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.
Bibliographical noteFunding Information:
Dr. Harmatz has received support for this project from the National Center for Advancing Translational Sciences , National Institutes of Health (NIH), through UCSF-CTSI grant number UL1 TR000004 . The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
Dr. Harmatz has received support for this project from the National Center for Advancing Translational Sciences, National Institutes of Health (NIH), through UCSF-CTSI grant number UL1 TR000004. The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
This study was supported by Ultragenyx Pharmaceutical Inc. We thank the patients, their parents/caregivers, and healthcare professionals who participated in this study. The authors thank James Signorovitch, PhD, P.K. Tandon, PhD, and the EveryLife Foundation for Rare Diseases for their help developing the Blind Start study design and the MDRI conception. The authors thank Edward Berkhoff, MS, of Ultragenyx for providing writing assistance. The authors thank all sub-investigators and coordinators participating in the trial.
- Blind Start study design
- Enzyme replacement therapy
- MPS VII
- Multi-domain responder index
- Urinary GAG
- Vestronidase alfa