期刊
MOLECULAR GENETICS AND METABOLISM
卷 123, 期 4, 页码 488-494出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.ymgme.2018.02.006
关键词
MPS VII; Urinary GAG; Enzyme replacement therapy; Blind Start study design; Multi-domain responder index; Vestronidase alfa
资金
- Ultragenyx Pharmaceutical Inc.
- National Center for Advancing Translational Sciences, National Institutes of Health (NIH) through UCSF-CTSI [UL1 TR000004]
- NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES [UL1TR000004] Funding Source: NIH RePORTER
Background: Drug development for ultra-rare diseases is challenging because small sample sizes and heterogeneous study populations hamper the ability of randomized, placebo-controlled trials with a single primary endpoint to demonstrate valid treatment effects. Methods: To overcome these challenges, a novel Blind Start design was utilized in a study of vestronidase alfa in mucopolysaccharidosis VII (Sly syndrome), an ultra-rare lysosomal disease, that demonstrates the strengths of this approach in a challenging drug-development setting. Twelve subjects were randomized to 1 of 4 blinded groups, each crossing over to active treatment in a blinded fashion at different timepoints with efficacy analysis comparing the last assessment before cross over to after 24 weeks of treatment. Study assessments included: Percentage change from baseline in urinary GAG (uGAG); a Multi-Domain Responder Index (MDRI) using prespecified minimal important differences (6-Minute Walk Test, Forced Vital Capacity, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency); fatigue as assessed by the Pediatric Quality of Life Inventory' Multidimensional Fatigue Scale; and safety. Results: Vestronidase alfa treatment for 24 weeks significantly reduced uGAG excretion (dermatan sulfate: 64.8%, p < 0.0001). Most subjects (10/12) had a clinically meaningful improvement in at least one MDRI domain with an overall mean change (+/- SD) of +0.5 (+/- 0.8) at Treatment Week 24 (p = 0.0527). Exposure adjusted incidence rates of adverse events were similar between groups. Conclusions: The Blind Start study and MDRI design improve statistical power that enhances detection of a positive treatment effect in this rare heterogeneous disease and could be utilized for other ultra-rare diseases.
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