Although there are already numerous drugs on the market for hypertension and heart failure, there remains a real need for better treatment options. Novartis is developing a combination therapy, LCZ-696, which combines the existing angiotensin II blocker valsartan, an antihypertensive, with a new agent, the neprilysin inhibitor AHU-377, in a 1:1 mixture.1 This stops natriuretic peptides that are released from the heart when it is under stress from being catabolised. These peptides reduce congestive symptoms by reducing vasodilation, natriuresis and diuresis, but they are very short lived. Preventing their breakdown should enable them to last longer within the bloodstream, and extend their beneficial effect.
It is being investigated as a treatment for both hypertension and heart failure. In a randomised, double blind, placebo-controlled, active comparator Phase II trial in 1328 patients with mild to moderate hypertension, subjects were given 100, 200 or 400mg LCZ-696, 80, 160 or 320mg valsartan, 200mg AHU-377 or placebo for eight weeks.2 A total of 1215 patients completed the study, and those given the new combination drug experienced a significantly greater average reduction in mean sitting diastolic blood pressure, particularly for the higher dose pairs. It was well tolerated, and no cases of angio-oedema were reported. None of the three reported serious adverse events were adjudged to be drug-related.
In heart failure, a Phase I trial in 30 patients with heart failure has been reported.3 They were given 100mg LCZ-696 twice a day for two weeks on top of their normal drug regimen, but after a short wash-out period having stopped taking ACE inhibitors.
Other drugs taken included β-blockers, statins, aspirin, calcium channel blockers, nitrites, diuretics and aldosterone antagonists. All bar three completed the study; these discontinued as a result of elevated potassium levels. Otherwise, the drug was well tolerated, with no serious adverse events reported. A Phase III trial in heart failure comparing LCZ-696 with enalapril is under way, and the company projects that it may be filed for approval in 2014, if all goes well.
1. J. Gu et al. J. Clin. Pharmacol. 2010, 50, 401
2. L.M. Ruilope et al. Lancet 2010, 375, 1255
3. Z. Kobalava et al. Circulation 2010, 122 (21, Suppl.) Abst 19378