Investigational drugs in development for focal segmental glomerulosclerosis

ABSTRACT

Introduction: Focal segmental glomerulosclerosis is an important cause of end stage kidney disease and is a paradigm for the study of glomerular scarring. There are no FDA approved treatments for this condition. Current therapies, assessed based on reduction in proteinuria, are generally effective in a subset of patients which suggests that FSGS is a heterogeneous group of glomerular disorders or podocytopathies that converge on a common histopathological phenotype.

Areas covered: We searched for investigational drugs agents that target different pathophysiological pathways using the key words ‘FSGS’ and ‘podocyte’ in American and European clinical trial registers (clinicaltrials.gov; clinicaltrialsregister.eu). Published articles were searched in PubMed, Medline, the Web of Science and the Cochrane Central Register of Controlled Trials Library.

Expert opinion: Progress is being made in defining the mechanism of action of subtypes of FSGS. Current and investigational therapies for FSGS target these different pathways of injury. It is anticipated that advances in systems biology will further refine the classification of FSGS by subdividing the disease based on the primary mechanism of glomerular injury, identify biomarkers to discriminate between different subtypes, and enable appropriate selection of appropriate therapy for each individual in accordance with the goals of precision medicine.

KEYWORDS:

• FSGS
• podocyte
• circulating factors
• genetics
• clinical trial

Article highlights

• There are a wide range of agents that are used to treat patients with FSGS. However, the response is generally low, in the range of 20–40%.

• Many of the drugs used to treat FSGS may exert off target actions, such as direct action on the podocyte, that attenuate glomerular injury and proteinuria.

• There is a need to develop biomarkers that characterize different pathways of injury that mediate disease in FSGS. This would allow more rational selection of drugs from the available treatments. In addition, it would enable short-term documentation of target engagement by novel therapies.

• New surrogate markers that correlate with clinically relevant outcomes such as 40-50% decline in GFR or the onset of ESKD are needed to increase te feasibility and yield of randomized clinical truals in FSGS and other glomerular disorders.

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Declaration of interest

H. Trachtman has served as a consultant to Otsuka Pharmaceutical and Kaneka Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded in part by the National Institute of Diabetes and Digestive and Kidney Diseases (DK100307 and DK100846).