A Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia

A Phase 2 Randomized, Double-Blind, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of BMN 111 in Infants and Young Children With Achondroplasia, Age 0 to < 60 Months

Study 111-206 is a Phase 2 randomized, double-blind, placebo-controlled clinical trial of BMN 111 in infants and young children with a diagnosis of achondroplasia.

Inclusion Criteria:

1. Diagnosis of achondroplasia (ACH), confirmed by genetic testing. If subjects had previous genetic testing, subjects must have a lab report from a certified laboratory with the study specific mutation documented.
2. Age 0 to < 60 months, at study entry (Day 1)
3. Cohort 1 and 2 subjects must have at least a 6-month period of pretreatment growth assessment in Study 111 901 immediately before screening, and have one documented measurement of height/body length a minimum of 6 months prior to the screening visit for 111-206. Cohort 3 subjects must have a minimum of 3 months of observation prior to treatment. This observational period can be obtained either (1) via prior enrollment in Study 111-901 or (2) via enrollment in this Study 111 206 for a minimum of 3 months of non-treatment observation prior to commencement of treatment.
4. Parent(s) or guardian(s) (and the subjects themselves, if required by local regulations or ethics committee) are willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure
5. Willing and able to perform all study procedures as physically possible
6. Parent(s) or caregiver(s) are willing to administer daily injections to the subjects and complete the required training

Exclusion Criteria:

1. Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)

2. Subject weighs < 5.0 kg (Cohort 1 and 2) or < 4.0 kg (Cohort 3)

3. Have any of the following:

   • Hypothyroidism or hyperthyroidism
   • Insulin-requiring diabetes mellitus
   • Autoimmune inflammatory disease (including celiac disease, systemic lupus erythematosus, juvenile dermatomyositis, scleroderma, etc.)
   • Inflammatory bowel disease
   • Autonomic neuropathy

4. Have a history of any of the following:

   • Renal insufficiency defined as serum creatinine > 2 mg/dL

   • Chronic anemia or Hgb <10.0 g/dL (based on screening clinical laboratory testing)

   • Baseline systolic blood pressure (BP) below age and gender specified normal range or recurrent symptomatic hypotension (defined as episodes of low BP generally accompanied by symptoms e.g., dizziness, fainting) or recurrent symptomatic orthostatic hypotension

   • Cardiac or vascular disease, including the following

     • Cardiac dysfunction (abnormal echocardiogram determined to be clinically significant by principal investigator PI and medical monitor) at Screening Visit
     • Hypertrophic cardiomyopathy
     • Pulmonary hypertension
     • Congenital heart disease with ongoing cardiac dysfunction
     • Cerebrovascular disease
     • Aortic insufficiency or other clinically significant valvular dysfunction
     • Clinically significant atrial or ventricular arrhythmias

5. Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or Fridericia's corrected QT interval (QTc-F) >450 msec on screening ECG

6. Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention within 60 days of Screening as determined by the Investigator based on the following assessments

   • Physical exam (e.g., neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins)
   • Polysomnography (e.g., severe central sleep apnea)
   • MRI indicating presence of severe CMC or spinal cord damage

7. Have an unstable medical condition likely to require surgical intervention in the next 6 months, or planned spine or long-bone surgery (i.e., surgery involving significant disruption of bone cortex) during the study period

8. Have documented uncorrected Vitamin D deficiency: 25(OH)D <=15 ng/mL (37.5 nmol/L)

9. Require any other investigational product prior to completion of the study period

10. Have received another investigational product or investigational medical device within 30 days prior to the Screening visit

11. Have used any other investigational product or investigational medical device for the treatment of achondroplasia or short stature at any time

12. Require current chronic therapy with antihypertensive medication or any medication that, in the investigator's judgment, may compromise the safety or ability of the subject to participate in this clinical study (Table 9.3.5.1)

13. Have been treated with growth hormone, insulin-like growth factor 1 (IGF-1), or anabolic steroids in the 6 months prior to screening, or long-term treatment (>3 months) at any time

14. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma, or intranasal steroids, are acceptable) in the 12 months prior to screening

15. Have ever had cervicomedullary decompression surgery (Cohorts 2 and 3 only), spine or long-bone surgery (i.e., surgery involving disruption of bone cortex) or have ever had bone-related surgery with chronic complications

    NOTE: Subjects with prior cervicomedullary decompression may be allowed into Cohort 1 only after discussion and agreement with Medical Monitor.

16. Have ever had limb-lengthening surgery or plan to have limb-lengthening surgery during the study period

17. Have had a fracture of the long bones or spine within 6 months prior to screening

18. Have aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or total bilirubin greater than upper limit of normal (ULN) at screening (except for subjects with a known history of Gilberts or newborns entering screening in Cohort 3)

19. Have evidence of severe untreated sleep apnea; or have newly initiated sleep apnea treatment (eg, Continuous positive airway pressure (CPAP) or sleep apnea-mitigating surgery) in the 2 months prior to screening

20. Have current malignancy, history of malignancy, or currently under work-up for suspected malignancy

21. Have known hypersensitivity to BMN 111 or its excipients

22. Have a history of hip surgery or severe hip dysplasia

23. Have a history of clinically significant hip injury in the 30 days prior to screening

24. Have a history of slipped capital femoral epiphysis or avascular necrosis of the femoral head

25. Have abnormal findings on baseline clinical hip exam or imaging assessments that are determined to be clinically significant as determined by the Investigator

26. 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

27. Have any concurrent disease or condition that, in the view of the Investigator, would interfere with study participation or safety evaluations, for any reason

Inclusion Criteria for Cohort 3 Observation Period

1. Parent(s) or guardian(s) willing and able to provide signed informed consent after the nature of the study has been explained and prior to performance of any research-related procedure. Also, willing and able to provide written assent (if applicable) after the nature of the study has been explained and prior to performance of any research-related procedure.
2. Birth to <= 3 months of age at study entry.
3. Have ACH, documented by genetic testing
4. Are willing and able to perform all study procedures as physically possible

Exclusion Criteria for Cohort 3 Observation Period

1. Have hypochondroplasia or short stature condition other than ACH (e.g., trisomy 21, pseudoachondroplasia)

2. Have any of the following disorders:

   • Hypothyroidism
   • Insulin-requiring diabetes mellitus
   • Autoimmune inflammatory disease (including celiac disease, lupus (SLE), juvenile dermatomyositis, scleroderma, and others)
   • Inflammatory bowel disease
   • Autonomic neuropathy

3. Have an unstable clinical condition likely to lead to intervention during the course of the study, including progressive cervical medullary compression

4. Have a history of any of the following:

   • Renal insufficiency
   • Anemia

5. Have a history of cardiac or vascular disease, including the following:

   • Cardiac dysfunction
   • Hypertrophic cardiomyopathy
   • Congenital heart disease
   • Cerebrovascular disease, aortic insufficiency
   • Clinically significant atrial or ventricular arrhythmias

6. Current treatment 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, drugs known to alter renal function that is expected to continue for the duration of the study

7. Have had regular long-term treatment (> 1 month) with oral corticosteroids (low-dose ongoing inhaled steroid for asthma is acceptable) in the previous 3 month

8. Concomitant medication that prolongs the QT/QTc interval within 14 days or 5 half-lives, whichever is longer, before the Screening visit

9. Have used any other investigational product or investigational medical device for the treatment of ACH or short stature

10. Planned or expected bone-related surgery (ie. surgery involving disruption of bone cortex), during the study period.

11. Planned or expected to have limb-lengthening surgery during the study period.

12. Have any condition that, in the view of the Investigator, places the subject at high risk of poor compliance with the visit schedule or of not completing the study.

13. Concurrent disease or condition that, in the view of the Investigator, would interfere with study participation