Intrathecal idursulfase-IT in patients with neuronopathic mucopolysaccharidosis II: Results from a phase 2/3 randomized study.

Two-thirds of patients with mucopolysaccharidosis II (MPS II; Hunter syndrome) have cognitive impairment. This phase 2/3, randomized, controlled, open-label, multicenter study (NCT02055118) investigated the effects of intrathecally administered idursulfase-IT on cognitive function in patients with MPS II. Children older than 3 years with MPS II and mild-to-moderate cognitive impairment (assessed by Differential Ability Scales-II [DAS-II], General Conceptual Ability [GCA] score) who had tolerated intravenous idursulfase for at least 4 months were randomly assigned (2:1) to monthly idursulfase-IT 10 mg (n = 34) via an intrathecal drug delivery device (IDDD; or by lumbar puncture) or no idursulfase-IT treatment (n = 15) for 52 weeks. All patients continued to receive weekly intravenous idursulfase 0.5 mg/kg as standard of care. Of 49 randomized patients, 47 completed the study (two patients receiving idursulfase-IT discontinued). The primary endpoint (change from baseline in DAS-II GCA score at week 52 in a linear mixed-effects model for repeated measures analysis) was not met: although there was a smaller decrease in DAS-II GCA scores with idursulfase-IT than with no idursulfase-IT at week 52, this was not significant (least-squares mean treatment difference [95% confidence interval], 3.0 [-7.3, 13.3]; p = 0.5669). Changes from baseline in Vineland Adaptive Behavioral Scales-II Adaptive Behavior Composite scores at week 52 (key secondary endpoint) were similar in the idursulfase-IT (n = 31) and no idursulfase-IT (n = 14) groups. There were trends towards a potential positive effect of idursulfase-IT across DAS-II composite, cluster, and subtest scores, notably in patients younger than 6 years at baseline. In a post hoc analysis, there was a significant (p = 0.0174), clinically meaningful difference in change from baseline in DAS-II GCA scores at week 52 with idursulfase-IT (n = 13) versus no idursulfase-IT (n = 6) among those younger than 6 years with missense iduronate-2-sulfatase gene variants. Overall, idursulfase-IT reduced cerebrospinal glycosaminoglycan levels from baseline by 72.0% at week 52. Idursulfase-IT was generally well tolerated. These data suggest potential benefits of idursulfase-IT in the treatment of cognitive impairment in some patients with neuronopathic MPS II. After many years of extensive review and regulatory discussions, the data were found to be insufficient to meet the evidentiary standard to support regulatory filings.
Competing Interests: Declaration of Competing Interest Joseph Muenzer has received consulting fees/other remuneration from Denali Therapeutics, JCR Pharmaceuticals, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, and Takeda (Shire); has participated in advisory boards for BioMarin Pharmaceutical, Denali Therapeutics, JCR Pharmaceuticals, Sanofi Genzyme, and Takeda; and has received research support from BioMarin Pharmaceutical, Denali Therapeutics, and Takeda. Barbara K. Burton has received consulting fees/other remuneration from Alexion Pharmaceuticals, Applied Therapeutics, BioMarin Pharmaceutical, Capsida Biotherapeutics, Denali Therapeutics, Horizon Therapeutics, JCR Pharmaceuticals, Moderna, Passage Bio, Sanofi Genzyme, Sio Gene Therapies, Takeda, and Ultragenyx Pharmaceutical; has participated in advisory boards or similar committees for Alexion Pharmaceuticals, BioMarin Pharmaceutical, and Takeda; and has received research support from Alexion Pharmaceuticals, BioMarin Pharmaceutical, Denali Therapeutics, Homology Medicines, JCR Pharmaceuticals, Sangamo Therapeutics, Takeda, and Ultragenyx Pharmaceutical. Paul Harmatz has received consulting fees/other remuneration from Aeglea, Alexion Pharmaceuticals, ArmaGen, AVROBIO, Audentes, BioMarin Pharmaceutical, Capsida Biotherapeutics, Chiesi, Denali Therapeutics, Enzyvant, Fondazione Telethon, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, Paradigm, PTC Therapeutics, REGENXBIO, Sangamo Therapeutics, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Alexion Pharmaceuticals, ArmaGen, BioMarin Pharmaceutical, Denali Therapeutics, Enzyvant, Inventiva Pharma, JCR Pharmaceuticals, Orphazyme, QED Therapeutics, REGENXBIO, Sangamo Therapeutics, Swedish Orphan Biovitrum, Takeda, and Ultragenyx Pharmaceutical. Luis González Gutiérrez-Solana has received consulting fees/other remuneration from BioMarin Pharmaceutical, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Matilde Ruiz-Garcia has received consulting fees/other remuneration and research support from Takeda. Simon A. Jones has received consulting fees/other remuneration from Alexion Pharmaceuticals, AVROBIO, BioMarin Pharmaceutical, Denali Therapeutics, Orchard Therapeutics, REGENXBIO, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; and has received research support from Takeda. Nathalie Guffon has received research support from BioMarin Pharmaceutical, Chiesi, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Michal Inbar-Feigenberg has received consulting fees from Takeda; has participated in advisory boards for Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical; is a member of the medical advisory board for the Canadian MPS Society and Allied Diseases; is Chair of the Garrod Association Guideline Committee; and has received research support from the Canadian Institute for Health Research, Sanofi Genzyme, Takeda, and Ultragenyx Pharmaceutical. Drago Bratkovic has received research support from Takeda. Michael Hale was an employee of Takeda Development Center Americas, Inc. at the time of this study, and is a stockholder of Takeda Pharmaceuticals Company Limited. Yuna Wu is an employee of Takeda Development Center Americas, Inc.; and is a stockholder of Takeda Pharmaceuticals Company Limited. Karen S. Yee is an employee of Takeda Development Center Americas, Inc.; a stockholder of Takeda Pharmaceuticals Company Limited, and is an unpaid member of the Critical Path Institute PRO consortium and Rare Disease COA consortium, sponsored by Takeda. David A.H. Whiteman is an employee of Takeda Development Center Americas, Inc. and a stockholder of Takeda Pharmaceuticals Company Limited. David Alexanderian was an employee of Takeda Development Center Americas, Inc. at the time of this study and of the writing of the manuscript, and is a stockholder of Takeda Pharmaceuticals Company Limited.
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