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

Study Overview
=================
Brief 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.

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

Conditions
-----------------
Achondroplasia

Intervention / Treatment
-----------------
* Drug: BMN 111


Participation Criteria
=================
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

Ages Eligible for Study
-----------------
Minimum Age: 5 Years
Maximum Age: 14 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1: 2.5 ug/kg | Drug: BMN 111<br>* BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.<br>* Other names: Vosoritide;|
| Experimental: Cohort 2<br>Cohort 2: 7.5 ug/kg, | Drug: BMN 111<br>* BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.<br>* Other names: Vosoritide;|
| Experimental: Cohort 3<br>Cohort 3: 15 ug/Kg | Drug: BMN 111<br>* BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.<br>* Other names: Vosoritide;|
| Experimental: Cohort 4<br>Cohort 4: 30 ug/kg | Drug: BMN 111<br>* BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.<br>* Other names: Vosoritide;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Summary of Adverse Events During Initial 6-Month Period | A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. Serious adverse event (SAE). | Up to Month 6 ± 7 Days | 
| Overall Summary of Adverse Events During Entire Study Period | A treatment-emergent Adverse Events (TEAE) is any Adverse Events that newly appeared, increased in frequency or worsened in severity following initiation of study drug administration. TEAE - Treatment-emergent adverse event. SAE - Serious adverse event. | Up to Month 25 ± 7 Days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Annualized Growth Velocity (AGV) During Initial 6-Month | Annualized Growth Velocity at Day 183 is assessed on standing height as ((Height at Day 183 Visit - Height at Baseline Visit)/(Date at Day 183 Visit - Baseline Visit Date)) x 365.25. | At 6 month (Day 183) | 
| Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 3 and 4 | Annualized Growth Velocity at Day 183 visit is assessed on standing height as ((Height at Day 183 Visit - Height at Baseline Visit)/(Date at Day 183 Visit - Baseline Visit Date)) x 365.25. | At month 24 | 
| Change From Baseline in Annualized Growth Velocity (AGV) During Entire Study Period - Cohort 1 and 2 Switchers | Annualized Growth Velocity at 1st visit with >= 12 months on 15ug/kg is assessed on standing height as ((Height at 1st Visit with >= 12 Months on 15 μg/kg - Height at 1st Visit on 15 μg/kg)/(Date of the 1st Visit with >= 12 months on 15 μg/kg - Date of at 1st Visit on 15 μg/kg)) x 365.25. | At month 24 | 
| Change From Baseline in Height Z-Scores Using Centers for Disease Control and Prevention (CDC) Reference Standard During Initial 6-Months | Height Z scores indicates how far a particular child is from the average height for children of the same sex and age. A positive height Z score indicates the child's height is above average whilst a negative Z score indicates the child's height is below average. Height Z scores below -2 Standard Deviation Scores (SDs) indicate a child's height is no longer within normal height range for average stature children of the same sex and age. Z-scores are derived using non-ACH age-sex-specific reference data (means and standard deviations) per Centers for Disease Control and Prevention (CDC). | At month 6 (Day 183) | 
| Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 3 and 4 | Height Z scores indicates how far a particular child is from the average height for children of the same sex and age. A positive height Z score indicates the child's height is above average whilst a negative Z score indicates the child's height is below average. Height Z scores below -2 SDs indicate a child's height is no longer within normal height range for average stature children of the same sex and age. Z-scores are derived using non-ACH age-sex-specific reference data (means and standard deviations) per Centers for Disease Control and Prevention (CDC). | At month 24 | 
| Change From Baseline in Height Z-Scores Using CDC Reference Standard During Entire Study Period - Cohort 1 and 2 Switchers | Height Z scores indicates how far a particular child is from the average height for children of the same sex and age. A positive height Z score indicates the child's height is above average whilst a negative Z score indicates the child's height is below average. Height Z scores below -2 SDs indicate a child's height is no longer within normal height range for average stature children of the same sex and age. Z-scores are derived using non-ACH age-sex-specific reference data (means and standard deviations) per Centers for Disease Control and Prevention (CDC). | At month 24 | 
| Change From Baseline in Upper to Lower Body Ratios During Initial 6-Months | The Upper to Lower Body ratio prior to treatment, at baseline, and through 6 months is assessed on Sitting Height / (Standing Height - Sitting Height) | At month 6 (Day 183) | 
| Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 3 and 4 | The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height) | At month 24 | 
| Change From Baseline in Upper Arm Length to Lower Arm (Forearm) Length Ratio During Initial 6-Months | The Upper Arm Length to Lower Arm (Forearm) Length ratio prior to treatment, at baseline, and through 6 months is assessed on Upper Arm Length / Lower Arm (Forearm) Length. | At month 6 (Day 183) | 
| Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 3 and 4 | The Upper Arm Length to Lower Arm (Forearm) Length ratio prior to treatment, at baseline, and through 24 months is assessed on Upper Arm Length / Lower Arm (Forearm) Length. | At month 24 | 
| Change From Baseline in Upper to Lower Body Ratios During Entire Study Period - Cohort 1 and 2 Switchers | The Upper to Lower Body ratio prior to treatment, at baseline, and through 24 months is assessed on Sitting Height / (Standing Height - Sitting Height) | At month 24 | 
| Change From Baseline in Upper Arm to Lower Arm Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | The Upper Arm Length to Lower Arm (Forearm) Length ratio prior to treatment, at baseline, and through 24 months is assessed on Upper Arm Length / Lower Arm (Forearm) Length. | At month 24 | 
| Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Initial 6-months | The Upper Leg Length (Thigh) to Knee to Heel Length Ratio prior to treatment, at baseline, and through 6 months is assessed on Upper Leg Length (Thigh) / Knee to Heel Length. | At month 6 (Day 183) | 
| Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 3 and 4 | The Upper Leg Length (Thigh) to Knee to Heel Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh) / Knee to Heel Length. | At month 24 | 
| Change From Baseline in Upper Leg Length (Thigh) to Knee to Heel Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | The Upper Leg Length (Thigh) to Knee to Heel Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh) / Knee to Heel Length. | At month 24 | 
| Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Initial 6-months | The Upper Leg Length (Thigh) to Tibial Length Ratio prior to treatment, at baseline, and through 6 months is assessed by Upper Leg Length (Thigh)/ Tibial Leg Length. | At month 6 (Day 183) | 
| Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 3 and 4 | The Upper Leg Length (Thigh) to Tibial Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh)/ Tibial Leg Length. | At month 24 | 
| Change From Baseline in Upper Leg Length (Thigh) to Tibial Length Ratio During Entire Study Period - Cohort 1 and 2 Switchers | The Upper Leg Length (Thigh) to Tibial Length Ratio prior to treatment, at baseline, and through 24 months is assessed by Upper Leg Length (Thigh)/ Tibial Leg Length. | At month 24 | 
| Change From Baseline in Arm Span to Height Ratio During Initial 6-months | The Arm Span to Height Ratio prior to treatment, at baseline, and through 6 months is assessed by Arm Span / Standing Height. | At month 6 (Day 183) | 
| Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 3 and 4 | The Arm Span to Height Ratio prior to treatment, at baseline, and through 24 months is assessed by Arm Span / Standing Height. | At month 24 | 
| Change From Baseline in Arm Span to Height Ratio During Entire Study Period - Cohort 1 and 2 Switchers | The Arm Span to Height Ratio prior to treatment, at baseline, and through 24 months is assessed by Arm Span / Standing Height. Values are not available for participants in cohort 1 switchers for Change from Baseline to >=12 Months on 15ug/kg. | At month 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Achondroplasia, Dwarfism, Bone Diseases, Developmental, Bone Diseases