Phase 2 Open-Label Extension Study of Infigratinib in Children with Hypochondroplasia: Safety, Tolerability, and Height Outcomes

Primary objective: assess safety and efficacy of long‑term once‑daily oral infigratinib in participants with Hypochondroplasia, with safety evaluated by incidence and severity of adverse events and efficacy by longitudinal change in standing height Z‑score. Secondary objectives: • evaluate temporal changes in additional growth and development parameters; • assess evolution of functional measures (X functions); • monitor alterations in comorbid conditions associated with the disease; • determine impact on health‑related quality of life; • capture perceived treatment benefit through qualitative interviews with participants and caregivers.

The trial enrolled 76 pediatric participants diagnosed with hypochondroplasia, encompassing both males and females aged 3 to <18 years who demonstrated growth potential and were ambulatory without assistance. All subjects had previously completed the ACCEL 2/3 or ACCEL study, provided documented clinical and molecular confirmation of the disorder, and possessed at least six months of growth assessment data from the preceding study. Inclusion required a negative pregnancy test for girls aged ≥10 years or any girl who had experienced menarche. Participants were selected on the basis of these criteria without additional lifestyle restrictions, reflecting a generally healthy cohort apart from the underlying skeletal dysplasia.

The study is a Phase 2, open‑label, long‑term extension evaluating the safety, tolerability, and efficacy of once‑daily oral hypochondroplasia treatment with infigratinib in participants aged 3 to <18 years who have completed the preceding ACCEL trials; the protocol specifies a recruitment period beginning 1 April 2026 with an anticipated final data collection by 31 May 2036. Eligible participants enter after a screening visit confirming age, ambulatory status, documented molecular diagnosis, growth potential, and a negative pregnancy test where applicable; subsequent visits occur at regular intervals (e.g., every 3 months) to administer the study drug, perform vital‑sign checks, laboratory tests, ophthalmic and dental examinations, imaging (X‑ray, DXA), and collect standing height measurements for Z‑score analysis. The primary safety endpoints include incidence, severity, and causality of adverse events, serious adverse events, and any events prompting dose reduction or discontinuation, while efficacy endpoints focus on longitudinal changes in standing height Z‑score and related growth parameters. Participants remain in the study until the scheduled end‑of‑study visit, unless early termination is warranted due to intolerable adverse events, protocol‑defined dose‑limiting toxicities, withdrawal of consent, or loss of eligibility criteria. Overall participant involvement may extend for many years, encompassing the full duration of the extension phase.

The experimental agent is infigratinib, an oral capsule formulated as a FGFR 1-3-selective tyrosine kinase inhibitor. The investigational product is administered once daily by the oral route at a dose of 0.25 mg/kg per administration. Capsules are supplied in a size appropriate for pediatric dosing and are taken with water without regard to meals. Dosing is calculated based on the participant’s body weight at each study visit, and the dose may be adjusted if weight changes exceed predefined thresholds. Treatment duration follows the long‑term extension protocol, with continuous daily dosing until discontinuation criteria are met.

No placebo or active comparator is included in this open‑label extension study. Participants receive no additional investigational therapy. Standard‑of‑care measures for hypochondroplasia may be continued at the discretion of the treating physician, provided they do not interfere with the assessment of the study drug. Compliance is monitored through pill counts, electronic medication diaries, and periodic serum drug concentration assessments. Dosing schedules are reviewed at each study visit, and any missed doses are documented and addressed according to protocol‑specified compliance management procedures.

Efficacy will be evaluated primarily by measurement of changes in standing height Z-score relative to both hypochondroplasia‑specific and age‑sex reference tables. Height will be obtained using standardized stadiometry at baseline and at each scheduled visit, and Z‑scores will be calculated accordingly. Secondary efficacy assessments will include longitudinal evaluation of annualized height velocity (AHV) and its Z‑score, body proportion ratios (upper‑to‑lower segment, arm‑to‑forearm, upper leg‑to‑lower leg, arm span‑to‑standing height, head circumference‑to‑standing height), weight Z‑score, BMI Z‑score, age of pubertal onset, and time to Tanner stage X. Body composition will be quantified by dual x-ray absorptiometry scans, and bone morphology and density will be assessed through conventional radiographs and DXA. Quality of life will be monitored using validated instruments such as the Pediatric Quality of Life Inventory, the Quality of Life in Short Stature Youth questionnaire, and the Patient/Parent Global Impression of Severity and Change scales. Participant and parent perceptions of treatment benefit will be captured through qualitative interviews.