Beyond Achondroplasia

Growing together with Clara

BioMarin presents report on phase 2 study of Vosoritide


BioMarin presented on the 19th October 2016 a press release on the data for Vosoritide in phase 2,  during the ASHG 2016 meeting. There is no overall novelty in this latest press release (19th Oct 2016) when comparing to the previous press release presented on the 20th April 2016, 6 months ago.

Nevertheless, the following text is a transcription of the recent press release that is public in BioMarin website in “press releases“. There will also be some explanations by Beyond Achondroplasia along the text, that will be presented in purple color. Only the text in grey was disclosed by BioMarin.

BioMarin Presents Vosoritide Data in Achondroplasia at American Society of Human Genetics (ASHG) 2016 Meeting


1. Highest Dose (30 µg/kg/day) shows approximately 50% increase in mean annualized growth velocity, comparable with 15 µg/kg/day dose » The data reveals that the administration of a higher dose, does not give a better result, but similar.
2. Consistent safety profile at high dose » The higher dose of 30 µg/kg/day showed to be as safe as the 15 µg/kg/day
3. Findings support 15 µg/kg/day in phase 3, randomized controlled study to start by end of 2016 » In a randomized controlled clinical trial, the patients are subjected to rigorous inclusion and exclusion criteria and, upon inclusion, are randomized into separate treatment and control groups (placebo). This protocol to conduct a trial is considered the golden standard for clinical trials (Solomon, 2009). Random allocation of patients in real trials is complex, but conceptually the process is like tossing a coin. After randomization, the two (or more) groups of patients are followed in exactly the same way and the only differences between them is the care (medicine) they receive. In this case, one group receives the drug and the other receives placebo. 


SAN RAFAEL, Calif., Oct. 19, 2016 (GLOBE NEWSWIRE) — BioMarin Pharmaceutical Inc. (NASDAQ:BMRN) today 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.

“Vosoritide in children with achondroplasia: updated results from an ongoing phase 2, open-label, seuencial cohort, dose-escalating study. Principal author: Dr. Julie Hoover-Fong. Poster presented at ASHG meeting 2016

In this poster, it can be read in the Results that: “No worsening of body proportions was observed as measured by the upper-to-lower segment ratio”.

Upper-to-lower body ratio
The lower body segment is the measurement of the length from the pubic bone to the floor while the upper body segment is the height minus the lower body segment. The U/L ratio (upper body segment divided by the lower body segment) at birth, in a average-height child, is about 1.7; at age 3 years it is 1.3; at ages greater than 7 years, it is 1.0 with the upper body segment and lower body segment being about equalSo the ideal ratio is near 1.
Higher U/L ratios are noted in short-limb dwarfism, as in achondroplasia. So the “no worsening U/L ratio” result stated in the poster, indicates that the disproportionality (regular torso, short legs and arms) was not aggravated in the children under the trial. The ideal would be to observe an improvement of the ratio (a value closer to 1).  No measurements related to the U/L ratio were presented


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.

The placebo is an innocuous treatment (like an injection of saline) to make a patient comfortable and is used as control in a clinical trial (Gupta & Verma “Placebo in clinical trials, 2013). The patients in a randomized placebo-controlled clinical trial do not know in which group they are: if they’re in the group that is getting the drug or in the group that is getting placebo. In this way, the research team involved in the trial can conclude if the results are due to the action/efficacy of the medicine or due to a psychobiological phenomenon.
Open-label trial »  is when both researchers and participants know which treatment is being administered. In this specific clinical trial, in phase 3, some children will receive vosoritide and others will receive placebo for a specific period of time, which duration is still unknown.

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 natural history of a disease is the natural course of a disease from the time immediately prior to its inception, progressing through its pre-symptomatic phase and different clinical stages to the point where the disease has ended without external intervention. Natural history studies track the course of disease overtime, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes in the absence of treatment. (in National Institute of health)

The company believes based on discussions with global health authorities that change in growth velocity from baseline as an endpoint could lead to registration (and have market authorization). The company plans to augment these data with supportive evidence concerning proportionality and functionality.

Improving functionality, as stated in this last sentence, will be highly interesting, but there is still no data regarding this point. Also, other major point of interest for patients would be the improvement of the dimension of the spinal canal, in order to reduce medullar compression and the improvement of the facial hypoplasia (that potentiates respiratory pathology). No data revealed on these points. Overall, achondroplasia is far beyond a question of height.

A significant increase of height will improve, with no doubt, the quality of life of patients. Nevertheless, achondroplasia affects multiple biologic systems and relevant issues as the ones mentioned above, have not been addressed during the studies with Vosoritide. Also, the decision of approval of vosoritide by the regulatory agencies, FDA and EMA, will most certainly focus on the value of the data: if vosoritide contributes to the general reduction of health complications in achondroplasia, providing better outcomes for patients. The correct choice of the Endpoint is of the utmost relevance for vosoritide approval.

What is an ENDPOINT and why is of crucial relevance in a clinical trial?
A clinical endpoint describes a valid measure of clinical benefit due to intervention: the impact of the intervention on how a subject feels, functions and survives. It is clinically relevant, sensitive (responsive to change) and is both accepted and used by physicians and patients. Clinical endpoints may be a clinical event (e.g. mortality,) a composite of several events, a measure of clinical status (e.g. blood pressure), or health related quality of life (HRQoL). (EunetHTA, 2013)

As is often the case, discussion of ancillary evidence to be collected, such as final adult height, 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
Category Cohorts 1 and 2
Switched to
15 µg/kg/day
Cohort 3
15 µg/kg/day
Cohort 4
30 µg/kg/day
Children Enrolled and Treated at 15 µg/kg/day 12 (100%) 10 (100 %) 9 (100%)
Children Who Completed 6 Months at 15 µg/kg/day 12 (100%) 10 (100%) N/A
Children Who Completed 12 Months at 15 µg/kg/day N/A 10 (100%) N/A
Children Who Completed 6 Months at 30 µg/kg/day N/A N/A 8 (89%)
Age (years) at Enrollment
Mean (SD) 7.6 (1.88) 8.0 (1.63) 6.9 (1.17)
Min, Max 5, 10 6, 11 5, 8
Gender (n, %)
Male 6 (50%) 4 (40%) 4 (44%)
Female 6 (50%) 6 (60%) 5 (56%)
*Children increased the 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 the 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, 2
15 µg/kg/daily



Cohort 3   
15 g/kg/daily



Cohort 3
15 g/kg/daily


 Cohort 4
30 µg/kg/daily
(n= 8)***
Mean (SD), cm/Year 3.6 (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/year 5.9 (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/year 2.3 (1.9)   1.9 (2.0) 2.0 (2.0)   2.1 (2.1)
Nominal p-value* 0.002  0.02 0.01 0.03
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 missed the majority of doses between 6 and 12 months he/she was 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 of six months of the natural history study, 901, 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.


Leave a Reply

Required fields are marked *.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Translate »