Betting big on hearts

How Novartis built clinical case to replace generics in heart failure

Though saturation by cheap generics and a high-profile failure of another compound led some companies to exit the heart failure space, results from the PARADIGM-HF trial suggest Novartis AG made the right call by doubling down in its Phase III program for LCZ696. The key was the pharma's decision to design a robust trial that would show outcomes relevant to multiple stakeholders, with the goal of thoroughly supplanting angiotensin-converting enzyme inhibitors in the indication.

The study design is a model for how companies can provide robust data - even against generics - in the brave new world in which regulators, payers, physicians and patients all have different data requirements.

An early sign of success came in March, when Novartis announced that a DMC recommended stopping PARADIGM-HF early because LCZ696 had already beaten enalapril, a generic angiotensin-converting enzyme (ACE) inhibitor, on the composite primary endpoint of delaying the time to first occurrence of cardiovascular death or heart failure hospitalization.

At the European Society of Cardiology meeting on Aug. 30, Novartis revealed the magnitude of the victory: a hazard ratio of 0.8 favoring LCZ696.

Crucial to the pharma's plans were secondary outcomes meant to persuade physicians, patients and payers to switch to a new therapy. In each case, LCZ696 trumped enalapril.

"This was head to head vs. enalapril studied at an evidence-based dose. So the hurdle for benefit was high," said Ameet Nathwani, Novartis' global business franchise head of critical care.

Four doctors who spoke to BioCentury agreed the endpoints were clinically meaningful, and saw no red flags in the data that would preclude approval. Barring unforeseen issues from an in-depth regulatory review, they expected LCZ696 would replace ACE inhibitors widely, so long as its price was not prohibitive.

"It's an extremely important finding. Since 1991, nothing has proven better than ACE inhibitors," said

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