a study of safety, tolerability and effectiveness of recifercept in children with achondroplasia

Conditions: Achondroplasia

Summary: approximately 63 participants will be randomized to one of three doses to receive recifercept either * low dose * medium dose * high dose participants will will attend the clinic at baseline and at day 1, 4, 8, 15, 29 \& then month 2, 3 6, 9 \& 12. assessments include safety, blood sampling, physical examination, vital signs, anthropometric body measurements \& patient/caregiver quality of life questionnaires participants will received treatment with recifercept for 12 months. all participants who complete the study and in the opinion of the investigator, continue to have a positive risk:benefit profile, will be offered to enroll into an open-label extension (ole) study. a pk cohort will include 12 participants who will randomly receive a single dose of 3 mg/kg of phase 2 study (process 1c) formulation and a single dose of 3 mg/kg of the proposed phase 3 (process 2) study formulation in a cross over study. dose of the cohort could be changed due to emerging safety and efficacy data in the study.

this is a phase 2 randomized, 3 arm (3 active doses of recifercept), parallel group dose finding study of safety, tolerability, pk and efficacy the total number of participants is 63 in 2 age straified cohorts of 0-2 years and 6-10 years old. the study will enroll approximately 54 children with achondroplasia aged 2-10 years (inclusive) who will be enrolled and randomized to receive one of three doses of recifercept * low dose * medium dose * high dose a total of 18 participants will be enrolled per dose 18 per dosesuch that at least 15 participants per dose are evaluable. an interim analysis is planned when at least 15 participants per dose aged ≥2 to \<11 years have received 6 months of treatment with recifercept. edmc will review safety, pk and efficacy data to confirm ongoing positive benefit:risk in participants. additionally, an exploratory cohort of approximately 9 children with achondroplasia, ages 0-2 years, will be enrolled later in the study (n=3 per dose). enrollment will follow an age and dose-staggered approach (descending age and ascending dose) with review of safety and pk data by the study team before progression to the next enrollment block if certain pre-defined safety signals occur then a meeting of the edmc will be convened to make a decision on progression of enrollment. the pk data collected in block a will be used in the poppk model (developed using healthy adult data) to confirm the dosing for younger children (ie, ≥2 to \<6 years and 0-\<2 years). participants will will attend the clinic at baseline and at day 1, 4, 8, 15, 29 \& then month 2, 3 6, 9 \& 12. assessments include safety, blood sampling, physical examination, vital signs, anthropometric body measurements \& patient/caregiver quality of life questionnaires all participants will receive recifercept for 12 months. all participants who complete the study and in the opinion of the investigator, continue to have a positive risk:benefit profile, will be offered to enroll into an open-label extension (ole) study. pk cohort: multiple changes have been made in the manufacturing process of the drug product (process 2) which will be used in phase 3. therefore, an additional pk cohort (at selected sites only) has been added, to evaluate the pk of phase 2 formulation (process 1c) and phase 3 formulation (process 2). pk cohort: at selected sites only, an additional pk cohort has been added to evaluate the pk of two recifercept formulations. a total of 12 children with achondroplasia aged 2- \<11 years will be enrolled in the pk cohort (6 in each treatment sequence). each participant will receive 2 treatments (3 mg/kg phase 2 formulation \[process 1c\] and 3 mg/kg phase 3 formulation \[process 2\]) in a randomized manner. dose of the cohort could be changed due to emerging safety and efficacy data in the study. pk samples collected following each dose will be analyzed to evaluate the exposures of two formulations.

Eligibility criteria:
inclusion criteria: * main cohort: aged ≥2 years to \<11 years (up to the day before 11th birthday inclusive) at time of enrollment; or exploratory cohort: aged ≥3 months to \<2 years (up to the day before 2nd birthday inclusive) at time of enrollment * documented, confirmed genetic diagnosis of achondroplasia from historical medical records prior to entry into this trial (test must have been performed at a laboratory fully accredited for genetic testing under local regulations). * completed the c4181001 natural history study with at least 2 valid height/length measurements (at least 3 months apart) prior to enrollment in this study. one of these measurement timepoints must be within the 3 months prior to enrollment in c4181005. * tanner stage 1 based on investigator assessment during physical examination (must include assessment of breast development for females, testicular stage for males). * able to stand independently for height measurements (if ≥2 years of age at enrollment). * if aged \<2 years at enrollment, has a documented historical mri brain/cervical spine performed in the previous 12 months. exclusion criteria: * presence of co-morbid conditions or circumstances that, in the opinion of the investigator, would affect interpretation of growth data or ability to complete the trial procedures. * other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. * presence of severe obesity (bmi \>95th percentile on hoover-fong bmi charts) \[hoover-fong et al, 2008\].14 * known closure of long bone growth plates (cessation of height growth). * body weight \ 30 kg. * moderate or severe renal impairment crcl gfr \ 1.5 uln). * history of hypersensitivity to study intervention or any excipients. * history of any prior treatment with human growth hormone or related products (including insulin-like growth factor 1 \[igf-1\]). * history of receipt of any treatment that are known to potentially affect growth (including oral steroids \>5 days in the last 6 months, high dose inhaled corticosteroids (\>800 mcg/day beclametasone equivalent) and medication for attention deficit hyperactivity disorder). * history of limb lengthening surgery (defined as distraction osteogenesis/ilizarov/callostasis technique following submetaphyseal osteotomy to extend bone length). * any limb lengthening/corrective orthopaedic surgery planned at any point during the trial period. * less than 6 months since fracture or surgical procedure of any bone determined from the screening visit date. * presence of any internal guided growth plates/devices. * history of removal of internal guided growth plates/devices within less than 6 months. * history of receipt of any investigational product for achondroplasia or that may affect growth/interpretation of growth parameters. * history of receipt of an investigational product (not for achondroplasia/growth affecting) within the last 30 days or 5 half-lives (whichever is longer).

Keywords: skeletal dysplasia