IgA nephropathy (IgAN) is an important cause of ESKD for which there are no approved therapies. A challenge for evaluating treatments for IgANis the usual long time course for progression to ESKD. The aimof this Kidney Health Initiative projectwas toidentify surrogate endpoints thatcouldserve as reliable predictorsofa treatment’s effecton long-termkidney outcomes inIgANandbe used as abasis for approval. Proteinuriawas identifiedas themost widely recognized andwell studied risk factor for progression to ESKDin IgAN. Theworkgroup performed a critical review of the data on proteinuria reduction as a surrogate endpoint for a treatment’s effect on progression to ESKDin IgAN. Epidemiologic data indicate a strong and consistent relationship between the level and duration of proteinuria and loss of kidney function. Trial-level analyses of data from 13 controlled trials also show an association between treatment effects on percent reduction of proteinuria and treatment effects on a composite of time to doubling of serum creatinine, ESKD, or death.Weconclude that data support the use of proteinuria reduction as a reasonably likely surrogate endpoint for a treatment’s effectonprogression toESKDin IgAN.In theUnited States, reasonably likely surrogate end points can be used as a basis for accelerated approval of therapies intended to treat serious or life-threatening conditions, such as IgAN. The clinical benefit of products approved under this program would need to be verified in a postmarketing confirmatory trial.
|Original language||English (US)|
|Number of pages||13|
|Journal||Clinical Journal of the American Society of Nephrology|
|State||Published - Mar 7 2019|
Bibliographical noteFunding Information:
This work was supported by the Kidney Health Initiative (KHI), a public-private partnership between the American Society of Nephrology, the US FDA, and .90 member organizations and companies to enhance patient safety and foster innovation in kidney disease. KHI funds were used to defray costs incurred during the conduct of the project, including project management support, which was expertly provided by American Society of Nephrology staff members Melissa West, Meaghan Allain, and Elle Silverman. There was no honorarium or other financial support provided to KHI workgroup members. The authors of this paper had final review authority and are fully responsible for its content. KHI makes every effort to avoid actual, potential, or perceived conflicts of interest that may arise as a result of industry relationships or personal interests among the members of the workgroup. More information on KHI, the workgroup, or the conflict of interest policy can be found at www.kidneyhealthinitiative.org.
A.T. and P.H.N. cochaired the workgroup. K.J.C. and L.A.I. conducted the repeat trial-level meta-analysis. J.F. and V.P. provided data from Supportive Versus Immunosuppressive Therapy for the Treatment of Progressive IgA Nephropathy and Therapeutic Evaluation of Steroids in IgA Nephropathy Global, respectively. S.B.-S., R.W.M., and J.I.S. extracted and tabulated data from the epidemiologic studies and clinical trials. All authors reviewed the data, discussed the findings and conclusions, and contributed to and reviewed the manuscript. P.H.N. is currently employed by University of Minnesota. He has received research funding from National Institutes of Health (NIH) and FDA, and as site PI for clinical trials (ChemoCentryx, Otsuka, Aurinia, InflaRx, Omeros), has received honoraria from ASN (BRCU) and is a scientific advisor or member of ASN (PGE Committee Chair, Education Committee). A.T. is currently employed by the FDA. The following are members of the workgroup: J.B. is currently employed by University of Leicester Consultancy Agreements. He has received research funding from Calliditas, GlaxoSmithKline, Novartis, has received honoraria from AstraZeneca and is scientific advisor or Member of Editorial Board of KidneyInternational,CJASN&ClinicalScience.HeissitePIforclinical trials for Calliditas, Retrophin, Novartis EMD Serono, Akebia, Astra-Zeneca,Otsuka,Astellas,andBayer.K.C.iscurrentlyemployedbyKJC Statistics Limited and serves as a consultant for GSK Pharmaceuticals, Otsuka Pharmaceuticals, Retrophin, Omeros. He is a member of Kidney Health Initiative. D.C.C. is currently employed by Toronto General Hospital and serves as a consultant for Chemocentryx, Dimerix, Calliditas, Analyn. He has received research funding from Genetech, has received honoraria from Mallincrodt and is a scientific advisor or member of the Kidney International and NephCure. J.F. is currently employed by RWTH University of Aachen and serves as a consultantforAmgen,Calliditas,Chugai,Fresenius,Omeros,Vifor.He has received honoraria from Amgen, Boehringer, Fresenius, Vifor and is a scientific advisor or member of the Chugai Speakers Bureau. He is site PI for clinical trials for Calliditas, Retrophin, and Omeros. B.S.G. is currently employed by Covance Clinical Research Organizatiom. She is a scientific advisor or member of the Kidney Health Initiative Board of Directors, National Kidney Disease CKD Registry, Scientific Advisory Board, NKF/FDA/EMA Renal Workshop, and Stakeholder Committee. L.A.I. is currently employed by Tufts Medical Center in Boston and serves as a consultant for Tricidia and Omeros. She has received research funding from the NIH, NKF, Retrophin, and Reata, and is site PI for clinical trials by Reata and Omeros. Patents and InventionsincludeProvisionalpatent[Coresh,InkerandLevey]filed8/ 15/2014,PCT/US2015/044567. The technology is not licensedinwhole or in part to any company. Tufts Medical Center, John Hopkins University and Metabolon Inc. have a collaboration agreement to develop a product to estimate GFR from a panel of markers. Her other interests and relationships memberships from National Kidney Disease Education Program, American SocietyofNephrology,andNKF.A.T.K. is currently employed by Allena Pharmaceuticals, Inc. She has ownership interest with Keryx Biopharmaceuticals, Inc. and is a member of the Oxalosis Hyperoxaluria Foundation Working Group. A.W.M. is currently employed by JAMCO and serves as a consultant for
Retrophin, Inc. V.P. is currently employed by The George Institute for Global Health. He has received research funding from Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant). He has received honoraria from Boehringer Ingelheim and Astra Zeneca. He is a scientific advisor or member for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, and Pfizer. He has also served on advisory boards and/or has spoken at scientific meetings for AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Roche, Sanofi, Servier and Vitae. H.N.R. is a member of the editorial board of the Kidney International and serves as a scientificadvisorforOmeros.ShehasreceivedhonorariafromASN(ASN Early program, ASN Highlights). B.H.R. is currently employed by the Ohio State University Wexner Medical Center. He is a consultant for Alexion, Aurinia, Biogen, Biomarin, Bristol Myers Squibb, Calliditas, Chemocentryx, EMD-Serono, Genentech, Janssen, Lilly, Mallinckrodt, MedImmune, Morphosys, Novartis, Omeros, Pfizer, Pharmalink, Ra Pharmaceuticals, Rigel, Retrophin, and Takeda. He has received research funding from EMD-Serono and has received honoraria from Lilly, Genentech, Mallinckrodt, Chemocentryx, Roche, Pharmalink, Alexion, Aurinia, Biogen, Biomarin, Bristol Myers Squibb, Calliditas, RA and Retrophin. He is site PI for clinical trials for AstraZeneca, Chemo-centryx, EMD Serono, Hoffman-LaRoche, Human Genome Sciences, Retrophin, Rigel, the RILITE Foundation, and the NIH/ NIDDK. He serves as scientific advisor or is a member of Kidney International, Kidney international Reports, Nephrology Dialysis and transplantation and Lupus Foundation of America. His other Interests/relationships are work with ASN educational courses and the Central Society.
© 2019 by the American Society of Nephrology.