Biomarin Pharmaceuticals: Vosoritide (BMN111) for the Treatment of Achondroplasia (Short Stature)

                                             Highlights of Vosoritide Program

- Vosoritide is the FDA approved drug for the treatment of Achondroplasia 
- Developed by Biomarin, and received orphan designation from FDA and EMA
- New Drug Application Under Review by FDA with Set PDUFA August 2020
- EMA validated the marketing authorization application
- Publication of positive outcome data from Phase 3 study in Lancet

Achondroplasia is the most common form of disproportionate short stature in humans, it is characterized by slowing of endochondral ossification, which results in disproportionate short stature and disordered architecture in the long bones, spine, face, and base of the skull. 
This condition is caused by a mutation in the fibroblast growth factor receptor 3 gene (FGFR3), a negative regulator of bone growth.

Beyond disproportionate short stature, people with achondroplasia can experience serious health complications, including foramen magnum compression, sleep apnea, bowed legs, mid-face hypoplasia, permanent sway of the lower back, spinal stenosis, and recurrent ear infections. 
Some of these complications can result in the need for invasive surgeries such as spinal cord decompression and straightening of bowed legs. In addition, studies show increased mortality at every age.

The worldwide incidence rate of achondroplasia is about one in 25,000 live births. Vosoritide is being tested in children whose growth plates are still "open", typically those under 18 years of age. This is approximately 25% of people with achondroplasia. There is no treatment available for achondroplasia.


Regulatory Status of Vosoritide Program

U.S. Food and Drug Administration (FDA)
November 2020: FDA accepted the New Drug Application (NDA) and the PDUFA. Vosoritide received orphan drug designation from the FDA for the treatment of children with achondroplasia.

European Medicines Agency (EMA)
August 2020: EMA validated the Company's Marketing Authorization Application.

Clinical Study Update of  Vosoritide Program

Summary of results from Phase 3 Study (Published in Lancet)

The primary endpoint was change from baseline in AGV at 52 weeks in participants administered daily subcutaneous injections of vosoritide, at a dose of 15.0 µg/kg/day, compared with placebo. 
The findings demonstrated that the adjusted mean difference in AGV between children in the vosoritide group and placebo group was 1.57cm per year in favor of vosoritide (95% CI: 1.22 - 1.93, p value <0·0001), a substantial proportion of the approximately 2 cm/yr AGV deficit relative to average-stature children.
A prespecified analysis of the secondary endpoint of change from baseline in height Z score, (which measures the height deficit in standard deviations relative to the mean forage- and gender-matched average stature children), was also performed. 
The findings demonstrated that the adjusted mean difference in height Z score change from baseline between children in the vosoritide group and placebo group was +0.28 in favor of vosoritide (95% CI: 0.17 – 0.39, p value <0.0001). 

Vosoritide, administered at 15.0 ug/kg/day in this Phase 3 randomized, double-blinded placebo-controlled study over one year, was generally well tolerated. The majority of adverse events (AEs) were mild and no serious adverse events were reported as study drug-related. Injection site reactions were the most common drug-related AEs, and all were transient. 
No clinically significant blood pressure decreases, or new safety findings were observed. 

Baseline and 52 Weeks Annualized Growth Velocity in Treatment and Placebo Control Group (Lancet 2020)