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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

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

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At the time of data cutoff, a total of 62 patients, including 11 patients in the sentinel group and 51 patients in the randomized group, were enrolled. The breakdown was as follows: 4 and 31 patients, respectively, in Cohort 1, 4 and 16, respectively, in Cohort 2, and 3 and 4, respectively, in Cohort 3. Of the 62 patients, 8 patients were Japanese and all of them were enrolled in the randomized group: 5 patients in Cohort 1, 2 in Cohort 2, and 1 in Cohort 3. The maximum duration of treatment in the sentinel group at the time of data cutoff was 375 days in Cohort 1, 382 days in Cohort 2, and 330 days in Cohort 3.

Patients were enrolled sequentially into Cohort 1 (24 to < 60 months: Voxzogo 15 mcg/kg), Cohort 2 (6 to < 24 months: Voxzogo 30 mcg/kg), or Cohort 3 (< 6 months: Voxzogo 30 mcg/kg), and received subcutaneous administration of Voxzogo once daily for 52 weeks. In all cohorts, at least 3 patients in the sentinel group (treated with Voxzogo in an open-label manner throughout the study period) were treated with Voxzogo for 8 days and the short-term safety and pharmacokinetics (PK) of Voxzogo were evaluated. After that, the remaining patients were stratified by age (< 6 months, 6 to < 15 months, 15 to < 24 months, 24 to < 36 months, and 36 to < 60 months) within the cohort, were randomly assigned to the Voxzogo group or the placebo group at a 1:1 ratio, and received Voxzogo. In Cohort 2, sentinel patients were initially treated at the dose of 15 mcg/kg, but the results of evaluation of PK data showed that the optimal dose for achieving the desired exposure level is 30 mcg/kg/day. Thus, the dose was subsequently increased to 30 μg/kg for 3 sentinel patients, and all randomized patients in Cohort 2 received 30 mcg/kg. The dose was switched to once daily subcutaneous administration of 15 mcg/kg when patients reached 2 years of age.

Adverse events occurred in all 11 patients in the sentinel group and 64 patients in the randomized group. Common AEs (occurrence in >= 2 patients in the sentinel group and incidence of >= 30% in the randomized group) were injection site reactions and injection site erythema in 4 patients each (100%), and vomiting, otitis media, and fall in 2 patients each (50%) in the sentinel group (N = 4), and injection site reactions in 18 patients (58.1%), injection site erythema and upper respiratory tract infection in 14 patients (45.2%), and pyrexia and vomiting in 12 patients each (38.7%) in the randomized group (N = 31) in Cohort 1; epipharyngitis and vomiting in 3 patients each (75.0%), and injection site reactions, injection site erythema, teething, rhinorrhoea, viral infection, and fall in 2 patients each (50.0%) in the sentinel group (N = 4), and injection site erythema in 10 patients (62.5%), teething in 9 patients (56.3%), injection site reactions and pyrexia in 8 patients (50.0%), conjunctivitis in 6 patients (37.5%), and upper respiratory tract infection, epipharyngitis, and otitis media in 5 patients each (31.3%) in the randomized group (N = 16) in Cohort 2; and injection site reactions, injection site erythema, pyrexia, upper respiratory tract infection, teething, and ear infection in 2 patients each (66.7%) in the sentinel group (N = 3) , and injection site erythema, and pyrexia in 13 patients each (76.5%), injection site reactions in 12 patients (70.6%), teething in 9 patients (52.9%), nasal congestion in 7 patients (41.2%), and vomiting in 6 patients (35.5%) in the randomized group (N = 17) in Cohort 3. ADRs occurred in 8 of 11 patients (72.7%) in the sentinel group, and 45 of 64 patients (70.3%) in the randomized group. The breakdown by cohort was as follows: 4/4 patients (100.0%) and 19/31 patients (61.3%), respectively, in Cohort 1, 2/4 patients (50.0%) and 11/16 patients (68.8%), respectively, in Cohort 2, and 2/3 patients (66.7%) and 15/17 patients (88.2%), respectively, in Cohort 3. Among common AEs, all cases of injection site reactions and injection site erythema were ADRs. As ADRs other than those related to the injection site, diarrhea and blood pressure decreased occurred in 1 patient each (3.2%) in the randomized group in Cohort 1, blood pressure decreased occurred in 1 patient (6.3%) in the randomized group in Cohort 2, and pyrexia occurred in 1 patient (5.9%) in the randomized group in Cohort 3. •SAEs occurred in 2 patients (oxygen saturation decreased, and petit mal epilepsy in 1 patient each) in the randomized group in Cohort 1, 2 patients (autism spectrum disorder, and gastroenteritis in 1 patient each) in the randomized group in Cohort 2, and 5 patients (otitis media and skull fracture in 1 patient, parainfluenzae virus infection, pneumonia, respiratory syncytial (RS) virus bronchiolitis, dyspnoea, and vomiting in 1 patient each) in the randomized group in Cohort 3. All these events were assessed as not related to the investigational product. • No AEs leading to discontinuation of the study or discontinuation of treatment with the investigational product or deaths were reported by the time of data cut-off.

Height Z-score (primary endpoint) Preliminary data from the sentinel group showed improvements in height Z-scores in all cohorts.

Annual growth velocity (secondary endpoint) Preliminary data from the sentinel group showed an overall trend of either an increase (Cohort 1) or a slight decrease (Cohorts 2 and 3) in AGV relative to the decrease in AGV assumed in the same age group. Upper-body segment to lower-body segment ratio (secondary endpoint) Preliminary data from the sentinel group showed a trend toward improvement in the US/LS ratio in all cohorts.

Preliminary data from the sentinel group showed improvements in height Z-scores in all cohorts. Adverse events occurred in all 1 patients in the sentinel group and 64 patients in the randomized group. SAEs occurred in 2 patients (oxygen saturation decreased, and petit mal epilepsy in 1 patient each) in the randomized group in Cohort 1, 2 patients (autism spectrum disorder, and gastroenteritis in 1 patient each) in the randomized group in Cohort 2, and 5 patients (otitis media and skull fracture in 1 patient, parainfluenzae virus infection, pneumonia, respiratory syncytial (RS) virus bronchiolitis, dyspnoea, and vomiting in 1 patient each) in the randomized group in Cohort 3. All these events were assessed as not related to the investigational product. No AEs leading to discontinuation of the study or discontinuation of treatment with the investigational product or deaths were reported by the time of data cut-off.

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EPS Corporation

2-23 Shimomiyabicho, Shinjuku-ku, Tokyo

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EPS Corporation

2-23 Shimomiyabicho, Shinjuku-ku, Tokyo

FAX 03-3868-5254

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completed

Sept. 05, 2019

Interventional

Allocation: Randomized Intervention Model: Parallel Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Treatment

treatment purpose

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-Diagnosis of ACH,confirmed by genetic testing
-Age 0 to < 60 months at study entry (Day1)
-At least 6 month period of pretreatment growth assessment in Study 111-901 immediately before study entry (for cohort 1 and 2) or at least 3 months of observation in either Study 111-901 or Study 111-206 prior to treatment (for cohort 3)

1.Have hypochondroplasia or short-stature condition other than achondroplasia (e.g., trisomy 21, pseudoachondroplasia, etc.)
2.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
3.Have a clinically significant finding or arrhythmia that indicates abnormal cardiac function or conduction or QTc-F > 450 msec on screening ECG
4.Have evidence of cervicomedullary compression (CMC) likely to require surgical intervention within 60 days of Screening as determined by the Investigator and informed by the following assessments:
-Physical exam (eg, neurologic findings of clonus, opisthotonus, exaggerated reflexes, dilated facial veins)
-Polysomnography (eg, severe central sleep apnea)
-MRI indicating presence of severe CMC or spinal cord damage
5.Subject weight < 5.0 kg (cohort 1 & 2) or < 4.0 kg (cohort 3)
6.Treatment with growth hormone within 6-months prior to screening or prolonged treatment (> 3 months) at any time
7.Any history of spine or long-bone surgery or any bone-related surgery with chronic complications
8.Any history of limb-lengthening surgery or planned limb-lengthening during the study
9.Fracture of the long bones within 6 months prior to screening

Both

Achondroplasia

investigational material(s)
Generic name etc : Modified recombinant human C-type natriuretic peptide
INN of investigational material : Vosoritide
Therapeutic category code : 249 Other hormone preparations (including antihormone preparations)
Dosage and Administration for Investigational material : Subcutaneous injection of 15 micro g/kg of BMN 111 daily, Subject to adjustment per protocol

control material(s)
Generic name etc : placebo
INN of investigational material : -
Therapeutic category code : --- Other
Dosage and Administration for Investigational material : -

efficacy
Evaluate the effect of BMN 111 on change from baseline in length/height Z-scores [Time frame: One year]

safety
efficacy
1.Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: One year ]
2.Evaluate the effect of BMN 111 on change from baseline in AGV [ Time Frame: One year ]
3.Evaluate the effect of BMN 111 on bone morphology/quality by X-ray and dual X-ray absorptiometry (DXA) [ Time Frame: One year ]
4.Characterize maximum concentration (Cmax) of BMN 111 in plasma [ Time Frame: One year ]
5.Characterize the area under the plasma concentration time-curve from time 0 to infinity (AUC 0-infinity) [ Time Frame: One year ]
6.Characterize the area under the plasma concentration time-curve from time 0 to the last measurable concentration (AUC0-t) [ Time Frame: 52 Weeks ]
7.Characterize the elimination half-life of BMN 111 (t1/2) [ Time Frame: 52 weeks ]
8.Characterize the apparent clearance of drug [ Time Frame: 52 weeks ]
9.Characterize the apparent volume of distribution based upon the terminal phase (Vz/F) [ Time Frame: 52 weeks ]
10.Characterize the amount of time BMN 111 is present at maximum concentration (Tmax) [ Time Frame: 52 weeks ]
11.Potential Changes in health-related quality of life as measured by the quality of life in Short- statured youth [ Time Frame: One year ]
12.BMN 111 activity will be assessed by measuring bone and collagen metabolism [ Time Frame: One year ]
13.Evaluate the effect of BMN 111 on growth parameters and body proportions, including change from baseline in upper:lower segment body ratio [ Time Frame: One year ]
14.Evaluate the effect of BMN 111 on Sleep study scores by polysomnography [ Time Frame: One year ]

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July. 05, 2019