Serelaxin: A potential new drug for the treatment of acute heart failure

Expert Opinion on Investigational Drugs

Volumn 23, Issue 7, 2014, Pages 1017-1026

  Neverova, Natalia ^a   Teerlink, John R ^a,b  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b SAN FRANCISCO VETERANS AFFAIRS MEDICAL CENTER   (United States)

Author keywords

Acute heart failure; Dyspnea; Relaxin; Serelaxin; Vasodilator

Indexed keywords

NEW DRUG; SERELAXIN; RECOMBINANT PROTEIN; RELAXIN; SERELAXIN PROTEIN, HUMAN;

ACUTE HEART FAILURE; ARTICLE; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; HEMODYNAMICS; HUMAN; HYPERTENSION; KIDNEY DYSFUNCTION; KIDNEY FAILURE; LENGTH OF STAY; MORTALITY; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); SYMPTOMATOLOGY; ACUTE DISEASE; ANIMAL; CHEMISTRY; HEART FAILURE;

ACUTE DISEASE; ANIMALS; HEART FAILURE; HUMANS; RECOMBINANT PROTEINS; RELAXIN;

EID: 84902324106     PISSN: 13543784     EISSN: 17447658     Source Type: Journal    
DOI: 10.1517/13543784.2014.924504     Document Type: Article

References (66)

1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics - 2014 update: A report from the American Heart Association. Circulation 2014;129(3):e28-292
2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62(16):e147-239
3. Teerlink Jr. Treatment of acutely decompensated heart failure. In: Greenberg BH, Barnard DD, Narayan SM, Teerlink JR, editors. Management of heart failure. John Wiley & Sons, USA; 2010. p. 327-56
4. Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: Current state and framework for future research. Circulation 2005;112(25):3958-68 (Pubitemid 43739494
5. Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100, 000 cases in the Acute Decompensated Heart Failure National Registry (ADHERE). Am Heart J 2005;149(2):209-16 (Pubitemid 40348525
6. Hobbs FD, Jones MI, Allan TF, et al. European survey of primary care physician perceptions on heart failure diagnosis and management (Euro-HF). Eur Heart J 2000;21(22):1877-87
7. Fonarow GC, Abraham WT, Albert NM, et al. Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): Rationale and design. Am Heart J 2004;148(1):43-51 (Pubitemid 38900479
8. Massie BM, O'Connor CM, Metra M, et al. Rolofylline, an adenosine A1- receptor antagonist, in acute heart failure. N Engl J Med 2010;363(15):1419-28
9. Felker GM, Pang PS, Adams KF, et al. Clinical trials of pharmacological therapies in acute heart failure syndromes: lessons learned and directions forward. Circ Heart Fail 2010;3(2):314-25
10. Vaduganathan M, Greene SJ, Ambrosy AP, et al. The disconnect between phase II and phase III trials of drugs for heart failure. Nat Rev Cardiol 2013;10(2):85-97
11. Givertz MM, Teerlink JR, Albert NM, et al. Acute decompensated heart failure: Update on new and emerging evidence and directions for future research. J Card Fail 2013;19(6):371-89
12. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised, placebo-controlled trial. Lancet 2013;381(9860):29-39
13. Mentz RJ, Felker GM, Ahmad T, et al. Learning from recent trials and shaping the future of acute heart failure trials. Am Heart J 2013;166(4):629-35
14. Metra M, Teerlink JR, Voors AA, et al. Vasodilators in the treatment of acute heart failure: What we know, what we don't. Heart Fail Rev 2009;14(4):299-307
15. Teerlink JR, Alburikan K, Metra M, Rodgers JE. Acute decompensated heart failure update. Curr Cardiol Rev 2013. [Epub ahead of print]
16. Felker GM, Lee KL, Bull DA, et al. Diuretic strategies in patients with acute decompensated heart failure. N Engl J Med 2011;364(9):797-805
17. Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med 2000;343(4):246-53 (Pubitemid 30490392
18. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA 2002;287(12):1531-40
19. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365(1):32-43
20. Chen HH, AbouEzzeddine OF, Anstrom KJ, et al. Targeting the kidney in acute heart failure: Can old drugs provide new benefit? Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE AHF) trial. Circ Heart Fail 2013;6(5):1087-94
21. Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med 1991;325(21):1468-75
22. Oliva F, Latini R, Politi A, et al. Intermittent 6-month low-dose dobutamine infusion in severe heart failure: DICE multicenter trial. Am Heart J 1999;138(2 Pt 1):247-53 (Pubitemid 29379674
23. Cuffe MS, Califf RM, Adams KF Jr, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: A randomized controlled trial. Jama 2002;287(12):1541-7 (Pubitemid 34269999
24. Follath F, Cleland JG, Just H, et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): A randomised double-blind trial. Lancet 2002;360(9328):196-202 (Pubitemid 34804646
25. Mebazaa A, Nieminen MS, Packer M, et al. Levosimendan vs dobutamine for patients with acute decompensated heart failure: The SURVIVE Randomized Trial. JAMA 2007;297(17):1883-91 (Pubitemid 46707842
26. Packer M, Colucci W, Fisher L, et al. Effect of levosimendan on the short-term clinical course of patients with acutely decompensated heart failure. JACC Heart Fail 2013;1(2):103-11
27. Teerlink JR, Clarke CP, Saikali KG, et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: A first-in-man study. Lancet 2011;378(9792):667-75
28. Cleland JG, Teerlink JR, Senior R, et al. The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011;378(9792):676-83
29. Valentova M, von Haehling S. An overview of recent developments in the treatment of heart failure: Update from the ESC Congress 2013. Expert Opin Investig Drugs 2014;23(4):573-8
30. Giamouzis G, Butler J, Starling RC, et al. Impact of dopamine infusion on renal function in hospitalized heart failure patients: Results of the Dopamine in Acute Decompensated Heart Failure (DAD-HF) Trial. J Card Fail 2010;16(12):922-30
31. Jennings AL, Davies AN, Higgins JP, Broadley K. Opioids for the palliation of breathlessness in terminal illness. Cochrane Database Syst Rev 2001(4):Cd002066
32. Johnson MJ, McDonagh TA, Harkness A, et al. Morphine for the relief of breathlessness in patients with chronic heart failure - A pilot study. Eur J Heart Fail 2002;4(6):753-6 (Pubitemid 35403084
33. Peacock WF, Hollander JE, Diercks DB, et al. Morphine and outcomes in acute decompensated heart failure: An ADHERE analysis. Emerg Med J 2008;25(4):205-9 (Pubitemid 351493056
34. McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14(8):803-69
35. Chan LJ, Hossain MA, Samuel CS, et al. The relaxin peptide family-structure, function and clinical applications. Protein Pept Lett 2011;18(3):220-9
36. Bathgate RA, Halls ML, van der Westhuizen ET, et al. Relaxin family peptides and their receptors. Physiol Rev 2013;93(1):405-80
37. Samuel CS, Hewitson TD, Unemori EN, Tang ML. Drugs of the future: The hormone relaxin. Cell Mol Life Sci 2007;64(12):1539-57 (Pubitemid 46954152
38. Miyares MA, Davis KA. Serelaxin, a 'breakthrough' investigational intravenous agent for acute heart failure. P T. 2013;38(10):606-11
39. Bullesbach EE, Schwabe C. Functional importance of the A chain loop in relaxin and insulin. J Biol Chem 1994;269(18):13124-8 (Pubitemid 24206073
40. Teichman SL, Unemori E, Dschietzig T, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev 2009;14(4):321-9
41. Stewart DR, Celniker AC, Taylor CA Jr, et al. Relaxin in the peri-implantation period. J Clin Endocrinol Metab 1990;70(6):1771-3
42. Johnson MR, Okokon E, Collins WP, et al. The effect of human chorionic gonadotropin and pregnancy on the circulating level of relaxin. J Clin Endocrinol Metab 1991;72(5):1042-7 (Pubitemid 21921804
43. Taylor MJ, Clark CL. Evidence for a novel source of relaxin: Atrial cardiocytes. J Endocrinol 1994;143(2):R5-8
44. Hsu SY, Kudo M, Chen T, et al. The three subfamilies of leucine-rich repeatcontaining G protein-coupled receptors (LGR): Identification of LGR6 and LGR7 and the signaling mechanism for LGR7. Mol Endocrinol 2000;14(8):1257-71 (Pubitemid 32260486
45. Hsu SY, Nakabayashi K, Nishi S, et al. Activation of orphan receptors by the hormone relaxin. Science 2002;295(5555):671-4 (Pubitemid 34111824
46. Dschietzig T, Alexiou K, Kinkel HT, et al. The positive inotropic effect of relaxin-2 in human atrial myocardium is preserved in end-stage heart failure: Role of G(i)-phosphoinositide-3 kinase signaling. J Card Fail 2011;17(2):158-66
47. Jeyabalan A, Shroff SG, Novak J, Conrad KP. The vascular actions of relaxin. Adv Exp Med Biol 2007;612:65-87
48. Bani-Sacchi T, Bigazzi M, Bani D, et al. Relaxin-induced increased coronary flow through stimulation of nitric oxide production. Br J Pharmacol 1995;116(1):1589-94
49. Conrad KP. Mechanisms of renal vasodilation and hyperfiltration during pregnancy. J Soc Gynecol Investig 2004;11(7):438-48 (Pubitemid 39349195
50. Dschietzig T, Bartsch C, Richter C, et al. Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: Attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 2003;92(1):32-40 (Pubitemid 36105604
51. Novak J, Ramirez RJ, Gandley RE, et al. Myogenic reactivity is reduced in small renal arteries isolated from relaxin-treated rats. Am J Physiol Regul Integr Comp Physiol 2002;283(2):R349-55
52. McGuane JT, Debrah JE, Sautina L, et al. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology 2011;152(7):2786-96
53. Xu Q, Chakravorty A, Bathgate RA, et al. Relaxin therapy reverses large artery remodeling and improves arterial compliance in senescent spontaneously hypertensive rats. Hypertension 2010;55(5):1260-6
54. Siryk-Bathgate A, Dabul S, Lymperopoulos A. Current and future G protein-coupled receptor signaling targets for heart failure therapy. Drug Des Devel Ther 2013;7:1209-22
55. Du XJ, Hewitson TD, Nguyen MN, Samuel CS. Therapeutic effects of serelaxin in acute heart failure. Circ J 2014;78(3):542-52
56. Mordenti J, Chen SA, Moore JA, et al. Interspecies scaling of clearance and volume of distribution data for five therapeutic proteins. Pharm Res 1991;8(11):1351-9
57. Cossum PA, Dwyer KA, Roth M, et al. The disposition of a human relaxin (hRlx-2) in pregnant and nonpregnant rats. Pharm Res 1992;9(3):419-24
58. O'Byrne EM, Brindle S, Quintavalla J, et al. Tissue distribution of injected 125I-labeled porcine relaxin: Organ uptake, whole-body autoradiography, and renal concentration of radiometabolites. Ann N Y Acad Sci 1982;380:187-97 (Pubitemid 12128057
59. Cheah SH, Sherwood OD. Target tissues for relaxin in the rat: Tissue distribution of injected 125I-labeled relaxin and tissue changes in adenosine 3', 5'- monophosphate levels after in vitro relaxin incubation. Endocrinology 1980;106(4):1203-9 (Pubitemid 10135777
60. Gavino ES, Furst DE. Recombinant relaxin: A review of pharmacology and potential therapeutic use. BioDrugs 2001;15(9):609-14
61. Dschietzig T, Teichman S, Unemori E, et al. Intravenous recombinant human relaxin in compensated heart failure: A safety, tolerability, and pharmacodynamic trial. J Card Fail 2009;15(3):182-90
62. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): A multicentre, randomised, placebocontrolled, parallel-group, dose-finding phase IIb study. Lancet 2009;373(9673):1429-39
63. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: Correlation with outcomes. J Am Coll Cardiol 2013;61(2):196-206
64. Filippatos G, Teerlink JR, Farmakis D, et al. Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: Results from the RELAX-AHF trial. Eur Heart J 2014;35(16):1041-50
65. Ponikowski P, Mitrovic V, Ruda M, et al. A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure. Eur Heart J 2014;35(7):431-41
66. Voors AA, Meyer S, Stepinska J, et al. Renal hemodynamic effects of serelaxin in patients with chronic heart failure: Main results of a randomized, placebo- Controlled, multiCenter study. Heart Failure Society of America, Orlando, FL, USA; 2013.