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

The intent and design of this Phase 3 study is to assess BMN 111 as a therapeutic option for the treatment of 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.

Eligibility Criteria:
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