MON-225 - A Multicenter, Phase 2, Dose-Escalation/Dose-Expansion Study of Dabogratinib (Formerly TYRA-300) in Children with Achondroplasia with Open Growth Plates: BEACH301

Objectives

An FGFR3 G380R gain of function genetic variant accounts for approximately 99% of achondroplasia (ACH). Dabogratinib (formerly TYRA-300) is a potential first-in-class, once-daily, oral FGFR3-selective inhibitor that targets the underlying cause of ACH. This multicenter, open-label, Phase 2 study (BEACH301) aims to evaluate safety, tolerability, and preliminary efficacy of ascending oral doses of dabogratinib in children aged 3–10 years with genetically confirmed ACH and open growth plates. Primary objectives assess safety and tolerability and evaluate changes from baseline in annualized growth velocity (AGV) to determine the dose(s) for further development. Secondary/exploratory objectives include changes in height z-score, proportionality, pharmacokinetics (PK), and imaging-based orthopedic assessments.

Methods

Approximately 90 participants will enroll into three cohorts. A Sentinel Safety Cohort (N≥12; ages 5–10) will undergo dose escalation across four dose levels (0.125–0.50 mg/kg daily, at least 3 participants/dose level), with an independent Data Safety Monitoring Committee (DSMC) review prior to escalation. Cohorts 1 and 2 (N=40 each; ages 3–10) will complete a minimum 6-month natural history lead-in prior to initiating 12 months of open-label treatment at doses previously cleared by the DSMC. Cohort 1 will enroll treatment-naïve participants while Cohort 2 will enroll those previously exposed to growth-accelerating therapy. Cohorts 1 and 2 will enroll 6 participants at each dose, with expansion to up to 10 participants. Following the initial 12-month treatment period, all participants may enter an optional 36-month extension phase where they can escalate to a higher dose level if their total AGV has not exceeded 9 cm/year.

Planned Outcomes

Primary outcomes include incidence and severity of treatment-emergent adverse events and change from baseline in AGV. Secondary/exploratory outcomes include changes in height z-score, standing/sitting height, limb segment lengths, body proportions, PK parameters, and radiographic assessments.

Conclusions

BEACH301 is designed to establish the safety profile and identify dose(s) of dabogratinib with clinical improvements in growth parameters in children with ACH. The inclusion of dose escalation guided by safety, treatment-naïve and treatment-experienced cohorts, and comprehensive PK, anthropometric and imaging assessments provide a robust framework to support optimal dose selection in late-stage clinical studies of dabogratinib.

*Unless otherwise noted, all abstracts presented at ENDO must not be released to the press or the public until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.*