Oral Infigratinib Improves Growth in Children with Achondroplasia, finds NEJM study

Achondroplasia is a result of inherited gain-of-function pathogenic FGFR3 variant leading to disrupted endochondral ossification. As of today, only the drug vosoritide has been approved as therapy given once a day via subcutaneous injection, with no available oral therapy. Infigratinib is a selective tyrosine kinase inhibitor for FGFR1-3 and has a high level of oral bioavailability.

The trial randomized 72 children into five dose cohorts administered sequentially: 0.016 mg/kg (cohort 1), 0.032 mg/kg (cohort 2), 0.064 mg/kg (cohort 3), 0.128 mg/kg (cohort 4), and 0.25 mg/kg (cohort 5). Subjects were treated with daily infigratinib for six months, with an optional follow-up dose escalation for 12 months. The primary safety endpoint was the rate of adverse events requiring dose adjustment or discontinuation, and the primary efficacy endpoint was the change in annualized growth velocity from baseline.

Results

• All 72 children experienced at least one adverse event, though most were mild to moderate, and none led to treatment discontinuation.

• In cohort 5, the highest dose group, a significant and sustained increase in annualized height velocity was observed.

• At 18 months, the mean change in height velocity was 2.50 cm per year (95% CI, 1.22 to 3.79; p=0.001).

• The average change in height z score was 0.54 (95% CI, 0.35 to 0.72) against an untreated achondroplasia reference group.

• Also, the average change in the upper-to-lower body segment ratio was −0.12 (95% CI, −0.18 to −0.06), reflecting a proportional improvement in growth.

Infigratinib presented an acceptable safety profile and resulted in a markedly elevated annualized height velocity, height z score, and body proportionality improved at 18 months in the achondroplasia subjects, especially within the highest dosage group. It brings to limelight its usage as an effective treatment for hereditary bone disease.

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