A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia

A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia

This is a Phase 2, open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. The primary objective is to assess the safety and tolerability of daily BMN 111 administered to children with achondroplasia.

Inclusion Criteria:

• Parent(s) or guardian(s) are willing and able to provide written, signed informed consent
• 5 to 14 years old at end of study
• ACH, documented by clinical grounds, confirmed by genetic testing
• At least 6-month of pretreatment growth assessment in Study 111-901 before study entry, and one standing height at least 6 months prior to screening for 111-202
• Negative pregnancy test at the Screening Visit for females ≥ 10 years old or who have begun menses
• If sexually active, willing to use a highly effective method of contraception while participating in the study
• Ambulatory, able to stand without assistance
• Willing and able to perform all study procedures as physically possible
• Parents/caregivers willing to administer daily injections to the subjects

Additional inclusion Criteria Optional, Open-label Extension Phase:

• Appropriate written informed consent

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
  • Recent acute illness associated with volume dehydration not completely resolved prior to the first dose of study drug

• Unstable condition requiring surgical intervention during the study

• Growth plates have fused

• Have a history of any of the following:

  • Renal insufficiency, defined as creatinine > 2 mg/dl

  • Anemia

  • Baseline systolic BP < 75 mm Hg or recurrent symptomatic hypotension or recurrent symptomatic hypotension, recurrent symptomatic orthostatic hypotension

  • Cardiac or vascular disease, including the following:

    • Cardiac dysfunction (abnormal echocardiogram [ECHO] including left ventricle [LV] mass) at Screening Visit
    • Hypertrophic cardiomyopathy
    • Pulmonary Hypertension
    • Congenital heart disease with ongoing cardiac dysfunction
    • Cerebrovascular disease
    • Aortic insufficiency
    • Clinically significant atrial or ventricular arrhythmias

• Have an ECG showing any of the following:

  • Right or left atrial enlargement or ventricular hypertrophy
  • PR (period of time from the beginning of atrial depolarization until the beginning of ventricular depolarization) interval > 200 msec
  • QRS (The Q, R, and S heart waves that are measured on an electrocardiogram) interval > 110 msec
  • Corrected QTc-F (Measure of the corrected time between the start of the Q wave and end of the T wave in the heart's electrical cycle) > 450 msec
  • Second- or third-degree atrioventricular block

• Documented Vitamin D deficiency

• Require any investigational agent prior to completion of study period

• Have received another investigational product or investigational medical device within 30 days before the Screening visit

• Use of any other investigational product or investigational medical device for the treatment of ACH or short stature

• Current chronic therapy with antihypertensive medications, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, diuretics, beta-blockers, calcium-channel blockers, cardiac glycosides, systemic anticholinergic agents, any medication that may impair or enhance compensatory tachycardia, diuretics, or other drugs known to alter renal or tubular function

• Treatment with growth hormone, IGF-1 (Insulin-like growth factor), or anabolic steroids in the previous 6 months or long-term treatment (> 3 months) at any time

• Long-term treatment (> 1 month) with oral corticosteroids

• Concomitant medication that prolongs the QT/QTc-F interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit

• Pregnant or breastfeeding at the Screening Visit or planning to become pregnant (self or partner) at any time during the study

• Limb-lengthening or bone-related surgery < 18 months prior to study enrollment

• Had a fracture of the long bones or spine within 6 months prior to screening (except for fracture of digits or toes)

• AST (Aspartate Transaminase) or ALT (Alanine Transaminase) at least 3x upper limit of normal (ULN) or total bilirubin at least 2x ULN

• Evidence of severe sleep apnea requiring surgery or new initiation of CPAP (Continuous positive airway pressure).

• History of malignancy and chemotherapy/radiation or currently under work-up for suspected malignancy

• Known hypersensitivity to BMN 111 or its excipients

• Have a condition or circumstance that, in the view of the Investigator, places the subject at high risk for poor treatment compliance or for not completing the study

• Concurrent disease or condition that would interfere with study participation or safety

• Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the PI.

• Have a history of hip surgery or severe hip dysplasia

• Have a 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.

• Are unable to lie flat when in prone position

Additional Exclusion Criteria for Optional, Open-label Extension Phase:

• Use of restricted therapies during the initial 6 months of the study
• Permanently discontinued BMN 111 during the initial 6 months of the study