Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction

Sadayoshi Ito, Minoru Satoh, Yuko Tamaki, Hiromi Gotou, Alan Charney, Naoko Okino, Mizuki Akahori, Jack Zhang, Sadayoshi Ito, Minoru Satoh, Yuko Tamaki, Hiromi Gotou, Alan Charney, Naoko Okino, Mizuki Akahori, Jack Zhang

Abstract

This 8-week, multi-center, open-label study assessed the safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Patients (n=32) with mean sitting systolic blood pressure (msSBP) ⩾140 mm Hg (after a 2-5-week washout of previous antihypertensive medications) and estimated glomerular filtration rate (eGFR) ⩾15 and <60 ml min(-1) 1.73 m(-2) received LCZ696 100 mg with an optional titration to 200 and 400 mg in a sequential manner starting from Week 2 in patients with inadequate BP control (msSBP ⩾130 mm Hg and mean sitting diastolic blood pressure (msDBP) ⩾80 mm Hg) and without safety concerns. Safety was assessed by monitoring and recording all adverse events (AEs) and change in potassium and creatinine. Efficacy was assessed as change from baseline in msSBP/msDBP. The mean baseline BP was 151.6/86.9 mm Hg, urinary albumin/creatinine ratio (UACR) geometric mean was 7.3 mg mmol(-1) and eGFR was ⩾30 and <60 in 25 (78.1%) patients and was ⩾15 and <30 in 7 (21.9%) patients. Fourteen (43.8%) patients reported at least one AE, which were mild in severity. No severe AEs or deaths were reported. There were no clinically meaningful changes in creatinine, potassium, blood urea nitrogen and eGFR. The geometric mean reduction in UACR was 15.1%, and the mean reduction in msSBP and msDBP was 20.5±11.3 and 8.3±6.3 mm Hg, respectively, from baseline to Week 8 end point. LCZ696 was generally safe and well tolerated and showed effective BP reduction in Japanese patients with hypertension and renal dysfunction without a decline in renal function.

Figures

Figure 1
Figure 1
Study design.
Figure 2
Figure 2
Mean change in mean sitting blood pressure from baseline to Week 8 end point with LCZ696.
Figure 3
Figure 3
Scatter plot (baseline vs. change) of UACR.

References

    1. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, Flack JM, Carter BL, Materson BJ, Ram CV, Cohen DL, Cadet JC, Jean-Charles RR, Taler S, Kountz D, Townsend R, Chalmers J, Ramirez AJ, Bakris GL, Wang J, Schutte AE, Bisognano JD, Touyz RM, Sica D, Harrap SB. Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens. 2014;32:3–15.
    1. Konta T, Ikeda A, Ichikawa K, Fujimoto S, Iseki K, Moriyama T, Yamagata K, Tsuruya K, Yoshida H, Asahi K, Kurahashi I, Ohashi Y, Watanabe T. Blood pressure control in a Japanese population with chronic kidney disease: a baseline survey of a nationwide cohort. Am J Hypertens. 2012;25:342–347.
    1. Yano Y, Fujimoto S, Sato Y, Konta T, Iseki K, Moriyama T, Yamagata K, Tsuruya K, Yoshida H, Asahi K, Kurahashi I, Ohashi Y, Watanabe T. Association between prehypertension and chronic kidney disease in the Japanese general population. Kidney Int. 2012;81:293–299.
    1. Japan nephrology society [Special issue: evidence-based practice guideline for the treatment of CKD (Japanese article)] Nihon Jinzo Gakkai Shi. 2013;55:585–860.
    1. Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M, Imai Y, Imaizumi T, Ishimitsu T, Ito M, Ito S, Itoh H, Iwao H, Kai H, Kario K, Kashihara N, Kawano Y, Kim-Mitsuyama S, Kimura G, Kohara K, Komuro I, Kumagai H, Matsuura H, Miura K, Morishita R, Naruse M, Node K, Ohya Y, Rakugi H, Saito I, Saitoh S, Shimada K, Shimosawa T, Suzuki H, Tamura K, Tanahashi N, Tsuchihashi T, Uchiyama M, Ueda S, Umemura S. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014) Hypertens Res. 2014;37:253–387.
    1. Drawz PE, Rosenberg ME. Slowing progression of chronic kidney disease. Kidney Int Suppl (2011) 2013;3:372–376.
    1. Sarafidis PA, Sharpe CC, Wood E, Blacklock R, Rumjon A, Al-Yassin A, Ariyanayagam R, Simmonds S, Fletcher-Rogers J, Vinen K. Prevalence, patterns of treatment, and control of hypertension in predialysis patients with chronic kidney disease. Nephron Clin Pract. 2012;120:c147–c155.
    1. Fraser SD, Roderick PJ, McIntyre NJ, Harris S, McIntyre CW, Fluck RJ, Taal MW. Suboptimal blood pressure control in chronic kidney disease stage 3: baseline data from a cohort study in primary care. BMC. Fam Pract. 2013;14:88.
    1. Plantinga LC, Miller ER, III, Stevens LA, Saran R, Messer K, Flowers N, Geiss L, Powe NR. Blood pressure control among persons without and with chronic kidney disease: US. trends and risk factors 1999-2006. Hypertension. 2009;54:47–56.
    1. Charra B. Fluid balance, dry weight, and blood pressure in dialysis. Hemodial Int. 2007;11:21–31.
    1. Klein IH, Ligtenberg G, Neumann J, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic nerve activity is inappropriately increased in chronic renal disease. J Am Soc Nephrol. 2003;14:3239–3244.
    1. Rüster C, Wolf G. Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol. 2006;17:2985–2991.
    1. Fliser D, Kronenberg F, Kielstein JT, Morath C, Bode-Böger SM, Haller H, Ritz E. Asymmetric dimethylarginine and progression of chronic kidney disease: the mild to moderate kidney disease study. J Am Soc Nephrol. 2005;16:2456–2461.
    1. Kalra PR, Anker SD, Coats AJ. Water and sodium regulation in chronic heart failure: the role of natriuretic peptides and vasopressin. Cardiovasc Res. 2001;51:495–509.
    1. Vanderheyden M, Bartunek J, Goethals M. Brain and other natriuretic peptides: molecular aspects. Eur J Heart Fail. 2004;6:261–268.
    1. Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A, Burnett JC., Jr Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34:886–893c.
    1. Gardner DG, Chen S, Glenn DJ, Grigsby CL. Molecular biology of the natriuretic peptide system: implications for physiology and hypertension. Hypertension. 2007;49:419–426.
    1. Potter LR, Abbey-Hosch S, Dickey DM. Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocr Rev. 2006;27:47–72.
    1. Richards AM, Wittert GA, Crozier IG, Espiner EA, Yandle TG, Ikram H, Frampton C. Chronic inhibition of endopeptidase 24.11 in essential hypertension: evidence for enhanced atrial natriuretic peptide and angiotensin II. J Hypertens. 1993;11:407–416.
    1. Boerrigter G, Burnett JC., Jr. Recent advances in natriuretic peptides in congestive heart failure. Expert Opin Investig Drugs. 2004;13:643–652.
    1. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol. 2009;191:341–366.
    1. Renkin EM, Tucker VL. Atrial natriuretic peptide as a regulator of transvascular fluid balance. News Physiol Sci. 1996;11:138–143.
    1. Brenner BM, Ballermann BJ, Gunning ME, Zeidel ML. Diverse biological actions of atrial natriuretic peptide. Physiol Rev. 1990;70:665–699.
    1. Baxter GF. The natriuretic peptides. Basic Res Cardiol. 2004;99:71–75.
    1. Chopra S, Baby C, Jacob JJ. Neuro-endocrine regulation of blood pressure. Indian J Endocrinol Metab. 2011;15 (Suppl 4:S281–S288.
    1. Kidney Disease Outcomes Quality Initiative (K/DOQI). NKF guidelines – Goals of antihypertensive therapy in CKD. Am J Kidney Dis. 2004;43 (Suppl 1:S65–S73.
    1. Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255–1266.
    1. Kario K, Sun N, Chiang FT, Supasyndh O, Baek SH, Inubushi-Molessa A, Zhang Y, Gotou H, Lefkowitz M, Zhang J. Efficacy and safety of LCZ696, a first-in-Class angiotensin receptor neprilysin inhibitor, in Asian patients with hypertension: a randomized, double-blind, placebo-controlled study. Hypertension. 2014;63:698–705.
    1. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–992.
    1. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, Sever PS, McG Thom S. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004-BHS IV. J Hum Hypertens. 2004;18:139–185.
    1. Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) J Clin Pharmacol. 2010;50:401–414.
    1. Kobalava Z, Pavlikova E, Averkov O, Moiseev V, Albrecht D, Feng A, Chandra P, Jordaan PJ.First experience with concomitant AT1 and neprilysin (NEP 24.11) inhibition with LCZ696 in patients with chronic heart failure Circulation 2010122A19378(Abstract).
    1. Mangrum AJ, Bakris GL. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in chronic renal disease: safety issues. Semin Nephrol. 2004;24:168–175.
    1. Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, King AJ, Klahr S, Massry SG, Seifter JL. Blood pressure control, proteinuria, and the progression of renal disease. The Modification of Diet in Renal Disease Study. Ann Intern Med. 1995;123:754–762.
    1. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, Shi V, Bransford T, Takeuchi M, Gong J, Lefkowitz M, Packer M, McMurray JJ. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380:1387–1395.
    1. Plum J, Bünten B, Nèmeth R, Grabensee B. Effects of the angiotensin II antagonist valsartan on blood pressure, proteinuria, and renal hemodynamics in patients with chronic renal failure and hypertension. J Am Soc Nephrol. 1998;9:2223–2234.
    1. Palmer BF. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what to do if the serum creatinine and/or serum potassium concentration rises. Nephrol Dial Transplant. 2003;18:1973–1975.
    1. O'Seaghdha CM, Perkovic V, Lam TH, McGinn S, Barzi F, Gu DF, Cass A, Suh I, Muntner P, Giles GG, Ueshima H, Woodward M, Huxley R. Blood pressure is a major risk factor for renal death: an analysis of 560 352 participants from the Asia-Pacific region. Hypertension. 2009;54:509–515.
    1. Tozawa M, Iseki K, Iseki C, Kinjo K, Ikemiya Y, Takishita S. Blood pressure predicts risk of developing end-stage renal disease in men and women. Hypertension. 2003;41:1341–1345.
    1. Martinez-Castelao A, Górriz JL, Portolés JM, De Alvaro F, Cases A, Luño J, Navarro-González JF, Montes R, De la Cruz-Troca JJ, Natarajan A, Batlle D. Baseline characteristics of patients with chronic kidney disease stage 3 and stage 4 in Spain: the MERENA observational cohort study. BMC Nephrol. 2011;12:53.
    1. Peralta CA, Hicks LS, Chertow GM, Ayanian JZ, Vittinghoff E, Lin F, Shlipak MG. Control of hypertension in adults with chronic kidney disease in the United States. Hypertension. 2005;45:1119–1124.
    1. Prøsch LK, Saelen MG, Gudmundsdottir H, Dyrbekk D, Hunderi OH, Arnesen E, Paulsen D, Skjønsberg H, Os I. Blood pressure control is hard to achieve in patients with chronic renal failure: results from a survey of renal units in Norway. Scand J Urol Nephrol. 2005;39:242–248.
    1. Agarwal R. Blood pressure components and the risk for end-stage renal disease and death in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4:830–837.
    1. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, de Jong PE, de Zeeuw D, Shahinfar S, Toto R, Levey AS. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta- analysis. Ann Intern Med. 2003;139:244–252.
    1. Kiberd BA, Larson TS, Robertson CR, Jamison RL. Effect of atrial natriuretic peptide on vasa recta blood flow in the rat. Am J Physiol. 1987;252:F1112–F1117.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する