Safety Study of Sodium Pentosan Polysulfate for Adult Patients with Mucopolysaccharidosis Type II.

Kenji Orii,Shunji Tomatsu,Calogera M Simonaro,Yasuyuki Suzuki,Toshiyuki Fukao,Edward H Schuchman,Molly Stapleton,Tadashi Matsumoto,Alaena Lim

doi:10.3390/diagnostics9040226

Abstract

Current therapies for the mucopolysaccharidoses (MPS) do not effectively address skeletal and neurological manifestations. Pentosan polysulfate (PPS) is an alternative treatment strategy that has been shown to improve bone architecture, mobility, and neuroinflammation in MPS animals. The aims of this study were to a) primarily establish the safety of weekly PPS injections in attenuated MPS II, b) assess the efficacy of treatment on MPS pathology, and c) define appropriate clinical endpoints and biomarkers for future clinical trials. Subcutaneous injections were administered to three male Japanese patients for 12 weeks. Enzyme replacement therapy was continued in two of the patients while they received PPS and halted for two months in one patient before starting PPS. During treatment, one patient experienced an elevation of alanine transaminase, and another patient experienced convulsions; however, these incidences were non-cumulative and unrelated to PPS administration, respectively. Overall, the drug was well-tolerated in all patients, and no serious drug-related adverse events were noted. Generally, PPS treatment led to an increase in several parameters of shoulder range of motion and decrease of the inflammatory cytokines, MIF and TNF-α, which are potential clinical endpoints and biomarkers, respectively. Changes in urine and serum glycosaminoglycans were inconclusive. Overall, this study demonstrates the safety of using PPS in adults with MPS II and suggests the efficacy of PPS on MPS pathology with the identification of potential clinical endpoints and biomarkers.

Highlights

The mucopolysaccharidoses (MPS) are a group of inherited metabolic disorders caused by deficiencies of the individual lysosomal enzyme(s) needed to break down glycosaminoglycans (GAGs).GAGs are long chains of carbohydrates that serve as major components of proteoglycans present in the extracellular matrix (ECM)
For Patients 2 and 3, injections were administered for 12 consecutive weeks; due to an unrelated convulsion experienced by Patient 1 after injection 6, Pentosan polysulfate (PPS) treatment was halted for two weeks and resumed
At week 6, alanine transaminase (ALT) levels were detected slightly above the normal range (5 IU/L above a range of 5 to 40 IU/L); the levels decreased over time and were close to baseline by week 13

Summary

Introduction

The mucopolysaccharidoses (MPS) are a group of inherited metabolic disorders caused by deficiencies of the individual lysosomal enzyme(s) needed to break down glycosaminoglycans (GAGs). GAGs are long chains of carbohydrates that serve as major components of proteoglycans present in the extracellular matrix (ECM). They function to regulate the movement of molecules through the ECM and to enhance sliding between adjacent tissue; GAGs are essential to construct all connective tissues, including bones, cartilage, tendons, and skin. There are 11 known enzyme deficiencies, which give rise to seven distinct MPS types that collectively affect one in every 25,000 births [2,3,4,5,6,7,8]. Depending on MPS type and severity, an affected individual may experience skeletal dysplasia, neurological complications, developmental delay, retinal degeneration, recurrent respiratory infection, and/or cardiac involvement [1]

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