title: Anti-TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy.
abstract: TGF-βhas been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF-β1 activity with a TGF-β1-specific, humanized, neutralizing monoclonal antibody (TGF-β1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3-3.3 mg/dl for women and 1.5-3.5 mg/dl for men (or eGFR of 20-60 ml/min per 1.73 m2), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF-β1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF-β1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF-β1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; voelker_james_r@lilly.com.
authors.forename: James
authors.initials: J
authors.lastname: Voelker
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Berg
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Matthew
authors.initials: M
authors.lastname: Sheetz
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Kevin
authors.initials: K
authors.lastname: Duffin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Tong
authors.initials: T
authors.lastname: Shen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Brian
authors.initials: B
authors.lastname: Moser
authors.affiliation: Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
authors.forename: Tom
authors.initials: T
authors.lastname: Greene
authors.affiliation: Department of Medicine, Zablocki Veterans Administration Medical Center, Milwaukee, Wisconsin.
authors.forename: Samuel S
authors.initials: SS
authors.lastname: Blumenthal
authors.affiliation: Second Department of Medicine, Third Faculty of Medicine, Charles University, Prague, Czech Republic.
authors.forename: Ivan
authors.initials: I
authors.lastname: Rychlik
authors.affiliation: Barzilai University Medical Center, Department of Nephrology and Hypertension, Ashkelon and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Yagil
authors.affiliation: Clinique Universitaire de Néphrologie, Centre Hospitalier Universitaire de Grenoble Alpes, Grenoble, France; and.
authors.forename: Philippe
authors.initials: P
authors.lastname: Zaoui
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Julia B
authors.initials: JB
authors.lastname: Lewis
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000276:immunology*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D053773:Transforming Growth Factor beta1 / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D053773:Transforming Growth Factor beta1
keywords: Diabetic Kidney Disease; Transforming growth factor beta; proteinuria; renal fibrosis