This is a multicenter, non-randomized, open-label, phase I/II study in children with ACH. This study will start with a dose escalation of ABSK061 in children with ACH to evaluate the safety, tolerability, PK, and efficacy. The RDE confirmation part will evaluate the safety and efficacy of ABSK061 at the recommended doses for expansion (RDEs) in children with ACH. All patients enrolled in the dose escalation part and RDE confirmation part can enter the extended treatment period to further evaluate the long-term safety, tolerability, and long-term efficacy of ABSK061 in children with ACH.
Prior to screening, the guardians and children with ACH (if applicable) must voluntarily provide signed informed consent.
Patients with a clear clinical diagnosis of ACH confirmed by genetic testing for an FGFR3 mutation.
Have completed at least 6 months (i.e., the "Day 181" visit) of growth assessment and observation of natural history of ACH in the observational study (ABSK061-001) before study entry.
Tanner Stage 1 breast development for females or Tanner Stage 1 external genitalia development for males at screening
Known allergy or hypersensitivity to any component of the study drug.
Bone age ≥ 14 years as assessed by the investigator based on hand and wrist X-ray.
Have a form of skeletal dysplasia other than ACH or known medical conditions that result in short stature or abnormal growth, including but not limited to severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), Turner syndrome, pseudoachondroplasia, inflammatory bowel disease, chronic renal insufficiency, active celiac disease a, Vitamin D deficiency b, untreated hypothyroidism c, poorly controlled diabetes (HbA1c ≥8.0%) or diabetic complications
History or presence of injury or disease of the growth plate(s), other than ACH, that affects growth potential of long bones.
Single group
ABSK061
DrugABSK061 is supplied as minitablets filled in capsules. Four strengths of capsules will be provided: 0.2 mg, 2 mg, 3 mg, and 5 mg. Each patient can only be administered with a single strength. All patients will be administered orally once daily under the fasted state, i.e., fast from 2 hours before dosing to 1 hour after dosing. Dose will be calculated based on the patient's weight, and detailed rules for dose calculation are provided. Take out the ABSK061 capsule containing minitablets, take off the capsule cap and decant the content (minitablets), swallow the minitablets completely with water without chewing (the recommended water volume is 50-180 mL). If there is difficulty swallowing all the minitablets at once, they may be taken in several portions as needed, but the entire dose should be taken within 10 minutes. If needed, yogurt or apple sauce can be used as vehicles to facilitate swallowing of the minitablets.
Incidence of dose-limiting toxicities (DLTs)
Incidence of dose-limiting toxicities (DLTs) in the DLT observation period, defined as Day 1 to Day 28 of dosing
Incidence and severity of adverse events (AEs)
Incidence and severity of adverse events (AEs), adverse events of special interest (AESIs), and serious adverse events (SAEs) using Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0), and relatedness, rate of dose modifications (including dose interruption and dose reduction) or discontinuation of study drug due to toxicity, and changes from baseline in safety assessments such as laboratory parameters, x-ray, electrocardiograms (ECGs), echocardiograms, vital signs, and physical examinations (including ophthalmic examinations)
Changes from baseline in the Annualized Growth Velocity (AGV, cm/year)
Changes from baseline in the Annualized Growth Velocity (AGV, cm/year) over 52 weeks \[baseline is defined as the AGV obtained through at least 6 months of observation in the observational study (ABSK061-001)\]
Cmax
maximum observed concentration
Tmax
time to maximum observed concentration
AUC
area under the concentration-time curve
t1/2
half-life
Range of Motion (ROM)
Mean change from baseline in ROM of the affected joint
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