Long-Term Evaluation of Infigratinib, an FGFR1-3-Selective Tyrosine Kinase Inhibitor, in Pediatric Patients with Achondroplasia: A Phase 2 Open-Label Extension Study

The primary objective of this study is to evaluate the **safety** and tolerability of long-term administration of daily doses of oral **infigratinib** in subjects with **achondroplasia** (ACH). Additionally, the study aims to assess the efficacy of this treatment by observing changes over time in standing height Z-score. These objectives are clinically relevant as they address both the potential therapeutic benefits and safety profile of infigratinib, which is crucial for its use in pediatric patients with ACH.

Secondary objectives include evaluating changes in other indicators of growth and development in subjects with ACH receiving long-term treatment with oral infigratinib, such as:

• Change over time in height velocity (HV) Z-score in relation to ACH and non-ACH growth charts.
• Changes over time in other anthropometric parameters after administration of oral infigratinib.
• Age at puberty onset and progression of pubertal development.

Further secondary objectives are to evaluate changes over time in ACH disease burden with long-term administration of oral doses of infigratinib, including disease-specific complications, health-related quality of life (HRQoL), overall body pain, and functional abilities. Additionally, the study aims to evaluate treatment benefit as assessed by a qualitative interview of the subject and caregiver, and to evaluate potential changes in cognitive functions as part of a safety evaluation.

The clinical trial involves a total of **120 participants** diagnosed with **achondroplasia**, a genetic condition characterized by dwarfism. The study population includes both male and female subjects, with an age range of 3 to less than 18 years, indicating a pediatric focus. Participants were selected based on their completion of a previous QED-sponsored interventional study with infigratinib or as treatment-naïve subjects with documented clinical and genetic confirmation of achondroplasia. The trial population is required to have growth potential, and subjects must be able to swallow oral medication. Lifestyle considerations such as diet and physical activity are not specified, but compliance with study visits and procedures is necessary. The study includes a vulnerable population, emphasizing the need for informed consent from parents, legal guardians, or caregivers, along with the subject's assent when applicable. The trial does not specify any particular health status beyond the diagnosis of achondroplasia, and both genders are equally represented in the study.

The clinical trial is designed as a **Phase 2, open-label, long-term extension study** to evaluate the safety and efficacy of **infigratinib**, an FGFR 1-3-selective tyrosine kinase inhibitor, in pediatric subjects with **achondroplasia**. The trial will involve oral administration of infigratinib in capsule or tablet form, with a maximum daily dose of 0.25 mg/kg and a total dose not exceeding 911.75 mg/kg over a treatment period of up to 120 days. The study is expected to run until January 3, 2029, with recruitment having commenced on February 8, 2022.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, ability to swallow oral medication, and a confirmed diagnosis of achondroplasia. The inclusion criteria also require a negative pregnancy test for applicable female subjects and a commitment to using effective contraception if sexually active. The trial will include follow-up visits to monitor safety and efficacy, with primary endpoints focusing on the incidence of treatment-emergent adverse events and changes in height Z-score. Secondary endpoints will assess changes in body proportions, weight, BMI, and other health-related quality of life measures.

The expected length of participant involvement will vary, but the maximum treatment period is 120 days. Conditions that may lead to early termination from the study include the occurrence of serious adverse events or the inability to comply with study procedures. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the long-term effects of infigratinib on growth and development in children with achondroplasia.

The clinical trial involves the administration of **Infigratinib**, a selective tyrosine kinase inhibitor targeting FGFR 1-3, in pediatric patients with achondroplasia. **Infigratinib** is provided in various pharmaceutical forms, including capsules and tablets, all intended for **oral use**. The medication is manufactured by QED Therapeutics and is identified by several synonyms, including BGJ398 and BBP-831. The active substance, **Infigratinib**, is of chemical origin and is designated as an orphan drug under the designation number EU/3/21/2475.

The dosing regimen for **Infigratinib** involves a maximum daily dose of 0.25 mg/kg, with a total maximum dose of 911.75 mg/kg over a treatment period of up to 120 days. The study ensures that the formulation is suitable for pediatric use, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments. The focus is solely on evaluating the safety, tolerability, and efficacy of long-term administration of **Infigratinib** in the target population.

The efficacy of the clinical trial involving **infigratinib** will be assessed through a series of primary and secondary endpoints. The primary endpoints include the incidence of treatment-emergent adverse events (TEAE) and serious TEAE, as well as changes over time in height Z-score in relation to achondroplasia (ACH) and non-ACH growth charts. These parameters will provide insights into the safety and growth impact of long-term administration of infigratinib in children with ACH.

Secondary endpoints will further evaluate the efficacy by measuring changes over time in various growth and health-related parameters. These include absolute height velocity expressed as height velocity Z-score, body proportions, weight Z-score, and body mass index (BMI). Additionally, the study will assess the age of puberty onset, time to Tanner stage ≥4, and changes in the number of episodes of otitis media and sleep apnea severity. Other assessments include range of motion in the elbow, skeletal abnormalities of the lower extremities and spine, and health-related quality of life (HRQoL) using the Pediatric Quality of Life Inventory (PedsQL) and Quality of Life in Short Stature Youth questionnaire (QoLISSY).

Further evaluations will involve overall pain assessment using the Numeric Rating Scale for pain (Pain-NRS), functional abilities via the Functional Independence Measure for Children (WeeFIM), and the severity of physical functioning challenges through the Patient/Parent Global Impression of Severity (PGI-S) and Change (PGI-C). Subject and caregiver evaluations of treatment benefit will be gathered through qualitative interviews, and changes in cognitive functions will be assessed using age-appropriate computerized tests. These comprehensive assessments will be conducted at various time points throughout the trial to ensure a thorough evaluation of infigratinib's efficacy in the target population.