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As two drugs that technically failed in clinical trials for heart failure with preserved ejection fraction (HFpEF) head into an FDA advisory panel gauntlet, reviews by agency staff give some reason for optimism.

Sacubitril/valsartan (Entresto), which gets an by the Cardiovascular and Renal Drugs Advisory Committee on Tuesday, missed its primary endpoint in the PARAGON-HF trial. It failed to reduce HF hospitalization and death from cardiovascular causes versus valsartan alone in those with a left ventricular EF of 45% or higher (RR 0.87, P=0.06).

Spironolactone (Aldactone), headed for a on Wednesday, likewise failed the primary endpoint in the . It didn't reduce death from cardiovascular causes, aborted cardiac arrest, or HF hospitalization in those with an EF of 45% or more compared with placebo (HR 0.89, P=0.14).

"Approval under this circumstance is unusual but not unprecedented," the preface to the voting documents for both drugs noted.

While "the extenuating circumstances were different," the documents pointed to examples of approval of other drugs that didn't make the primary endpoint in their pivotal trials, such as enalapril on the basis of 's secondary endpoint benefits and bivalirudin (Angiomax) on the basis of .

Sacubitril/Valsartan

PARAGON-HF really only missed its target by a little, , pointing out that it "encouraged the applicant," Novartis, to try for an HFpEF indication and even suggested some of the post-hoc analyses.

For one thing, requiring events in the primary endpoint to be adjudicated cost some events that would have tipped the P-value under the 0.05 threshold but didn't materially change the risk ratios. Also, the "yes/no" determination of events also wasted some data, the FDA reviewers pointed out. The negative adjudication of 562 events was often due to a lack of information or alternative practices that lessen, but don't eliminate, the degree of confidence that they were real events.

"We favor giving 'partial credit' to events based on the level of evidence provided, rather than a dichotomous 'yes' or 'no,'" the reviewers suggested.

The briefing documents suggested the possibility of further parsing the HFpEF group, since PARAGON-HF participants closer to the range for patients with heart failure with reduced ejection fraction (HFrEF, which is already an approved indication for sacubitril/valsartan) had better results. In the group with an EF of 57% or less, the primary endpoint was statistically significant (RR 0.78, 95% CI 0.64-0.95). "Retrospectively, that still seems relevant," the FDA reviewers wrote.

The advisory panelists will vote on whether PARAGON-HF, with other studies, is enough to support any indication.

Spironolactone

TOPCAT's failure appeared to be in part due to poor results with spironolactone among the 49% of participants from sites in Eastern Europe, whereas it bested placebo by a relative 18% for the primary endpoint in the remaining participants from North and South America.

Excluding a large region from the data considered for a drug indication would be unprecedented, noted the . However, "the review team devoted a considerable effort to look for criteria for the inclusion or exclusion of sites based on baseline data; none seem as compelling as 'region.'"

The Eastern European participants differed in characteristics -- being younger, more often with a history of coronary disease or aspirin treatment, and less often entering the trial on the basis of elevated natriuretic peptide levels -- they had substantially lower than expected event rates in the placebo group, and there were strong signals of poor drug adherence versus participants in the Americas.

On the other hand, the interaction between region and treatment effect wasn't even close to significant. Also, patients who qualified for the trial by prior HF hospitalization showed no treatment effect in either region, which undermines the explanation that different populations between two regions led to different outcomes.

"If one were to conclude that the Americas results were an appropriate basis for a regulatory decision, approval based on a single study is supported by the reduction in death and HF hospitalization, either subjects with any HF hospitalization (part of the primary composite) or cumulative events," the FDA reviewers wrote.

The panel will be asked to vote on whether TOPCAT can support any indication.

Notably, the FDA couldn't find any company willing to apply for such an indication in HFpEF -- TOPCAT was sponsored by the National Institutes of Health, not by a drug company, and spironolactone is available from multiple manufacturers in generic form. So the agency took the initiative to consider the HFpEF indication anyway, "to respond to an important, unmet medical need for treatments to improve clinical outcomes in patients with HFpEF, a serious and sometimes fatal condition for which there are presently no treatments approved to affect the course of the disease."

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