A Phase 2 Study of BMN 111 to Evaluate Safety, Tolerability, and Efficacy in Children With Achondroplasia
Condition: Achondroplasia
MeSH terms: Achondroplasia
Intervention: BMN 111
Intervention description: BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.
Intervention MeSH terms: Natriuretic Peptide, C-Type
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 5 Years
Maximum age: 14 Years
Healthy volunteers: No
Keywords: Achondroplasia; Dwarfism; Bone Diseases, Developmental; Bone Diseases

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