Firibastat, the first-in-class brain aminopeptidase a inhibitor, in the management of hypertension: a review of clinical trials

Abstract

An unfortunate subset of hypertensive patients develops resistant hypertension in which optimal doses of three or more first-line antihypertensive drugs fail to sufficiently control blood pressure. Patients with resistant hypertension represent a high-risk and difficult-to-treat group, and such patients are at amplified jeopardies for substantial hypertension-related multi-organ failure, morbidity, and mortality. Thus, there is a pressing requirement to better improve blood pressure control through the pharmaceutical generation of novel classes of antihypertensive drugs that act on newer and alternative therapeutic targets. The hyperactivity of the brain renin-angiotensin system (RAS) has been shown to play a role in the pathogenesis of hypertension in various experimental and genetic hypertensive animal models. In the brain, angiotensin-II is metabolized to angiotensin-III by aminopeptidase A (APA), a membrane-bound zinc metalloprotease enzyme. A large body of evidence has previously established that angiotensin-III is one of the main effector peptides of the brain RAS. Angiotensin-III exerts central stimulatory regulation over blood pressure through several proposed mechanisms. Accumulating evidence from preclinical studies demonstrated that the centrally acting APA inhibitor prodrugs (firibastat and NI956) are very safe and effective at reducing blood pressure in various hypertensive animal models. The primary purpose of this study is to narratively review the published phase I–II literature on the safety and efficacy of APA inhibitors in the management of patients with hypertension. Moreover, a summary of ongoing clinical trials and future perspectives are presented.

Keywords

Angiotensin III - blood pressure - brain aminopeptidase a - brain renin-angiotensin system - firibastat - hypertension

Publication History

Article published online:
06 August 2021

• References

• 1 Collaborators GRF Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990–2017. A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1923-94
• 2 Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP. et al American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2019 update: A report from the American Heart Association. Circulation 2019; 139: e56-e528
• 3 Nguyen Q, Dominguez J, Nguyen L, Gullapalli N. Hypertension management: An update. Am Health Drug Benefits 2010; 3: 47-56
• 4 Doroszko A, Janus A, Szahidewicz-Krupska E, Mazur G, Derkacz A. Resistant hypertension. Adv Clin Exp Med 2016; 25: 173-83
• 5 Carey RM, Calhoun DA, Bakris GL, Brook RD, Daugherty SL, Dennison-Himmelfarb CR. et al American Heart Association Professional/Public Education and Publications Committee of the Council on Hypertension; Council on Cardiovascular and Stroke Nursing; Council on Clinical Cardiology; Council on Genomic and Precision Medicine; Council on Peripheral Vascular Disease; Council on Quality of Care and Outcomes Research; and Stroke Council. Resistant hypertension: Detection, evaluation, and management: A scientific statement from the American Heart Association. Hypertension 2018; 72: e53-90
• 6 Aronow WS. Approaches for the management of resistant hypertension in 2020. Curr Hypertens Rep 2020; 22: 3
• 7 Ganten D, Hermann K, Bayer C, Unger T, Lang RE. Angiotensin synthesis in the brain and increased turnover in hypertensive rats. Science 1983; 221: 869-71
• 8 Basso N, Ruiz P, Mangiarua E, Taquini AC. Renin-like activity in the rat brain during the development of DOC-salt hypertension. Hypertension 1981; 3: II-14
• 9 Davisson RL, Yang G, Beltz TG, Cassell MD, Johnson AK, Sigmund CD. The brain renin-angiotensin system contributes to the hypertension in mice containing both the human renin and human angiotensinogen transgenes. Circ Res 1998; 83: 1047-58
• 10 Saavedra JM. Brain and pituitary angiotensin. Endocr Rev 1992; 13: 329-80
• 11 Xu Q, Jensen DD, Peng H, Feng Y. The critical role of the central nervous system (pro)renin receptor in regulating systemic blood pressure. Pharmacol Ther 2016; 164: 126-34
• 12 Llorens-Cortes C, Touyz RM. Evolution of a new class of antihypertensive drugs: Targeting the brain renin-angiotensin system. Hypertension 2020; 75: 6-15
• 13 Zini S, Fournie-Zaluski MC, Chauvel E, Roques BP, Corvol P. Llorens-Cortes C Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: Predominant role of angiotensin III in the control of vasopressin release. Proc Natl Acad Sci U S A 1996; 93: 11968-73
• 14 Wright JW, Harding JW. Brain angiotensin receptor subtypes AT1, AT2, and AT4 and their functions. Regul Pept 1995; 59: 269-95
• 15 Keck M, Hmazzou R. Llorens-Cortes C Orally active aminopeptidase A inhibitor prodrugs: Current state and future directions. Curr Hypertens Rep 2019; 21: 50
• 16 Batt CM, Klein EW, Harding JW, Wright JW. Pressor responses to amastatin, bestatin and plummer’s inhibitors are suppressed by pretreatment with the angiotensin receptor antagonist sarthran. Brain Res Bull 1988; 21: 731-5
• 17 Wright JW, Jensen LL, Roberts KA, Sardinia MF, Harding JW. Structure-function analyses of brain angiotensin control of pressor action in rats. Am J Physiol 1989; 257: R1551-7
• 18 Wright JW, Mizutani S, Murray CE, Amir HZ, Harding JW. Aminopeptidase-induced elevations and reductions in blood pressure in the spontaneously hypertensive rat. J Hypertens 1990; 8: 969-74
• 19 Chauvel EN, Llorens-Cortès C, Coric P, Wilk S, Roques BP. Fournié-Zaluski MC Differential inhibition of aminopeptidase A and aminopeptidase N by new beta-amino thiols. J Med Chem 1994; 37: 2950-7
• 20 Fournié-Zaluski MC, Coric P, Turcaud S, Bruetschy L, Lucas E, Noble F. et al. Potent and systemically active aminopeptidase N inhibitors designed from active-site investigation. J Med Chem 1992; 35: 1259-66
• 21 Reaux A, Fournie-Zaluski MC, David C, Zini S, Roques BP, Corvol P. et al. Aminopeptidase A inhibitors as potential central antihypertensive agents. Proc Natl Acad Sci U S A 1999; 96: 13415-20
• 22 Fournie-Zaluski MC, Fassot C, Valentin B, Djordjijevic D, Reaux-Le Goazigo A, Corvol P. et al. Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension. Proc Natl Acad Sci U S A 2004; 101: 7775-80
• 23 Réaux A, de Mota N, Zini S, Cadel S, Fournié-Zaluski MC, Roques BP. et al. PC18, a specific aminopeptidase N inhibitor, induces vasopressin release by increasing the half-life of brain angiotensin III. Neuroendocrinology 1999; 69: 370-6
• 24 Zini S, Demassey Y, Fournié-Zaluski MC, Bischoff L, Corvol P, Llorens-Cortès C. et al. Inhibition of vasopressinergic neurons by central injection of a specific aminopeptidase A inhibitor. Neuroreport 1998; 9: 825-8
• 25 Keck M, De Almeida H, Compère D, Inguimbert N, Flahault A, Balavoine F. et al. NI956/QGC006, a potent orally active, brain-penetrating aminopeptidase A inhibitor for treating hypertension. Hypertension 2019; 73: 1300-7
• 26 Bodineau L, Frugière A, Marc Y, Inguimbert N, Fassot C, Balavoine F. et al. Orally active aminopeptidase A inhibitors reduce blood pressure: A new strategy for treating hypertension. Hypertension 2008; 51: 1318-25
• 27 Bodineau L, Frugière A, Marc Y, Claperon C, Llorens-Cortes C. Aminopeptidase A inhibitors as centrally acting antihypertensive agents. Heart Fail Rev 2008; 13: 311-9
• 28 Marc Y, Gao J, Balavoine F, Michaud A, Roques BP, Llorens-Cortes C. Central antihypertensive effects of orally active aminopeptidase A inhibitors in spontaneously hypertensive rats. Hypertension 2012; 60: 411-8
• 29 Marc Y, Hmazzou R, Balavoine F, Flahault A, Llorens-Cortes C. Central antihypertensive effects of chronic treatment with RB150: An orally active aminopeptidase A inhibitor in deoxycorticosterone acetate-salt rats. J Hypertens 2018; 36: 641-50
• 30 Wright JW, Tamura-Myers E, Wilson WL, Roques BP, Llorens-Cortes C, Speth RC. et al. Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats. Am J Physiol Regul Integr Comp Physiol 2003; 284: R725-33
• 31 Balavoine F, Azizi M, Bergerot D, De Mota N, Patouret R, Roques BP. et al. Randomised, double-blind, placebo-controlled, dose-escalating phase I study of QGC001, a centrally acting aminopeptidase a inhibitor prodrug. Clin Pharmacokinet 2014; 53: 385-95
• 32 Azizi M, Courand PY, Denolle T, Delsart P, Zhygalina V, Amar L. et al. A pilot double-blind randomized placebo-controlled crossover pharmacodynamic study of the centrally active aminopeptidase A inhibitor, firibastat, in hypertension. J Hypertens 2019; 37: 1722-8
• 33 Ferdinand KC, Balavoine F, Besse B, Black HR, Desbrandes S, Dittrich HC. et al. Efficacy and safety of firibastat, A first-in-class brain aminopeptidase A inhibitor, in hypertensive overweight patients of multiple ethnic origins. Circulation 2019; 140: 138-46
• 34 Zhang ZH, Francis J, Weiss RM, Felder RB. The renin-angiotensin-aldosterone system excites hypothalamic paraventricular nucleus neurons in heart failure. Am J Physiol Heart Circ Physiol 2002; 283: H423-33
• 35 Wang H, Huang BS, Ganten D, Leenen FH. Prevention of sympathetic and cardiac dysfunction after myocardial infarction in transgenic rats deficient in brain angiotensinogen. Circ Res 2004; 94: 843
• 36 Leenen FH. Brain mechanisms contributing to sympathetic hyperactivity and heart failure. Circ Res 2007; 101: 221-3
• 37 Huang BS, Ahmad M, White RA, Marc Y, Llorens-Cortes C, Leenen FH. Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction. Cardiovasc Res 2013; 97: 424-31
• 38 Leenen FHH, Ahmad M, Marc Y, Llorens-Cortes C. Specific inhibition of brain angiotensin III formation as a new strategy for prevention of heart failure after myocardial infarction. J Cardiovasc Pharmacol 2019; 73: 82-91
• 39 Boitard SE, Marc Y, Keck M, Mougenot N, Agbulut O, Balavoine F. et al. Brain renin-angiotensin system blockade with orally active aminopeptidase A inhibitor prevents cardiac dysfunction after myocardial infarction in mice. J Mol Cell Cardiol 2019; 127: 215-22
• 40 Study of the Product QGC001 as a Single Dose and Multiple Doses Administered Orally to Healthy Adult Subjects. 2020 Available from: https://clinicaltrials.gov/ct2/show/NCT01900184. [Last accessed on 2020 May 23]
• 41 Evaluation of the PK Profile of Firibastat Following Administration of Firibastat Prototype Tablet Formulations. 2020 Available from: https://clinicaltrials.gov/ct2/show/NCT03714685. [Last accessed on 2020 May 23]
• 42 QUantum Genomics Incremental Dosing in Heart Failure - QUID-HF (QUID-HF). 2020 Available from: https://clinicaltrials.gov/ct2/show/NCT02780180. [Last accessed on 2020 May 23]
• 43 Firibastat or Ramipril After Acute Myocardial Infarction for Prevention of Left Ventricular Dysfunction (QUORUM). 2020 Available from: https://clinicaltrials.gov/ct2/show/NCT03715998. [Last accessed on 2020 May 23]
• 44 Firibastat in Treatment-resistant Hypertension (FRESH). 2020 Available from: https://clinicaltrials.gov/ct2/show/NCT04277884. [Last accessed on 2020 May 23]