A phase 1, single-dose study of fresolimumab, an anti-TGF-β antibody, in treatment-resistant primary focal segmental glomerulosclerosis.

Primary focal segmental glomerulosclerosis (FSGS) is a disease with poor prognosis and high unmet therapeutic need. Here, we evaluated the safety and pharmacokinetics of single-dose infusions of fresolimumab, a human monoclonal antibody that inactivates all forms of transforming growth factor-β (TGF-β), in a phase I open-label, dose-ranging study. Patients with biopsy-confirmed, treatment-resistant, primary FSGS with a minimum estimated glomerular filtration rate (eGFR) of 25  ml/min per 1.73  m(2), and a urine protein to creatinine ratio over 1.8  mg/mg were eligible. All 16 patients completed the study in which each received one of four single-dose levels of fresolimumab (up to 4  mg/kg) and was followed for 112 days. Fresolimumab was well tolerated with pustular rash the only adverse event in two patients. One patient was diagnosed with a histologically confirmed primitive neuroectodermal tumor 2 years after fresolimumab treatment. Consistent with treatment-resistant FSGS, there was a slight decline in eGFR (median decline baseline to final of 5.85 ml/min per 1.73  m(2)). Proteinuria fluctuated during the study with the median decline from baseline to final in urine protein to creatinine ratio of 1.2  mg/mg with all three Black patients having a mean decline of 3.6  mg/mg. The half-life of fresolimumab was ∼14 days, and the mean dose-normalized Cmax and area under the curve were independent of dose. Thus, single-dose fresolimumab was well tolerated in patients with primary resistant FSGS. Additional evaluation in a larger dose-ranging study is necessary

A phase 2, double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis

Introduction: Steroid-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. Methods: Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti transforming growth factor b 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. Results: Of 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 ¼ 0.008), þ10.5% (P ¼ 0.52), and þ9.0% (P ¼ 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. Discussion: The 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

A phase 2, double-blind, placebo-controlled, randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis

Introduction: Steroid-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. Methods: Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti transforming growth factor b 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. Results: Of 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 ¼ 0.008), þ10.5% (P ¼ 0.52), and þ9.0% (P ¼ 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. Discussion: The 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