Dwarfism. New hopes for treatment.

By Pauline Fréour - Le Figaro

A height well below average (1,31 m for men, 1,24 m for women), short legs, a long and narrow torso, a large head with a protruding forehead. These are the physical characteristics of achondroplasia, the most common form of dwarfism. It is well known, as it is frequent: it affects one child in every 25 births.

There is currently no treatment on the market. The only option sometimes considered for these people to gain height is leg lengthening surgery, but this is a lengthy and painful process. That is why this type of intervention is performed very rarely. But the discovery, about twenty years ago, of the genetic mutation responsible for this form of dwarfism, opened the way for drug research that has been yielding quite encouraging results in humans.

maximum dose

The molecule tested, Vosoritide, was developed by the American company Biomarin. It was administered to 26 children aged 5 to 14 years in four countries. Two of these patients are being monitored in France by Professor Valeria Cormier-Daire, from the reference center for constitutive bone diseases at the Institut Imagine, at the Necker Hospital in Paris. According to results published by Biomarin in a press release at an international medical congress in the United States, treatment with daily injections promoted a 50% increase in growth in ten children treated with stronger doses compared to the six months prior to treatment.

“The growth curve of these children has been completely modified,” says Laurence Legeai-Mallet, director of research (Inserm), who supervised the pre-clinical trials of Vosoritide in France and is co-discoverer of the defective FGFR3 gene. “It’s the first time we’ve shown that it’s possible to do something for them,” she says, but cautiously: “Six months is a short time.” The study does not yet say whether the facial morphology anomalies can be corrected.

Based on these promising results, the laboratory extended the tests for eighteen months. “We will know if the gain can be maintained over time and if these children can expect to gain between 15 and 30 centimeters in total.” This time, all children in the group will receive the maximum dose for which effects were observed. Vosoritide allows the attenuation of the activity of a cellular receptor, whose natural function is to restrict bone growth. In people with achondroplasia, this receptor is hyperactive, a bit like walking with the handbrake on.

The treatment was well tolerated, reports Biomarin, citing, among the side effects, headaches, back pain, cough, skin reactions at the injection site, the most concerning being a drop in blood pressure, although without severity. Since it is a growth accelerator, the treatment is intended for children who have not yet reached puberty. Unfortunately, once in adulthood, the medication will no longer be able to correct the lack of growth.

Encouraging results

“These results are very encouraging, but they still need to be proven and be the subject of rigorous publication in a specialized scientific journal,” says Professor William Horton, an expert in achondroplasia at [institution name]. Oregon Health and Science Universityin the United States. In an analysis of the five different therapeutic approaches against this disease followed worldwide, published in October in Human Molecular GeneticsHe noted that Vosoritide is the only drug to have reached the clinical trial stage. Other molecules, some of which have been known and used for several years in other pathologies (statins, the antihistamine meclizine), have demonstrated efficacy, but so far only in mice.

The results of the second part of the trial should be followed with interest. William Horton, who was a consultant for Biomarin, points to the unanswered questions: “Will the growth be sustained long enough to allow the treated children to reach a normal size? Will this relatively long therapy have long-term side effects?” Only time will tell.