Phase 2 Study of LCZ696 for Heart Failure with Preserved Ejection Fraction

Novartis announced results from the Phase 2 PARAMOUNT study showing that the investigational compound LCZ696 significantly reduced a key predictor of morbidity and mortality in patients with a heart failure with preserved ejection fraction (HF-PEF).

PARAMOUNT was an international 36-week, randomized, double-blind, multicenter, parallel group, active-controlled study that compared the efficacy, safety, and tolerability profile of LCZ696 with valsartan (DiovanNovartis) in patients with HF-PEF. The study consisted of a 12-week core study and a 24-week extension phase. 

The study included 301 patients (mean age 71 years) with HF-PEF (left ventricular ejection fraction >45%). They all had elevated NT-proBNP (N-terminal pro-B-type natriuretic peptide; a marker of stress on the heart and a predictor of patient outcomes) (>400pg/mL) and at least one of the following symptoms of HF-PEF: shortness of breath on exertion, shortness of breath when lying flat, episodes of shortness of breath at night, and swollen ankles. After stopping any treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB), they were randomized to LCZ696 (50mg twice daily) or valsartan 40 mg twice daily. Doses of both drugs were doubled after one week and doubled again after a further week to a maximum dose of 200mg and 160mg twice daily, respectively.

The PARAMOUNT study showed that after 12 weeks of treatment, reduction in NT-proBNP was 23% greater with LCZ696 than valsartan (P=0.005). In addition, there was a greater reduction (P=0.003) in left atrial size (cardiac remodeling) in LCZ696-treated patients at the end of the 36 week study. This suggests that LCZ696 could provide an effective treatment for patients with HF-PEF. The study also showed that LCZ696 had an acceptable safety profile and was well tolerated in patients with HF-PEF.

LCZ696 is the first in a new class of medicines called angiotensin receptor neprilysin inhibitors (ARNIs). It works by inhibiting an enzyme (neprilysin, or NEP) in order to promote the body's protective mechanisms, and blocking receptors involved in the narrowing of blood vessels (angiotensin receptors).

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