a phase 2 study of bmn 111 to evaluate safety, tolerability, and efficacy in children with achondroplasia

Conditions: Achondroplasia

Summary: 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

Keywords: achondroplasia dwarfism bone diseases, developmental bone diseases