Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension

Pierre Verweij, Parisa Danaietash, Bruno Flamion, Joël Ménard, Marc Bellet, Pierre Verweij, Parisa Danaietash, Bruno Flamion, Joël Ménard, Marc Bellet

Abstract

This study examined the dose-response characteristics of aprocitentan, a dual endothelin A/endothelin B receptor antagonist, in patients with essential hypertension. In a randomized, double-blind, parallel study design, eligible patients with a sitting diastolic blood pressure (BP) of 90-109 mm Hg received aprocitentan 5, 10, 25, or 50 mg, placebo, or lisinopril 20 mg as a positive control once daily for 8 weeks. Multiple automated office BP readings were obtained with patients resting unattended (unattended automated office BP) at baseline, weeks 2, 4, and 8. Ambulatory BP was monitored for 24 hours at baseline and week 8. After a single-blind placebo run-in period, 490 eligible patients were randomized to the double-blind phase, with 409 patients completing 8 weeks of therapy per protocol. Aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office BP from baseline to week 8 (placebo-corrected decreases: 7.05/4.93, 9.90/6.99, and 7.58/4.95 mm Hg, respectively, P≤0.014 versus placebo), compared with an unattended automated office BP reduction of 4.84/3.81 mm Hg with lisinopril 20 mg. For patients with valid ambulatory BP, aprocitentan 10, 25, and 50 mg significantly decreased placebo-corrected 24-hour BP by 3.99/4.04, 4.83/5.89, and 3.67/4.45 mm Hg, respectively. Incidence of adverse events was similar in the aprocitentan groups (22.0%-40.2%) and the placebo group (36.6%). Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, an increase in estimated plasma volume, but no change in weight versus placebo. These findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02603809.

Keywords: aprocitentan; blood pressure; endothelin; essential hypertension.

Figures

Figure 1.
Figure 1.
Disposition of patients during the trial. *For protocol deviations see online-only Data Supplement.
Figure 2.
Figure 2.
Change in unattended automated office blood pressure. Mean change from baseline in (A) sitting diastolic blood pressure (SiDBP) and (B) sitting systolic blood pressure (SiSBP) over time (per-protocol set, n=409).
Figure 3.
Figure 3.
Results from multiple comparison procedure - modeling analysis. Change from baseline to week 8 in (A) sitting diastolic blood pressure (SiDBP) and (B) sitting systolic blood pressure (SiSBP)–quadratic model; (C) hemoglobin-linear in log dose model.

References

    1. Whelton PK, Carey RM, Aronow WS, Casey DE, Jr, Collins KJ, Dennison Himmelfarb C, DePalma SM, Gidding S, Jamerson KA, Jones DW, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Hypertension. 2018;71:e13–e115. doi: 10.1161/HYP.0000000000000065.
    1. FDA. Hypertension: Conducting studies of drugs to treat patients on a background of multiple antihypertensive drugs guidance for industry. 2018. Available at: . Accessed July 16, 2019.
    1. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411–415. doi: 10.1038/332411a0.
    1. Iglarz M, Clozel M. At the heart of tissue: endothelin system and end-organ damage. Clin Sci (Lond) 2010;119:453–463. doi: 10.1042/CS20100222.
    1. Schiffrin EL. Role of endothelin-1 in hypertension and vascular disease. Am J Hypertens. 2001;14(6)(pt 2):83S–89S. doi: 10.1016/s0895-7061(01)02074-x.
    1. Trensz F, Bortolamiol C, Kramberg M, Wanner D, Hadana H, Rey M, Strasser DS, Delahaye S, Hess P, Vezzali E, et al. Pharmacological characterization of aprocitentan, a dual endothelin receptor antagonist, alone and in combination with blockers of the renin angiotensin system, in two models of experimental hypertension. J Pharmacol Exp Ther. 2019;368:462–473. doi: 10.1124/jpet.118.253864.
    1. Krum H, Viskoper RJ, Lacourciere Y, Budde M, Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan hypertension investigators. N Engl J Med. 1998;338:784–790. doi: 10.1056/NEJM199803193381202.
    1. Weber MA, Black H, Bakris G, Krum H, Linas S, Weiss R, Linseman JV, Wiens BL, Warren MS, Lindholm LH. A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment-resistant hypertension: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;374:1423–1431. doi: 10.1016/S0140-6736(09)61500-2.
    1. Bakris GL, Lindholm LH, Black HR, Krum H, Linas S, Linseman JV, Arterburn S, Sager P, Weber M. Divergent results using clinic and ambulatory blood pressures: report of a darusentan-resistant hypertension trial. Hypertension. 2010;56:824–830. doi: 10.1161/HYPERTENSIONAHA.110.156976.
    1. Kaoukis A, Deftereos S, Raisakis K, Giannopoulos G, Bouras G, Panagopoulou V, Papoutsidakis N, Cleman MW, Stefanadis C. The role of endothelin system in cardiovascular disease and the potential therapeutic perspectives of its inhibition. Curr Top Med Chem. 2013;13:95–114. doi: 10.2174/1568026611313020003.
    1. Mann JF, Green D, Jamerson K, Ruilope LM, Kuranoff SJ, Littke T, Viberti G ASCEND Study Group. Avosentan for overt diabetic nephropathy. J Am Soc Nephrol. 2010;21:527–535. doi: 10.1681/ASN.2009060593.
    1. Sidharta PN, Melchior M, Kankam MK, Dingemanse J. Single- and multiple-dose tolerability, safety, pharmacokinetics, and pharmacodynamics of the dual endothelin receptor antagonist aprocitentan in healthy adult and elderly subjects. Drug Des Devel Ther. 2019;13:949–964. doi: 10.2147/DDDT.S199051.
    1. Maguire JJ, Davenport AP. Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12. Br J Pharmacol. 2014;171:5555–5572. doi: 10.1111/bph.12874.
    1. Treiber A, Äänismaa P, de Kanter R, Delahaye S, Treher M, Hess P, Sidharta P. Macitentan does not interfere with hepatic bile salt transport. J Pharmacol Exp Ther. 2014;350:130–143. doi: 10.1124/jpet.114.214106.
    1. Vercauteren M, Trensz F, Pasquali A, Cattaneo C, Strasser DS, Hess P, Iglarz M, Clozel M. Endothelin ETA receptor blockade, by activating ETB receptors, increases vascular permeability and induces exaggerated fluid retention. J Pharmacol Exp Ther. 2017;361:322–333. doi: 10.1124/jpet.116.234930.
    1. Gomez HJ, Cirillo VJ, Sromovsky JA, Otterbein ES, Shaw WC, Rush JE, Chrysant SG, Gradman AH, Leon AS, MacCarthy EP. Lisinopril dose-response relationship in essential hypertension. Br J Clin Pharmacol. 1989;28:415–420. doi: 10.1111/j.1365-2125.1989.tb03521.x.
    1. Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques in dose-response studies. Biometrics. 2005;61:738–748. doi: 10.1111/j.1541-0420.2005.00344.x.
    1. Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding under model uncertainty using general parametric models. Stat Med. 2014;33:1646–1661. doi: 10.1002/sim.6052.
    1. Villa G, Le Breton S, Ibram G, Keefe DL. Efficacy, safety, and tolerability of aliskiren monotherapy administered with a light meal in elderly hypertensive patients: a randomized, double-blind, placebo-controlled, dose-response evaluation study. J Clin Pharmacol. 2012;52:1901–1911. doi: 10.1177/0091270011426432.
    1. EMA. Qualification opinion of MCP-Mod as an efficient statistical methodology for model-based design and analysis of phase II dose finding studies under model uncertainty. 2014. Available at: . Accessed July 16, 2019.
    1. FDA. Qualification of the MCP-Mod procedure. 2015. Available at: . Accessed July, 16 2019.
    1. Bornkamp B, Pinheiro J, Bretz F. Dosefinding: Planning and analyzing dose finding experiments. 2018. Available at: . Accessed July 16, 2019.
    1. O’Brien E, Parati G, Stergiou G. Ambulatory blood pressure measurement: what is the international consensus? Hypertension. 2013;62:988–994. doi: 10.1161/HYPERTENSIONAHA.113.02148.
    1. Strauss MB, Davis RK, Rosenbaum JD, Rossmeisl EC. Water diuresis produced during recumbency by the intravenous infusion of isotonic saline solution. J Clin Invest. 1951;30:862–868. doi: 10.1172/JCI102501.
    1. Desai M, Stockbridge N, Temple R. Blood pressure as an example of a biomarker that functions as a surrogate. AAPS J. 2006;8:e146–e152. doi: 10.1208/aapsj080117.
    1. Burnier M, Brede Y, Lowy A. Impact of prolonged antihypertensive duration of action on predicted clinical outcomes in imperfectly adherent patients: comparison of aliskiren, irbesartan and ramipril. Int J Clin Pract. 2011;65:127–133. doi: 10.1111/j.1742-1241.2010.02616.x.
    1. Myers MG, Godwin M, Dawes M, Kiss A, Tobe SW, Kaczorowski J. Measurement of blood pressure in the office: recognizing the problem and proposing the solution. Hypertension. 2010;55:195–200. doi: 10.1161/HYPERTENSIONAHA.109.141879.
    1. Muntner P, Shimbo D, Carey RM, Charleston JB, Gaillard T, Misra S, Myers MG, Ogedegbe G, Schwartz JE, Townsend RR, et al. Measurement of blood pressure in humans: a scientific statement from the American Heart Association. Hypertension. 2019;73:e35–e66. doi: 10.1161/HYP.0000000000000087.
    1. Roerecke M, Kaczorowski J, Myers MG. Comparing automated office blood pressure readings with other methods of blood pressure measurement for identifying patients with possible hypertension: a systematic review and meta-analysis. JAMA Intern Med. 2019;179:351–362. doi: 10.1001/jamainternmed.2018.6551.
    1. Pool JL, Schmieder RE, Azizi M, Aldigier JC, Januszewicz A, Zidek W, Chiang Y, Satlin A. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens. 2007;20:11–20. doi: 10.1016/j.amjhyper.2006.06.003.
    1. Messerli FH, Bangalore S, Schmieder RE. Wilder’s principle: pre-treatment value determines post-treatment response. Eur Heart J. 2015;36:576–579. doi: 10.1093/eurheartj/ehu467.
    1. Mancia G, Omboni S, Parati G, Ravogli A, Villani A, Zanchetti A. Lack of placebo effect on ambulatory blood pressure. Am J Hypertens. 1995;8:311–315. doi: 10.1016/0895-7061(94)00250-F.
    1. O’Brien E. The value of 24-h blood pressure monitoring to assess the efficacy of antihypertensive drug treatment. Hot Topics Hypertens. 2011;4:7–23.
    1. Grossman E, Messerli FH. Effect of calcium antagonists on plasma norepinephrine levels, heart rate, and blood pressure. Am J Cardiol. 1997;80:1453–1458. doi: 10.1016/s0002-9149(97)00722-4.
    1. Kohan DE, Cleland JG, Rubin LJ, Theodorescu D, Barton M. Clinical trials with endothelin receptor antagonists: what went wrong and where can we improve? Life Sci. 2012;91:528–539. doi: 10.1016/j.lfs.2012.07.034.
    1. Bauer JH, Jones LB, Gaddy P. Effects of prazosin therapy on BP, renal function, and body fluid composition. Arch Intern Med. 1984;144:1196–1200.
    1. EMA. Report from dose finding workshop december 2014. 2015. Available at: . Accessed July 16, 2019.
    1. Menard J, Bellet M, Brunner HR. Clinical development of antihypertensive drug. In: Laragh JH, Brenner BM, editors. In: Hypertension: Pathology, diagnosis and management. New York: Raven Press Limited; 1995. pp. 3049–3063.
    1. Dhaun N, Johnston NR, Goddard J, Webb DJ. Chronic selective endothelin A receptor antagonism reduces serum uric acid in hypertensive chronic kidney disease. Hypertension. 2011;58:e11–e12. doi: 10.1161/HYPERTENSIONAHA.111.175646.
    1. Dhaun N, Vachiery JL, Benza RL, Naeije R, Hwang LJ, Liu X, Teal S, Webb DJ. Endothelin antagonism and uric acid levels in pulmonary arterial hypertension: clinical associations. J Heart Lung Transplant. 2014;33:521–527. doi: 10.1016/j.healun.2014.01.853.

Source: PubMed

Sponsors et collaborateurs

Les conditions médicales

Interventions en matière de drogue

3
S'abonner