Ularitide this time it is different.
- 1. Emerging Therapies in AHF: Ularitide Stefan D. Anker Innovative Clinical Trials, University Medicine Göttingen (UMG) at Göttingen, Germany s.anker@cachexia.de Sevilla, 23 May, 2015 Conflict of Interest: Consultancy, honoraria for speaking and/or research grants from Bayer, BG Medicine, BioVentrix, Brahms GmbH, Cardiorentis, LonestarHeart, Novartis, Vifor.
- 2. ASCEND-HF: Death from any cause or rehospitalization for HF at 30 days O’Connor et al. NEJM 2011
- 3. Native natriuretic peptides First generation chimeric peptides Ularitide
- 4. Synthesis Sites of the Natriuretic Peptides DR I M K R G SSS S G L GF C CS S G SGQVM K V LRR H KPS NH2 HOOC- Thr Ala ProArgSer Leu Arg Arg Tyr Arg Phe Ser Asn Cys Gly Leu GlySerGin Ala Gly IIe Arg Asp MetArgGly Gly Phe Cys Ser Ser S S NH2N- COOH- NH2N-Ser Leu Arg Arg Ser SerCys Phe Gly Gly Arg Cys Gly Arg Tyr Asn Phe Ser Gly Leu SerGin Ala Gly IIe Arg Asp Met COOH- S S ANP BNP Urodilatin
- 5. Urodilatin is synthesized in the distal tubulus cells is luminally secreted binds downstream in inner medullar-collecting duct to NPR-A and acts via cGMP and inhibits Na-reabsorption Physiology of Urodilatin (INN: Ularitide) NPR-A Natriuresis Diuresis
- 6. Summary of the Pharmacological Effects of Ularitide Hemodynamic (vasodilation) • veins • arteries Neurohumoral ¯RAAldosterone ¯Endothelin diuresis natriuresis Renal Thr Ala Pro Arg Ser Leu Arg Arg Tyr Arg Phe Ser Asn Cys Gly Leu Gly Ser Gin Ala Gly IIe Arg Asp Met ArgGly Gly Phe Cys Ser Ser S S NH2 Bronchodilation Flüge T, Regul.Pept. 1995;59:357-70. Carstens JT, Clin Sci. 1997;92:397-407 Bestle, MH, Am J Physiol, 1999, R684-R695 Carstens JT, Clin Sci. 1997;92:397-407 Bestle, MH, Am J Physiol, 1999, R684-R695 Carstens JT, Clin Sci. 1997;92:397-407 Bestle, MH, Am J Physiol, 1999, R684-R695
- 7. SIRIUS I Trial – Study Design Design: • In total, 24 patients with decompensated heart failure requiring hospitalisation as well as right heart catheterisation were included into the study (6 pts in each group) • Infusion of Ularitide 7.5, 15, and 30 ng/kg body weight/min, or placebo over 24 hours Main Inclusion Criteria • Symptomatic, decompensated chronic heart failure • Dyspnea at rest or during minimal activity • PCWP 18 mmHg, CI 2.5 l/min/m2 Primary Endpoints: • Change in PCWP at 6 hrs compared to placebo • Change in patient-assessed dyspnea at 6 hrs compared to placebo Mitrovic et al, Am Heart J, 2005, 150: 1239 Am Heart J 2005; 150:1239.e1-1239.e8
- 8. SIRIUS I – PCWP is ReducedPCWPChangefronBaseline(mmHg) Time (h) control 30 ng/kg/min 15 ng/kg/min 7,5 ng/kg/min PCWP = pulmonary capillary wedge pressure Primary Endpoint at 6 hours (n=6 per group) Am Heart J 2005; 150:1239.e1-1239.e8
- 9. SIRIUS II Trial – Study Endpoints Design: • Infusion of Ularitide 7.5, 15, and 30 ng/kg body weight/min, or placebo over 24 hours • In total, 221 patients with decompensated heart failure requiring hospitalisation as well as right heart catheterisation were included into the study (6 pts in each group) Main Inclusion Criteria: • Symptomatic, decompensated chronic heart failure • Dyspnea at rest or during minimal activity • PCWP 18 mmHg, CI 2.5 l/min/m2 Primary Endpoints: • Change in PCWP at 6 hrs compared to placebo • Change in patient-assessed dyspnea at 6 hrs compared to placebo Placebo: 53 pts 7.5 ng: 60 pts 15 ng: 53 pts 30 ng: 55 pts EHJ 2006; 27:2823–2832
- 10. Baseline Characteristics SIRIUS II N=221 LIDO N=203 VMAC N=204 Age (yrs) 60 58 62 Male (%) 70 91 73 PCWP (mmHg) 26 25 28 CI (L min-1m-2) 1.9 1.9 2.2 RAP (mmHg) 10.0 10.4 15 Syst. BP (mmHg) 125 112 120 PCWP = pulmonary capillary wedge pressure CI = cardiac index RAP = right atrial pressure Sys BP= systolic blood pressure EHJ 2006; 27:2823–2832
- 11. *p<0.05 vs placebo 24 hrs 6 hrs %Patients 0 10 20 30 40 50 60 70 Placebo * * * * * * 7.5 ng/kg/min 15 ng/kg/min 30 ng/kg/min SIRIUS II Trial – Patient-Assessed Dyspnea Proportion Moderately or Markedly Better PCWP = pulmonary capillary wedge pressureEHJ 2006; 27:2823–2832
- 12. Ularitide improves the Cardiac Index Time (Hours) -1 0 1 2 4 6 8 24 26 1.8 2.0 2.2 2.4 CI(l/min/m2) * * * * * * ** † † † Placebo 7.5 ng /kg/min 15 ng /kg/min 30 ng /kg/min Ularitide Decreases Myocardial Consumption (Change from BL) Placebo 7.5 ng /kg/min 15 ng /kg/min 30 ng /kg/min EHJ 2006; 27:2823–2832
- 13. SIRIUS II Trial – Ularitide Reduces PCWP Primary Endpoint at 6 hours Placebo 7.5 ng /kg/min 15 ng /kg/min 30ng /kg/min * p<0.01 vs Placebo * * * * * * * * * * * * † † p<0.05 vs Placebo - 12 - 10 - 8 - 6 - 4 - 2 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (Hours) PCWP(mmHg) † † † PCWP = pulmonary capillary wedge pressure EHJ 2006; 27:2823–2832
- 14. Ularitide does not worsen renal function – analyses through 72 hours – 1000 1200 1400 1600 1800 2000 2200 2400 ml/24h Placebo 7.5 15 30 Urine Output / 24 h -8 -7 -6 -5 -4 -3 -2 -1 0 1 2 ml/min Creatinine Clearance Placebo 7.5 ng 15 ng 30 ng 24 h 48 h 72 h Total Incidences of Creatinine Increases (> 25%) %Patients 0 5 10 15 20 25 30 Placebo 7.5 ng 15 ng 30 ng Serum Creatinine -0.10 -0.05 0.00 0.05 0.10 0.15 0.20 Placebo 7.5 15 30 mg/dL EHJ 2006; 27:2823–2832
- 15. SIRIUS-II – Safety Results 30 d Mortality 13.2 3.3 3.8 1.8 0 5 10 15 %ofpatients Placebo 7.15 15 30 Ularitide, ng/kg/min Serious adverse events up to 30 d 17 8.3 9.4 10.9 0 5 10 15 20 %ofpatients Placebo 7.15 15 30 Ularitide, ng/kg/min EHJ 2006; 27:2823–2832
- 16. The TRUE-AHF programme: Ularitide in patients with AHF shifting a paradigm
- 17. • Multicenter, randomized, double blind, placebo-controlled trial, to evaluate the efficacy and safety of intravenous (IV) ularitide in patients suffering from AHF • Patient enrolment has started across approximately 190 centres in the US, Europe and Canada • Treatment: placebo or ularitide (15 ng/kg/min), 48 hrs. on top of standard care • Patients: up to 4,304 patients with AHF, randomisation 1:1 • Screening: AHF, symptoms at rest, congestion, SBP ≥116mmHg, BNP ≥500 or NT-BNP ≥2000 pg/mL, GFR ≥30, Furosemide i.v. bolus ≥40mg Placebo i.v. (n=1,076–2,152) Ularitide i.v. (n=1,076–2,152)
- 18. TRUE-AHF – Key Efficacy Measures Primary Endpoint Secondary Endpoint 2,157 patients recruited as off 20th May, 2015
- 20. Thank you !