Oral Drug Safe, Effective in Kids With Achondroplasia

The oral FGFR1-3 selective tyrosine kinase inhibitor infigratinib was found to be safe and effective at the highest studied dose among children with achondroplasia in a phase II dose-finding study.

During treatment, all 72 participants had at least one adverse event, though most were mild (54%) or moderate (39%) in severity, and none resulted in treatment discontinuation, reported Ravi Savarirayan, MBBS, MD, of Royal Children’s Hospital and the University of Melbourne in Australia, and colleagues.

Furthermore, among kids in the fifth of five sequential cohorts who received infigratinib 0.25 mg/kg, there was an increase in annualized height velocity observed, with a mean change from baseline at 18 months of 2.5 cm per year (95% CI 1.22-3.79, P=0.001), the authors noted in the New England Journal of Medicine.

The mean change from baseline at 18 months in height z score was 0.54 (95% CI 0.35-0.72) relative to an untreated achondroplasia reference population, while the mean change from baseline in upper-to-lower body segment ratio was -0.12 (95% CI -0.18 to -0.06).

“At the moment the only medication approved for the treatment of children with achondroplasia is vosoritide [Voxzogo], which requires a daily subcutaneous injection,” Savarirayan told MedPage Today. “This oral treatment appears safe and at least as effective as the injectable form. This will be of great potential interest and also important in countries where injections might not be practical.”

“The future clinical implications include the ease of administration of an oral medication and the effectiveness on height and proportionality in children with achondroplasia,” he added, “that we hope will translate into better functionality and independence.”

Infigratinib has had a somewhat rocky regulatory path, but may have found new life in achondroplasia. The FGFR inhibitor had been granted accelerated approval in 2022 as a treatment for bile duct cancer (under the trade name Truseltiq), but that approval was withdrawn earlier this year.

Achondroplasia is a genetic skeletal condition that results in disproportionately short stature and health complications throughout life, such as an exaggerated inward curve of the lumbar spine, spinal stenosis, and hydrocephalus. It is characterized by limited range of motion at the elbows, macrocephaly, small fingers, and normal intelligence, and is caused by changes in the FGFR3 gene.

In the study, grade 3 adverse events occurred in five kids and included hydrocephalus, adenoidal hypertrophy, and tonsillar hypertrophy in the group of kids who received infigratinib 0.032 mg/kg (cohort 2); sleep apnea syndrome and cholesteatoma in those who received 0.064 mg/kg (cohort 3); and bacillus infection in those who received 0.128 mg/kg (cohort 4).

Seven kids had adverse events assessed as being related to the study drug. These events, which were mild in severity, included dyspepsia and flatulence in cohort 2, decreased vitamin D levels in cohorts 3 and 4, decreased appetite in cohort 4, and hyperphosphatemia in cohort 3.

A dose-dependent increase in the annualized height velocity was observed after 6 months of treatment with infigratinib, with changes from baseline to month 6 of:

• Cohort 1: -1.82 cm per year (95% CI -4.96 to 1.32)
• Cohort 2: 1.13 cm per year (95% CI 0.47-1.79)
• Cohort 3: -0.06 cm per year (95% CI -0.93 to 0.81)
• Cohort 4: 0.94 cm per year (95% CI 0.15-1.74)
• Cohort 5: 3.38 cm per year (95% CI 1.67-5.10)

In cohort 5, increased annualized height velocity persisted throughout the 12-month extended-treatment period (18 months in total). At 12 months, the mean change from baseline in annualized height velocity was 2.51 cm per year (95% CI 1.02-3.99), and this was sustained at 18 months.

Increases in height velocity were observed in 10 of 11 patients at 18 months, and in eight of these patients, the increase was at least 25% over baseline. “This cumulative increase in linear growth corresponds to an increase in the height z score,” Savarirayan and colleagues noted.

This study was conducted at 19 sites in the U.K., U.S., Spain, France, Australia, and Canada starting in July 2020, and included children ages 3 to 11 years with a confirmed genetic diagnosis of achondroplasia.

Across the five cohorts, mean age was 7.5 years, 58% were girls, and 61% were white.

Participants received daily infigratinib for 6 months, followed by 12 months of extended treatment in which the dose in cohorts 1 and 2 could be escalated to the next ascending level at months 6 and 12.

One limitation to the study was the small sample size at the selected dose, Savarirayan and colleagues noted.

“On the basis of the safety and preliminary efficacy results from the dose-escalation portion of this study, infigratinib at a daily dose of 0.25 mg per kilogram is being evaluated in a pivotal, phase 3, double-blind, placebo-controlled trial that aims to enroll 110 children with achondroplasia between the ages of 3 years and less than 18 years who have the potential to grow,” they wrote.

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