PHILADELPHIA (FRONTLINE MEDICAL NEWS)– Anti-TGF-beta 1 therapy was safe and well-tolerated, but failed to slow disease progression in patients with advanced diabetic nephropathy in a randomized, double-masked, phase 2 dose-ranging study.
In fact, the trial was terminated 4 months early for efficacy futility, Dr. James R. Voelker reported at Kidney Week 2014.
In 416 patients with type 1 or type 2 diabetes and a likelihood of rapid disease progression who were randomized to receive subcutaneous treatment with either placebo or various doses of a beta-1-specific humanized monoclonal neutralizing antibody known as LY2382770 (LY).
Treatment at any dose was not significantly more effective than placebo with respect to the primary outcome measure of mean change in serum creatinine. Mean serum creatinine increased from 2.22 to 2.48 mg/dl in the placebo group, and in the treatment groups it increased from 2.15 to 2.49 mg/dl (2 mg/month group), from 2.13 to 2.49 mg/dl (10 mg/month group), and from 2.15 to 2.50 mg/dl (50 mg/month group), Dr. Voelker of Eli Lilly and Co., Indianapolis, said at the meeting, which was sponsored by the American Society of Nephrology.
Patients in the study were adults aged 25 years or older (mean 62.2 years ) with serum creatinine of 1.3 to 3.3 mg/dl for women, and 1.5 to 3.5 mg/dl for men, or estimated glomerular filtration rate of 20 to 60 ml/min/1.73 m2, and they had a 24-hour urine protein/creatinine ratio of at least 800 mg/g. The groups were similar with respect to demographics and baseline characteristic, and most (75%) were men with type 2 diabetes (90%). All patient were receiving stable renin-angiotensin-system inhibition (RASi) therapy.
The intent was to select a population with a likelihood of fairly rapid disease progression during the course of the study to enable detection of a treatment effect, Dr. Voelker explained.
“Diabetic nephropathy is a disease of significant unmet medical need, as it is the leading cause of end-stage renal disease in much of the world. Thus. it is incumbent upon the nephrology community to identify new and more effective treatments than are currently available,” Dr. Voelker said.
TGF-beta over-activity has been implicated as a key pathogenic factor in diabetic neuropathy, and it was previously demonstrated that a TGF-beta 1-specific humanized monoclonal antibody was as effective as an antibody against all three TGF-beta isoforms, he said.
“We also had demonstrated that beta 1-specific inhibition in preclinical animal toxicology testing was far more tolerated than when you inhibit all 3 TGF-beta isoforms, which I should mention are all differentially expressed and regulated, but all signal through the same receptor complex,” he added, noting that based on these and other data, it was hypothesized that modulating excessive beta 1 activity with LY would safely slow renal progression in patients with diabetes on background RASi therapy.
The study was overseen by an independent data safety monitoring committee that reviewed unblinded safety data at periodic intervals. No safety issues emerged, but in the later stages of the study the committee did recommend that an unscheduled utility analysis be performed. Based on the results of that analysis, the decision was made to prematurely terminate the study about 4 months before its scheduled completion.
“Unfortunately there was no evidence in any of the study arms of a slowing of the rate of (serum creatinine increase),” Dr. Voelker said, adding that there also was no evidence of a benefit in numerous subgroup analyses, including analyses based on diabetes type.
Dr. Voelker is an employee of Eli Lilly and Co, which sponsored this study.