Novartis’ Entresto Labeling Expansion Bid Heads To US FDA Panel
Executive Summary
Cardiovascular and Renal Drugs Advisory Committee will consider whether exploratory analyses from the PARAGON-HF trial, which narrowly missed its primary endpoint, plus demonstrated efficacy in an adjacent indication, support a new claim for heart failure patients with preserved ejection fraction.
The US Food and Drug Administration is asking its external experts whether Novartis AG’s Entresto (sacubitril/valsartan) should add an indication for use in heart failure patients with preserved ejection fraction (HFpEF) despite narrowly missing the primary efficacy endpoint in the pivotal trial.
In briefing documents released ahead of a 15 December meeting of the Cardiovascular and Renal Drugs Advisory Committee, the agency suggested the overall results from the PARAGON-HF trial, including various prespecified and post hoc exploratory analysis, potentially could support a claim to reduce the worsening of heart failure in a subpopulation of HFpEF patients.
The benefits seen in PARAGON-HF appeared to be driven mostly by subjects with left ventricular ejection fraction (LVEF) toward the lower end of the range studied, meaning they are closer in range to those of heart failure patients with reduced ejection fraction, the FDA said.
Advisory Committee Voting Question
- Does PARAGON-HF, perhaps supported by previous studies, provide sufficient evidence to support ANY indication?
Entresto already is approved for HFrEF. However, there are no drugs approved in the US for HFpEF, a serious condition with significant unmet need.
“The prevalence of HF with LVEF ≥ 45% is increasing in the US, with increasing life expectancy, and epidemics of metabolic syndrome and [diabetes mellitus],” the agency’s briefing document states, adding that these patients experience significant morbidity associated with recurrent hospitalization for heart failure with no approved treatment.
“The overall benefit-risk considerations may support approval of sacubitril/valsartan to treat patients with HF with LVEF ≥45%.”
In addition to the lone voting question (see box), the agency seeks advisory committee input on whether the various prespecified and post hoc analyses do or do not contribute to the strength of evidence supporting an indication.
If Entresto warrants a new indication, the FDA asks the committee how to describe the patients in whom such benefit applies. If a new indication is not granted on the basis of the available data, the agency seeks input on what additional information data would be needed.
LVEF-Based Classification
Entresto is approved to reduce the risk of cardiovascular death and hospitalization in HFrEF, a claim that was based on the results from the 8,442-patient PARADIGM-HF study. (Also see "Entresto Label: Strong Efficacy, Complex Dosing" - Pink Sheet, 13 Jul, 2015.) The fixed-dose combination also is approved for treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients.
On 21 April, Novartis submitted an efficacy supplement seeking approval to reduce worsening heart failure (total heart failure hospitalizations and urgent heart failure visits) in patients with chronic HFpEF. (Also see "Keeping Track: Submissions From Sanofi, Merck, Novartis; Breakthrough Designations For GSK And Takeda" - Pink Sheet, 4 May, 2020.) In September, the sponsor revised the proposed indication, limiting the target population to HFpEF patients “with LVEF below normal.”
Heart failure is a complex clinical syndrome resulting from structural or functional impairment of ventricular filling or ejection of blood. The 2013 American College of Cardiology Foundation/American Heart Association guidelines classified heart failure based on LVEF as follows:
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HFrEF – LVEF <40%
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HFpEF – LVEF >50%
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HFpEF borderline – LEVF = 41%-49%
The American Society of Echocardiography defines a "normal" LVEF range for men of 52%-72% and women 54%-74%.
Approximately half of all heart failure cases are attributed to HFpEF. Compared to HFrEF, patients with HFpEF tend to be older, have a higher prevalence of hypertension and obesity, and a lower prevalence of ischemic heart disease, the FDA’s briefing document states.
A Near-Miss On The Primary Endpoint
Novartis’ supplemental application, which has a February user fee goal date, is based on results from PARAGON-HF, a Phase III, randomized trial comparing Entresto to valsartan in 4,822 patients with symptomatic NYHA class II-IV heart failure with LVEF >45%.
The primary efficacy endpoint was an adjudicated composite of total hospitalization for heart failure (HHF) (first hospitalization plus recurrent hospitalization) and CV death. The trial narrowly missed reaching statistical significance on the primary endpoint, with a rate ratio of 0.87 and a p-value of 0.06. (Also see "PARAGON-HF: Novartis Hangs Onto Hope For Entresto In HFpEF" - Scrip, 8 Sep, 2019.)
There were 894 (12.8 per 100 patient-years) primary composite events in the Entresto arm compared to 1,009 events (14.6 per 100 patient-years) in the valsartan arm, for a difference of 115 events. Entresto’s effect on the primary endpoint was driven primarily by the total HHF component; there was no difference between treatment arms with regard to CV death risk.
A prespecified exploratory analysis that combined the primary efficacy endpoint with urgent HF visits yielded a nominally significant result favoring Entresto, the FDA said. The briefing document also includes results from two post hoc exploratory analyses that used investigator-reported primary efficacy endpoints and are supportive of a benefit with Entresto.
Story continues after table.…
|
Type of Analysis |
Endpoints |
Results |
|
Primary efficacy analysis |
Adjudicated composite of HHF and CV death |
Rate ratio (RR) = 0.87; 95% CI 0.75, 1.01; 1-sided p = 0.029; 2-sided p = 0.06 |
|
Prespecified exploratory analysis |
Primary efficacy endpoint + urgent HF visits |
RR = 0.86; 95% CI 0.75, 0.99; 2-sided p = 0.04 |
|
Post hoc exploratory analysis |
Investigator-reported primary efficacy endpoint events in lieu of adjudicated events |
RR = 0.84; 95% CI 0.74, 0.97; 2-sided p = 0.01 |
|
Post hoc exploratory analysis |
Investigator-reported primary efficacy endpoint events + urgent HF visits |
RR = 0.83; 95% CI 0.73, 0.95; 2-sided p = 0.006 |
|
Source: FDA advisory committee briefing document |
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Although the primary efficacy endpoint failed to meet statistical significance, the observed rate ratios were generally consistent across the primary efficacy analyses and the various prespecified exploratory and post hoc analyses, ranging from 0.87 to 0.83, the agency said.
“The study failed to reject the null hypothesis for the prospectively planned primary efficacy endpoint; however, reasonable exploratory analyses, planned and unplanned, were able to reject the null hypothesis,” the FDA said.
“Failure to reject a null hypothesis should not be interpreted as evidence that sacubitril/valsartan does not have any effect,” the briefing document states in a discussion of the statistical results.
“Rather, we interpret this as the study itself does not provide the level of evidence for a treatment effect that was laid out in the protocol using the prespecified primary endpoint and analysis population. Weaker than anticipated evidence against the null hypothesis should be considered in context with the rest of the study results.”
Subgroups That Derived Benefit
Subgroup analyses suggest that Entresto has a greater treatment effect in females and in patients with LVEF at the lower end of the spectrum for HFpEF, such as <57%, where there may be some overlap with patients in the HFrEF category, the agency said.
“The sub-subgroup of females with LVEF below the median seem to be achieving the most benefit from the study treatment,” the FDA said. “Conversely, it is questionable whether males in any sub-subgroup of this study population are gaining benefit from treatment.”
The FDA briefing document does not discuss safety except to say that Entresto’s safety profile in heart failure patients with LVEF <40% is well known, and no new safety signals were identified in HF patients with LVEF >45%.
In its briefing document, Novartis said the effectiveness of Entresto in the proposed HFpEF indication is supported by the totality of evidence. This includes the PARAGON-HF study results, “the established efficacy in the closely related adjacent HFrEF population” from the PARADIGM-HF trial, and “strong mechanistic support provided by biomarker and cardiac remodeling data” from the Phase II PARAMOUNT trial in HFpEF.