Novel Agent Shows Promise as First Possible Therapy for Achondroplasia

The results are preliminary, but a novel investigative agent has shown promise in a small trial in children for the treatment of achondroplasia, the most common form of human dwarfism.

A phase 2 proof of concept study found that treatment with vosoritide (BioMarin Pharmaceutical), a recombinant C-type natriuretic peptide analogue, demonstrated a favorable safety profile and efficacy at a dose of 15 μg/kg. The findings were published online June 18 in the New England Journal of Medicine.

The side effect profile was generally mild and study participants had a sustained increase in annualized growth velocity for up to 42 months.

"Those are the two main findings of the study, which is still ongoing," said the lead author Ravi Savarirayan, MBBS, MD, clinical geneticist and group leader of skeletal biology and disease, Murdoch Children's Research Institute, Parkville, Melbourne, Australia.

"This is the first precision therapy for this condition," he stressed.

Treatment for the condition is currently extremely limited.

"Growth hormone isn't used anywhere apart from Japan," Savarirayan said in an interview with Medscape Medical News. "Children with achondroplasia don't have growth hormone deficiency so it can cause more problems [than it solves], and basically, is not a very good treatment."

The only real treatment available is limb lengthening surgery. "So there is really nothing that treats the underlying pathology, until potentially now," he explained.

This was a dose finding study, and the researchers are now continuing onto a phase 3 randomized placebo-controlled trial with children aged 5 to 18 years.

"Hopefully, we will have some early results for that study by the end of this year," said Savarirayan. "We've also started another study with children aged 0 to 5 where we'd like to address some of the medical complications of the condition, such as spinal growth."

"This will be really important, as we may be able to prevent a lot of the medical problems associated with this condition," he added.

Few Serious Adverse Events

Achondroplasia, a nonlethal form of chondrodysplasia, is the most common type of short-limb dwarfism, with about 80% of cases caused by a de novo autosomal dominant mutation in the fibroblast growth factor receptor 3 gene (FGFR3).

The hallmark clinical features are short stature with limb shortening and macrocephaly. Medical complications include hydrocephalus, hypotonia, back and leg pain, conductive hearing loss, and speech delay. Tonsillar hypertrophy may result in obstructive sleep apnea and respiratory insufficiency. Foramen magnum stenosis and cervicomedullary compression may result in central apnea, leading to an increased risk of sudden death in infancy.

These functional limitations affect quality of life and cause chronic pain, which lead to psychological challenges. Mortality is increased from birth to 4 years of age, and in the fourth and fifth decades of life.

There are currently no pharmacologic treatments for this disorder, other than growth hormone, which has only been approved for this indication in Japan.

In experimental studies, subcutaneous administration of vosoritide given once a day promoted long bone growth in juvenile mice and monkeys with normal skeletons, and also corrected dwarfism in mouse models. Based on these preclinical findings, Savarirayan and colleagues conducted their phase 2 dose-finding study and its ongoing extension to evaluate the use of vosoritide in children with achondroplasia.

A total of 35 children aged 5 to 14 years were enrolled in four sequential cohorts. Vosoritide was administered at a once-daily subcutaneous dose of 2.5 μg/kg of body weight (eight patients in cohort 1), 7.5 μg/kg (eight patients in cohort 2), 15 μg/kg (10 patients in cohort 3), or 30 μg/kg (nine patients in cohort 4).

After 6 months, the dose in cohort 1 was increased to 7.5 μg/kg and then to 15 μg/kg. In cohort 2, the dose was increased to 15 μg/kg, and dosing in the other groups stayed the same. At data cutoff, the 24-month dose-finding study had been completed and 30 patients entered an ongoing long-term extension.

Median follow-up for both studies was 42 months. Safety data were available for up to 52 months for 12 patients in cohorts 1 and 2, up to 45 months in cohort 3, and up to 34 months in cohort 4.

Adverse events occurred in all patients during the dose finding and extension studies. The most common events in the 15 μg/kg cohorts were injection site reactions, erythema, and pyrexia. All injection-site reactions were mild (grade 1) and transient.

In both study groups, serious adverse events were observed in four (11%) patients, and these included grade 3 obstructive sleep apnea, grade 1 tonsillar hypertrophy, grade 3 thyroglossal cyst, and grade 3 syrinx (fluid-filled cyst). There were no deaths or events that were related to disproportionate skeletal growth or clinically significant cardiovascular effects.

Annualized Growth Velocity of 5.5 cm/year With 15-μg/kg Dose

A dose-dependent increase in the annualized growth velocity was observed at 6 months in patients who received a dose of up to 15 μg/kg.

Increases were seen in cohort 2 (1.28 cm/year; 95% CI, 0.07 - 2.48), in cohort 3 (2.01 cm/year; 0.58 - 3.44), and in cohort 4 (2.08 cm/year; 95% CI, 0.30 - 3.87) but not in cohort 1 (−0.37 cm/year; 95% CI, −1.84 to 1.10).

Patients who received the 15-μg/kg dose had a mean annualized growth velocity of 5.51 cm/year, as calculated between 30 and 42 months, representing an average annual increase of 1.46 cm (95% CI, −0.15 to 3.07) from baseline.

The mean annualized growth velocity was 5.60 cm/year, as calculated between 18 and 30 months in the 30-μg/kg dose cohort.

This change represented a mean annual increase of 1.10 cm (95% CI, −0.27 to 2.48) from baseline.

When looking at biomarkers, the authors found that there were dose-dependent increases in urinary cyclic guanosine monophosphate (cGMP) and serum collagen X marker (CXM) concentrations during the first 6 months of treatment in all groups, and these remained elevated from baseline through 24 months.

These findings, they note, suggest that the pharmacologic activity of vosoritide is sustained during the entire treatment period. The highest doses (15 and 30 μg/kg) produced the maximum responses.

A New Treatment Option?

Based on the results to date, senior author Julie Hoover-Fong, MD, PhD, director, Greenberg Center for Skeletal Dysplasias, Johns Hopkins University School of Medicine, Baltimore, Maryland, explained that vosoritide could be a new treatment option for "people with achondroplasia who are still experiencing linear growth."

However, the optimal age to begin treatment has yet to been determined, she noted.

"Since the drug has its effect on the growth plate before it has fused, any time before closure occurs would be possible for treatment," Hoover-Fong told Medscape Medical News.

"Some could argue that the earlier the better but complications of achondroplasia that are part of its natural history may still occur and should be monitored closely at all ages — especially in the young."

Long-term results and adverse events are yet unknown, but it "has been safe thus far and the trials continue," she concluded.

The study was funded by BioMarin Pharmaceutical. Savarirayan has reported grants and personal fees from BioMarin Pharmaceuticals. Hoover-Fong has reported grants, personal fees, and nonfinancial support from BioMarin Pharmaceuticals, and personal fees from Therachon and Ascendis Pharma.

N Engl J Med. Published on June 18, 2019. Abstract

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