A randomized, controlled, open-label clinical trial with an open-label extension to investigate the safety of BMN 111 in infants and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery

INTERVENTION: Product Name: modified recombinant human C‐type natriuretic peptide Product Code: BMN 111 Pharmaceutical Form: Lyophilisate for solution for injection INN or Proposed INN: vosoritide CAS Number: 1480724‐61‐5 Current Sponsor code: BMN 111 Other descriptive name: MODIFIED RHCNP Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 0.8‐ Product Name: modified recombinant human C‐type natriuretic peptide Product Code: BMN 111 Pharmaceutical Form: Lyophilisate for solution for injection INN or Proposed INN: vosoritide CAS Number: 1480724‐61‐5 Current Sponsor code: BMN 111 Other descriptive name: MODIFIED RHCNP Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 2‐ CONDITION: achondroplasia ; MedDRA version: 20.0 Level: LLT Classification code 10000452 Term: Achondroplasia System Organ Class: 100000004850 Therapeutic area: Body processes [G] ‐ Bones and nerves physological processes [G11] PRIMARY OUTCOME: Main Objective: The primary objective of the study is to evaluate the safety of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery. Primary end point(s): Safety will be evaluated by the incidence of AEs, SAEs, laboratory test results (chemistry and hematology), vital signs (heart rate, blood pressure, respiratory rate, and temperature), physical examination, electrocardiogram, echocardiography, and concomitant medications. Clinical laboratory tests will be limited to the minimum necessary for evaluation of safety in order to minimize the required blood draw volume in this young pediatric population. Secondary Objective: The secondary objective of the study is to evaluate the efficacy of BMN 111 in children who are at risk of requiring cervicomedullary decompression surgery. Timepoint(s) of evaluation of this end point: AE, SAE recording: All visits; Concomitant meds: All visits; Clin lab assessments: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260, Safety Follow up; Vital Signs: Screening, Day 1, Day 2 and 3 for subjects randomized to BMN 111+ SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing‐over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety FU; ; Phys exam: Screen, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260 Safety Follow up; ; ECG: Screen, Day 1, Day 2 and 3 for subjects randomized to BMN 111 + SoC only, Weeks 6, 13, 26, 39, 52, 65, 78, 91, 104, week 104 Day 2 and 3 for subjects crossing‐over to BMN 111 + SoC only, every 26 weeks up to Week 260, Safety Follow up; ; SECONDARY OUTCOME: Secondary end point(s): Efficacy will be assessed by careful neurological clinical examination, MRI including the brain stem, foramen magnum, and spine, and age‐specific developmental milestone acquisition (Bayley‐III score). A board‐certified, fellowship‐trained (or equivalent) pediatric anesthesiologist will administer anesthesia during MRI measurements. Independent expert review of all MRI assessments will be performed to standardize eligibility assessment and interpretation of changes during study). Specific criteria for evaluation of signs and symptoms of foramen magnum stenosis leading to CMC include: ; • Incidence of surgical interventions for CMC including cervicomedullary decompression. ; • The effect of BMN 111 on the foramen magnum and neuroanatomy at the cervicomedullary junction. ; • The effect of BMN 111 on the anatomy of the spine including the thoracolumbar spine. ; • The effect of BMN 111 on neurological signs and symptoms of CMC. ; • The effect of BMN 111 on age‐specific developmental milestones using the Bayley‐III score. ; In addition, the effect of BMN 111 on sleep apnea will be evaluated and anthropometric measurements will be performed ; Timepoint(s) of evaluation of this end point: Anthropometric measurements: Day 1, Weeks 13, 26, 39, 52, 65, 78, 91, 104, every 26 weeks up to Week 260 ; ; MRI measurements: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260 ; ; Bayley‐III: Screening, Weeks 26, 52, 78, 104, every 52 weeks up to Week 260 ; ; Neurological examination: Screening, Day 1, Weeks 6, 13, 26, 39, 52, 65, 78, 91, ; 104, every 52 weeks up to Week 260, Safety Follow up ; INCLUSION CRITERIA: Individuals eligible to participate in this study must meet all of the following criteria: 1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research related procedure. 2. Have ACH, documented by genetic testing. 3. Are willing and able to perform all study procedures as physically possible. 4. Age from 0 months to =12 months, at study entry (Day 1). 5. Parent(s) or caregiver(s) are willing to administer daily injections to the subject and complete the required training. 6. Have evidence of cervicomedullary compression (CMC) that “may” require surgical intervention defined as: o Baseline MRI assessment from central blinded evaluation showing at least one of the following findings: ‐Narrowing of the foramen magnum with loss of cerebrospinal fluid space surrounding the cord. ‐Narrowing of the forame