BioMarin Pharma (BMRN) Presents Updated Vosoritide Phase 2 Data in Achondroplasia; Mean Annualized Growth Velocity Similar to Lower Dose

October 19, 2016 5:03 PM EDT

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BioMarin Pharmaceutical Inc. (Nasdaq: BMRN) provided an update on its Phase 2 study of vosoritide, an analog of C-type Natriuretic Peptide (CNP), in children with achondroplasia, the most common form of dwarfism, at the American Society of Human Genetics 2016 Meeting. Results from 8 children in cohort 4, who completed six months of daily dosing at 30 µg/kg/daily experienced a 46% or 2.1 cm/year increase in mean annualized growth velocity from baseline (p-value = 0.03). These data are comparable to those observed at the lower dose of 15 µg/kg/day in cohort 3. Results from 10 children in cohort 3, who completed six months of daily dosing at 15 µg/kg/day experienced a 50% or 2.0 cm/year increase in mean annualized growth velocity from baseline (p-value = 0.01). (See Table 2.)

Vosoritide was generally well tolerated at all doses. The majority of adverse events (AEs) were mild and no serious AEs were reported as study drug-related. Across all doses, injection site reactions and hypotension were the most common drug-related AEs. All injection site reaction events were mild and transient. AEs of hypotension were mild, transient and resolved without medical intervention, and the majority were asymptomatic and reported in context of routine blood pressure measurements. No new safety findings were observed at the 30 µg/kg/day dose.

“Studying the higher dose in Phase 2 informed the design of our Phase 3 study in vosoritide. While vosoritide at the higher dose of 30 µg/kg/day was generally well-tolerated, the data support our use of the lower dose of 15 µg/kg/day in the Phase 3 study,” said Hank Fuchs, MD, Chief Medical Officer at BioMarin. “We believe that growth velocity is an important measurement in developing vosoritide, which has the potential to address the complications associated with achondroplasia. We are grateful to the children and their families who are participating in this study.”

“Vosoritide represents a potential, first-of-its-kind treatment for this form of dwarfism, and these clinical studies could provide new insights into improved management of this condition,” said Julie Hoover-Fong Director, Greenberg Center for Skeletal Dysplasias, Johns Hopkins University and lead author of the poster of the Vosoritide Phase 2 data update at ASHG.

By the end of 2016, BioMarin intends to initiate a one-year, randomized, placebo-controlled Phase 3 study in children with achondroplasia ages 5-14 with a subsequent open-label extension. Children in this study will have completed a minimum six-month natural history study to determine their respective baseline growth velocity prior to entering the Phase 3 study. The company believes based on discussions with global health authorities that change in growth velocity from baseline as an endpoint could lead to registration. The company plans to augment these data with supportive evidence concerning proportionality and functionality. As is often the case, discussion of ancillary evidence, such as final adult height to be collected, is ongoing. In addition, BioMarin is planning a separate Phase 2 study evaluating the effect of vosoritide in infants and toddlers. Vosoritide has Orphan designation in both the United States and Europe.

Table 1: Phase 2 Trial Disposition and Demographics

CategoryCohorts 1 and 2 Switched to 15 µg/kg/day (n=12)*Cohort 3 15 µg/kg/day(n=10)Cohort 430 µg/kg/day(n=9)**
Children Enrolled and Treated at 15 µg/kg/day12 (100%)10 (100 %)9 (100%)
Children Who Completed 6 Months at 15 µg/kg/day12 (100%)10 (100%)N/A
Children Who Completed 12 Months at 15 µg/kg/dayN/A10 (100%)N/A
Children Who Completed 6 Months at 30 µg/kg/dayN/AN/A8 (89%)
Age (years) at Enrollment
Mean (SD)7.6 (1.88)8.0 (1.63)6.9 (1.17)
Min, Max5, 106, 115, 8
Gender (n, %)
Male6 (50%)4 (40%)4 (44%)
Female6 (50%)6 (60%)5 (56%)

*Children increased dose to 15 µg/kg/day after at least 6 months at 2.5 and/or 7.5 µg/kg/day; 4 of original 16 subjects in Cohorts 1 and 2 did not initiate dosing at 15 µg/kg/day due to subject decision to withdraw from the study (2), declining extension study (1), and growth plate closure (1)**One child in cohort 4 discontinued from treatment due to finding of a rare congenital abnormality of conduction identified on routine study of ECG monitoring, which was not associated with symptoms, and patient was removed from treatment for precautionary reasons.

Table 2: Phase 2 Summary of Efficacy Results in Children with Achondroplasia

Efficacy Analysis: Annualized Growth Velocity
Time Point 6 Months 12 Months ** 6 Months 6 Months
Annualized Growth Velocity Cohorts 1, 215 µg/kg/daily(n=12) Cohort 3 15 g/kg/daily(n=10) Cohort 315 g/kg/daily(n=10) Cohort 430 µg/kg/daily(n= 8)***
Mean (SD), cm/Year3.6 (1.0)4.0 (2.3)4.0 (2.3)4.5 (1.2)
Median 3.5 4.1 4.1 4.5
Mean, (SD), cm/year5.9 (1.6)5.9 (0.9)6.1 (1.1)6.6 (1.2)
Median 5.6 5.6 5.9 7.0
Change from Baseline
Mean (SD), cm/year2.3 (1.9) 1.9 (2.0)2.0 (2.0) 2.1 (2.1)
Nominal p-value*0.002
Percent increase from Baseline 65% 46% 50% 46%
Based on means (%)

* Nominal p-value, not adjusted for multiplicity** Mean Annualized Growth Velocity change from baseline increases to 2.0 cm/year (50% increase) if one patient who missed majority of doses between 6 and 12 months is excluded ***8 children have non-missing annualized growth velocity at both baseline and 6 months.

Phase 2 Study Design

Children in this study completed a minimum six month natural history 901 study to determine their respective baseline growth velocity prior to entering the Phase 2 study with vosoritide. The Phase 2 trial was an open-label, sequential cohort dose-escalation study of vosoritide in children with achondroplasia. In this four dose cohort study, children were treated with either 2.5 µg/kg/day, 7.5 µg/kg/ day, 15 µg/kg/ day or 30 µg/kg/ day, respectively. A total of 35 children with achondroplasia with an average age of 7.6 years were enrolled in the study. Based on the efficacy and safety profile observed, all children participating in the first two cohorts of the Phase 2 study, who remained in the study, were offered the higher dose of 15 µg/kg/day during the 18 month extension study. Children in the third (15 ug/kg/day) and fourth (30 ug/kg/day) cohorts will remain on their current dose during the extension study.

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