A first of its kind drug called vosoritide may increase bone growth in children with achondroplasia, the most common form of dwarfism, according to findings from a recent clinical trial published in The Lancet.
“The hope and expectation are that if this therapy is started early, we can achieve a normal or near normal growth rate in children,” said Joel Charrow, MD, GME ’77, ’79, ’81, professor of Pediatrics in the Division of Genetics, Birth Defects and Metabolism and a co-author of the study.
Achondroplasia is the most common type of short-limbed human dwarfism and can be diagnosed at birth or prenatally. Children with achondroplasia have an average sized torso, short arms and legs, an enlarged head, and because of this may also experience challenges navigating society due to being of shorter stature.
Physical complications include the narrowing of the foremen magnum, an opening at the base of the skull through which the spinal cord passes, potentially compressing the spinal cord and putting the child at risk for sudden death if left unrecognized and untreated. Shortening of the base of the skull also causes the foreshortening of the nasopharynx, which can lead to upper airway obstruction and obstructive apnea.
On a biochemical level, achondroplasia occurs when there is a mutation in the FGFR3 gene, and this mutation causes the gene receptor to act as if a ligand called the fibroblast growth factor is bound to it. This then inhibits the mineralization of chondrocytes, or cartilage cells, in the growth plate, the growing tissue near the ends of the long bones.
In roughly 80 percent of individuals who have achondroplasia, the condition develops as a result of a random mutation in the FGFR3 gene during formation of the egg or sperm prior to fertilization, and neither parent has the condition. The remaining 20 percent of people with achondroplasia inherit the genetic condition from at least one of their parents who have achondroplasia.
Surgery is common among individuals with achondroplasia, which can help alleviate physical complications from bone problems and promote better quality of life. Limb lengthening surgery is also an option, but isn’t popular in the United States as it requires multiple surgeries over a long period of time and presents high risk of infection, according to Charrow.
Vosoritide, on the other hand, is the first drug of its kind, acting by increasing bone growth in children with achondroplasia. The drug is essentially an analogue for a naturally occurring substance in the body called C-type natriuretic peptide and prevents the inhibition of the mineralization of chondrocytes caused by the FGFR3 gene mutation. This double-negative inhibition then permits the chondrocytes to proliferate and mineralize normally, ultimately increasing bone growth.
In the current clinical trial, the investigators tested vosoritide in children with achondroplasia at 24 clinical sites around the world. Eligible participants were involved for six months in a baseline growth study and were between the ages of 5 and 18 years. Participants randomly received either one dose of vosoritide or a placebo daily for 52 weeks.
Overall, those who received vosoritide daily saw an increase in growth velocity of 1.57 centimeters (0.6 inches) per year by the end of the trial period. This growth velocity is similar to what is considered normal for this age group, according to Charrow.
Despite the drug’s success, however, Charrow said it’s also important to acknowledge that not everyone with achondroplasia supports this type of therapy, as there is a commonly shared feeling in the dwarfism community that dwarfism should not be treated as an illness or a disorder, even considering the physical problems and risks associated with the condition.
“If the drug does mitigate those other physical problems, then there’s no question in my mind that it would be beneficial because it would prevent morbidity and potential mortality,” Charrow added.
As for next steps, additional clinical trials for the drug are currently underway and involve participants with achondroplasia who are under the age of six months, with the aim of determining the drug’s effectiveness over a longer period of time.
“The hope and expectation are that if this therapy is started early, we can achieve a normal or near-normal growth rate. What we’re hoping, but remains to be seen, is whether some of the other things that go along with achondroplasia, like the narrowing of the foramen magnum and upper airway problems, are also mitigated by this therapy,” Charrow said.
This work was funded by BioMarin Pharmaceutical.