medwireNews: Once daily oral treatment with infigratinib has a tolerable side effect profile and a significant positive benefit on both annualised height velocity and upper-to-lower body segment ratio in children with achondroplasia, indicates research published in The New England Journal of Medicine.
“As a FGFR3 [fibroblast growth factor receptor 3] inhibitor, infigratinib acts at the primary source of the patho-physiological cause of achondroplasia and blocks all downstream inhibitor signaling on bone growth”, explain Ravi Savarirayan (University of Melbourne, Victoria, Australia) and co-workers.
Their phase 2, dose-finding PROPEL 2 trial included 72 children aged 3–11 years (average age 7.5 years, 58% girls) who were assigned to receive daily infigratinib for 6 months at a dose of 0.016, 0.032, 0.064, 0.128 or 0.250 mg/kg. The two lowest dosages were increased to the next level after 6 and 12 months.
At time of reporting, 67 patients had completed 18 months of therapy, with one patient each given the lowest and the highest dose withdrawing at week 12 and week 6 of the 6-month escalation phase, respectively. A further three patients in the 0.016, 0.032 and 0.250 mg/kg dose cohorts withdrew during the 12-month extension phase after 11, 11 and 9 months, respectively.
None of the withdrawals were due to treatment-emergent adverse events (TEAEs) or efficacy concerns related to treatment, Savarirayan et al emphasize, despite each patient experiencing one or more TEAEs. The most common TEAEs across the treatment cohorts were nasopharyngitis (40%), COVID-19 (33%), headache (33%), vomiting (31%), limb pain (28%), ear infection (26%) and pyrexia (25%).
Overall, 54% of TEAEs were mild and 39% were of moderate severity. Five (7%) children had grade 3 TEAEs – namely hydrocephalus, adenoidal hypertrophy, tonsillar hypertrophy, sleep apnoea, cholesteatoma and bacillus infection – but none of these were considered related to treatment and no grade 4, 5 or serious TEAEs were reported.
Of the 10% of patients who had AEs considered related to infigratinib, all had mild effects, namely dyspepsia and flatulence, a decrease in vitamin D or a decrease in appetite. There was also one case of grade 1 hyperphosphatemia that required treatment interruption and dose reduction to 0.032 mg/kg.
“No accelerated progression of bone age, changes in bone mineral density, or other bone-related adverse events were reported”, the investigators say, nor were there any disorders of the cornea or retina.
The changes in the primary efficacy endpoint of annualised height velocity after 6 months of treatment in the 0.016, 0.032, 0.064, 0.128 and 0.25 mg/kg treatment cohorts were –1.82, 1.13, –0.06, 0.94 and 3.38 cm/year, respectively. And these changes correlated with the percent change from baseline in collagen X biomarker concentrations, the authors write.
Among patients given the highest 0.25 mg/kg dose, the increase in annualised height velocity was maintained throughout the 18-month treatment period, at 2.51 cm/year after 12 months and 2.50 cm/year at 18 months. Indeed, increases in height velocity were reported for 91% of the 11 patients at 18 months, with 73% achieving at least a 25% increase.
“This cumulative increase in linear growth corresponds to an increase in the height z score”, write Savarirayan et al.
In addition, patients given the 0.25 mg/kg daily dose experienced a decrease in their average upper-to-lower body segment ratio from 2.02 at baseline to 1.88 after 18 months. The team describes this as being “noteworthy because children with achondroplasia have short stature with disproportionate limb shortening in comparison to their truncal height.”
This body segment ratio, in combination with a large head circumference, affects achievement of gross motor milestones in the first 5 years of life and long-term outcomes such as self-care, independent walking, driving and other daily tasks, the researchers point out. They therefore recommend further research “to determine whether the improvement in the upper-to-lower body segment ratio observed in these children at 18 months will continue and be associated with improvements in functionality.”
The investigators conclude: “The patients in this study continue to receive treatment with infigratinib in an open-label extension study (NCT05145010) in which the safety and efficacy of long-term administration of infigratinib is being evaluated.”
By Lynda Williams
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