Peter Winkle1, Steven Goldsmith2, Michael J Koren3, Serge Lepage4, Jennifer Hellawell5, Ashit Trivedi6, Kate Tsirtsonis7, Siddique A Abbasi6, Allegra Kaufman6, Richard Troughton8, Adriaan Voors9, Jean-Sebastien Hulot10,11, Erwan Donal12, Navid Kazemi13, Joel Neutel14. 1. Anaheim Clinical Trials, 2441 W La Palma Ave, Anaheim, CA, 92801, USA. 2. Hennepin Healthcare and the University of Minnesota, 715 S 8 St, Minneapolis, MN, 55415, USA. 3. Jacksonville Center for Clinical Research, 4085 University Blvd S #1, Jacksonville, FL, 32216, USA. 4. Department of Medicine, Université de Sherbrooke, 3001, 12e Avenue Nord, Sherbrooke, Québec, J1H 5N4, Canada. 5. Amgen Inc., 1120 Veterans Blvd, South San Francisco, CA, 94080, USA. jhellawe@amgen.com. 6. Amgen Inc., One Amgen Center Dr, Thousand Oaks, CA, 91320, USA. 7. Amgen Limited, 1 Uxbridge Business Park, Sanderson Rd, Uxbridge, UB8 1DH, UK. 8. Department of Medicine, Christchurch Heart Institute, University of Otago, PO Box 4345, Christchurch, 8140, New Zealand. 9. Department of Cardiology (AB31), University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands. 10. Université de Paris, INSERM, PARCC, F-75006, Paris, France. 11. CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, F-75015, Paris, France. 12. Universitaire Rennes, Centre Hospitalier Universitaire de Rennes, INSERM, LTSI - UMR 1099, 2 rue Henri Le Guilloux 35033, 35000, Rennes, France. 13. Palm Research Center, Inc., 9280 W Sunset Rd, Suite 306, Las Vegas, NV, 89148, USA. 14. Orange County Research Center, 14351 Myford Rd, Suite B, Tustin, CA, 92780, USA.
Abstract
PURPOSE: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). METHODS: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). PRIMARY ENDPOINT: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function. RESULTS: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler). CONCLUSIONS: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03276728. DATE OF REGISTRATION: September 8, 2017.
PURPOSE: AMG 986 is a novel apelin receptor (APJ) agonist that improves cardiac contractility in animal models without adversely impacting hemodynamics. This phase 1b study evaluated the safety/tolerability, pharmacokinetics, and pharmacodynamics of AMG 986 in healthy subjects and patients with heart failure (HF). METHODS: Healthy adults (Parts A/B) and HF patients (Part C) aged 18-85 years were randomized 3:1 to single-dose oral/IV AMG 986 or placebo (Part A); multiple-dose oral/IV AMG 986 or placebo (Part B); or escalating-dose oral AMG 986 or placebo (Part C). PRIMARY ENDPOINT: treatment-emergent adverse events, laboratory values/vital signs/ECGs; others included AMG 986 pharmacokinetics, left ventricular (LV) function. RESULTS: Overall, 182 subjects were randomized (AMG 986/healthy: n = 116, placebo, n = 38; AMG 986/HF: n = 20, placebo, n = 8). AMG 986 had acceptable safety profile; no clinically significant dose-related impact on safety parameters up to 650 mg/day was observed. AMG 986 exposures increased nonlinearly with increasing doses; minimal accumulation was observed. In HF with reduced ejection fraction patients, there were numerical increases in percent changes from baseline in LV ejection fraction and stroke volume by volumetric assessment with AMG 986 vs placebo (stroke volume increase not recapitulated by Doppler). CONCLUSIONS: In healthy subjects and HF patients, short-term AMG 986 treatment was well tolerated. Consistent with this observation, clinically meaningful pharmacodynamic effects in HF patients were not observed. Changes in ejection fraction and stroke volume in HF patients suggest additional studies may be needed to better define the clinical utility and optimal dosing for this molecule. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03276728. DATE OF REGISTRATION: September 8, 2017.
Authors: John J V McMurray; Scott D Solomon; Silvio E Inzucchi; Lars Køber; Mikhail N Kosiborod; Felipe A Martinez; Piotr Ponikowski; Marc S Sabatine; Inder S Anand; Jan Bělohlávek; Michael Böhm; Chern-En Chiang; Vijay K Chopra; Rudolf A de Boer; Akshay S Desai; Mirta Diez; Jaroslaw Drozdz; Andrej Dukát; Junbo Ge; Jonathan G Howlett; Tzvetana Katova; Masafumi Kitakaze; Charlotta E A Ljungman; Béla Merkely; Jose C Nicolau; Eileen O'Meara; Mark C Petrie; Pham N Vinh; Morten Schou; Sergey Tereshchenko; Subodh Verma; Claes Held; David L DeMets; Kieran F Docherty; Pardeep S Jhund; Olof Bengtsson; Mikaela Sjöstrand; Anna-Maria Langkilde Journal: N Engl J Med Date: 2019-09-19 Impact factor: 91.245
Authors: John G F Cleland; Jean-Claude Daubert; Erland Erdmann; Nick Freemantle; Daniel Gras; Lukas Kappenberger; Luigi Tavazzi Journal: N Engl J Med Date: 2005-03-07 Impact factor: 91.245