Safety and potential efficacy of gemfibrozil as a supportive treatment for children with late infantile neuronal ceroid lipofuscinosis and other lipid storage disorders

Abstract

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care. Many of the therapeutic advances require invasive procedures but some progress in slowing the disease has been found and more options can be expected in the future. We also review the literature on children with disease/conditions other than NCL for the non-invasive use, safety, and tolerability of a lipid-lowering drug, gemfibrozil, as a potential treatment for NCLs. Gemfibrozil has shown efficacy in an animal model of NCL known as CLN2 (late infantile classic juvenile) and has been shown to be safe for lowering lipids in children. Among the 200 non-NCL children found in the published literature who were treated with gemfibrozil for NCL-related problems, only 3 experienced adverse events, including 2 with muscle pain and 1 with localized linear IgA bullous dermatitis. We conclude that gemfibrozil is safe for long-term use in children, causes minimal adverse events, is well tolerated, and may delay the progression of NCLs. Gemfibrozil may potentially be an alternative to more invasive therapeutic approaches currently under investigation and has the potential to be used in combination with other therapeutic approaches.

A Pediatrics Utilization Study in The Netherlands to Identify Active Pharmaceutical Ingredients Suitable for Inkjet Printing on Orodispersible Films

“…The Summary of Products Characteristics of gemfibrozil states that use in children is not recommended because of a lack of data [24]. In the literature, however, use in pediatrics is described to treat neuronal ceroid lipofuscinosis [25,26]. One medication, ivermectin, was used by 38 patients.…”

FDA orphan drug designations for lysosomal storage disorders – a cross-sectional analysis

“…Targeting the affected enzyme: TPP1 enhancer, chaperone, enzyme/ chaperone co-administration [37][38][39][40][41][42] Gemfibrozil…”

Drug Repurposing Patent Applications April–June 2020

“…Gemfibrozil is an old lipid-lowering agent, still available as a generic one, but as all fibrates it has been almost totally eclipsed by the statins. Recently, it started a second career in the rare disease field as an approved drug for the supportive treatment of neuronal ceroid lipofuscinosis, 16 a group of neuronal lipid storage disorders collectively known as Batten disease (see WO/2018/126000). Gemfibrozil has also been reported to stimulate ADAM-10-mediated proteolysis of the amyloid precursor protein, explained by the fact that the ADAM10 promoter harbors PPAR-responsive elements, thereby linking to gemfibrozil's PPAR-a agonist action, which is responsible for its antidyslipidemic activity.…”