Slide 1: A Randomized Controlled Trial of Vosoritide in Infants and Toddlers with Achondroplasia
A Randomized Controlled Trial of Vosoritide in Infants and Toddlers with Achondroplasia Carlos Bacino Baylor College of Medicine Houston, Texas, USA
Slide 2: Financial Disclosure
Financial Disclosure Carlos Bacino does not have any relevant disclosures. #ACMGMtg23
Slide 3: Achondroplasia (ACH) Disease Overview
Achondroplasia (ACH) Disease Overview ▪ Achondroplasia (ACH) is the most common form of disproportionate short stature (approx. 1:25,000 live births)1,2 ▪ Caused by a pathogenic variant in FGFR3 that constitutively activates the downstream inhibitory signaling pathway in chondrocytes, leading to imp
Slide 4: Vosoritide: Targeted Therapy for ACH
Vosoritide: Targeted Therapy for ACH ▪ CNP down-regulates aberrant FGFR3 signaling in chondrocytes by inhibiting the MAPK-ERK pathway1,2 ▪ Vosoritide is based on naturally- occurring CNP engineered to resist degradation and increase the half-life3 1. Yasoda A et al. Overexpression of CNP in chondroc
Slide 5: Vosoritide: Targeted Therapy for ACH
Vosoritide: Targeted Therapy for ACH ▪ An open-label, 52-week phase 2 trial (BMN 111-202) and its extension study (BMN 111-205) in children with ACH showed that vosoritide treatment resulted in sustained increases in annualized growth velocity (AGV)1 ▪ A phase 3 randomized placebo-controlled trial (
Slide 6: Vosoritide Clinical Development Program in Context of Growth Pattern in Children with ACH
Vosoritide Clinical Development Program in Context of Growth Pattern in Children with ACH 6 ACH growth curve adapted from Hoover-Fong J et al. Am J Clin Nutr 2008
Slide 7: BMN 111-206 Study in Children with ACH Aged 0–5 Years
BMN 111-206 Study in Children with ACH Aged 0–5 Years ▪ Primary Objectives: – Evaluate safety and tolerability of vosoritide in children with achondroplasia – Evaluate the effect of vosoritide on change from baseline in height/body length Z-scores ▪ Secondary Objectives include Height, AGV, Upper to
Slide 8: Statistical Methods
Statistical Methods ▪ Randomization by Age Strata – Cohort 1: age stratification ≥ 24 to < 36, ≥ 36 to < 60 months – Cohort 2: age stratification ≥ 6 to < 15, ≥ 15 to < 24 months – Cohort 3: age stratification 0 to < 6 months ▪ Populations Analyzed – All enrolled (randomized + sentinels) – All rando
Slide 9: Subject Demographics
Subject Demographics Overall Cohort 1 Cohort 2 Cohort 3 Vosoritide Placebo Vosoritide Placebo Vosoritide Placebo Vosoritide Placebo (N=43) (N=32) (N=19) (N=16) (N=12) (N=8) (N=12) (N=8) Age on Day 1, Months Mean (SD) 24.47 (17.66) 27.82 (19.25) 41.48 (11.07) 44.33 (11.54) 16.59 (5.11) 16.87 (6.21) 5
Slide 10: Baseline Growth Characteristics
Baseline Growth Characteristics Height Z-score Cohort 1: Ages 24 to <60 months Cohort 2: Ages 6 to <24 months Cohort 3: Ages 0 to <6 months Box plot displays the 25th and 75th percentiles (box edges), the median (midline), the mean (diamond symbol) and the 2.5th and 97.5th percentiles (whiskers). As
Slide 11: Baseline Growth Characteristics
Baseline Growth Characteristics AGV 11 Cohort 1: Ages 24 to <60 months Cohort 2: Ages 6 to <24 months Cohort 3: Ages 0 to <6 months
Slide 12: Overview of SAEs
Overview of SAEs Sentinel Vosoritide Placebo All Vosoritide Treated SOC and PT (N=11) (N=32) (N=32) (N=43) Subjects with any SAE, n (%) 0 3 (9.4) 6 (18.8) 3 (7.0) Infections and infestations, n (%) 0 2 (6.3) 3 (9.4) 2 (4.7) Pneumonia 0 1 (3.1) 0 1 (2.3) Respiratory syncytial virus bronchiolitis 0 1
Slide 13: Incidence of TEAE by SOC by Cohort
Incidence of TEAE by SOC by Cohort Cohort 1 Cohort 2 Cohort 3 Vosoritide Placebo Vosoritide Placebo Vosoritide Placebo SOC (n=19) (N=16) (n=12) (N=8) (n=12) (N=8) General disorders and administration site conditions 16 (84.2) 10 (62.5) 10 (83.3) 6 (75.0) 12 (100.0) 8 (100.0) Infections and infestati
Slide 14: Incidence of TEAE Reported with > 5% Higher Frequency in Vosoritide vs Placebo
Incidence of TEAE Reported with > 5% Higher Frequency in Vosoritide vs Placebo Placebo Vosoritide (N=32) (N=43) Incidence Events Incidence Events Preferred Term n (%) m (rate) n (%) m (rate) Injection site reaction 13 (40.6) 154 (4.8) 34 (79.1) 3057 (71.5) Injection site erythema 13 (40.6) 1738 (54.
Slide 15: Improvement in Growth with Vosoritide vs Placebo
Improvement in Growth with Vosoritide vs Placebo ▪ Vosoritide (n=43), compared to placebo (n=32) (All Enrolled): – increased height Z-score by 0.30 SD (95% CI 0.07, 0.54) – increased AGV by 0.92cm/year (95% CI 0.24, 1.59) – did not significantly change upper-to-lower body segment ratio, which change
Slide 16: Positive Change in Height Z-Score in Children Treated with Vosoritide in All Cohorts
Positive Change in Height Z-Score in Children Treated with Vosoritide in All Cohorts Height Z-score Cohort 1: Ages 24 to <60 months Cohort 2: Ages 6 to <24 months Cohort 3: Ages 0 to <6 months ▪ Increased variability at youngest age group reflects rapidly changing growth pattern in young children 16
Slide 17: Height Gain
Height Gain All Enrolled Analysis population Height Gain (cm) After One Year Placebo Vosoritide Cohort 1 Cohort 2 Cohort 3 Cohort 1 Cohort 2 Cohort 3 24-60 months 6-24 months 0-6 months 24-60 months 6-24 months 0-6 months (n=16) (n=8) (n=8) (n=19) (n=12) (n=12) Average Stature* 7.06 10.69 15.05 6.98
Slide 18: MRI: Face and Sinus Volumes and Foramen Magnum Area
MRI: Face and Sinus Volumes and Foramen Magnum Area Cohort 1 Cohort 2 Cohort 3 24-60 months 6-24 months 0-6 months Vosoritide Placebo Vosoritide Placebo Vosoritide Placebo (n=19) (N=16) (n=12) (N=8) (n=12) (N=8) Face volume (cm3) Baseline, N 16 13 12 8 11 8 Mean ± SD 582.41 ± 88.15 573.83 ± 91.02 45
Slide 19: Conclusions
Conclusions ▪ Daily injections of vosoritide were well tolerated with no treatment limiting adverse events with the safety profile consistent with that in treated children over 5 years of age ▪ Most common adverse events observed were mild and self-limiting injection site reactions – No clinically r
Slide 20: Acknowledgements
Acknowledgements ▪ Study participants ▪ Investigators and study teams ▪ Study sponsor: BioMarin Pharmaceutical Inc. ▪ Co-authors: – Ravi Savarirayan, M.D., Murdoch Children’s Research Institute, Royal Children’s Hospital Victoria, University of Melbourne, Parkville, Victoria, Australia – William W.