Effects of Bardoxolone Methyl in Alport Syndrome

Background: Alport syndrome is an inherited kidney disease characterised by type IV collagen abnormalities and progressive loss of kidney function. We aimed to evaluate the safety and efficacy of bardoxolone methyl in patients with Alport syndrome.  Methods: We randomly assigned patients with Alport syndrome, ages 12 to 70 years and estimated GFR (eGFR) 30 to 90 mL/min/1·73m2, to bardoxolone methyl (n=77) or placebo (n=80). Primary efficacy endpoints were change from baseline in eGFR in patients randomised to bardoxolone methyl versus placebo after 48 and 100 weeks of treatment. Key secondary efficacy endpoints were change from baseline in eGFR in patients randomised to bardoxolone methyl versus placebo at 52 and 104 weeks, four-weeks after the last administration of study drug. The trial was registered with ClinicalTrials.gov (NCT03019185) and EudraCT (2016-004395-22). Findings: Patients randomised to bardoxolone methyl experienced significant preservation in eGFR relative to placebo at 48 and 100 weeks (between-group differences of 9·5 ± 1·8 (97· 5% CI: 5·4, 13·6; p<0·0001) and 7·7 ± 2·1 mL/min/1·73 m2 (95% CI: 3·4, 11·9; p=0·005), respectively). Following a four-week off-treatment period, corresponding mean differences in eGFR were 5·1 ± 1·7 (97·5% CI: 1·4, 8·8; p=0·0021) and 4·3 ± 1·9 mL/min/1·73 m 2 (95% CI: 0·6, 7·9; p=0·023), respectively. Discontinuations from study treatment were more frequent among patients randomised to bardoxolone methyl; serious adverse events were more frequent among patients randomised to placebo. Three patients in each group developed kidney failure. There were no reported episodes of heart failure or fluid accumulation.  Interpretation: In adolescent and adult patients with Alport syndrome receiving standard of care, treatment with bardoxolone methyl resulted in significant preservation in eGFR relative to placebo on- and off-treatment after a two-year study period.   Trial Registration: The trial was registered with ClinicalTrials.gov (NCT03019185) and EudraCT (2016-004395-22). Funding: Funded by Reata Pharmaceuticals. Declaration of Interest: Dr. Pergola reports honoraria and being a consultant for Reata Pharmaceuticals. He was also consultant and on advisory board of Akebia, Bayer, Gilead, Corvidia, Fibrogen, Tricida, Unicycive Therapeutics, and Ardelyx, as well as consultant, Speaker Bureau for AstraZeneca; and an employee at Renal Associates, PA. Dr. Agarwal reports being on steering committee and doing consulting for Reata Pharmaceuticals as well as having his travel, lodging and food paid for. He was on steering committee for Bayer Healthcare Pharmaceuticals Inc., Janssen Research & Development LLC, Relypsa Inc., Sanofi US Services Inc., Sanofi-Aventus U.S. LLC, and Akebia Therapeutics Inc.; adjudication committee for Bayer Healthcare Pharmaceuticals Inc., Janssen Research & Development LLC, and Boeringer Ingelheim International GMBH; data safety monitoring board of AstraZeneca AB, Ironwood Pharmaceuticals Inc., and Chinook; performing consulting services for Bayer Healthcare Pharmaceuticals Inc., Janssen Research & Development LLC, Relypsa Inc, Vifor Fresenius Medical Care Renal Pharma LTD., Boeringer Ingelheim International GMBH, Sanofi US Services Inc., Eli Lily and Company, AstraZeneca Pharmaceuticals LP, Boeringer Ingelheim B.V., Boeringer Ingelheim International GMBH, Sanofi-Aventus U.S. LLC, Boeringer Ingelheim International GMBH C paid for speaking by Fresenius USA Marketing Inc., and having travel, lodging and food paid for by Bayer Healthcare Pharmaceuticals Inc., Janssen Research & Development LLC, Relypsa Inc., Vifor Fresenius Medical Care Renal Pharma LTD., Boeringer Ingelheim International GMBH, Sanofi US Services Inc., Eli Lily and Company, AstraZeneca Pharmaceuticals LP, Boeringer Ingelheim B.V., Boeringer Ingelheim International GMBH , Sanofi-Aventus U.S. LLC, Fresenius USA Marketing Inc., Boeringer Ingelheim International GMBH &Co.KG, Otsuka America Pharmaceutical Inc., Opko Pharmaceuticals LLC, E.R. Squibb&Sons LLC, Merck&Co, andAkebia Therapeutics Inc. Dr. Appel had research grants from Sanofi- Genzyme, Achillion, BM Squibb, EMD Serono, Retrophin, Aurinia, Calliditas, ChemoCentryx, Zyversa, Mallinkrodt, Genentech, and NIH. He had consultantships with Alexion, Achillion, Ionis, Genentech, Mallinkrodt, Pfizer, Merck, Roche, Bristol-Myers Squibb, Up-to-Date, Genzyme-Sanofi, EMD Serono, Omeros, Regulus, and Zyversa. Dr. Bangalore was on advisory board and received grants from Reata Pharmaceuticals. Dr. Block was an employee at Reata Pharmaceuticals prior to the reported study, and currently owns stock of Reata Pharmaceuticals. Dr. Chapman was on the Reata Pharmaceuticals steering committee for ADPKD and received grants from Reata Pharmaceuticals. She also received grants and was on the steering committee for Sanofi Genzyme. Dr. Chin, Ms Goldsberry, Dr. Meyer and Dr. O’Grady are employees of Reata Pharmaceuticals Dr. Gibson was on CKD advisory board of Reata Pharmaceuticals.She was also on pediatric advisory board of Aurinia Inc. and advisory board of Retrophin Inc., and a clinical trial coinvestigator for Aurinia Inc.and Retrophin Inc. Dr. Iijima reports honoraria and consulting fees from Kyowa Kirin Co., Ltd. and honoraria from Integrated Development Associates. He also received honoraria from Zenyaku Kogyo Co., Astellas Pharma Inc , Shionogi & Co., Ltd, and Chugai Pharmaceutical Co., Ltd, consulting fees from Zenyaku Kogyo Co, JCR Pharmaceutical Co, Takeda Pharmaceutical Co., Ltd., Tejin Pharma Ltd., Ono Pharmaceutical Co., Ltd., and Sanofi K.K, grants from Zenyaku Kogyo Co, Daiichi Sankyo, Co., Ltd., Astellas Pharma Inc., Air Water Medical Inc., Eisai Co., Ltd. , Otsuka Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Shionogi & Co., Ltd., Enomoto- Yakuhin Co. Ltd., JCR Pharmaceutical Co., Ltd., and Nihon Pharmaceutical Co., Ltd. In addition, Dr. Iijima has a patent “Antisense nucleotides for exon skipping therapy in Alport syndrome” issued. Dr. Inker reports grants from Reata Pharmaceuticals. She also received grants from Omeros Corporation, Retrophin, and Otsuka, and other support from Tricida and Omeros Corporation. Dr. Kashtan has current or recent research funding from Reata Pharmaceuticals, Sanofi- Genzyme and the Novartis Institute for Biomedical Research and consulting relationships with Boerhinger-Ingelheim, Retrophin, Ono Pharmaceuticals and Daiichi-Sankyo. Dr. Mariani was on advisory boards for Reata Pharmaceuticals. Additionally, she was on advisory board for Calliditas Therapeutics and Travere Therapeutics and received grants from NIH-NIDDK and Boehringer-Ingelheim. Dr. Nozu reports lecture fees from Novartis Pharmaceuticals Corporation and consultation fee from Kyowa Kirin. In addition, Dr. Nozu has a patent issued titled “Antisense nucleotides for exon skipping therapy in Alport syndrome”. Dr. Rheault reports clinical trial payments to institution from Reata Pharmaceuticals as site PI for this study. She also performed DSMB service for Advicenne and was a clinical trial site PI for Travere, Sanofi, and Genentech trials. Dr. Silva reports consulting fee and being at advisory board for Reata Pharmaceuticals. In addition, he received research support from ProKidney, AstraZeneca, Ardelyx, GSK, Akebia, and Gldfinch Bio, was a speaker at AstraZeneca and Aurina, was on the advisory board for Ardelyx. Dr. Stenvinkel reports personal fees from Reata Pharmaceuticals. He also received personal fees Baxter, AstraZeneca, Astellas, Pfizer, and FMC, as well as grants from AstraZeneca and Bayer. Dr. Chertow was on advisory board for Reata Pharmaceuticals. He was also on advisory board for Ardelyx, Baxter, CloudCath, Cricket, DiaMedica, Durect, and Miromatrix, steering committee for Akebia, AstraZeneca, Gilead, Sanifit, and Vertex, and on board of directors of Satellite Healthcare. He had grants from Amgen. Dr Chertow performed DSMB service for Angion, Bayer, and ReCor. He has stock options of Ardelyx, CloudCath, Durect, and Miromatrix. Dr. Warady, Dr. Knebelmann, Dr. Andreoli, and Dr. Torra have nothing to disclose. Ethical Approval: The trial protocol was approved by the institutional review board at each participating study site.