LAS VEGAS – Having scored a spectacular success with its investigational agent LCZ696 for the treatment of heart failure with reduced ejection fraction in the landmark PARADIGM-HF trial, Novartis has placed a large bet that it can do the same in patients with heart failure with preserved ejection fraction in the ongoing PARAGON trial.
The phase III study, which began this summer, will enroll roughly 4,300 patients with symptomatic heart failure with preserved ejection fraction (HFpEF) in 37 countries. They are being randomized to the novel, first-in-class angiotensin receptor neprilysin inhibitor (ARNI) known for now as LCZ696 at 200 mg b.i.d. or valsartan at 160 mg b.i.d., PARAGON principal investigator Dr. Scott D. Solomon explained at the annual meeting of the Heart Failure Society of America.
The study is a bit of a gamble because, to date, there is no effective treatment for HFpEF, which accounts for at least half of all cases of heart failure. Four prior major clinical trials testing various candidate therapies have all gone down in flames, failing to achieve their primary endpoints, but there are multiple reasons to believe PARAGON will be different, according to Dr. Solomon, professor of medicine at Harvard Medical School, Boston.
For one thing, previous major trials enrolled some participants without clear evidence that they even had HFpEF. Not so in PARAGON, which requires subjects to have symptomatic heart failure, an ejection fraction of 45% or more, and evidence of structural heart disease along with either a hospitalization for heart failure within the previous 9 months or elevated natriuretic peptides.
Also, unlike the prior disappointing studies involving other agents, PARAGON is supported by positive findings in a phase II proof-of-concept study. In the phase II, double-blind PARAMOUNT trial, also led by Dr. Solomon, 301 patients with HFpEF were randomized to LCZ696 or valsartan for 36 weeks. The primary study endpoint was change in N-terminal of the prohormone brain natriuretic hormone (NT-proBNP), a biomarker of left ventricular wall stress, through 12 weeks. The result was positive, with a 23% greater reduction in elevated baseline levels in the LCZ696 group, compared with those on valsartan (Lancet 2012;380:1387-95).
By 36 weeks, the ARNI-treated patients also showed a significant reduction in left atrial volume as well as improvement in New York Heart Association functional class, the cardiologist added.
PARAGON features a novel primary endpoint: a composite of cardiovascular death and total hospitalizations for heart failure, rather than time to the first hospitalization, as used in previous trials. “Total hospitalizations for heart failure better captures the full burden of the disease,” Dr. Solomon explained.
Results of PARAGON are expected in 2019.
Dr. Solomon has received research grants and honoraria from Novartis, which is funding the PARAGON trial.