Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins: A Phase 2, Open-Label, Multicenter, Dose-Titrating Study

Keith C. Ferdinand, Fabrice Balavoine, Bruno Besse, Henry R. Black, Stephanie Desbrandes, Howard C. Dittrich, Shawna D. Nesbitt

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

Background: Despite existing therapy, successful control of hypertension in the United States is estimated at less than 50%. In blacks, hypertension occurs earlier, is more severe, controlled less often and has a higher morbidity and mortality than in whites. Blacks are also less responsive to monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers. Obesity, higher salt-sensitivity and low plasma renin activity are possible reasons of this poor blood pressure (BP) control, especially in blacks. The aim of the study was to assess efficacy and safety of firibastat, a first-in-class aminopeptidase A inhibitor preventing conversion of brain angiotensin-II into angiotensin-III, in BP lowering in a high-risk diverse hypertensive population. Methods: Two hundred fifty-six overweight or obese hypertensive patients, including 54% black and Hispanic individuals, were enrolled in a multicenter, open-label, phase II study. After a 2-week wash-out period, subjects received firibastat for 8 weeks (250 mg BID orally for 2 weeks, then 500 mg BID if automated office blood pressure (AOBP) >140/90 mm Hg; hydrochlorothiazide 25 mg QD was added after 1 month if AOBP ≥160/110 mm Hg). The primary end point was change from baseline in systolic AOBP after 8 weeks of treatment, and secondary end points include diastolic AOBP, 24-hour mean ambulatory BP and safety. Results: Firibastat lowered systolic AOBP by 9.5 mm Hg (P<0.0001) and diastolic AOBP by 4.2 mm Hg (P<0.0001). 85% of the subjects did not receive hydrochlorothiazide and were treated with firibastat alone. Significant BP reduction was found across all subgroups regardless age, sex, body mass index, or race. Systolic AOBP decreased by 10.2 mm Hg (P<0.0001) in obese patients, by 10.5 mm Hg (P<0.0001) in blacks, and 8.9 mm Hg (P<0.0001) in nonblacks. Most frequent adverse events were headaches (4%) and skin reactions (3%). No angioedema was reported. No change in potassium, sodium, and creatinine blood level were observed. Conclusions: Our results demonstrate the efficacy of firibastat in lowering BP in a high-risk diverse population where monotherapy with angiotensin-I converting enzyme inhibitors or angiotensin-II receptor type 1 blockers may be less effective and support the strategy to further investigate firibastat in subjects with difficult-to-treat or potentially resistant hypertension. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03198793.

Original languageEnglish (US)
Pages (from-to)138-146
Number of pages9
JournalCirculation
Volume140
Issue number2
DOIs
StatePublished - Jul 9 2019

Keywords

  • angiotensin II
  • angiotensin III
  • angiotensin-converting enzyme inhibitors
  • blood pressure
  • hypertension
  • obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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