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