Two therapies show growth gains for children with achondroplasia

The FDA has approved a once-weekly therapy to improve growth for children aged 2 years and older with achondroplasia, while topline phase 3 results for an investigational oral medication showed the highest growth velocity reported to date in a randomized achondroplasia trial.

Navepegritide (Yuviwel, Ascendis Pharma), a prodrug of C-type natriuretic peptide, is the first once-weekly treatment approved for children who have achondroplasia with open epiphyses. The medication is designed to provide continuous exposure of active C-type natriuretic peptide in body tissue and counteract overactive fibroblast growth factor receptor 3 signaling observed in patients with achondroplasia.

The FDA approved navepegritide based on data from three randomized, double-blind placebo-controlled trials and 3 years of open-label extension data. In a phase 2b trial, children and adolescents receiving navepegritide had a mean annualized growth velocity of 5.89 cm per year compared with an annualized growth velocity of 4.41 cm per year with placebo (P < .001). Navepegritide also conferred greater increases in achondroplasia-specific height z score and CDC-based height z score from baseline to 1 year compared with placebo. No children receiving navepegritide discontinued the trial due to adverse events.

The medication was reviewed under the FDA's accelerated approval program, and continued approval may be contingent upon verification of clinical benefit in confirmatory trials. The FDA also issued a rare pediatric disease priority review voucher with the approval. The medication is expected to be available in the U.S. during the early part of the second quarter of 2026.

Infigratinib (BridgeBio Pharma), an oral tyrosine kinase inhibitor under investigation for the treatment of achondroplasia, showed positive results in the PROPEL 3 phase 3 trial. The drug was granted FDA breakthrough therapy designation in September 2024 after data from the PROPEL 2 phase 2 trial showed the medication was associated with increased annualized height velocity at 1 year that was maintained at 18 months.

In the PROPEL 3 phase 3 trial, children aged 3 to 17 years with achondroplasia and open growth plates were randomly assigned 2:1 to infigratinib or placebo for 1 year. The primary endpoint was change in annualized height velocity from baseline to 1 year.

Children receiving infigratinib had a 1.74 cm per year greater least-squares mean increase in annualized height velocity than those receiving placebo (P < .0001). The infigratinib group experienced a 5.96 cm per year rise in annualized height velocity compared with a 4.22 cm per year increase with placebo. The infigratinib group had a 0.32 standard deviation greater increase in height z score compared with placebo (P < .0001). The infigratinib group's increase in height z score was 0.41 standard deviation. Both figures were the highest observed in a randomized trial investigating an achondroplasia therapy.

In a prespecified exploratory analysis of children younger than 8 years, those receiving infigratinib had a 0.05 greater decline in upper-to-lower body proportionality than placebo at 1 year (P < .05). This is the first statistically significant improvement in upper-to-lower body proportionality for children with disproportionate short stature reported for any therapy approved or in development for this condition.

There were no serious adverse events related to infigratinib or discontinuations related to the drug. There were three reports of hyperphosphatemia in the trial, all of which were mild, transient and asymptomatic. There were no adverse events related to the inhibition of fibroblast growth factor receptors 1 and 2 (FGFR1/2), and no adverse events tied to C-type natriuretic peptide analogs.

Infigratinib is the first oral therapy designed to target FGFR3 and directly address the underlying cause of achondroplasia. Based on the trial's results, BridgeBio plans to submit new drug applications and marketing authorization applications to regulatory agencies in the second half of 2026. The company is also planning to conduct phase 3 trials on infigratinib to treat hypochondroplasia and to assess the medication in children younger than 3 years with achondroplasia.