Oral treatment for mucopolysaccharidosis VI: Outcomes of the first phase IIa study with odiparcil

Abstract

Mucopolysaccharidosis (MPS) disorders are a group of rare, progressive lysosomal storage diseases characterized by the accumulation of glycosaminoglycans (GAGs) and classified according to the deficient enzyme. Enzyme replacement therapy (ERT) of MPS VI has limited effects on ophthalmic, cardiovascular, and skeletal systems. Odiparcil is an orally available small molecule that results in the synthesis of odiparcil‐linked GAGs facilitating their excretion and reducing cellular and tissue GAG accumulation. Improve MPS treatment was a Phase 2a study of the safety, pharmacokinetics/pharmacodynamics, and efficacy of two doses of odiparcil in patients with MPS VI. The core study was a 26‐week, randomized, double‐blind, placebo‐controlled trial in patients receiving ERT and an open‐label, noncomparative, single‐dose cohort not receiving ERT. Patients aged ≥ 16 years receiving ERT were randomized to odiparcil 250 or 500 mg twice daily or placebo. Patients without ERT received odiparcil 500 mg twice daily. Of 20 patients enrolled, 13 (65.0%) completed the study. Odiparcil increased total urine GAGs (uGAGs), chondroitin sulfate, and dermatan sulfate concentrations. A linear increase in uGAG levels and odiparcil exposure occurred with increased odiparcil dose. Odiparcil demonstrated a good safety and tolerability profile. Individual analyses found more improvements in pain, corneal clouding, cardiac, vascular, and respiratory functions in the odiparcil groups vs placebo. This study confirmed the mechanism of action and established the safety of odiparcil with clinical beneficial effects after only a short treatment duration in an advanced stage of disease. Further assessment of odiparcil in younger patients is needed.

Generation of a novel disease model mouse for mucopolysaccharidosis type VI via c. 252T>C human ARSB mutation knock-in

“…In these studies, availability of odiparcil was demonstrated in vitro and in vivo assays including administration test using ARSB knock-out mice. The availability of odiparcil as therapeutic drug for MPS VI is examined in phase II trials [ 24 ]. The generated MPS VI human mutation knock-in mice are useful models for trials of novel therapeutic approaches.…”

Biomarkers of Glycosaminoglycans (GAG) accumulation in patients with mucopolysaccharidosis type VI—LeukoGAG, Corneal Opacification (COM) and Carotid Intima Media Thickening (CIMT)

“…Other studies have confirmed beneficial effects of odiparcil in animal models of MPS VI [ 15 , 17 , 23 ]. Evidence for improvement in COM was observed in a Phase 2a study of odiparcil in patients with MPS VI [ 24 ]. To apply the new therapy in the clinical setting, a quantitative measurement is necessary to evaluate and monitor the severity of corneal clouding in MPS VI patients.…”

“…This finding was in good agreement with previous studies demonstrating higher CIMT in various types of MPS patients compared with controls [ 19 , 30 , 32 ]. In the Phase 2 study, improvement in CIMT was observed in patients treated with odiparcil [ 24 ]. CIMT is correlated with carotid pathology and has been used as a marker predictive of cerebrovascular accidents in other chronic conditions including diabetes mellitus and hypertension [ [32] , [32] , [33] , [34] ].…”

Molecular Mechanisms in Pathophysiology of Mucopolysaccharidosis and Prospects for Innovative Therapy

“…Although not approved, this reagent was originally developed as an anticoagulant [390,391]. Subsequently, its role in reducing accumulated GAGs was reconsidered, and a phase 2 clinical trial for MPS VI patients was completed [392]. Participants in this study were between 16 and 64 years of age, so, as Guffon et al pointed out, further evaluation of odiparcil in younger patients should be considered.…”