A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy 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.


Eligibility Criteria:
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