Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis

Gabriel C Barsotti; Randy Luciano; Ashwani Kumar; Kristin Meliambro; Vijayakumar Kakade; Joji Tokita; Abhijit Naik; Jia Fu; Elizabeth Peck; John Pell; Anand Reghuvaran; E M Tanvir; Prashant Patel; Weijia Zhang; Fan Li; Gilbert Moeckel; Sudhir Perincheri; Lloyd Cantley; Dennis G Moledina; F Perry Wilson; John C He; Madhav C Menon

doi:10.1016/j.ekir.2024.02.006

Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis

Kidney Int Rep. 2024 Feb 13;9(5):1354-1368. doi: 10.1016/j.ekir.2024.02.006. eCollection 2024 May.

Authors

Gabriel C Barsotti¹, Randy Luciano¹, Ashwani Kumar¹, Kristin Meliambro², Vijayakumar Kakade¹, Joji Tokita², Abhijit Naik³, Jia Fu², Elizabeth Peck⁴, John Pell¹, Anand Reghuvaran¹, E M Tanvir¹, Prashant Patel⁵, Weijia Zhang², Fan Li⁶, Gilbert Moeckel⁷, Sudhir Perincheri⁷, Lloyd Cantley¹, Dennis G Moledina¹, F Perry Wilson¹, John C He², Madhav C Menon¹

Affiliations

¹ Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
² Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
³ Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
⁴ Clinical Research Coordinator, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
⁵ Investigational Drug Service, Department of Pharmacy Services, Yale New Haven Hospital, Connecticut, USA.
⁶ Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.
⁷ Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.

Abstract

Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted.

Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies.

Results and conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.

Keywords: AMP-activated protein kinase; adjunctive therapy; focal segmental glomerulosclerosis; metformin; phase 2; randomized trial.