BioMarin´s Research and Development day 2017 presentation

On the 18th October 2017, BioMarin held the R&D day 2017, and presented

potential future products in different areas of therapeutic research and development. Adam Shaywitz, M.D., Ph.D, presented "Vosorite for achondroplasia",

Firstly, it was shown an overview of the clinical program, which is currently in the 111-301 study. All children enrolled in this 111-301 study, have to first be enrolled in the 111-901 study, like the figure shows. The dose at this stage is 15 ug/kg per day, injectable.

After that, it was presented the results of 30 months 111-202 study, phase 2, in 10 children receiving 15 ug/kg/day of vosoritide. 

In the above slide, the 10 children in this study showed a Linear Growth Response (AGV) of 4 cm over 30 months. The Δ symbol means "Difference or change" that was observed during that timeframe. For example: at 12 months data collection, the company observed an increase of 1,9 cm in average while at 24 months, they observed an increase of 1,7 cm. This was the height increase added to the natural growth. The median height velocity of children with achondroplasia is 5 cm/y from 2 to 10 y of age. 1

So, after 30 months of study, children have grown 4cm plus their natural growth. There is no reference at what level this growth in height took place: if on legs, spine or both.

Z-scores is the number of standard deviations from the mean a data point is.This relates to the difference between a score and the average of the population. Although individual z-scores are not presented, in average, the difference between participants growth is higher at month 30.


The next slide reflects about proportionality with the U/L ratio, meaning the result of the length of the body Upper segment (head to pubic symphysis) divided by the Lower segment (pubic symphysis to feet). Ideally, the U/L ratio equals 1 (1 dividing by 1 is 1). 

In the average height population, this ratio is at birth around 1,7:1 while around 3 years-old improves to 1,3:1 reaching 1:1 after 7 years old. The results show improvements in proportionality.

With a 1,9 ratio at baseline, this means that in average the Upper segment (trunk) was longer than the lower segment (legs) and that with treatment the legs have grown slightly so that the ratio has slightly reduced. For example, imagine that the Upper segment measured 50 cm, so in order to get a 1,9 ratio, the lower segment would measure 26,31 cm. At 24 months, data shows that that the difference between U/L ratios from the baseline to 24 months vosoritide intake, was of minus 0,07, thus the ratio now is 1,83. This shows a slight improvement in the ratio.


BioMarin presented the new information that infants and toddlers will be included in the phase 3 study, the 111-206. 


Also, BioMarin stated that Vosoritide has been well tolerated by children until now, showing no serious adverse event (SAE). As it is known, Vosoritide slightly affects the blood pressure, producing some hypotension and increases heart rate, but the company said that no child gave up the study due to symptoms related to that. Also, in the graphs below, the term "correlation" is referred.

Correlation is an analysis that measures the strengths of association between two variables and the direction of the relationship. The correlation coefficient varies between +1 and -1.What BioMarin did was study different doses of vosoritide and analyze the effect in Heart rate and Blood pressure and although the doses were quite different, even the smallest dose of 2,5 ug/kg/day produced a decrease in blood pressure and increase in heart rate, that is transitory (meaning, after some time, the symptoms disappear). But this effects exists.

In conclusion, the company said there was no evidence of tachyphylaxis, that is related to a continued or repeated exposure to a drug which may lead to a weakened pharmacological response. 4

And for the infant/toddler study, the company predicts to will start enrolment in the first half of 2018.




All slides: BioMarin Events and presentations, 2017

1. Hoover-Fong J et al, 2008 " Age-appropriate body mass index in children with achondroplasia: interpretation in relation to indexes of height"

2. Statistics "How to"

3. Statistics Solutions

4. Webb N, 2011 "Tachyphylaxis"