The panel could not reach consensus on what an expanded label might look like in an area where there are no approved therapies.
This story has been updated.
An FDA panel agreed Tuesday that Novartis’ heart failure drug, Entresto (sacubitril/valsartan), should be given to more patients, but just who those patients will be is up to regulators.
Entresto, which is approved for patients with heart failure with reduced ejection fraction (HFrEF), could become the first drug approved to treat heart failure with preserved ejection fraction (HFpEF), even though a trial designed to prove efficacy for this group of patients narrowly missed the mark last year. Novartis plowed ahead nonetheless, based on evidence within subgroups in the trial and data from other studies.
By a 12-1 vote, the FDA’s Cardiovascular and Renal Drugs Advisory Committee found that Entresto was worthy of some indication based on the PARAGON-HF trial, which studied patients with left ventricular ejection fraction (LVEF) of ≥45%. But during a lengthy discussion of what that indication might be, or what other evidence might be needed, opinion varied.
If there was a consensus, it was that HFpEF is something of a misnomer and that LVEF above 40% but below 57% may constitute its own range. “Mildly reduced” was offered as a description, but others deemed this too vague for primary care doctors who rely on precise guidance to treat patients with heart failure. And some thought the range for a new indication should stop at an LVEF of 55%.
Panelists discussed whether ejection fraction, which describes how much blood the left ventricle pumps with each contraction, is an inadequate measure of heart failure or whether the FDA should look instead to standards outlined by the American Society of Echocardiography. Panelist Steven Nissen, MD, of Cleveland Clinic, discussed a label that would include reducing heart failure hospitalization.
The panel’s consumer representative, Cynthia Chauhan, MSW, said a new trial is needed that would have greater representation of minorities and patients with “significant comorbidities, including renal failure and pulmonary hypertension,” that are commonly seen in patients with heart failure.
"We recognize the importance of representing a diverse patient population in clinical studies, including Black patients, a population that has been shown to be at higher risk of heart failure and are often affected at an earlier age," said David Soergel, Global Head of Cardiovascular, Renal and Metabolic Drug Development at Novartis, in an email to The American Journal of Managed Care.
He cited the PIONEER-HF trial, in which 36% of patients self-identifed as Black, to show that the number of Black patients in Entresto trials has risen since the PARADIGM-HF study. Slightly more than half of the participants in PARAGON-HF (52%) were women, although Chauhan said the share of women with HFpEF is even higher.
A Combination of Trial Results
Entresto was first approved by the FDA under its priority review program on July 8, 2015, for patients with New York Heart Association class II through IV heart failure, to reduce the risk of both cardiovascular death and hospitalization. Subsequent approved indications include for patients with HFrEF and those 1 year or older with symptomatic heart failure with systemic left ventricular systolic dysfunction.
An important issue the committee considered was that the phase 3, randomized, double-blind, double-dummy, active controlled PARAGON-HF trial results did not reach statistical significance for reducing morbidity and mortality among individuals with HFpEF, when comparing sacubitril/valsartan to valsartan alone. The primary efficacy endpoint for the trial was a reduction in hospitalizations for heart failure and cardiovascular death.
Results from PARAGON-HF submitted to support Novartis’ supplemental new drug application (sNDA) demonstrated a rate ratio (RR) of 0.87 (95% CI, 0.75-1.01; 1-sided P = .029; 2-sided P = .06). The prespecified threshold for 1-sided P had been P < .024 in order for the null hypothesis to be rejected. So, Novartis just missed its primary end point. Additionally, Novartis’ overall sNDA package included data from the PARADIGM-HF trial, hoping to establish “totality of evidence” for the approval among patients with LVEFs that “overlap HFrEF and the lower end of HFpEF.”
Other results shed more light on the combination medication’s effectiveness for patients with HFpEF. For instance, sacubitril/valsartan was shown to have a nominally significant benefit over valsartan (RR, 0.84; 95% CI, 0.75-0.99; 2-sided P = .04) in a prespecified exploratory analysis, while post-hoc exploratory analyses produced RRs of 0.84 (95% CI, 0.74-0.97; 2-sided P = .01) and 0.83 (95% CI, 0.73-0.95; 2-sided P = .006) when investigator-reported primary efficacy endpoints in lieu of adjudicated events and data on the use of investigator-reported primary efficacy and urgent heart failure visits were substituted.
Data Novartis released last year showed Entresto was most effective in patients with LVEF < 57% and women. The FDA staff memo noted those differences:
“Although there are underlying differences in the pathophysiology and epidemiology of patients with HFrEF and HFpEF, the LVEF boundaries separating the 2 patient populations is ill-defined,” the memo said. “It is conceivable that there is some overlap in pathophysiology between patients with LVEF < 40% and LVEF 45% evaluated in PARADIGM and PARAGON-HF, respectively. In PARAGON-HF, the relationship of RR with LVEF as a continuous variable indicates that the patients in the lower LVEF range benefit the most with sacubitril/valsartan.”
Soergel said Novartis is also studying Entresto in the phase 3 PARAGLIDE-HF trial. This trial is examining treatment of HFpEF in patients with acute decompensated heart failure after stabilization during hospitalization; the drug is started during the hospital stay or within 30 days after discharge. This is important for managed care, given the rise of reimbursement incentives that are tied to 30-day readmission rates for heart failure hospitalization.
"We expect initial data from this trial first quarter of 2022," he said.
Near the end of the hearing, Norman Stockbridge, MD, PhD, director of the Office of Cardiology, Hematology, Endocrinology and Nephrology at the FDA, noted that in trying to define the parameters of a potential label, “Almost everybody avoided using the word preserved. And I think that's exactly right.”
“We will eventually work out what a reasonable way of describing the heart failure spectrum,” he said. “Preserved and reduced probably is not a very useful description.”
FDA. FDA briefing document: Cardiovascular and Renal Drugs Advisory Committee Meeting, December 15, 2020: NDA 207620: sacubitril/valsartan. Accessed December 14, 2020. https://www.fda.gov/media/144377/download