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

ABSTRACT: 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-? 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 = 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. 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.

SUBMITTER: Vincenti F

PROVIDER: S-EPMC5733825 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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

Vincenti Flavio F Fervenza Fernando C FC Campbell Kirk N KN Diaz Montserrat M Gesualdo Loreto L Nelson Peter P Praga Manuel M Radhakrishnan Jai J Sellin Lorenz L Singh Ajay A Thornley-Brown Denyse D Veronese Francisco Veríssimo FV Accomando Beverly B Engstrand Sara S Ledbetter Steven S Lin Julie J Neylan John J Tumlin James J

Kidney international reports 20170407 5

<h4>Introduction</h4>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.<h4>Methods</h4>Patients 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 (NCT01 ...[more]

PMID: 29270487

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Project description:Focal segmental glomerulosclerosis (FSGS) is a leading cause of kidney disease worldwide. The presumed etiology of primary FSGS is a plasma factor with responsiveness to immunosuppressive therapy and a risk of recurrence after kidney transplant-important disease characteristics. In contrast, adaptive FSGS is associated with excessive nephron workload due to increased body size, reduced nephron capacity, or single glomerular hyperfiltration associated with certain diseases. Additional etiologies are now recognized as drivers of FSGS: high-penetrance genetic FSGS due to mutations in one of nearly 40 genes, virus-associated FSGS, and medication-associated FSGS. Emerging data support the identification of a sixth category: APOL1 risk allele-associated FSGS in individuals with sub-Saharan ancestry. The classification of a particular patient with FSGS relies on integration of findings from clinical history, laboratory testing, kidney biopsy, and in some patients, genetic testing. The kidney biopsy can be helpful, with clues provided by features on light microscopy (e.g, glomerular size, histologic variant of FSGS, microcystic tubular changes, and tubular hypertrophy), immunofluorescence (e.g, to rule out other primary glomerulopathies), and electron microscopy (e.g., extent of podocyte foot process effacement, podocyte microvillous transformation, and tubuloreticular inclusions). A complete assessment of renal histology is important for establishing the parenchymal setting of segmental glomerulosclerosis, distinguishing FSGS associated with one of many other glomerular diseases from the clinical-pathologic syndrome of FSGS. Genetic testing is beneficial in particular clinical settings. Identifying the etiology of FSGS guides selection of therapy and provides prognostic insight. Much progress has been made in our understanding of FSGS, but important outstanding issues remain, including the identity of the plasma factor believed to be responsible for primary FSGS, the value of routine implementation of genetic testing, and the identification of more effective and less toxic therapeutic interventions for FSGS.

Project description:BackgroundChuankezhi (CKZ) injection is a traditional Chinese medicine (TCM) injection extracted from Chinese herbs Epimedium sagittatum (Yin Yang Huo) and Morinda officinalis (Bai Ji Tian). Studies have shown that CKZ has a positive effect on improving diabetic nephropathy and regulating immune function. Focal segmental glomerulosclerosis (FSGS) is a kind of refractory nephropathy, which has been confirmed as closely associated with immunity. Whether CKZ is effective against FSGS and how it works warrant further study. This study aimed to verify the efficacy of CKZ in rats with steroid-resistant (SR) FSGS and explore its mechanism of action.MethodsWe established an SR FSGS model in male Sprague Dawley (SD) rats by injecting adriamycin into the tail vein. Based on group intervention and comparison, the primary efficacy parameters of FSGS were observed, including general condition, 24-hour urine protein, serum albumin, cholesterol, triglyceride, and renal pathological changes. Network pharmacological analysis and molecular docking were used to predict the mechanism of action of CKZ. Finally, we used quantitative polymerase chain reaction (qPCR) and western blot (WB) to detect messenger RNA (mRNA) expression and protein phosphorylation at specific targets in rat kidney tissue to validate the predicted results.ResultsIntramuscular injection of CKZ had a dose-dependent effect in SR FSGS model rats, including lowering urine protein, increasing serum albumin, lowering cholesterol and triglyceride, and treating pathological lesions in the kidney. Network pharmacological analysis and Molecular docking revealed that 5 active components (Icariin, Icariside II, Epimedin C, Icaritin, and Noricaritin) might be the critical components. The findings also revealed that Akt was perhaps the critical target gene, the PI3K-Akt signaling pathway was perhaps the critical pathway, and reversible protein phosphorylation was probably the critical biological process. The qPCR and WB analyses showed that CKZ significantly increased the relative mRNA expression and protein phosphorylation of PI3K and Akt, respectively.ConclusionsThis study showed that intramuscular injection of CKZ has a significant therapeutic effect in SR FSGS rats, which may be associated with the activation of PI3K-Akt signaling by CKZ.

Dataset Information

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

Publications

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

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