Ewelina Kulikowski1, Christopher Halliday1, Jan Johansson2, Mike Sweeney2, Kenneth Lebioda1, Norman Wong1, Mathias Haarhaus3, Vincent Brandenburg4, Srinivasan Beddhu5, Marcello Tonelli6, Carmine Zoccali7, Kamyar Kalantar-Zadeh8,9,10. 1. Resverlogix Corp. Research and Development, Calgary, Alberta, Canada. 2. Resverlogix Corp. Clinical Development, San Francisco, California, USA. 3. Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. 4. Department of Cardiology, University Hospital RWTH Aachen, Aachen, Germany. 5. Division of Nephrology and Hypertension and Medical Service, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA. 6. Department of Medicine, University of Calgary, Calgary, Alberta, Canada. 7. Division of Nephrology and Hypertension and Renal Transplantation, Ospedali Riuniti, Reggio Calabria, Italy. 8. Harold Simmons Center for Kidney Disease Research and Epidemiology, Division of Nephrology and Hypertension, University of California Irvine Medical Center, Orange, California, USA. 9. Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach, California, USA. 10. Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA.
Abstract
BACKGROUND/AIMS: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKD patients. METHODS: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. RESULTS: Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m2) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m2) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. CONCLUSION: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKD patients. This is being examined in the phase III trial BETonMACE.
RCT Entities:
BACKGROUND/AIMS: The association between serum alkaline phosphatase (ALP) with adverse cardiovascular outcomes, in Chronic Kidney Disease (CKD) patients has previously been reported and may be a result of increased vascular calcification and inflammation. Here we report, for the first time, the effects of pharmacologic epigenetic modulation on levels of ALP and kidney function via a novel oral small molecule BET inhibitor, apabetalone, in CKDpatients. METHODS: A post-hoc analysis evaluated patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2, who participated in the apabetalone phase 2 randomized controlled trials (SUSTAIN and ASSURE). 48 CKD subjects with a history of cardiovascular disease (CVD) were treated with 100mg twice-daily of 24 and 26 weeks of apabetalone or placebo. ALP and eGFR were measured prior to randomization and at final visits. RESULTS:Patients who received apabetalone (n=35) versus placebo (n=13) over 6 months showed significantly (p=0.02) lowered serum ALP -14.0% (p<0.0001 versus baseline) versus -6.3% (p=0.9 versus baseline). The eGFR in the apabetalone group increased by 3.4% (1.7 mL/min/1.73 m2) (p=0.04 versus baseline) and decreased by 5.8% (2.9 mL/min/1.73 m2) (p=0.6 versus baseline) in the placebo group. Apabetalone was well tolerated. CONCLUSION: A post-hoc analysis of CKD subjects from the SUSTAIN and ASSURE randomized controlled trials demonstrated favorable effects of apabetalone on ALP and eGFR, and generated the hypothesis that epigenetic modulation by BET inhibition may potentially offer a novel therapeutic strategy to treat CVD and progressive kidney function loss in CKDpatients. This is being examined in the phase III trial BETonMACE.
Authors: Kamyar Kalantar-Zadeh; Gregory G Schwartz; Stephen J Nicholls; Kevin A Buhr; Henry N Ginsberg; Jan O Johansson; Ewelina Kulikowski; Kenneth Lebioda; Peter P Toth; Norman Wong; Michael Sweeney; Kausik K Ray Journal: Clin J Am Soc Nephrol Date: 2021-04-27 Impact factor: 8.237
Authors: Julio M Martinez-Moreno; Miguel Fontecha-Barriuso; Diego Martin-Sanchez; Juan Guerrero-Mauvecin; Elena Goma-Garces; Beatriz Fernandez-Fernandez; Sol Carriazo; Maria D Sanchez-Niño; Adrian M Ramos; Marta Ruiz-Ortega; Alberto Ortiz; Ana B Sanz Journal: Int J Mol Sci Date: 2020-06-09 Impact factor: 5.923
Authors: Laura M Tsujikawa; Li Fu; Shovon Das; Christopher Halliday; Brooke D Rakai; Stephanie C Stotz; Christopher D Sarsons; Dean Gilham; Emily Daze; Sylwia Wasiak; Deborah Studer; Kristina D Rinker; Michael Sweeney; Jan O Johansson; Norman C W Wong; Ewelina Kulikowski Journal: Clin Epigenetics Date: 2019-07-12 Impact factor: 6.551
Authors: Dean Gilham; Audrey L Smith; Li Fu; Dalia Y Moore; Abenaya Muralidharan; St Patrick M Reid; Stephanie C Stotz; Jan O Johansson; Michael Sweeney; Norman C W Wong; Ewelina Kulikowski; Dalia El-Gamal Journal: Biomedicines Date: 2021-04-18
Authors: Jose Luis Morgado-Pascual; Sandra Rayego-Mateos; Lucia Tejedor; Beatriz Suarez-Alvarez; Marta Ruiz-Ortega Journal: Front Pharmacol Date: 2019-11-08 Impact factor: 5.810