Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction

Abstract

This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2–5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min−1 1.73 m−2 received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol−1 and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

Effect of renal function on the pharmacokinetics of LCZ696 (sacubitril/valsartan), an angiotensin receptor neprilysin inhibitor

“…As expected, the majority of AEs were related to blood pressure reduction which is considered to be related to the pharmacodynamics of LCZ696. These safety results are consistent to those observed in the efficacy and safety studies of LCZ696 in patients with HFrEF with mild and moderate renal dysfunction (eGFR >30 mL/min/1.73 m 2 ) [3] and in patients with hypertension (eGFR ≥15 and >30 mL/min/1.73 m 2 ) [17].…”

Sex Influence on the Efficacy and Safety of Sacubitril/Valsartan

“…Although no sex-related meaningful differences have been reported in SV pharmacokinetics and pharmacodynamics [20, 21], a more sex-balanced recruitment would be desirable. A subanalysis of the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF) showed that the beneficial effect of beta-blockers was extensible to women [19, 22, 23].…”

LCZ696, a First‐in‐Class Angiotensin Receptor‐Neprilysin Inhibitor: The First Clinical Experience in Patients With Severe Hypertension

“…The incidence of nasopharyngitis was similar to that in a study conducted in Japanese patients with hypertension and renal dysfunction. 24 With regard to the liver enzyme elevation, the investigator stated that the patient who experienced SAEs had a concurrent condition of alcohol allergy (reported as such by the investigator) and the patient consumed beer 2 days before day 10; therefore, an effect of drinking alcohol could not be ruled out. However, the reported increase in aspartate aminotransferase and alanine aminotransferase (to >8 times the upper limit of normal) returned to normal levels after temporary cessation of LCZ696 and did not recur after resuming LCZ696.…”