In a phase II dose-finding study, the oral FGFR1-3 selective tyrosine kinase inhibitor infigratinib was discovered to be both safe and effective at the highest studied dose among children with achondroplasia. This finding holds significant implications for the treatment of this genetic skeletal condition.

Unveiling the Potential of Oral Infigratinib in Achondroplasia Treatment

Study Overview

During the treatment period, all 72 participants experienced at least one adverse event. Most of these events were mild (54%) or moderate (39) in severity, and none led to treatment discontinuation. This highlights the relatively good tolerance of infigratinib in this patient population.Furthermore, among children in the fifth sequential cohort who received infigratinib at a dose of 0.25 mg/kg, an increase in annualized height velocity was observed. The mean change from baseline at 18 months was 2.5 cm per year (95% CI 1.22 - 3.79, P = 0.001). This indicates a positive impact on growth in these children.The mean change from baseline at 18 months in height z score was 0.54 (95% CI 0.35 - 0.72) compared to an untreated achondroplasia reference population. Additionally, the mean change from baseline in the upper-to-lower body segment ratio was -0.12 (95% CI -0.18 to -0.06), suggesting a potential improvement in body proportion.

Comparison with Other Treatments

Currently, the only approved medication for the treatment of children with achondroplasia is vosoritide [Voxzogo], which requires daily subcutaneous injections. In contrast, this oral treatment appears to be at least as effective as the injectable form. This offers a significant advantage in terms of ease of administration, especially in countries where injections may not be practical.The future clinical implications of infigratinib include the ease of oral administration and its effectiveness on height and proportionality in children with achondroplasia. It is hoped that these benefits will translate into better functionality and independence for these patients.

Regulatory Journey

Infigratinib has had a somewhat complex regulatory path. It was granted accelerated approval in 2022 as a treatment for bile duct cancer (under the trade name Truseltiq), but this approval was withdrawn earlier this year. However, its potential in the treatment of achondroplasia has emerged as a new area of interest.Achondroplasia is a genetic skeletal condition characterized by disproportionately short stature and various health complications throughout life. It is caused by changes in the FGFR3 gene and is associated with limited range of motion at the elbows, macrocephaly, small fingers, and normal intelligence.

Adverse Events and Dose-Dependent Effects

In the study, grade 3 adverse events occurred in five children. These included hydrocephalus, adenoidal hypertrophy, and tonsillar hypertrophy in the group receiving 0.032 mg/kg (cohort 2), sleep apnea syndrome and cholesteatoma in those receiving 0.064 mg/kg (cohort 3), and bacillus infection in those receiving 0.128 mg/kg (cohort 4).Seven children had adverse events assessed as related to the study drug, and these events were mild in severity. They 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. The changes from baseline to month 6 were as follows: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, the 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, as noted by Savarirayan and colleagues.

Study Details

This study was conducted at 19 sites in the U.K., U.S., Spain, France, Australia, and Canada starting in July 2020. It included children aged 3 to 11 years with a confirmed genetic diagnosis of achondroplasia. Across the five cohorts, the 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 cohorts 1 and 2, the dose could be escalated to the next ascending level at months 6 and 12.One limitation of the study was the small sample size at the selected dose. However, based on the safety and preliminary efficacy results from the dose-escalation portion, infigratinib at a daily dose of 0.25 mg per kilogram is now 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.