BridgeBio Pharma, Inc. (Nasdaq: BBIO) (BridgeBio), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, today announced positive interim results from PROPEL 2, a Phase 2 trial of the investigational therapy infigratinib in children with achondroplasia. Achondroplasia (ACH) is the most common cause of disproportionate short stature. Achondroplasia 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 (US) 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 (0.128 mg/kg once daily), mean increase in annualized height velocity (AHV) was 1.52 cm/yr over baseline (p=0.02, n=11) for all follow-up data available at time of data cut in children 5 years of age and older. In this group, 64% were responders (defined with a strict criterion of an increase ≥25% in AHV from baseline) and the average percent change from baseline in AHV was 60%.
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 (p=0.54, n=38) 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 <5 years old. In this age group, the average increase in ACH height Z-score at 6 months was 0.21 standard deviation score (SDS) and an increase in AHV of 0.61 cm/yr over baseline (n=5) 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. We look forward to completing enrollment in Cohort 5 with the goal of presenting the full study results next year,” said Professor Ravi Savarirayan, M.D., Ph.D., clinical geneticist and group leader of skeletal therapies research at the Murdoch Children’s Research Institute in Australia, the lead investigator for PROPEL 2.
Median follow-up across the entire study is 48.1 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% 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% 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.
A single case of mild hyperphosphatemia (Grade 1) led to a dose reduction in a participant in Cohort 3 (dose: 0.064 mg/kg once daily), the only dose adjustment made to date in the study. Phosphorus levels for this participant only exceeded upper limit of normal by <10% and returned to and remain normal at the reduced dose (0.032 mg/kg once daily). No other cases of hyperphosphatemia have been observed in any other cohort (including Cohort 5) to date, and no trends in phosphorous by dose have been observed. No other AEs required dose modifications or interruptions.
No children have discontinued treatment as the result of an adverse event. No bone-related AEs were observed to date.
“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. 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. We look forward to exploring the potential of infigratinib in achondroplasia and related skeletal dysplasias in the near future,” said Neil Kumar, Ph.D., founder and CEO of BridgeBio.
BridgeBio, after discussions with regulatory agencies, has begun enrolling Cohort 5. Cohort 5 participants are receiving approximately twice the dose of Cohort 4 (0.25 mg/kg once daily vs 0.128 mg/kg once daily in 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 US and Europe, building on this positive interim data from PROPEL 2 as well as preclinical data in hypochondroplasia presented at the Endocrine Society (ENDO) 2022 Annual Conference earlier this year.
Infigratinib is not approved in any country for the treatment of children or adults with achondroplasia. For more information on infigratinib, please see the following link
