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

• Published in: Molecular genetics and metabolism Vol. 137; no. 1-2; pp. 127 - 139
• Main Authors: Muenzer, Joseph, Burton, Barbara K., Harmatz, Paul, Gutiérrez-Solana, Luis González, Ruiz-Garcia, Matilde, Jones, Simon A., Guffon, Nathalie, Inbar-Feigenberg, Michal, Bratkovic, Drago, Hale, Michael, Wu, Yuna, Yee, Karen S., Whiteman, David A.H., Alexanderian, David
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-09-2022
• Subjects: Child; Child, Preschool; Cognitive impairment; Enzyme Replacement Therapy - methods; Glycosaminoglycans; Humans; Iduronate Sulfatase - genetics; Iduronic Acid; Idursulfase; Intrathecal; MPS II; Mucopolysaccharidosis II; Mucopolysaccharidosis II - drug therapy; Mucopolysaccharidosis II - genetics; Multiple Myeloma; MPS II; ABC; AE; GCA; CI; ECG; Mucopolysaccharidosis II; HS; I2S; IT; CRIM; GAG; IV; SD; SE; DAS-II; Idursulfase; CSF; IDDD; IDS; VABS-II; Intrathecal; Cognitive impairment; MMRM
• ISSN: 1096-7192; 1096-7206; 1096-7206
• DOI: 10.1016/j.ymgme.2022.07.017

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.
•Trends towards cognitive benefits with intrathecal idursulfase for some patients.•Significant effects in those <6 years with missense iduronate-2-sulfatase variants•After 52 weeks, cerebrospinal glycosaminoglycan levels decreased by 72%.•Most adverse events were mild or moderate; none led to discontinuation.•Overall, the data did not meet evidentiary standards for regulatory filing.