Dual-Acting Investigational Drug Shows Promise


The experimental drug LCZ696, which inhibits both the angiotensin II receptor and neprilysin, has been shown to reduce blood pressure more effectively than the established angiotensin receptor blocker valsartan—and without apparent risk of angioedema, in a phase II trial.

LCZ696 is a single molecule, developed by Novartis, that contains properties of both valsartan (Novartis, Diovan) and AHU377, an experimental neprilysin inhibitor also developed by Novartis. In a randomized, double-blind, phase II trial sponsored the manufacturer, all three agents were compared for efficacy, and the dual-acting molecule did better than either comparator (Lancet 2010 March 16 [DOI:10.1016/S0140-6736(09)61966-8]).

“There is synergistic effect when the two are put together,” Dr. Luis Miguel Ruilope of the Hospital 12 de Octubre in Madrid, the lead investigator of the study, said in an interview.

Dr. Ruilope and colleagues enrolled 1,328 patients, with a mean age 53, all with mild to moderate essential hypertension (mean sitting diastolic blood pressure of 90-109 mm Hg after antihypertensive washout, or 95-109 mm Hg for untreated patients).

Enrollees were divided into eight paired groups of between 156 and 173 patients each. Six of the groups were randomized to receive oral LCZ696 100 mg, 200 mg, 200 mg daily switched after 5 weeks to 400 mg daily, or a comparable-strength regimen of valsartan (80 mg, 160 mg, or 320 mg daily). A seventh group received 200 mg of AHU377 daily, the neprilysin inhibitor, and was paired with an eighth group that received placebo. A total of 91% of patients completed the 8-week treatment period.

The primary outcome was the lowering of mean sitting diastolic BP during the 8-week treatment period The investigators found greater reductions in mean sitting diastolic BP from baselines in all groups taking LCZ696 over those taking valsartan—of the three paired dose groups, the LCZ696 arm saw a mean drop −2.17/–4.20 mm Hg.

The difference in reduction was not significant at the lowest dose but became marked at the higher doses, and the contrast widened with the dose increases.

The neprilysin inhibitor AHU377, tested only at the 200-mg dose, performed better than placebo but not as well as LCZ696 at any dose, with a change from baseline in mean sitting blood pressure of −4.20/–2.99 mm Hg

Adverse effects across all study groups were minimal, even at the highest doses. Though patients with previous angioedema were not allowed to enroll, there were no reports of angioedema in any of the study categories.

Dr. Bernard Waeber and Dr. Fran ois Feihl of the Universit de Lausanne in Switzerland, noted the “great potential” of LCZ696 in an accompanying editorial (DOI:10. 1016/S0140-6736[10]60363-7).

The absence of angioedema during the trial is especially encouraging, they wrote, since a previous hypertension drug candidate with somewhat similar dual activity, omapatrilat (Bristol-Myers Squibb), had shown great promise in reducing BP, but could not be marketed because of a high association with angioedema.

Dr. Ruilope and two of his co-authors have financial relationships with Novartis; two more authors are employees of Novartis, and one declared no conflicts of interest.

Dr. Waeber and Dr. Feihl declared no conflicts of interest.

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