A Study to Evaluate the Efficacy and Safety of BMN 111 in Children With Achondroplasia

This is a Phase 3 randomized, placebo-controlled, double-blind multicenter study with approximately 110 subjects, aged 5 to < 18 years old. Subjects with documented Achondroplasia confirmed by genetic testing will have been enrolled in Study 111-901 for at least a 6-month period immediately before entering into the 111-301 study. Eligible subjects will be randomly assigned to one of two treatment groups: placebo or BMN 111 at 15 μg/kg. The route of administration is subcutaneous injection and the frequency is daily.

Inclusion criteria

• Parent(s) or guardian(s) consent
• 5 to < 18 years old
• ACH, documented and confirmed by genetic testing
• At least a 6-month period of pretreatment growth assessment in Study 111-901 before study entry
• If sexually active, willing to use a highly effective method of contraception
• Ambulatory and able to stand without assistance

Exclusion criteria

• Hypochondroplasia or short stature condition other than ACH
• Have any of the following:

• Hypothyroidism or hyperthyroidism
• Insulin-requiring diabetes mellitus
• Autoimmune inflammatory disease
• Inflammatory bowel disease
• Autonomic neuropathy
• History of any of the following:

• Renal insufficiency defined as serum creatinine > 2 mg/dL
• Chronic anemia
• Baseline systolic blood pressure (BP) < 70 millimeters of mercury (mm Hg) or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms ie, dizziness, fainting) or recurrent symptomatic orthostatic hypotension
• Cardiac or vascular disease

• Have a clinically significant finding or arrhythmia on screening electrocardiogram (ECG) that indicates abnormal cardiac function or conduction or Fridericias corrected QTc-F > 450 msec
• Have an unstable condition likely to require surgical intervention during the study (including progressive cervical medullary compression or severe untreated sleep apnea)
• Decreased growth velocity (< 1.5 cm/yr) over a period of 6 months or evidence of growth plate closure (proximal tibia, distal femur)
• Treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the previous 6 months or treatment greater than 6 months at any time
• Greater than 1 month treatment with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the previous 12 months
• Planned or expected to have limb-lengthening surgery during the study period. Subjects with previous limb- lengthening surgery may enroll if surgery occurred at least 18 months prior to the study and healing is complete without sequelae.
• Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex, excluding tooth extraction), during the study period. Subjects with previous bone-related surgery may enroll if surgery occurred at least 6 months prior to the study and healing is complete without sequelae.
• Had a fracture of the long bones or spine within 6 months prior to screening
• History of severe untreated sleep apnea
• New initiation of sleep apnea treatment (e.g. CPAP or sleep apnea-mitigating surgery) in the previous 2 months prior to screening
• History of hip surgery or hip dysplasia atypical for achondroplastic subjects
• History of clinically significant hip injury in the 30 days prior to screening
• History of slipped capital femoral epiphysis or avascular necrosis of the femoral head
• Abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant
• Concurrent disease or condition that would interfere with study participation or safety evaluations, for any reason
• Condition or circumstance that places the subject at high risk for poor treatment compliance or for not completing the study