecamtiv mecarbil increases the risk of myocardial ischemia and heart failure. There was a positive exposure-response relationship for serious adverse events, primarily driven by cardiac failure serious adverse events.
They added that the optimal therapeutic range was not well-established, as the proposed therapeutic range of 300-750 ng/mL was considered wide and not supported by the available data from GALACTIC-HF.
“The potential risk of OM-associated cardiotoxicity is likely to increase without a mandatory requirement of measuring plasma concentration for the purpose of dose adjustment in the real-world setting,” the FDA said.
Ultimately, they added it is not certain whether the benefit of the therapy outweighs the risk. The small, not statistically persuasive, treatment effect from the single pivotal trial may not be adequate to establish effectiveness. Risk may vary depending on how well a PK-guided dosing strategy is followed and the benefit-risk assessment was complicated by varying results in particular subgroups.
10:30AM: The GALACTIC-HF trial enrolled over 8,000 patients around the world and was the second largest heart trial ever conducted.
The primary composite endpoint was reduced by 8% with a P-value of 0.025 and absolute risk reduction of 2.1 per 100 patient-years. The primary outcome was driven by the reduction in first heart failure events, but the trial did not meet a secondary endpoint looking at cardiovascular death. Those with lower ejection fraction had a significantly larger treatment benefit in this trial, over double that of the overall population.
The agent improved cardiac function with positive effects on cardiac structure and biomarkers predictive of a therapeutic benefit. The phase 3 trial was reported to achieve a statistically significant effect on the pre-specified primary outcome robust to sensitivity analysis.
The company noted the driver of greater clinical benefit, or LVEF, is biologically plausible due to the mechanism of action of omecamtiv mecarbil. With the phase 3 GALACTIC-HF trial and confirmatory evidence from COSMIC-HF, they have persuasive substantial evidence of its effectiveness.
The company noted the treatment should focus on patients who stand the benefit the most and the label should provide physicians with clear guidance on how to identify those patients. Particular focus would be on patients in the lower ejection fraction subgroup, proposed in the initial submission in November 2021. This proposed approach would treat the patient population where the greatest effectiveness was demonstrated.
The incidence of adverse events of interest was reported to be similar in both the omecamtiv mecarbil and placebo groups. The safety profile was similar in higher risk patients with LVEF ≤28%.
There were no adverse effects from omecamtiv mecarbil on blood pressure, heart rate, renal function, or potassium hemostasis. An increased rate of heart failure outcomes was observed in patients with atrial fibrillation and higher LVEF, which the company noted may be related to digoxin use.
The heart failure drug is specifically designed to target the primary pathophysiologic abnormality in heart failure with reduced ejection fraction, which is myocardial contractile dysfunction.
The company noted the characteristics of the agent allow its use where current standards of care may be challenging. Overall, they said the benefits outweigh the risks and make it a “compelling addition to therapies we have available to treat our neediest patients with HFrEF.”
9:30AM: Today, the US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee (CRDAC) will meet to discuss the new drug application (NDA) for omecamtiv mecarbil from Cytokinetics, Inc.
The proposed indication for omecamtiv mecarbil tablets aims to reduce the risk of cardiovascular death and heart failure events in patients with symptomatic chronic heart failure with reduced ejection fraction (HFrEF).
The committee will discuss the findings from the phase 3 GALACTIC-HF trial on whether the trial establishes substantial evidence of effectiveness of omecamtiv mecarbil and whether the benefit of the agent outweighs the risks when used according to the proposed dosing regimen.
Cytokinetics, Inc. reported the cardiac myosin inhibitor showed increased benefit the lower the left ventricular ejection fraction (LVEF) in the trial. This included a positive effect of omecamtiv mecarbil on the primary composite endpoint of cardiovascular death or worsening heart failure events, with a greater benefit observed in patients with increased risk. Safety data suggest no imbalances in adverse events and the safety profile was similar to that of the placebo group.
Based on GALACTIC-HF and COSMIC-HF, the company is looking to provide substantial evidence of effectiveness based on one clinical trial and confirmatory evidence. The FDA criteria requires an adequate and well-controlled clinical trial supported by data that provide strong mechanistic support.
Follow along for real-time updates.
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