Phase 3 Multicenter Double-Blind Randomized Placebo-Controlled Trial Evaluating Infigratinib Efficacy and Safety in Pediatric Achondroplasia Patients

The primary objective of this study is to evaluate the **efficacy** of infigratinib in pediatric subjects with **achondroplasia** (ACH) aged 3 to less than 18 years who have the potential to grow. This is clinically relevant as achondroplasia is a genetic disorder that affects bone growth, leading to disproportionate short stature and other skeletal abnormalities. Assessing the efficacy of infigratinib could provide insights into potential therapeutic benefits for improving growth outcomes in affected children.

Secondary objectives include:

• Evaluating changes in other key indicators and parameters of growth and body proportions.
• Assessing the safety and tolerability of infigratinib in children with ACH.
• Evaluating the efficacy of infigratinib in children with ACH who are 5 years of age or older.
• Assessing the impact of changes in growth and body proportions on the physical functioning of children.
• Evaluating changes in cognitive functions.
• Assessing the pharmacokinetic (PK) profile of infigratinib and its active metabolites in children with ACH after oral administration.
• Evaluating pharmacodynamic (PD) indicators of bone growth.
• Assessing the acceptability and palatability of infigratinib.

The clinical trial involves a total of **48 participants** diagnosed with **achondroplasia**, a genetic condition affecting bone growth. The study population consists of pediatric subjects aged 3 to less than 18 years, encompassing both male and female participants. These individuals are characterized by their potential for growth, as indicated by an annual height velocity of more than 1.5 cm per year. Participants were selected based on their completion of at least 26 weeks in the PROPEL observational study and their ability to swallow oral medication. The trial includes subjects who are ambulatory and can stand without assistance. Lifestyle considerations such as the ability to comply with study visits and procedures, as well as the willingness to use effective contraception if sexually active, are noted. The trial population includes a vulnerable group, as it involves children and adolescents. The selection criteria ensure that participants have a documented clinical and genetic diagnosis of achondroplasia and that the licensed treatment option, vosoritide, is either contraindicated, unavailable, or not viable for them.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of **infigratinib** in children aged 3 to less than 18 years with **achondroplasia**. The trial will involve a maximum treatment period of 52 weeks, with participants receiving either infigratinib or a placebo. The primary objective is to assess the change from baseline in annualized height velocity (AHV) compared to placebo over the 52-week period. Secondary endpoints include changes in height Z-score, body segment ratios, and various other growth and developmental parameters.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, growth potential, and the ability to swallow oral medication. Following the screening, participants will be randomized to receive either the active drug or placebo. Regular follow-up visits will be scheduled to monitor safety, efficacy, and adherence to the study protocol. These visits will include assessments of growth parameters, physical examinations, and laboratory tests. The end-of-study visit will occur at the conclusion of the 52-week treatment period, where final assessments will be conducted to evaluate the overall impact of the treatment.

The expected length of participant involvement is approximately 52 weeks, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with study procedures. Participants who complete the study will contribute valuable data to determine the potential benefits of infigratinib in managing achondroplasia in the pediatric population. The trial is anticipated to conclude by April 2026, with recruitment starting in March 2024.

The clinical trial involves the administration of **Infigratinib**, a tyrosine kinase inhibitor and selective ATP-competitive inhibitor of FGFR, in the form of capsules. The active substance, **Infigratinib**, is chemically synthesized and is also known by the synonyms BGJ398 and BBP-831. The pharmaceutical form is a capsule, and the medication is administered orally. The dosage is calculated based on body weight, with a maximum daily dose of 0.25 mg/kg. The treatment period extends up to 52 weeks. The formulation is available in both pediatric and non-pediatric versions, with the pediatric formulation specifically designed for children aged 3 to less than 18 years with achondroplasia.

A placebo is also utilized in this study to match the **Infigratinib** sprinkle capsules. The placebo is designed to mimic the appearance and administration route of the active medication but contains no active pharmaceutical ingredient. The use of a placebo allows for a double-blind, randomized, and controlled study design, ensuring the reliability and validity of the trial results. The placebo is administered in the same manner as the active drug, maintaining consistency in the study protocol.

The efficacy of **infigratinib** in the clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoint is the change from baseline in annual height velocity (AHV) compared to placebo, measured at Week 52. Secondary endpoints include changes from baseline in height Z-score in relation to achondroplasia (ACH) tables, upper to lower body segment ratio, and height Z-score in relation to non-ACH tables, all compared to placebo at Week 52. Additional secondary endpoints involve absolute and change from baseline measurements in various body proportions and ratios, such as upper arm to forearm length, upper leg to lower leg length, arm span to standing height, and head circumference to standing height, as well as body mass index. The incidence of adverse events will also be monitored.

Further assessments include changes in AHV in children aged 5 years and older, changes in the Physical Functioning Scale of the PedsQL child report, and changes in psychomotor function, attention, visual learning, and working memory, all compared to placebo at Week 52. Pharmacokinetic profiles of infigratinib will be evaluated by assessing maximum concentration (Cmax) and time-to-maximum concentration (Tmax). Pharmacodynamic parameters will be assessed by evaluating the collagen X marker. The acceptability and palatability of infigratinib will be evaluated using a 5-point hedonic scale at Week 13.