Firibastat, a brain aminopeptidase A (APA) inhibitor, was effective in controlling hypertension in a high-risk diverse population of patients with a known reduced blood pressure (BP) response to systemic renin-angiotensin system (RAS) blockers such as angiotensin-I converting enzyme (ACE) inhibitors or angiotensin-II receptor type 1 blockers, according to a study published in Circulation.
Black patients experience more severe hypertension earlier, with higher morbidity and mortality than white patients, and black patients are also less responsive to monotherapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. This open-label, 8-week, phase 2b study was designed to assess the safety and efficacy of firibastat, a first-in-class aminopeptidase A inhibitor that prevents the conversion of brain angiotensin-II into angiotensin-III, in a diverse population of patients with overweight or obesity (N=256, 54% self-identifying as black [38%] or Hispanic, including 28% with type 2 diabetes) being treated for stage II primary hypertension at 40 US treatment centers.
After a 2-week washout period with no hypertensive medications, eligible participants began the trial and were given firibastat 250 mg twice daily for 2 weeks. At that point, participants with automated office blood pressure (AOBP) >140/90 mm Hg had their dosages increased to 500 mg twice daily. After one month of treatment, participants with AOBP ≥160/110 mm Hg began taking hydrochlorothiazide (HCTZ) 25 mg once daily in combination with firibastat. Automated office blood pressure was assessed at 2, 4, and 8 weeks, and ABP measurements were assessed over 24 hours at baseline at end of treatment (day 56). The primary endpoint was changed from baseline systolic AOBP, and secondary endpoints included diastolic AOBP, safety, and 24-hour mean ambulatory BP.
Overall, firibastat treatment decreased systolic AOBP by 9.5 mm Hg (P <.0001) and decreased diastolic AOBP by 4.2 mm Hg (P <.0001). The majority of participants (85%) did not receive hydrochlorothiazide and were only treated with firibastat. Significant reductions in BP were seen across all subgroups regardless of sex, age, race, or body mass index. Systolic AOBP decreased by 10.5 mm Hg (P <.0001) in black patients, by 8.9 mm Hg (P <.0001) in nonblack patients, and by 10.2 mm Hg (P <.0001) in obese patients with obesity. The most prevalent adverse events were skin reactions (3%) and headaches (4%), with no reported angioedema and no observed change in sodium, potassium, and creatinine blood levels.
Study investigators concluded that despite the uncontrolled, open-label design, “The results reported here are a useful guide to the design of a larger, randomized parallel-group trial to investigate the use of firibastat as add-on therapy to complex drug regimens for the treatment of difficult-to-treat or potentially resistant [hypertension] in order to improve BP control and ultimately reduce morbidity and mortality rates among high-risk patients.”
The study funding was provided by Quantum Genomics SA, Paris, France.
Ferdinand KC, Balavoine F, Besse B, et al. 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 [published online April 24, 2019]. Circulation. doi: 10.1161/CIRCULATIONAHA.119.040070