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 1, single-dose study of fresolimumab, an anti-TGF-Β antibody, in treatment-resistant primary focal segmental glomerulosclerosis / H. Trachtman, F.C. Fervenza, D.S. Gipson, P. Heering, D.R.W. Jayne, H. Peters, S. Rota, G. Remuzzi, L.C. Rump, L.K. Sellin, J.P.W. Heaton, J.B. Streisand, M.L. Hard, S.R. Ledbetter, F. Vincenti. - In: KIDNEY INTERNATIONAL. - ISSN 0085-2538. - 79:11(2011 Jun), pp. 1236-1243.
|Titolo:||A phase 1, single-dose study of fresolimumab, an anti-TGF-Β antibody, in treatment-resistant primary focal segmental glomerulosclerosis|
|Parole Chiave:||clinical study; fresolimumab; FSGS; TGF-beta antagonism|
|Settore Scientifico Disciplinare:||Settore MED/14 - Nefrologia|
|Data di pubblicazione:||giu-2011|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/ki.2011.33|
|Appare nelle tipologie:||01 - Articolo su periodico|