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Clinical Trials

Date: 2017-10-18

Type of information: Presentation of results at a congress

phase: 2

Announcement: update

Company: Biomarin Pharmaceutical (USA - CA)

Product: BMN 111 (vosoritide)

Action mechanism:

  • peptide/natriuretic peptide. Vosoritide is an analog of C-type Natriuretic Peptide (CNP). Vosoritide has orphan designation in both the United States and Europe.
 

Disease: achondroplasia

Therapeutic area: Rare diseases - Genetic diseases

Country: Australia, France, UK, USA

Trial details:

  •  The Phase 2 trial was an open-label, sequential cohort dose-escalation study of vosoritide 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 were offered the dose of 15 µg/kg/daily during the 18 month extension study. An additional 9 patients were enrolled into a fourth cohort of 30 µg/kg/daily at the end of 2015.  (NCT02055157)

Latest news:

  • • On October 18, 2017, BioMarin Pharmaceutical provided an update on its open-label Phase 2 study of vosoritide, an analog of C-type Natriuretic Peptide (CNP), in children with achondroplasia. Vosoritide for achondroplasia demonstrates sustained increase in average growth velocity over 30 months of treatment in 10 children, who completed 30 months of daily dosing at 15 µg/kg/day. Over this period of time, patients have experienced mean absolute growth increase of approximately 4 cm over what their baseline growth velocity would have predicted. The sustained increase in annualized growth velocity was accompanied by sustained improvements over time in height compared to age- and gender-matched unaffected children as measure by z-scores. In addition, treatment with vosoritide shows continued improvement over time in proportionality as measured by a ratio of the upper and lower body measurements or U/L ratio.
  • • On October 19, 2016, BioMarin Pharmaceutical  provided an update on its Phase 2 study of vosoritide in children with achondroplasia 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. 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. In addition, BioMarin is planning a separate Phase 2 study evaluating the effect of vosoritide in infants and toddlers.
  • • On April 20, 2016, BioMarin Pharmaceutical provided an update on its Phase 2 study of vosoritide in children with achondroplasia. After 12 months of daily dosing at 15 µg/kg/day, the cohort 3 patients (n=10) experienced a 46% or 1.9 cm/year increase in mean annualized growth velocity from baseline (p-value = 0.02). (See Table 2). These findings provide evidence of durability of effect consistent with previously presented 6-month data for these patients, which demonstrated an annualized increase of 50% or 2.0 cm/year in mean annualized growth velocity. In addition, 6-month data for 12 patients who were initiated on a lower dose and switched to 15 µg/kg/day showed an increase of 65% or 2.3 cm/year in mean annualized growth velocity from baseline (p-value = 0.002). Vosoritide at 15 µg/kg/day was well tolerated and there were no treatment-related serious adverse events or adverse events leading to discontinuation. Consistent with the initial 6-month data, in the newly released data, all adverse events assessed as related to study drug were mild to moderate. Over 12 months of dosing at 15 µg/kg/day, injection site reactions and hypotension (asymptomatic decreases in blood pressure) were the most common drug related adverse events, reported by 90% and 40% of cohort 3 patients, respectively. All injection site reaction events were mild and the majority were resolved in one hour. All adverse events of hypotension were mild, transient and resolved without intervention. Safety data from lower dose cohort subjects who increased their dose to 15 µg/kg/day for at least 6 months was generally comparable to the 12-month safety data; however, two subjects experienced symptomatic events associated with a decrease in blood pressure, only one of which was deemed by the investigator to be related to study drug. Both subjects continued to receive their daily dose of vosoritide without dose modification. The phase 2 study is also evaluating a higher dose of 30 ug/kg/day. Preliminary data after several months of treatment has shown that this dose is similarly well tolerated with no new safety findings. A consistent effect in increasing urinary cyclic guanosine monophosphate (cGMP), a urinary pharmacodynamic biomarker, provides further evidence of durable pharmacologic activity of the 15 µg/kg/day dose over the 12-month observation period in cohort 3. By the end of 2016, BioMarin is planning to initiate a single Phase 3 randomized controlled study over 12 months in children with achondroplasia ages 5-14 with a subsequent long-term open-label extension subject to discussions with regulatory authorities. In addition, BioMarin is planning a separate Phase 2 study evaluating the effect of vosoritide in infants and toddlers.
  • Table 1:  Subject Disposition and Demographics
Category Cohort 3 (n=10) Cohorts 1 and 2 (n=12)*
Subjects Enrolled and Treated at 15 µg/kg/day 10 (100 %) 12 (100%
Subjects Who Completed 6 Months at 15 µg/kg/day 10 (100%) 12 (100%)
Subjects Who Completed 12 Months at 15 µg/kg/day 10 (100%) N/A
Age (years) at Enrollment
Mean (SD) 8.0 (1.63) 7.6 (1.88)
Min, Max 6, 11 5, 10
Gender (n, %)
Male 4 (40%) 6 (50%)
Female 6 (60%) 6 (50%)
  • *Subjects 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)
  • Table 2:  Vosoritide Summary of Efficacy Results from Phase 2 Study in Children with Achondroplasia
Efficacy Analysis: Annualized Growth Velocity
Time Point 6 Months 12 Months ** 6 Months
Annualized Growth Velocity Cohort 3 15 µg/kg/daily (n=10)   Cohort 3   15 µg/kg/daily (n=10)   Cohorts 1, 2 15 µg/kg/daily (n=12)  
Baseline  
     Mean (SD), cm/Year 4.0 (2.3) 4.0 (2.3) 3.6 (0.96)
Median 4.1 4.1 3.5
Post-Treatment
       
      Mean, (SD), cm/year 6.1 (1.1) 5.9 (0.92) 5.9 (1.6)
Median 5.9 5.6 5.6
Change from Baseline      
       
      Mean (SD), cm/year 2.0 (2.0) 1.9 (2.0) 2.3 (1.9)
        Nominal p-value* 0.01    0.02   0.002
Percent increase from Baseline Based on means (%) 50 % 46 % 65 %
  • * 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
  • • On June 17, 2015, BioMarin Pharmaceutical announced positive results of a Phase 2 proof-of-concept and dose finding study of BMN 111 (vosoritide) in children with achondroplasia. 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.
  • 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 ug/kg/daily 7.5 ug/kg/daily 15 ug/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.
  • 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 ug/kg/daily, 7.5 ug/kg/ daily or 15 ug/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 ug/kg/ daily for the duration of the 18 month extension study.

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