A year of daily subcutaneous vosoritide was associated with a 0.6-inch (1.5-cm) greater increase in height than placebo in children with achondroplasia, the most common form of human dwarfism.
There was no difference in the incidence of side effects in patients receiving the drug or placebo in this phase 3 study of the investigational drug from BioMarin Pharmaceuticals.
“To our knowledge, this study provides the first, robust evidence for an effective, precision therapy for achondroplasia that could fundamentally change the clinical management policies, growth trajectory, and treatment recommendations for children affected by this condition,” Ravi Savarirayan, MD, University of Melbourne, Australia, and colleagues report.
The study was recently published online in The Lancet.
“Over many years [this therapy] could lead to quite a significant increase in height [and] there were very few side effects that were attributable to the medication,” coauthor Joel Charrow, MD, Ann and Robert H. Lurie Children’s Hospital of Chicago, Illinois, summarized to Medscape Medical News.
And, he noted, it is also hoped “that it will affect other features of achondroplasia and prevent them, such as foramen magnum stenosis and shortening of the nasopharynx.”
“In theory, [infancy] would be the ideal time to start treatment to maximize the benefit,” he continued, and a trial of vosoritide that is enrolling infants with achondroplasia has just begun.
However, therapy for children with achondroplasia to make them taller is controversial, Charrow noted.
“In the dwarf community there are many people who are opposed to this kind of treatment because they don’t think that dwarfism should be medicalized or treated like a disease,” he said.
Asked to comment, David Ornitz, MD, PhD, who was not involved with the study, told Medscape Medical News that vosoritide appeared to be safe during 1 year of use, with no treatment-related adverse effects.
The efficacy results were “encouraging” for this “first potential pharmacological therapy to increase growth of achondroplasia patients.”
The drug could be “a pharmacological alternative to traditional surgical treatments or to not treating this genetic disease,” or it “could be used to augment the effectiveness of surgical therapies,” speculated Ornitz, of the Washington University School of Medicine, St Louis, Missouri.
Caveats include that daily injections might limit patient compliance and drug effectiveness, and it is not known whether efficacy would be sustained over the many years of treatment that would be required or if adverse effects would emerge later on, he noted.
Rare Genetic Mutation, Medical Complications in Addition to Short Stature
Achondroplasia is caused by a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene that results in inhibited mineralization of chondrocytes (cartilage cells) in the growth plate (growing tissue near the ends of the long bones).
The mutation occurs in about one in 25,000 live births worldwide. And more than 80% of children with achondroplasia have parents of average height.
Achondroplasia results in a disproportionately short stature and disordered architecture in the long bones, spine, face, and base of the skull; affected children have an average-sized torso, short arms and legs, and an enlarged head.
Complications include a narrowing of the foremen magnum (the opening at the base of the skull that the spinal cord passes through), which potentially compresses the spinal cord, and foreshortening of the nasopharynx leading to partial upper airway obstruction and obstructive apnea.
Other complications include bowed legs, midface hypoplasia, permanent lower-back sway, spinal stenosis, recurrent ear infections, and obesity.
Children may need invasive surgeries such as spinal cord decompression and straightening of bowed legs. Some people with achondroplasia suffer from chronic pain.
Currently, there is no FDA-approved therapy for achondroplasia.
In Japan, human growth hormone is approved to treat achondroplasia, but the drug has failed to show significant effects on final adult height and does not address the underlying disease pathogenesis.
Vosoritide, a biologic analog of C-type natriuretic peptide, prevents the inhibition of mineralization of chondrocytes caused by the FGFR3 mutation. The drug is being tested in children younger than 18 whose bones are still growing.
BioMarin has submitted a new drug application for vosoritide to the US Food and Drug Administration (FDA), and the company’s marketing authorization application was validated by the European Medicines Agency (EMA).
Vosoritide has orphan drug designation from the FDA and EMA for the treatment of children with achondroplasia.
As reported in 2019, a phase 2 dosing study in 35 children with achondroplasia found generally mild side effects and dose-related increases in annualized growth velocity — but this was an open-label trial with no placebo group.
In the current study, 121 children who were aged 5 to less than 18 years were randomized to vosoritide (15 µg/kg) or placebo for 52 weeks. Almost all patients (119) completed the trial.
The study involved 24 sites in seven countries (Australia, Germany, Japan, Spain, Turkey, the United States, and the United Kingdom).
The mean difference in growth velocity from baseline to 1 year was 1.57 cm/year in favor of vosoritide (P < .001).
Almost all patients had at least one adverse event (98% of patients in each group), but most events were mild, and no new adverse events emerged.
There were no significant improvements in upper-to-lower-body segment proportionality in the children who received vosoritide.
“The shortening of the bones in achondroplasia is primarily in the proximal segments in the upper arm and the upper leg — the humerus and the femur; so they will have relatively short limbs compared to the trunk,” Charrow explained.
“In this trial, with a year of therapy, there was no change in that proportion, but it was only a year,” he said.
Because vosoritide has a similar structure as atrial natriuretic peptide, pulse rate and blood pressure were monitored frequently. However, vosoritide was only associated with mild, transient, self-limiting, clinically inconsequential blood pressure changes.
None of the serious adverse events were treatment related. There were no deaths.
More Studies of Vosoritide, Other Therapies
Vosoritide is being studied in two ongoing trials.
In the open-label extension study of the current trial, data will continue to be collected until participants reach their adult height. The study could provide long-term information about potential harms, quality of life, activities of daily living, frequency and type of medical and surgical interventions, and a potential pubertal growth spurt (which is lacking in achondroplasia).
In addition, a phase 2, randomized, double-blind, placebo-controlled trial of vosoritide in infants and younger children (aged 3 months to < 60 months) with achondroplasia is underway, which will provide insights into how early treatment might affect body proportionality, growth, and complications such as foramen magnum stenosis with brainstem compression.
Additional potential therapies for achondroplasia being studied including a C-type natriuretic product (TransCon CNP, Ascendis Pharma). The drug, which has a longer half-life than vosoritide and is administered as a weekly subcutaneous injection, is being evaluated in a phase 2 study.
A soluble FGFR3 molecule used as a ligand trap (recifercept, Pfizer) and a selective oral tyrosine kinase/FGFR3 inhibitor (infigratinib, QED Therapeutics) have shown efficacy in mouse models of achondroplasia and are in early clinical development.
“It will be of interest to compare the safety and efficacy profiles of these potential therapeutic options with vosoritide as they progress through clinical trials and whether any of their actions might be synergistic for possible future combination therapy,” say Savarirayan and colleagues.
The study was funded BioMarin. Savarirayan has reported receiving consulting fees and grants form BioMarin. Charrow has reported receiving grants from BioMarin and several authors are company employees. Ornitz has reported no relevant financial relationships.
Lancet. Published online September 5, 2020. Abstract
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