BridgeBio Reports Positive Interim Results from a Phase 2 Trial of Infigratinib in Achondroplasia

BridgeBio Pharma reported positive interim results from PROPEL 2, a phase 2 trial of the investigational therapy infigratinib in children with achondroplasia demonstrating an increase in annualized height velocity in children five years of age and older.

Achondroplasia is the most common cause of disproportionate short stature. It impacts health and can lead to medical complications such as obstructive sleep apnea, middle ear dysfunction, kyphosis, and spinal stenosis. Achondroplasia affects approximately 55,000 people in the United States and Europe, including up to 13,000 children and adolescents with open growth plates. The condition is uniformly caused by an activating mutation in fibroblast growth factor receptor 3 (FGFR3). Infigratinib is an oral small molecule that inhibits FGFR3, therefore designed to target this well-described disease at its source.

At the highest dose level evaluated to date, mean increase in annualized height velocity (AHV) was 1.52 cm/yr over baseline for all follow-up data available at time of data cut in children five years of age and older. In this group, 64 percent were responders (defined with a strict criterion of an increase ≥25 percent in AHV from baseline) and the average percent change from baseline in AHV was 60 percent.

Earlier cohorts in PROPEL 2 did not achieve the target efficacious exposure as suggested by our preclinical data and no dose response was observed. An increase in AHV over baseline of 0.22 cm/yr was observed across these earlier combined cohorts for children 5 years of age and older.

PROPEL 2 enrolled children as young as 3 years of age in the study. Consistent with other trials in the younger age population, both AHV and height Z-scores were analyzed to help control for greater variability in growth seen by age and sex in children 3 to less than 5 years old. In this age group, the average increase in ACH height Z-score at six months was 0.21 standard deviation score (SDS) and an increase in AHV of 0.61 cm/yr over baseline was observed. Across Cohort 4, the median duration of follow-up was 26.9 weeks at time of data cut.

“These interim data demonstrate compelling initial proof-of-concept for an oral FGFR inhibitor in children with achondroplasia. We are encouraged by what we have seen to date, including the overall safety profile and promising initial efficacy data of infigratinib,” said Ravi Savarirayan, clinical geneticist and group leader of skeletal therapies research at the Murdoch Children’s Research Institute in Australia, the lead investigator for PROPEL 2. “We look forward to completing enrollment in Cohort 5 with the goal of presenting the full study results next year.”

Median follow-up across the entire study is 48. weeks across 62 participants included in the safety population at time of data cut. No treatment-related SAEs have been reported to date in any cohort. 90.3 percent of participants experienced at least one treatment-emergent adverse event (TEAE), the majority of which were Grade 1, unrelated to study drug, and consistent with a pediatric achondroplasia population. Only 9.7 percent of participants had a TEAE related to study drug, all of which were Grade 1, and included dyspepsia, decreased appetite, flatulence, hypercholesterolemia, hyperphosphatemia, and vitamin D decrease. No children have discontinued treatment as the result of an adverse event. No bone-related AEs were observed to date.

After discussions with regulatory agencies, BridgeBio has begun enrolling Cohort 5. Cohort 5 participants are receiving approximately twice the dose of Cohort 4. At the conclusion of the ongoing trial, BridgeBio intends to present full data at a medical conference in the first half of 2023. Additionally, BridgeBio expects to evaluate development of infigratinib in other FGFR-driven skeletal dysplasias, which affect more than 50,000 people in the United States and Europe, building on this positive interim data from PROPEL 2 as well as preclinical data in hypochondroplasia presented at the Endocrine Society 2022 Annual Conference earlier this year.

“I am encouraged by this interim efficacy and safety data and thankful, as ever, to be partnered with the healthcare providers, children, and families who are making this study possible,” said Neil Kumar, founder and CEO of BridgeBio. “These data, combined with our positive proof-of-concept data in LGMD2i and ADH1 earlier this year, highlight BridgeBio’s ability to efficiently prosecute high value programs in large areas of unmet need.”

Author: Rare Daily Staff