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

A Phase 3 Randomized, Double-Blind, Placebo-Controlled, Multicenter 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.

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