The oral FGFR1–3 selective tyrosine kinase inhibitor infigratinib improves height velocity and reduces the upper-to-lower body segment ratio in children with achondroplasia, an Australian-led study has shown.

The PROPEL 3 study, published in the NEJM [link here] and presented at the 12th International Conference on Children’s Bone Health in Montreal, Canada, said the findings, lack of safety events, and sprinkle capsule formulation for ease of administration support infigratinib’s potential as a targeted oral therapy for affected children.

“Treatment with once-daily oral infigratinib for 52 weeks led to larger increases in the annualised height velocity and height z score than placebo in children with achondroplasia between the ages of 3 and 17 years,” it said.

The study comprised 114 participants 3-17 years of age with genetically confirmed achondroplasia recruited from 10 countries. They were randomised 2:1 to either daily infigratinib at 0.25 mg per kilogram of body weight or placebo.

It found that the primary end point of mean change from baseline in the annualised height velocity at week 52 was 1.58 cm per year in the infigratinib group versus −0.16 cm per year in the placebo group (P<0.001), for a between-group difference of 1.74 cm per year.

In key secondary endpoints:

• mean change from baseline to week 52 in the achondroplasia-specific height z score was 0.32 (P<0.001)
• mean change in the upper-to-lower body segment ratio from baseline to week 52 was −0.02 in the whole group and -0.05 in the subgroup of 3-7-year-olds
• the least-squares mean annualised height velocity at week 52 was 5.96 cm per year with infigratinib and 4.22 cm per year.

Regarding safety, treatment-related adverse events were 8% in the infigratinib group and 15% in the placebo group. No serious adverse events were deemed treatment related.

Commonly reported adverse events including pyrexia, vomiting, cough, upper respiratory tract infection and headache were mostly mild to moderate in severity.

No accelerated progression of bone age or changes in bone mineral density were observed.

Professor Ravi Savarirayan

Despite two patients with hyperphosphatemia in the infigratinib group – considered to be treatment-related and resolved after a protocol-specified dose interruption – the study said there were no safety events related to the inhibition of FGFR1 or FGFR2.

No corneal or retinal disorders were identified by ophthalmic examination.

“We speculate that the infigratinib dose of 0.25 mg per kilogram per day that was used in this trial had no clinically significant effect on these FGFR receptors,”

The investigators, led by Professor Ravi Savarirayan from the Murdoch Children’s Research Institute, said infigratinib binds directly to FGFR3, thereby inhibiting its phosphorylation and all consequent downstream signaling with respect to bone growth.

“Because multiple signaling pathways are implicated in the pathogenesis of achondroplasia, this mechanism of action represents a possible therapeutic advantage,” they said.

Long-term efficacy and safety are being evaluated to assess outcomes such as health-related quality of life, medical complications, and adult height in an open-label extension study.

A phase 2–2b PROPEL Infant and Toddler study is also underway to evaluate infigratinib treatment in children younger than 3 years of age.

The PROPEL study program is funded by BridgeBio Pharma.