Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial.

BACKGROUND

Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.

METHODS

PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin-angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.

FINDINGS

Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6-110) was -2·7 mL/min per 1·73 m

INTERPRETATION

Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.

FUNDING

Travere Therapeutics.

Informations de copyright

Copyright © 2023 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests BHR reports consulting fees from Alexion Pharmaceuticals, Alpine Pharma, BioCryst Pharmaceuticals, Calliditas Therapeutics, Novartis, Q32 Bio, Omeros, Otsuka Pharmaceuticals, Travere Therapeutics, and Vera Therapeutics; and has a leadership role at NephroNet, Lupus ABC/LRA, and Lupus Foundation of America. JB reports a research grant and consulting fees from Travere Therapeutics. HJLH reports honoraria from Travere Therapeutics for membership of the DUPLEX clinical trial steering committee; grants for clinical trials and clinical research from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk paid to his institution; consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, CLS Behring, Chinook Therapeutics, Dimerix, Lilly, Gilead Sciences, Janssen, Mitsubishi Tanabe Pharma, Novartis, Novo Nordisk, and Travere Therapeutics paid to his institution; honoraria from AstraZeneca, Bayer, and Novo Nordisk; and travel support from AstraZeneca and Lilly. CEA reports consulting fees from Travere Therapeutics and honoraria from Travere Therapeutics for membership of the DUPLEX clinical trial steering committee. SB, UAD, JKI, RK, PP, and WER are employees and stockholders of Travere Therapeutics. JF reports consulting fees and honoraria from AstraZeneca, Boehringer Ingelheim, Calliditas Therapeutics, Chinook Therapeutics, CSL Vifor, Novartis, Omeros, STADApharm, Travere Therapeutics, and Vera Therapeutics, and serves on a data safety monitoring or advisory board for Novo Nordisk and Visterra. LG reports grant support from ABIONYX Pharma and Sanofi to his institution; has been a member of advisory boards for AstraZeneca, Baxter, Chinook Therapeutics, CSL Vifor, GSK, Mundipharma, Novartis, PharmaDoc, Roche, Sanofi, and Travere Therapeutics; and has been an invited speaker at meetings supported by AstraZeneca, Astellas Pharma, Estor, Fresenius, GSK, Medtronic, Travere Therapeutics, and Werfen. DEK reports consulting fees from AstraZeneca, Chinook Therapeutics, and Travere Therapeutics, and honoraria from Chinook Therapeutics and Travere Therapeutics. LAK is a principal investigator for studies sponsored by Akebia Therapeutics, AstraZeneca, Boehringer Ingelheim, Cara Therapeutics, Chinook Therapeutics, CSL Behring, Galderma, Omeros, Otsuka Pharmaceuticals, Reata Pharmaceuticals, Sanifit Therapeutics, Travere Therapeutics, and Visterra. RL reports research grants and consulting fees from Alexion Pharmaceuticals, Amgen, BeiGene, Calliditas Therapeutics, Chinook Therapeutics, Novartis, Omeros, Otsuka Pharmaceuticals, Roche, Travere Therapeutics, and Vera Therapeutics, and travel support from Calliditas Therapeutics and Novartis. RM reports honoraria from AstraZeneca, Bayer, Berlin-Chemie Menarini, Boehringer Ingelheim, Fresenius Kabi, Novartis, Novo Nordisk, and Lilly, and travel support from Aurovitas Pharma and Menarini. AM reports consulting fees from HI-Bio, Travere Therapeutics, and Vera Therapeutics. ILN reports grants and consulting fees from George Clinical; honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, and Lilly; and travel support from AstraZeneca. MP reports consulting fees from Alexion Pharmaceuticals, Apellis Pharmaceuticals, CSL Vifor, GSK, Novartis, Otsuka Pharmaceuticals, Sanofi, and Travere Therapeutics. JR reports grant funding for clinical trials from Travere Therapeutics paid to his institution; consulting fees from Travere Therapeutics; advisory board membership for Travere Therapeutics; and a leadership role at KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. MNR reports funding for clinical trials by Travere Therapeutics paid to her institution; grants from Akebia Therapeutics, Chinook Therapeutics, the US Department of Defense, the US National Institute of Diabetes and Digestive and Kidney Diseases, Reata Pharmaceuticals, River 3 Renal, and Sanofi paid to her institution; consulting fees from ENYO Pharma, Visterra, and Walden Biosciences; membership of the data safety monitoring board of Advicenne; and leadership roles at #NephJC, Pediatric Nephrology Research Consortium, and Women in Nephrology. SCWT reports honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, GSK, and Novartis, and has leadership roles at Asian Pacific Society of Nephrology and KDIGO. VT reports consulting fees from AstraZeneca, Boehringer Ingelheim, Calliditas Therapeutics, Novartis, Omeros, Otsuka Pharmaceuticals, and Travere Therapeutics, and had a leadership role at the International Society of Nephrology. HTra reports loyalties or licenses from UpToDate; consulting fees from Aclipse Therapeutics, Boehringer Ingelheim, Maze Therapeutics, Natera, Otsuka Pharmaceuticals, PhaseV, Travere Therapeutics, and Walden Biosciences; honoraria from the US National Kidney Foundation; travel support from Travere Therapeutics; membership of a data safety and monitoring or advisory board for ChemoCentryx, Otsuka Pharmaceuticals, and Travere Therapeutics; and leadership roles at Alport Syndrome Foundation, Glomerular Diseases, Kidney Health Initiative, and Pediatric Nephrology. HTri reports grants from AstraZeneca, Bayer, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Dimerix, George Clinical, Novartis, Omeros, Otsuka Pharmaceuticals, and Vera Therapeutics; consulting fees from AstraZeneca, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Dimerix, George Clinical, Novartis, Omeros, Travere Therapeutics, and Vera Therapeutics; honoraria from AstraZeneca, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, George Clinical, Novartis, and Travere Therapeutics; travel support from BioCryst Pharmaceuticals, Calliditas Therapeutics, and Chinook Therapeutics; and membership of a data safety monitoring or advisory board for AstraZeneca, BioCryst Pharmaceuticals, Calliditas Therapeutics, Chinook Therapeutics, Novartis, and Travere Therapeutics. JAT reports grants, consulting fees, and honoraria from Travere Therapeutics. MGW reports grants as a member of clinical trial steering committees for Alpine Pharma, CSL Behring, Eledon Pharma, Kira Pharma, Travere Therapeutics, Otsuka Pharmaceuticals, and TESTING trials; consulting fees from George Clinical via Travere Therapeutics; honoraria from AstraZeneca, Amgen, Baxter, Boehringer Ingelheim, and Travere Therapeutics; travel support from Amgen, Baxter, Chinook Therapeutics, George Clinical, Otsuka Pharmaceuticals, and Travere Therapeutics; membership of the data safety monitoring boards for the ARGX-133 and HFpEF Polypill trials and the advisory board of Alpine Pharma, Eledon Pharma, and Kira Pharma; and leadership roles at the Australia New Zealand Society of Nephrology and Asia Pacific Society of Nephrology. VP serves as Board Director for St Vincents Health Australia and several medical research institutes; has led or served on the steering committees of trials funded by AbbVie, Bayer, Boehringer Ingelheim, Chinook Therapeutics, Gilead Sciences, GSK, Janssen, Lilly, Novartis, Novo Nordisk, Otsuka Pharmaceuticals, Pfizer, Travere Therapeutics, and Tricida; and reports honoraria for steering committee roles, scientific presentations, or advisory board attendance from AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook Therapeutics, Gilead Sciences, GSK, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, Mundipharma, Novartis, Novo Nordisk, Otsuka Pharmaceuticals, Pfizer, Travere Therapeutics, and Tricida. All other authors declare no competing interests.