Infigratinib shows potential as a targeted oral therapy for children with achondroplasia.In the phase III PROPEL 3 trial, once-daily treatment with infigratinib results in a significantly greater increase in annualized height velocity (AHV) in children with achondroplasia.
Compared with baseline, the change in AHV was greater with infigratinib than with placebo at week 52 (mean, 1.48 cm/year vs −0.62 cm/year; least-squares mean [LSM], 1.58 cm/year vs −0.16 cm/year; p<0.001). [N Engl J Med 2026;395:859-869]
Infigratinib also outperformed placebo in terms of improvements in achondroplasia-specific height z score (difference in LSM change, 0.32; p<0.001) and upper-to-lower body segment (US/LS) ratio at week 52 (difference in LSM change, −0.02). Of note, the latter finding was more pronounced in children aged 3–7 years (difference, −0.05), which is the age range where body proportion changes become more obvious. [Genet Med 2022;24:2444-2452]
Safety profile
Approximately 95 percent of participants reported adverse events (AEs), but most were mild to moderate in severity. Eight percent of AEs were determined by investigators as related to infigratinib, whereas 15 percent were related to placebo.
Serious AE rates were similar between the experimental and placebo groups (5 percent and 3 percent), but none were deemed drug-related. There were no AEs leading to treatment discontinuation, and no deaths in either group.
Two infigratinib-treated patients reported AEs involving hyperphosphataemia. Another infigratinib recipient met the protocol criteria for elevated serum phosphate level, which led to a dose interruption, but this was not reported as an AE because it aligned with the patient’s baseline levels.
“[However,] the serum phosphate level changes were interpreted as transient, asymptomatic, and not clinically meaningful, given the conservative protocol-defined criteria for dose modification and … all three cases were mild, resolved with no specific treatment, and did not recur at the same dose,” the researchers explained.
“Furthermore, the elevations were no more than 0.6 mg/dL greater than baseline levels, an increase that falls within the expected range of variability in serum phosphate levels in the paediatric population,” they continued.
No safety events associated with FGFR1 or FGFR2 inhibition were reported. According to the researchers, this suggests that the infigratinib dose used may have had no clinically significant effect on these FGFR receptors.
Oral administration preferred
Currently approved treatments for children with achondroplasia include C-type natriuretic peptide (CNP) analogues, which are administered subcutaneously. [N Engl J Med 2019;381:25-35; JAMA Pediatr 2026;180:18-25] Since oral administration is the preferred medication route in paediatric patients, an oral treatment alternative in this setting remains an unmet need, the researchers noted.
Infigratinib, an orally bioavailable FGFR1–3 selective tyrosine kinase inhibitor being developed for achondroplasia, directly inhibits FGFR3 phosphorylation and attenuates key downstream signalling pathways, including MAPK and STAT1. [J Clin Invest 2016;126:1871-1884]
“Unlike CNP analogues that downregulate FGFR3 signalling solely through the MAPK pathway, infigratinib binds directly to FGFR3, thereby inhibiting its phosphorylation and all consequent downstream signalling with respect to bone growth. Because multiple signalling pathways are implicated in the pathogenesis of achondroplasia, this mechanism of action represents a possible therapeutic advantage,” they said.
PROPEL 3 builds on the results of the phase II PROPEL 2 study, which showed sustained increases in AHV and height z score and a decrease in US/LS ratio at 18 months with infigratinib. [N Engl J Med 2025;392:865-874]
In PROPEL 3, 114 participants (mean age 7.9 years, 58 percent male) were randomized 2:1 to infigratinib or placebo QD. Infigratinib was administered daily as oral sprinkle capsules at a dose of 0.25 mg/kg of body weight for 52 weeks. However, the short study duration precludes determination of infigratinib’s effect on function, health-related quality of life, complications, and adult height.
“[Nonetheless,] 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 researchers said. “Our findings indicate that infigratinib may have potential as a targeted oral therapy for children with achondroplasia.”