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

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

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

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) (%): -64.82 (2.468) LSM (SE) % CHG from Week 0 Treatment Week 24: LS mean (SE) (%) vs Placebo: -60.13 (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

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.

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