A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis

Abstract

IntroductionSteroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay end-stage renal disease.MethodsPatients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti−transforming growth factor−β antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria.ResultsOf 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m2 and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was –18.5% (P = 0.008), +10.5% (P = 0.52), and +9.0% (P = 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252.DiscussionThe study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power.

Transforming growth factor–β in tissue fibrosis

“…Treatment-emergent adverse events (including rash, headache, and gingival bleeding) were noted in treated patients; however, overall fresolimumab was safe and well tolerated. Vincenti et al, 2017 Diabetic nephropathy…”

Advanced therapeutics in focal and segmental glomerulosclerosis

“…Trachtman et al applied Fresolimumab to 16 patients with SR‐FSGS in a phase I clinical trial, with the results showing that urinary protein was reduced by more than 50% in three patients . In a recent phase II trial of fresolimumab in 26 SR‐FSGS patients, fresolimumab neither reduced urinary protein nor protected renal function compared with placebo; Sparsentan can antagonise both angiotensin receptor 1 (AT1) and endothelin receptor A (ETA) receptors and provide FSGS patients dual protection. A phase II RCT study (DUET study) included 100 FSGS patients.…”

Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies

“…Blockade of TGF‐β signaling with anti‐TGF‐β1 antibody protected mice from diet‐induced obesity and diabetes . An antibody against TGF‐β, fresolimumab (GC 1008), is being investigated for the treatment of glomerulosclerosis, systemic sclerosis, pulmonary fibrosis, and various cancer, but not in particular context of insulin resistance …”