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 m2, 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 m2). 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. 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 m2, 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 m2). 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. Focal segmental glomerulosclerosis (FSGS) is a clinical entity that impacts renal function through progressive fibrosis of the glomerulus. FSGS is not a single disease; rather, it is a heterogeneous clinicopathological process identified in renal biopsies that are generally performed in patients with proteinuria or nephrotic syndrome. Idiopathic or primary FSGS has a distinctive histopathological appearance, characterized by hyalinization and sclerosis of a portion of the glomerular tuft, minimal deposition of immune complexes, and effacement of visceral epithelial cell (podocyte) foot processes. Idiopathic FSGS can be distinguished from secondary causes of FSGS (for example, genetic mutations, medications, infections, reflux nephropathy, or surgical reduction in renal mass) by more widespread podocyte effacement together with the presence of nephrotic syndrome.1.Barisoni L. Schnaper H.W. Kopp J.B. Advances in the biology and genetics of the podocytopathies: implications for diagnosis and therapy.Arch Pathol Lab Med. 2009; 133: 201-216PubMed Google Scholar The implication for making the distinctions is that primary FSGS may respond to corticosteroids or other immunosuppression therapy, whereas secondary forms are treated by addressing the underlying cause. Regardless of the etiology of FSGS, the majority of cases are characterized by progressive renal fibrosis and steady deterioration in kidney function.2Levey A.S. Coresh J. 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This is with the pharmacokinetics of monoclonal that and of monoclonal and for 2010; PubMed Scopus Google Scholar The to be in studies be on both the and the of A of 2 is to result in minimal of the clinical were of in treatment-resistant primary FSGS was not a primary of this phase I study. the are of the small lack of a placebo-controlled and a single-dose treatment the in three patients. patients, were the only in the a in urine In one the patient a remission in the there was a remission reduction in to a and the a in other clinical or a reduction in proteinuria and response to the The is reduction of proteinuria is to a clinical remission of primary FSGS is to a patients have a J.S. Focal segmental glomerulosclerosis in adults.Nephrol Dial Transplant. 2003; 18: vi45-vi51Crossref PubMed Google Scholar in urine protein are also associated with patient This beneficial of treatments that reduce not proteinuria has been documented in children and adults with FSGS and other D.S. K. P.E. et to FSGS in Nephrol. 2007; 22: PubMed Scopus (30) Google Scholar, S. J.A. et and of a Int. 2004; 66: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J.A. et and segmental glomerulosclerosis: and of a Am Soc Nephrol. 2005; PubMed Scopus Google Scholar, S. J.M. et and the progression of renal disease.Ann Intern Med. 1995; PubMed Scopus Google Scholar However, is in the clinical in this small patient The in in this study cohort was and not This is with that over a in patients with resistant S. J.A. et and segmental glomerulosclerosis: and of a Am Soc Nephrol. 2005; PubMed Scopus Google Scholar, S. J.M. et and the progression of renal disease.Ann Intern Med. 1995; PubMed Scopus Google Scholar There was evidence that of the antibody the of the the other clinical to over the of the study with In the of this phase I clinical trial that fresolimumab, as a single-dose to 4 is and well tolerated in patients with treatment-resistant primary FSGS. This for with larger randomized clinical trials to of this agent in patients with primary FSGS are resistant to corticosteroids and other Patients with treatment-resistant primary FSGS years in the and the received a single fresolimumab and Patients with FSGS in the primary disease with eGFR ml/min per 1.73 and proteinuria and to or other agent were for in the that the patients were high of progression to kidney The patients not have to clinical evidence of nephrotic to for the study. were to the diagnosis and were to the J.A. et of focal segmental glomerulosclerosis: a J Kidney Dis. 2004; 43: Full Text Full Text PDF PubMed Scopus Google Scholar FSGS was on this FSGS Patients were from the study clinical evidence of secondary FSGS segmental renal renal surgical renal chronic or other cell reflux nephropathy, or other therapy, or human and or (for example, or of of a of other or a known disease; a or disease; or were or The and were and by an independent each All patients the of This was in with guidelines and This was a phase open-label, dose-ranging study. patients were and to one of four The that patients were to or However, on suggesting a response in patients received the the was to and 4 of fresolimumab to a minimal dose. was the of the and 4 were Patients were randomized to either or 4 to for In each patients received a single of fresolimumab over was to the for patients with patients with was Patients were followed for 112 and for safety and clinical outcome and patient of fresolimumab was study was to 4 fresolimumab was independent study safety after each cohort in to a on This clinical study was by The was by the in with the of The performed the and and the and the The of the was by the together with the was by all of the for the of the and the of the The to the a of all from the and the The and of for in study and and of the Fresolimumab were a with were in a in a final with a result the of were in a for were only on fresolimumab, as it with the were for this study. The was to for of pharmacokinetics each and also to for an of safety in this and were by in of to fresolimumab, and in and were from the trial were with from phase trials in patients with idiopathic fibrosis and S. J.A. et and of a Int. 2004; 66: Full Text Full Text PDF PubMed Scopus Google Scholar, S. J.A. et and segmental glomerulosclerosis: and of a Am Soc Nephrol. 2005; PubMed Scopus Google Scholar and effect A that the was on and was were to the effect of patient (for example, and disease on the pharmacokinetics of for area under the half-life half-life and of steady were for patients with FSGS the final and by from baseline in urine and were for each dose. The in this study New The of the UK are to the study and clinical for their and and especially the FSGS patients their and on of the study. This clinical study was by and in patients is to the of the