Mucopolysaccharidosis type III: current clinical trials, challenges and recommendations

ABSTRACT

Introduction: Mucopolysaccharidosis type III (MPS III) is a rare disorder characterized by progressive neurocognitive impairment. No disease-modifying treatment is yet available but many are currently under study. The aim of this review is to report on the results of the first clinical trials in MPS III and to discuss specific challenges and recommendations in trial design.

Areas covered: Gene therapy, enzyme replacement therapy and substrate reduction therapy for MPS III.

Expert opinion: Although some trials have been stopped because of lack of effect, several other phase I/II studies have reported data suggesting a positive effect of treatment. A number of treatment options will enter phase III trials in the very near future. However, several challenges have emerged. The rarity of the disease limits the number of potential patients per trial and competition for eligible patients is imminent. Furthermore, high quality natural history data will be essential to serve in trials as a comparator arm. This can only be achieved by rapid publication, full transparency and sharing of all available natural history data. Also, the broad phenotypic spectrum may complicate assessment of treatment efficacy, and phenotypic prediction is therefore essential. Finally, as early initiation of treatment is needed to demonstrate maximal, or even sufficient, treatment effect, newborn screening for MPS III will, in the end, be needed.

KEYWORDS:

• MPS III
• mucopolysaccharidosis type III
• natural history
• clinical trials

Article highlights

• A number of different disease-modifying treatment options for MPS III are currently under investigation.

• The extreme rareness of MPS III severely limits the number of patients eligible for inclusion in trials.

• Natural history data may serve as a comparator arm in future trials, which necessitates sharing of data.

• As the broad phenotypic spectrum may complicate assessment of treatment efficacy, phenotypic prediction by genotyping and enzymatic studies is essential.

• Pre-symptomatic diagnosis by newborn screening will be the only option for timely initiation of treatment and demonstration of full efficacy of treatment in the future.

This box summarizes key points contained in the article.

Declaration of interest

SCM. Nijmeijer declares to have no competing interests and nothing to disclose. FA Wijburg has received speakers fee, travel reimbursement and consultancy fees from Sanofi Genzyme, Shire HGT, Actelion, BioMarin and Lysogene. Research grants from Genzyme Sanofi, Actelion and BioMarin. 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded