Rare Daily Staff

The European Commission granted marketing authorization for BioMarin Pharmaceutical’s Voxzogo, a once daily injection to treat achondroplasia in children from the age of 2 until growth plates are closed, which occurs after puberty when children reach final adult height.

Achondroplasia is the most common cause of dwarfism. 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 change 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.

More than 80 percent of children with achondroplasia have parents of average stature and have the condition as the result of a spontaneous gene mutation. The worldwide incidence rate of achondroplasia is about one in 25,000 live births.

Voxzogo is the first medicine to be approved to treat children with achondroplasia in Europe. Voxzogo, a modified C-type natriuretic peptide (CNP), directly targets the underlying pathophysiology of achondroplasia by down regulating fibroblast growth factor receptor 3 (FGFR3) signaling and consequently promoting endochondral bone formation.

The EC based its decision on the totality of data from the Voxzogo clinical development program including the outcomes from the randomized, double-blind, placebo-controlled phase 3 study evaluating the efficacy and safety of Voxzogo. The phase 3 study was further supported by the ongoing long-term safety and efficacy from the phase 2 dose-finding study, which showed that growth rates have been sustained above participants’ baseline rates and above the expected annualized growth velocity for untreated children with achondroplasia throughout the five-year observation period for which data are currently available. No acceleration of bone age was observed, suggesting that Voxzogo is not reducing the total duration of growth. The data package included results from an ongoing phase 2 randomized double-blind study in infants and young children, including extensive pharmacokinetic and biomarker data, as well as preliminary growth data from participants in the 2 to 5-year age cohort. Data in sentinel study participants showed a positive effect on growth following two years of Voxzogo treatment in subjects aged 2 to 5 years. In addition, the data package included data from the phase 3 extension study and extensive natural history data.

Voxzogo was generally well tolerated at all doses, and approximately 38,000 injections have been administered to children around the world. The majority of adverse events (AEs) were mild and no serious adverse events (SAEs) 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 transient.

Voxzogo is being tested in children whose growth plates are still “open,” typically those under 18 years of age. This is approximately 25 percent of people with achondroplasia. In the United States, Europe, Latin America, the Middle East, and most of Asia Pacific, there are currently no licensed medicines for achondroplasia.

It is estimated that over 11,000 children across Europe, Middle East, and Africa are affected by achondroplasia and could be eligible for treatment with Voxzogo. Approximately a third of this population are in countries authorized under the EMA license. Also, the French National Agency for Medicines and Health Products Safety (ANSM) granted a Temporary Authorization for Use to allow access of Voxzogo to begin immediately under an authorized process. An ATU allows access to drugs not yet approved in France, when provided for rare diseases with no alternative options, and when the benefit/risk is presumed positive. The list price in France under the ATU process is $839 (712€) per vial and constitutes flat vial pricing across the spectrum of ages and weights translating to an estimated annual per patient cost of approximately $300,000 (260,00€) assuming 100 percent compliance and excluding any discounts.  BioMarin expects the initial German list price to be consistent with the French ATU price. These list prices will be subject, in one to two years, to material discounts after reimbursement negotiations in key markets such as Germany, France and Italy.

“We are committed to advancing the care of children affected by achondroplasia and are pleased to be able to offer a genetically targeted medicine that when administered in children over the age of two only while skeletal growth plates are open but could potentially offer benefit over a lifetime,” said Jean-Jacques Bienaimé, chairman and CEO of BioMarin. “Voxzogo is the most widely studied therapeutic option for achondroplasia with an ongoing robust clinical program built on more than a decade of research and development.”

The U.S. New Drug Application (NDA) for Voxzogo is under review by the U.S. Food and Drug Administration with a Prescription Drug User Fee Act (PDUFA) target action date of November 20, 2021. BioMarin successfully closed out the in-person FDA pre-approval inspection of its manufacturing facilities for Voxzogo earlier this year. FDA has granted Voxzogo Priority Review designation and Rare Pediatric Disease designation. Voxzogo also received orphan drug designation from the FDA and EMA for the treatment of children with achondroplasia. advance the evaluation and development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions.

Photo: Jean-Jacques Bienaimé, chairman and CEO of BioMarin

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