Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) disorders are a group of ultra-rare, inherited, lysosomal storage diseases caused by enzyme deficiencies that result in accumulation of glycosaminoglycans (GAGs) in cells throughout the body including the brain, typically leading to early death. Current treatments do not...

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Published in:Molecular genetics and metabolism 2024-08, Vol.142 (4), p.108535, Article 108535
Main Authors: Muenzer, Joseph, Ho, Carole, Lau, Heather, Dant, Mark, Fuller, Maria, Boulos, Nidal, Dickson, Patricia, Ellinwood, N. Matthew, Jones, Simon A., Zanelli, Eric, O'Neill, Cara
Format: Article
Language:English
Subjects:
Community consensus
CSF heparan sulfate
FDA accelerated approval
MPS therapeutic development
Neuronopathic MPS
Reagan-Udall Foundation
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Summary:Mucopolysaccharidoses (MPS) disorders are a group of ultra-rare, inherited, lysosomal storage diseases caused by enzyme deficiencies that result in accumulation of glycosaminoglycans (GAGs) in cells throughout the body including the brain, typically leading to early death. Current treatments do not address the progressive cognitive impairment observed in patients with neuronopathic MPS disease. The rarity and clinical heterogeneity of these disorders as well as pre-existing brain disease in clinically diagnosed patients make the development of new therapeutics utilizing a traditional regulatory framework extremely challenging. Children with neuronopathic MPS disorders will likely sustain irreversible brain damage if randomized to a placebo or standard-of-care treatment arm that does not address brain disease. The United States Food and Drug Administration (FDA) recognized these challenges, and, in 2020, issued final guidance for industry on slowly progressive, low-prevalence, rare diseases with substrate deposition that result from single enzyme defects, outlining a path for generating evidence of effectiveness to support accelerated approval based on reduction of substrate accumulation [1]. Neuronopathic MPS disorders, which are characterized by the accumulation of the GAG heparan sulfate (HS) in the brain, fit the intended disease characteristics for which this guidance was written, but to date, this guidance has not yet been applied to any therapeutic candidate for MPS. In February 2024, the Reagan-Udall Foundation for the FDA convened a public workshop for representatives from the FDA, patient advocacy groups, clinical and basic science research, and industry to explore a case study of using cerebrospinal fluid (CSF) HS as a relevant biomarker to support accelerated approval of new therapeutics for neuronopathic MPS disorders. This review provides a summary of the MPS presentations at the workshop and perspective on the path forward for neuronopathic MPS disorders. •Leading experts agree that CSF HS is a valid biomarker for neuronopathic MPS disorders•The FDA accelerated approval pathway for MPS will provide patients access to life-saving therapies•In animal models, CSF HS levels correlate with brain tissue HS levels and in turn with pathological and clinical outcomes•CSF HS is a predictor of clinical outcomes and downstream biomarkers of lysosomal and neuronal function
ISSN:1096-7192
1096-7206
1096-7206
DOI:10.1016/j.ymgme.2024.108535