1. Ultragenyx Pharmaceutical Inc., Novato, CA
A Novel Blind Start Study Design to Investigate Vestronidase Alfa for Mucopolysaccharidosis VII, an Ultra-Rare Genetic Disease
Wenjie Song, PhD, Chao-Yin Chen, PhD, Christine Haller, MD and Emil Kakkis, MD, PhD
Ultragenyx Pharmaceutical Inc., Novato, CA

2. Introduction –MPS III and Novel Study Design
Mucopolysaccharidosis VII (MPS VII)
Ultra-rare, chronically debilitating, life-threatening lysosomal disease
Deficiency of beta-glucuronidase enzyme activity leads to accumulation of dermatan (DS), and chondroitin sulfate (CS) glycosoaminoglycans in many tissues
Prevalence <1/1,000,000
Heterogeneous presentation and severity spectrum:
Enlarged liver/spleen, cardiac/pulmonary disease, joint and bone abnormalities, cognitive impairment, corneal clouding, short stature
Severity spectrum with premature death often in teens to 30s
Novel Blind Start Clinical Study Design
12 subjects randomized to 1 of 4 groups, each crossed over to treatment at different time points in a blinded manner
Placebo and blinded study allows for objective assessment of clinical endpoints
Utilize Multi-Domain Responder Index (MDRI) comprising 6 different domains reflecting different functional aspects

3. Analysis of % Change in uGAG
Primary analysis: comparing to Baseline (prior to cross over to treatment)
Sensitivity analysis: comparing treatment vs placebo
uGAG: urinary glycosaminoglycan

4. Results of the Primary Endpoint (uGAG %Chg)
Primary Analysis
Sensitivity Analysis
Treatment
Placebo 10 10
-10
-30
-40
-50
-60
-70
-80
-20
-10
-20
LSM (SE) of uGAG % CHG
-30
Treatment Week 24:
LS mean (SE) (%): (2.468)
LSM (SE) % CHG from Week 0
Treatment Week 24:
LS mean (SE) (%) vs Placebo: (7.046)
-40
-50
-60
-70
-80 2 4 6 8 10 12 14 16 18 20 22 24 2 4 6 8 10 12 14 16 18 20 22 24
Treatment Week
Treatment Week 11 12 n 9 7 6 3
Placebo n 11 12
Treatment n

5. Overall Improvement Seen in Multi-Domain Responder Index (MDRI) at Treatment Week 24
MDRI had an overall positive mean change (SD) of +0.5 (+/-0.8) at 24 weeks of treatment (p=0.0527)
The positive clinical domains outnumbered negative domains 3:1, demonstrating overall improvement.
6MWT
FVC pred
Shoulder Flexion
BOT2 Fine
BOT2 Gross
Visual Acuity
MDRI
Fatigue MID
uGAG
Subject 1 +1 2 3 4 5 6 7 8 -1 9 10 11 12 +2
Not Assessable at baseline
Missing post baseline +1 -1
Minimally Important Differences (MID) scores of: +1 (improvement), -1 (decline), or 0 (no change). uGAG responders = subjects ever reaching > 50% reduction from baseline in uGAG during the first 24 weeks of vestronidase alfa treatment.

6. Conclusions
The blind start study design addressed the development challenges associated with extremely rare, heterogeneous diseases by
Assessing the composite endpoint MDRI in all subjects, and also eliminating potential bias with a variable placebo run-in period.
Increasing power since all subjects were treated doubling the population for treatment effect size and each subject was his/her own control; between-subject variability and skewed randomization impact was limited
This study design allows for a treatment effect estimation equivalent to a parallel group RCT with all subjects contributing to the treatment effect estimate
This study served as the pivotal study to gain FDA approval of vestronidase alfa