Phase 2b, Randomized, Double-Blind, Placebo-Controlled Clinical Trial, Preceded by a Single Ascending Dose Portion and a Phase 2 Open-Label Portion, to Evaluate the Safety and Efficacy of Oral Infigratinib in Infants and Young Children with Achondroplasia

This clinical trial evaluates infigratinib, an oral investigational agent, in infants and young children with achondroplasia. The study comprises multiple phases including a single ascending dose portion, Phase 2, Phase 2b, and an extension phase. The primary objective is multifaceted across study phases. In the single ascending dose portion, the aim is to identify the appropriate dose of infigratinib based on safety and exposure following single ascending doses. In Phase 2, the objective is to confirm the doses for each age cohort based on safety and pharmacokinetic parameters. The Phase 2b primary objective is to evaluate the safety and efficacy of infigratinib in infants and young children under 3 years of age with achondroplasia. The extension phase aims to assess the safety and efficacy of infigratinib in participants who completed Phase 2 or Phase 2b until they reach 3 years of age plus 6 months. These objectives address the critical need for therapeutic interventions targeting growth abnormalities and disease-related complications in this pediatric population with a genetic skeletal disorder.

The secondary objectives include:

• Phase 2: To evaluate the safety of oral daily doses of infigratinib
• Phase 2: To evaluate changes in indicators of growth and body proportions
• Phase 2: To evaluate the potential effect of infigratinib on achondroplasia-related complications
• Phase 2b: To evaluate changes in other key indicators of growth and body proportions
• Phase 2b: To evaluate the pharmacokinetic profile of infigratinib and its active metabolites in participants with achondroplasia after administration of oral infigratinib
• Phase 2b: To evaluate changes in achondroplasia-related complications
• Extension: To evaluate the potential effect of infigratinib on achondroplasia-related complications

The clinical trial enrolled a total of **66 participants** diagnosed with **achondroplasia**, confirmed by genetic testing from a certified laboratory documenting the specific mutation. The study population consisted of infants and young children aged **0 to 32 months** (up to 2 years and 8 months) at the time of screening. Both **male** and **female** participants were included in the trial. This population was classified as a **vulnerable population** due to the young age of the participants. Key inclusion criteria required that participants be able to swallow age-appropriate oral medication and that their parent(s) or legal guardian provide signed informed consent and demonstrate willingness to attend all study visits and comply with study requirements. For **breastfeeding** infants and young children, mothers were required to discontinue treatment with drugs potentially harmful to the participant or stop nursing if discontinuation was not possible, to avoid confounding safety assessments or impacting the pharmacokinetics of infigratinib. Participants under 1 year of age were required to be compliant with recommended **vitamin D supplementation** of 5-10 μg/day or higher, according to country-specific guidelines. Parent(s) or guardian(s) were also expected to comply with routine care for infants and young children with achondroplasia according to local management guidance.

This clinical trial evaluates the safety and efficacy of oral **infigratinib** in infants and young children with **achondroplasia**. The study employs a multi-phase design consisting of a **single ascending dose** portion, followed by a **Phase 2 open-label** portion, a **Phase 2b randomized, double-blind, placebo-controlled** portion, and an extension phase. The investigational medicinal product is administered as a **tablet** via the **oral route**. Infigratinib is designated as an **orphan drug** and is being investigated at a maximum daily dose of 0.25 milligrams per kilogram with a maximum treatment period of one day for the single ascending dose evaluation. The study is classified as a **Phase 4** trial according to the trial category designation.

The single ascending dose portion aims to identify the appropriate dose of infigratinib for subsequent phases based on safety and exposure data. The Phase 2 portion confirms the doses to be used in each age cohort based on safety and **pharmacokinetic** parameters. The Phase 2b portion evaluates the safety and efficacy of infigratinib in infants and young children under three years of age with achondroplasia. The extension phase evaluates the safety and efficacy of infigratinib in participants who completed the Phase 2 or Phase 2b portions until they reach three years of age, with an additional six-month window.

Eligible participants include infants and young children aged 0 to 32 months at screening with a diagnosis of achondroplasia confirmed by genetic testing from a certified laboratory documenting the specific mutation. Participants must be able to swallow age-appropriate oral medication. For participants under one year of age, compliance with recommended vitamin D supplementation of 5 to 10 micrograms per day or higher is required. Signed informed consent must be obtained from the participant's parent or legal guardian, who must be willing and able to attend all study visits, comply with all study requirements, and adhere to routine care according to local guidance for managing infants and young children with achondroplasia. In breastfeeding infants, mothers must be willing to discontinue treatment with drugs that could be harmful to the participant or impact the pharmacokinetics of infigratinib, or alternatively, stop nursing the participant if discontinuation is not possible.

The primary endpoints for the single ascending dose portion include safety and pharmacokinetics of infigratinib and its active metabolites. For the Phase 2 portion, primary endpoints comprise **treatment-emergent adverse events** leading to dose decrease or discontinuation, and pharmacokinetics of infigratinib and its active metabolites. The Phase 2b portion evaluates **adverse events** and **serious adverse events**, including clinically significant changes in vital signs, laboratory assessments, physical examination including **fontanelles closure** when applicable, **electrocardiogram**, imaging including bone abnormalities not common in achondroplasia, laboratory test results including **hyperphosphatemia**, **ocular events**, abnormalities in teeth formation and eruption, and delays in developmental milestones based on milestone charts for achondroplasia. The primary efficacy endpoint for the Phase 2b portion is the change from baseline to Week 52 in body length **Z-score** in relation to achondroplasia tables, with baseline corresponding to the body length Z-score at Day 1. The extension phase primary endpoints include adverse events and serious adverse events with similar assessments as the Phase 2b portion, and change over time in body length Z-score in relation to achondroplasia tables.

Secondary endpoints for the Phase 2 portion include adverse events and serious adverse events with comprehensive safety assessments, mean and change from baseline in body length Z-score at Week 52 in relation to achondroplasia tables, mean and change from baseline to Week 52 in upper-to-lower body segment ratio, mean and change from baseline to Week 52 in head circumference to body length ratio, health-related quality of life using the **Infant Toddler Quality of Life** questionnaire, milestone development including social or emotional, language or communication, cognitive, movement or physical development and specific movement strategies used by children with achondroplasia, skull and brain morphology using **magnetic resonance imaging**, age at closure of cranial sutures and fontanelles, incidence of surgical interventions including cervical decompression, **adenotonsillectomy**, and **tympanostomy**, incidence and severity of **sleep apnea**, and bone morphology as assessed by bilateral **x-rays** of lower extremity and whole spine. For the Phase 2b portion, secondary endpoints include body length Z-score at Week 52 in relation to achondroplasia tables, mean and change from baseline to Week 52 in upper-to-lower body segment ratio, mean and change from baseline in head circumference to body length ratio, pharmacokinetics of infigratinib and its active metabolites, health-related quality of life using the Infant Toddler Quality of Life questionnaire, milestone development assessments, skull and brain morphology using magnetic resonance imaging, age at closure of cranial sutures and fontanelles, incidence of surgical interventions including but not limited to adenotonsillectomy and tympanostomy, incidence and severity of sleep apnea, and bone morphology assessed by bilateral x-rays of lower extremities and whole spine. The extension phase secondary endpoints include change over time in upper-to-lower body segment ratio, change over time in head circumference to body length ratio, health-related quality of life using the Infant Toddler Quality of Life questionnaire, milestone development assessments, age at closure of cranial sutures and fontanelles, incidence of surgical interventions including cervical decompression, adenotonsillectomy, and tympanostomy, and bone morphology assessed by bilateral x-rays of lower extremity and whole spine.

The estimated recruitment start date for the trial is November 20, 2025, with an estimated end date of February 10, 2030. The duration of participant involvement varies depending on the study phase, with participants in the extension phase continuing treatment until they reach three years of age plus six months. Conditions that may lead to early termination from the study include treatment-emergent adverse events requiring dose discontinuation, failure to comply with study requirements, withdrawal of informed consent by the parent or legal guardian, or other safety concerns identified during the course of the trial.

The experimental medication evaluated in this clinical trial is infigratinib, also known by its alternative designations BGJ398 and BBP-831. Infigratinib is a chemical substance with the systematic name 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-[6-[4-(4-ethylpiperazin-1-yl)anilino]pyrimidin-4-yl]-1-methylurea. The investigational medicinal product is manufactured by QED Therapeutics and has been granted orphan drug designation under the number EU/3/21/2475. Infigratinib is formulated as a tablet for oral administration. The dosing regimen is weight-based, with a maximum daily dose of 0.25 milligrams per kilogram body weight. The maximum total dose per treatment period is also 0.25 milligrams per kilogram. The maximum treatment period is defined as 1 day for the dosing cycle under investigation. The study employs a single ascending dose portion to identify the appropriate dose based on safety and exposure parameters, followed by a Phase 2 open-label portion to confirm dosing for each age cohort based on safety and pharmacokinetic profiles, and subsequently a Phase 2b randomized, double-blind, placebo-controlled portion to evaluate safety and efficacy in the target population of infants and young children with achondroplasia.

The trial design incorporates a placebo-controlled component during the Phase 2b portion of the study. The placebo serves as the comparator treatment in the randomized, double-blind phase to enable assessment of the efficacy and safety profile of infigratinib against an inactive control. Participants are randomly assigned to receive either infigratinib or placebo, maintaining blinding to treatment allocation throughout the Phase 2b portion. This design allows for rigorous evaluation of the therapeutic effect of the active substance while controlling for potential confounding factors and placebo effects in the pediatric population under investigation.

Efficacy will be assessed through multiple parameters across different study portions. In the Phase 2b portion, the primary efficacy endpoint is the change from baseline to Week 52 in body length Z-score in relation to achondroplasia tables, with baseline corresponding to the body length Z-score at Day 1. Secondary efficacy endpoints include body length Z-score at Week 52 in relation to achondroplasia tables, mean and change from baseline to Week 52 in upper-to lower-body segment ratio, and mean and change from baseline in head circumference/body length ratio. Additional efficacy assessments encompass health-related quality of life using the Infant Toddler Quality of Life instrument, milestone development including social/emotional, language/communication, cognitive, movement/physical development and specific movement strategies used by children with achondroplasia, skull and brain morphology using magnetic resonance imaging, age at closure of cranial sutures and fontanelles, incidence of surgical interventions including adenotonsillectomy and tympanostomy, incidence and severity of sleep apnea, and bone morphology as assessed by bilateral x-rays of lower extremities and whole spine.

In the Phase 2 portion, efficacy parameters include mean and change from baseline in body length Z-score at Week 52 in relation to achondroplasia tables with baseline values at Day 1, mean and change from baseline to Week 52 in upper- to lower-body segment ratio, mean and change from baseline to Week 52 in head circumference/body length ratio, health-related quality of life using Infant Toddler Quality of Life, milestone development including social/emotional, language/communication, cognitive, movement/physical development and specific movement strategies used by children with achondroplasia, skull and brain morphology using magnetic resonance imaging, age at closure of cranial sutures and fontanelles, incidence of surgical interventions including cervical decompression, adenotonsillectomy, and tympanostomy, incidence and severity of sleep apnea, and bone morphology as assessed by bilateral x-rays of lower extremity and whole spine.

In the Extension portion, efficacy will be evaluated through change over time in body length Z-score in relation to achondroplasia tables, change over time in upper- to lower-body segment ratio, change over time in head circumference/body length ratio, health-related quality of life using Infant Toddler Quality of Life, milestone development including social/emotional, language/communication, cognitive, movement/physical development and specific movement strategies used by children with achondroplasia, age at closure of cranial sutures and fontanelles, incidence of surgical interventions including cervical decompression, adenotonsillectomy, and tympanostomy, and bone morphology as assessed by bilateral x-rays of lower extremity and whole spine. Milestone development assessments are based on milestone charts for achondroplasia.