BMN 111 (vosoritide) Improves Growth Velocity in Children With Achondroplasia in Phase 2 Study

BioMarin Pharmaceutical Inc. BMRN today announced positive results of a Phase 2 proof-of-concept and dose finding study of BMN 111 (vosoritide), an analog of C-type Natriuretic Peptide (CNP), in children with achondroplasia. Achondroplasia is the most common form of human dwarfism. Vosoritide has Orphan designation in both the United States and Europe. Phase 2 Results and Safety Summary of First Six Months Data from the 26 children participating in the Phase 2 study demonstrated a favorable safety profile and efficacy at the 15 micrograms/kilogram/daily dose. The 10 children in Cohort 3 treated with 15 micrograms per kilogram per day had a mean increase of 50% (p-value = 0.01) in their annualized growth velocity compared to their annualized prior 6 month natural history baseline growth velocity. Changes from baseline in proportionality as measured by upper to lower body ratio were not observed. No Serious Adverse Events (SAEs) were observed for the duration of the study. The complete data from the study will be presented at a medical meeting later in the year. "We are very encouraged to have observed evidence of activity with vosoritide in children participating in our Phase 2 study," said Wolfgang Dummer, M.D., Ph.D., Vice President, Clinical Development of BioMarin. "In children receiving the highest dose of 15 micrograms per kilogram daily, we observed a 50% increase in mean annualized growth velocity compared to their own natural history control growth velocity. This increase in growth velocity, if maintained, could allow children with achondroplasia to resume a normalized growth rate." Dr. Dummer continued, "More importantly, vosoritide was well tolerated in all dose cohorts and we have observed no major safety concerns to date. Based on these results, we intend to move into pivotal registration study discussions with health authorities with a dose of 15 micrograms per kilogram daily. In addition, to support further exploration of a dose that may enable "catch-up" growth in the event of delayed treatment, we intend to study 30 micrograms per kilogram daily in ancillary studies. The next step in our development plan is to review this Phase 2 data with health authorities and our outside advisors to develop our path forward with registration enabling studies." "We are looking forward to working with health authorities worldwide as we continue to develop vosoritide for patients with achondroplasia globally," said Jean-Jacques Bienaimé, Chairman and Chief Executive officer at BioMarin. "It is estimated that about 96,000 patients in our established territories are afflicted with achondroplasia, so approximately 25%, or 24,000, are under 18 years of age and in our addressable market." Safety and Adverse Event Observations in the Phase 2 Study No serious adverse events (SAEs) were reported in any cohort during the study. The majority of AEs reported were mild (Grade 1) and included injection site reactions, headache, hypotension, back pain and cough. Blood pressure (BP) and heart rate (HR) were monitored frequently and during every site visit. Symptomatic hypotension was not documented in the study. Each patient had approximately 100 measurements of BP in the course of the study. 17 asymptomatic hypotension events in 10 patients were recorded out of the majority of blood pressure measurements obtained. The 17 events were mild (Grade 1), transient, self-limited and resolved without medical intervention. Events occurred across all dose cohorts and at varying times after dosing with no evidence of dose dependency. One subject in Cohort 1 was reported to have "dizziness due to hypotension" and the event resolved without medical intervention in 5 minutes. The event occurred at home and no blood pressure measurement available during the episode of dizziness. The patient continued therapy with no further events. No clinically significant changes in vital signs at any dose or time of exposure. No bone related adverse events (AEs) were reported. Table 1: BMN 111 (vosoritide) Summary of Efficacy Results from Phase 2 Study in Children with Achondroplasia Efficacy Analysis: Annualized 6-Months Growth Velocity Cohort 1 Cohort 2 Cohort 3 Growth Velocity 2.5 µg/kg/daily 7.5 µg/kg/daily 15 µg/kg/daily (n=8*) (n=8) (n=10) Baseline Mean (cm/Year) 3.8 2.9 4.0 Post-Treatment Mean (cm/year) 3.4 4.2 6.1 Change from Baseline Mean (cm/year) -0.4 1.3 2.0 95% Confidence Interval (cm/year) -1.8, 1.1 0.1, 2.5 0.6, 3.4 p-value** 0.56 0.04 0.01 Percent increase from Baseline Based on means (%) NM 45 50 * One subject withdrew from study prior to the 6-month visit, all summaries for Cohort 1 were based on 7 subjects. ** p-value, provided for descriptive purposes and based on the paired t-test comparing post-treatment GV and baseline GV, not adjusted for multiple comparisons. Additional Highlights from BMN 111 (vosoritide) Study in Children with Achondroplasia There was a dose-related increase in urinary excretion of cGMP measured over the 6 month duration of the study. cGMP is a biochemical marker that may indicate that BMN 111's biological effect will continue beyond 6 months. In dose cohort 3, the median annualized increase from baseline was 2.7 centimeter/year or 66% annualized increase over baseline. 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 BMN 111. The Phase 2 trial was an open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. In this three dose cohort study, patients were treated with either 2.5 µg/kg/daily, 7.5 µg/kg/ daily or 15 µg/kg/ daily, respectively. A total of 26 children with achondroplasia with an average age of 7.8 years were enrolled in the study. Based on the safety profile observed to date across the three dose cohorts, all subjects participating in the Phase 2 study have now been switched to the highest dose of 15 µg/kg/ daily for the duration of the 18 month extension study. BMN 111 was recently designated the generic name vosoritide by the International Nonproprietary Names (INN) system managed by the World Health Organization (WHO). Conference Call Details BioMarin will host a conference call and webcast to discuss Phase 2 results with BMN 111 on June 17, at 4:30 p.m. ET/1:30 .m. PT. This event can be accessed on the investor section of the BioMarin website at www.BMRN.com. U.S. / Canada Dial-in Number: 877.303.6313 International Dial-in Number: 631.813.4734 Conference ID: 68336725 Replay Dial-in Number: 855.859.2056 Replay International Dial-in Number: 404.537.3406 Conference ID: 68336725