- Achondroplasia — the most common form of dwarfism — is caused by pathogenic gain-of-function variants in the gene encoding fibroblast growth factor receptor 3.
- Treatment with the oral tyrosine kinase inhibitor infigratinib led to significant increases in growth among children with achondroplasia in the phase III PROPEL 3 study.
- The once-daily capsule targets FGFR1-3 and provides an alternative to injectable treatments.
Treatment with a once-daily FGFR1-3 tyrosine kinase inhibitor led to significant increases in growth among children with achondroplasia, the phase III PROPEL 3 study showed.
The least-squares mean change from baseline in the annualized height velocity at week 52 was 1.58 cm/year in the infigratinib group and -0.16 cm/year in the placebo group, for a between-group difference of 1.74 cm/year (95% CI 1.31-2.17), reported Ravi Savarirayan, MBBS, MD, of Royal Children’s Hospital in Parkville, Australia, and colleagues.
In addition, the difference between infigratinib and placebo in the least-squares mean change from baseline to week 52 in the achondroplasia-specific height z score was 0.32 (96% CI 0.23-0.41). There was also a trend toward a decrease in the upper-to-lower body segment ratio, but this did not reach significance (least-squares mean change -0.02, 95% CI -0.06 to 0.01).
“The treatment effect appeared to be favorable with infigratinib across all subgroup categories,” the authors wrote in the New England Journal of Medicine. The findings were simultaneously presented at the International Conference on Children’s Bone Health in Montreal.
The growth difference appeared to be more pronounced in the subgroup of children ages 3 to 7 years, which is “the age range in which changes in body proportions are more likely to be evident,” Savarirayan and team pointed out. The difference was also somewhat more pronounced in children at Tanner stage 1, also known as pre-puberty.
Achondroplasia — the most common form of dwarfism — is caused by pathogenic gain-of-function variants in the gene encoding fibroblast growth factor receptor 3 (FGFR3). This causes overactivity in downstream pathways, such as mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1).
Two therapies are approved for this rare skeletal disorder: the C-type natriuretic peptide analogues vosoritide (Voxzogo) and navepegritide (Yuviwel). In clinical trials, these drugs boosted growth, with mean differences in annualized growth velocity versus placebo of 1.57 cm/year and 1.49 cm/year, respectively.
“Unlike C-type natriuretic peptide analogues that down-regulate FGFR3 signaling solely through the MAPK pathway, infigratinib binds directly to FGFR3, thereby inhibiting its phosphorylation and all consequent downstream signaling with respect to bone growth,” Savarirayan and colleagues explained.
“Because multiple signaling pathways are implicated in the pathogenesis of achondroplasia, this mechanism of action represents a possible therapeutic advantage,” they noted. “As an orally administered medication, infigratinib averts the issues of administering injectable therapies, which makes it an attractive therapeutic option for children with achondroplasia.”
The double-blind trial was conducted at 27 sites in 10 countries. It screened 114 participants who had completed at least 26 weeks of participation in the observational PROPEL study from November 2023 through December 2024, and included those with growth potential. This was defined as:
- An annualized height velocity of more than 1.5 cm/year during PROPEL
- A pubertal Tanner stage of 4 or less
- A bone age of 13 years or less in girls and 15 years or less in boys
Participants were randomized 2:1 to receive infigratinib (n=75) or placebo (n=39). All were between the ages of 3 and 17 years and had a confirmed genetic diagnosis of achondroplasia. Mean age was 7.9 years, 58% were boys, 60% were white, and most (83%) were at Tanner stage 1 at baseline.
They received daily treatment with oral infigratinib as sprinkle capsules at a dose of 0.25 mg/kg of body weight or a placebo. Treatment could be paused and resumed at the same dose, or decreased to a lower dose if criteria for dose reduction or discontinuation were met.
Most adverse events were mild to moderate. The most common (occurring in ≥10% of the infigratinib group) included pyrexia, vomiting, cough, upper respiratory tract infection, headache, otitis media, nasopharyngitis, and ear pain.
Three cases of increased serum phosphate levels were noted at protocol-timed measurements, but they were considered transient, asymptomatic, and not clinically meaningful.
No adverse events led to treatment discontinuation, and no deaths occurred. Additionally, there were no reports of accelerated bone age progression, changes in bone mineral density, or between-group differences in serum chemistry or hematology.
The relatively short trial duration was a limitation, Savarirayan and team acknowledged, resulting in a lack of long-term data on outcomes such as functionality, health-related quality of life, medical complications, and final adult height.
Long-term efficacy and safety are currently being evaluated to assess these outcomes in the ongoing PROPEL OLE study, they said. The phase II/IIb PROPEL Infant and Toddler trial is also underway in children younger than 3 years.
Source link : https://www.medpagetoday.com/endocrinology/growthdisorders/121958
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Publish date : 2026-06-28 20:00:00
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