Trial of Novel Heart Failure Drug Terminated Early Based on ‘Compelling Efficacy'

Citing interim results that met parameters for efficacy in reducing cardiovascular mortality, an independent group of experts has put an early stop to a late-stage study on Novartis's novel oral medication for chronic heart failure.

Citing interim results that met parameters for efficacy in reducing cardiovascular (CV) mortality, an independent group of experts has put an early stop to a late-stage study on Novartis’s novel oral medication for chronic heart failure (CHF).

In what Novartis termed the “largest clinical trial in heart failure (HF) ever undertaken,” a team of investigators compared the efficacy and safety profile of the first-in-class angiotensin receptor neprilysin inhibitor (ARNI) known as LCZ696 to enalapril, a widely used angiotensin-converting-enzyme (ACE) inhibitor, in 8,436 patients with heart failure with reduced ejection fraction (HF-REF).

According to the independent Data Monitoring Committee (DMC) of the randomized, double-blind, PARADIGM-HF study, patients who received the twice-daily ARNI pill “lived longer without being hospitalized for HF than those who received standard care with the ACE-inhibitor” in an interim analysis. In other words, the phase 3 trial, which was “robustly designed to be able to detect a significant difference in CV death” between the 2 drugs, prematurely met its combined primary endpoint of “time to first occurrence of either CV death or HF hospitalization.”

“Based on the compelling efficacy and primary endpoint having been met, the trial will now close early,” Novartis announced, noting the early termination “follows 2 previous interim analyses that showed the safety profile of LCZ696 was acceptable.”

In a press release, co-principal study investigator Milton Packer, MD, professor and chair for the Department of Clinical Sciences at the University of Texas Southwestern Medical Center, called the trial results “truly impressive.”

“The finding that treatment with LCZ696 was superior to currently recommended doses of enalapril has profound implications for the care of patients with CHF,” Packer said. “We now have compelling evidence that supports LCZ696 as a new cornerstone in the management of CHF.”

Marc Alan Pfeffer, MD, PhD, of the Cardiovascular Division at Brigham and Women’s Hospital, told Forbes that he interprets the “stopping of a major clinical outcome trial for effectiveness by an experienced (Data and Safety Monitoring Board) as indicating that the final results will be both definitive and important.”

“Potentially, this is of incredible importance and could really be the breakthrough moment we’ve been seeking for some time,” Clyde Yancy, chief of the Division of Medicine-Cardiology at Northwestern University’s Feinberg School of Medicine, told Forbes. “There has been an ongoing question of whether or not we could ever challenge the primacy of ACE inhibitor therapy in HF. As good as ACE inhibitors have been in HF, perhaps there is something that is better, and better is what we need.”

Novartis Global Head of Development Tim Wright echoed that need in the press release, as he noted the PARADIGM-HF trial’s result demonstrates the company’s “commitment to developing innovative medicines that have an impact on the most important outcomes like CV mortality.”

According to Novartis, LCZ696 “acts in multiple ways on the neurohormonal systems of the heart, blocking receptors exerting harmful effects while simultaneously promoting protective mechanisms.” The novel therapy is also “thought reduce the strain on the failing heart, promoting the ability of the heart muscle to recover.”