Brain aminopeptidase A inhibitor reduces blood pressure in a high-risk diverse population

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

Literature - Ferdinand KC, Balavoine F, Besse B et al. - Circulation 2019; doi:10.1161/CIRCULATIONAHA.119.040070

Introduction and methods

Although different therapeutic classes of antihypertensive drugs are available, more than 50% of US adults taking these drugs have blood pressure (BP) above the treatment goal [1]. Especially, obese, black and other minority patients suffer from uncontrolled hypertension. ACE inhibitors and ARBs, that target the systemic reninangiotensin system (RAS), lower BP and thereby reduce CV and renal morbidity and mortality. However, it was reported that these agents are less effective in blacks and overweight or obese subjects [2,3].

Animal models have demonstrated that hyperactivity of RAS in the brain and specifically hyperactivity of brain aminopeptidase A (APA), a protease involved in conversion of Ang-II into Ang-III, plays a role in development of hypertension [4-6]. Inhibition of brain APA activity resulted in BP reduction in these models [7,8].

Firibastat is a selective and specific inhibitor of brain APA. It decreased BP in rat models of hypertension [9,10]. In normotensive rats without brain APA hyperactivity, repeated administrations of firibastat did not affect BP or heart rate (HR). First in-human studies showed that oral administration of firibastat up to 2000 mg or twice-daily (b.i.d.) doses up to 750 mg were well-tolerated without effect on BP and HR [11]. In patients with mild-to-moderate hypertension, four-week administration of 1000 mg/day of firibastat resulted in reduction of daytime systolic ambulatory BP (ABP) by 2.7 mmHg and office systolic BP (SBP) by 4.7 mmHg compared to placebo [12].

In this phase 2b trial, the efficacy and safety of firibastat 500 mg b.i.d in stage 2 primary hypertensive, overweight patients of multiple ethnic origins (n=256) was examined during a 8-week open-label treatment period. After screening, patients stopped antihypertensive medications followed by a wash-out period of 2 weeks. Thereafter, patients with SBP 145-170 mmHg and diastolic BP (DBP) ≤105 mmHg by fully automated unattended office BP (AOBP) measurements were included in the trial and received firibastat 250 mg b.i.d. for 2 weeks. If AOBP was ≤140/90 mmHg after 2 weeks, participants continued on the same dose otherwise dose was increased to 500 mg b.i.d. If AOBP was ≥160/110 mmHg after 1 month, hydrochlorothiazide was added to firibastat.

Primary endpoint was change in systolic AOBP from baseline to week 8. AOBP was based on 6 consecutive BP reading with 1- minute interval after 5 min resting period. Measurement 2-5 were used to average readings.

Main results

  • Mean BMI was 33.0 ± 5.2 kg/m², 65% were obese, 54% blacks or Hispanics.
  • After 8 weeks of treatment, BP reduction was significant; 9.5 mmHg for systolic AOBP (95%CI: -10.7 to -7.3, P<0.0001) and 4.2 mmHg for diastolic AOBP (95%CI: -5.5 to -3.3, P<0.0001).
  • Systolic daytime ABP was decreased after 8 weeks of firibastat by 3.1 ± 13.0 mmHg (P=0.0005) and diastolic daytime ABP by 1.6 ± 7.8 mmHg (P=0.003). 24h-ABP levels were decreased by 2.7 ± 12.4 mmHg for systolic 24h-ABP (P=0.002) and by 1.4 ± 7.2 mmHg for diastolic 24h-ABP (P=0.01).
  • No significant findings were observed for nighttime systolic and diastolic ABP.
  • Treatment with firibastat did not result in changes in HR.
  • 36 subjects (14.1%) reported a related treatment-emergent adverse event (TEAE), including headache (4%) and skin reaction (3%). 19 subjects (7.5%) stopped the medication due to adverse events (AEs). 5 serious AEs occurred. No deaths were reported during the study. There were no differences in laboratory results between baseline and 8 weeks.


In hypertensive, overweight patients of multiple ethnic origins, firibastat reduced systolic and diastolic AOBP, and systolic and diastolic daytime and 24h-ABP after 8 weeks and was well-tolerated. These results suggest that inhibition of brain APA is effective in reducing BP in a population less responsive to RAS inhibition.


1. Benjamin EJ, Virani SS, Callaway CW, et al. Heart Disease and Stroke Statistics-2018 Update: a report from the American Heart Association. Circulation. 2018;137:e67–e492.

2. Wright JT Jr, Dunn JK, Cutler JA, et al. Outcomes in hypertensive black and nonblack patients

treated with chlorthalidone, amlodipine, and lisinopril. JAMA. 2005;293:1595-1608.

3. Reisin E, Graves JW, Yamal JM, et al. Blood pressure control and cardiovascular outcomes in normal-weight, overweight, and obese hypertensive patients treated with three different antihypertensives in ALLHAT. J Hypertens. 2014;32:1503-1513.

4. Basso N, Ruiz P, Kurnjek ML, et al. The brain renin-angiotensin system and the development of DOCA-salt hypertension. Clin Exp Hypertens. 1985;7:1259–1268.

5. Ganten D, Hermann K, Bayer C, et al. Angiotensin synthesis in the brain and

increased turnover in hypertensive rats. Science. 1983;221:869–871.

6. Marc Y, Llorens-Cortes C. The role of the brain renin-angiotensin system in hypertension:

implications for new treatment. Prog Neurobiol. 2011;95:89–103.

7. Reaux A, Fournie-Zaluski MC, David C, et al. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci USA. 1999;96:13415–13420.

8. Fournie-Zaluski M-C, Fassot C, Valentin B, et al. Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. Proc Natl Acad Sci USA. 2004;101: 7775–7780.

9. Bodineau L, Frugière A, Marc Y, et al. Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension. Hypertension. 2008;51:1318–1325.

10. Marc Y, Gao J, Balavoine F, et al. Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. Hypertension. 2012;60:411–418.

11. Basting T, Lazartigues E. DOCA-Salt Hypertension: an Update. Current Hypertension

Reports. 2017;19:32.

12. Azizi M, Courand PY, Denolle T, et al. A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension. J Hypertension. 2019

Find this article online at Circulation

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free