Heart failure – LCZ696

Novartis is developing a treatment that may help to relieve preserved ejection fraction heart failure

Neprilysin inhibitor AHU-377

Around half the 20 million people in Europe and the US diagnosed with heart failure die within five years, suffering with acute episodes as well as fatigue, shortness of breath and swollen limbs. Chronic heart failure with preserved ejection fraction (PEF), where the percentage of blood pumped out of the heart is normal but the heart does not relax sufficiently to pump effectively, results in changes in the heart’s structure that progressively weaken it. No drug treatments are available to reduce morbidity and mortality.

A treatment that may help is being developed by Novartis. LCZ696 is a dual acting inhibitor that works on angiotensin II and neprilysin.1 It is a 1:1 mixture of the marketed antihypertensive valsartan and the neprilysin inhibitor AHU-377 (pictured). Valsartan blocks the angiotensin II receptor type 1, causing vasodilation and increases the excretion of sodium and water, leading to a reduction in blood volume. AHU-377 is a prodrug that is activated by enzyme activity in the body and inhibits the enzyme neprilysin. This degrades atrial and brain natriuretic peptide, both of which reduce blood volume.

Several clinical trials have been carried out, including a double blind Phase II trial in patients with mild to moderate hypertension.2 Subjects were given doses of between 100 and 400mg of the combination drug, between 80 and 320mg of valsartan, 200mg of the neprilysin inhibitor, or placebo. Significantly greater reductions were seen with the combination than with valsartan alone, and it was well tolerated, with no reports of angioedema.

In another double blind, randomised controlled trial, 301 patients suffering from heart failure with PEF were given 50mg of LCZ696 twice a day, or 40mg valsartan alone twice daily, for 12 weeks.3 The new drug reduced N-terminal pro-B-type natriuretic peptide, a marker of stress on the heart and predictor of patient outcomes, by 23% more than valsartan alone, as well as a greater reduction in let atrial size after 36 weeks. It was well tolerated, with a side-effect profile similar to that seen with valsartan alone. Phase III trials are also now under way in patients with heart failure with reduced ejection fraction, the other common type of heart failure.

References

1. J. Gu et al. J. Clin. Pharmacol. 2009, 50, 401

2. L.M. Ruilope et al. Lancet 2010, 375, 1255

3. S.D. Solomon et al. Lancet 2012, epub ahead of print Aug 2012

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