Safety and Exercise Study of Two Doses of BMN 110 for Morquio A Syndrome

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the safety of a 2.0 mg/kg/week and a 4.0 mg/kg/week of BMN 110 in patients with Morquio A syndrome for up to 196 weeks. Secondary objectives were to investigate the effect of the two doses on exercise capacity for up to 196 weeks. In addition, the pharmacokinetic (PK) parameters of both doses of BMN 110 was assessed.

Official Title
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A Randomized, Double-Blind, Pilot Study of the Safety and Physiological Effects of Two Doses of BMN 110 in Patients With Mucopolysaccharidosis IVA (Morquio A Syndrome)

Conditions
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Mucopolysaccharidosis IVA, Morquio A Syndrome, MPS IVA

Intervention / Treatment
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* Drug: BMN 110
* Drug: BMN 110


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is willing and able to provide written, signed informed consent (or patient's legally authorized representative) after the nature of the study has been explained and prior to performance of any research- related procedure. Also, patients who do not meet country and local age requirements for informed consent must be willing and able to provide written assent (if required) and written informed consent by a legally authorized representative after the nature of the study has been explained, and prior to performance of any research-related procedure. Has documented clinical diagnosis of Morquio A Syndrome (MPS IVA) based on clinical signs and symptoms of MPS IVA and documented reduced fibroblast or leukocyte N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity or genetic testing confirming diagnosis of MPS IVA. Is at least 7 years of age Is able to walk ≥ 200 meters as assessed by the 6-minute Walk Test (6MWT) If sexually active, is willing to use an acceptable method of contraception while participating in the study If female of childbearing potential, must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests during the study Is willing and able to perform all study procedures, including cardiopulmonary exercise testing (CPET) Exclusion Criteria: Inability to perform an exercise test due to limited mobility Body weight greater than 95 kg at Screening Severe, untreated sleep apnea as measured during Screening with a home sleep testing device Patients with a history of, or current condition of sleep apnea or sleep disordered breathing under adequate treatment may be enrolled if approved by the medical monitor. Requirement for supplemental oxygen Use of ventilator assistance in the 3 months prior to study entry Use of positive airway pressure (continuous positive airway pressure, CPAP, or bilevel airway pressure) for treatment of sleep apnea or sleep disordered breathing is allowed if settings have been stable for at least 1 month prior to study entry, and is approved by the medical monitor. Has a concurrent disease or condition, including but not limited to, symptomatic cervical spine instability, clinically significant spinal cord compression, or severe cardiac disease that would interfere with study participation, or pose a safety risk, as determined by the Investigator Has previous hematopoietic stem cell transplant (HSCT) Has received previous treatment with BMN 110 Has a known hypersensitivity to BMN 110 or its excipients Has had major surgery within 3 months prior to study entry or is planning to have a major surgery during the duration of the study Use of any other investigational product (IP) or investigational medical device within 30 days prior to the beginning of the Screening Period or requires any investigational agent prior to completion of all scheduled study assessments Is pregnant or breastfeeding during the Screening Period or planning to become pregnant (self or partner) at any time during the study Has a concurrent disease or condition that may interfere with study participation or safety, and/or ability to perform study procedures as determined by the Investigator Has any condition that, in the view of the Investigator, poses a safety risk to the patient Has any condition that, in the view of the Investigator, places the patient at high risk of poor treatment compliance or of not completing the study

Ages Eligible for Study
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Minimum Age: 7 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BMN 110 Weekly at 2.0 mg/kg/week<br> | Drug: BMN 110<br>* Weekly IV infusions of BMN 110 at 2.0 mg/kg/week over a period of approximately 4 hours per infusion for up to 192 weeks.<br>* Other names: elosulfase alfa;|
| Experimental: BMN 110 Weekly at 4.0 mg/kg/week<br> | Drug: BMN 110<br>* Weekly IV infusions of BMN 110 at 4.0 mg/kg/week over a period of approximately 4 hours per infusion for 27 weeks, and will eventually transition to 2.0 mg/kg/week for up to an additional 166 weeks.<br>* Other names: elosulfase alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Evaluation | The primary objective of the study is to evaluate the safety of weekly infusions of BMN 110; the safety variables included Adverse Events (AEs). The primary outcome measure data is presented in more detail under the Adverse Events section. | Entire Study Period, up to 192 weeks or ETV (early termination visit) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6-minute Walk Test (6MWT) | Change from baseline to Week 12, 24, and 52 as measured in distance walked (meters) in 6MWT. | Baseline, Week 12, 24, and 52 | 
| 3-minute Stair Climb Test (3MSCT) | Change from baseline to Week 12, 24, and 52 as measured in speed (stairs/min) in 3MSCT. | Baseline, Week 12, 24, and 52 | 
| Respiratory Function Test (MVV and FVC) | Respiratory Function was assessed by spirometry in accordance with American Thoracic Society standards. Percent change from baseline to Week 12, 24, and 52 as measured by Maximum Voluntary Ventilation (MVV, L/min) Percent change from baseline to Week 12, 24, and 52 as measured by Forced Vital Capacity (FVC, L) | Baseline, Week 12, 24, and 52 | 
| Normalized Urine Keratan Sulfate (uKS) | Urinary KS was measured by a quantitative method and normalized using the sample urinary creatinine measurement. Percent change from baseline to Week 12, 24, and 52 in normalized urine keratan sulfate (ug/mg). | Baseline, Week 12, 24, and 52 | 
| Cardiopulmonary Exercise Testing (CPET) - Duration of Exercise | Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Change from baseline to Week 25 and 52 as measured by the CPET Duration of Exercise (min) | Baseline, Week 25 and 52 | 
| Cardiopulmonary Exercise Testing (CPET) - Peak Workload | Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET Peak workload (watt) | Baseline, Week 25 and 52 | 
| Cardiopulmonary Exercise Testing (CPET) - O2 Pulse | Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET O2 pulse (ml/beat) | Baseline, Week 25 and 52 | 
| Cardiopulmonary Exercise Testing (CPET) - Aerobic Efficiency | Subjects performed maximal incremental exercise testing using an electronically braked upright cycle ergometer. Cycle ergometry is a method of CPET that may be feasible in subjects who have orthopedic, peripheral vascular, or neurological limitations that restrict weight bearing. Percent change from baseline to Week 25 and 52 as measured by the CPET Aerobic Efficiency (ml/watt). Note that decline in Aerobic Efficiency translate into an improvement | Baseline, Week 25 and 52 | 
| Muscle Strength Testing (MST) - Knee Extension Test | Change from baseline to Week 25 and 52 as measured by the peak force in MST knee extension test (newton meters). | Baseline, Week 25 and 52 | 
| Muscle Strength Testing (MST) - Knee Flexion Test | Percent change from baseline to Week 25 and 52 as measured by the peak force in MST knee flexion test (newton meters). | Baseline, Week 25 and 52 | 
| Muscle Strength Testing (MST) - Elbow Flexion Test | Percent change from baseline to Week 25 and 52 as measured by the peak force in MST elbow flexion test (newton meters). | Baseline, Week 25 and 52 | 
| Adolescent Pediatric Pain Tool (APPT) - Pain Intensity | The APPT is a validated, multidimensional tool to evaluate pain in children, adolescents, and young adults. The complete APPT is measured in three parts - Part 1 of the APPT scale determines the subject's pain locations using a body template. Part 2 of the APPT scale determines the intensity of the pain using a 10 cm visual analog scale (VAS) with the lowest point of the scale (0) labeled No Pain and the highest point on the scale (10) labeled Worst Possible Pain. Intermediate regions of the sale were labeled with 3 intermediate descriptors (Little Pain, Medium Pain, and Large Pain). Part 3 of the APPT scale characterizes the pain by tracking the number and percentage of words selected by subjects to describe their pain from a total of 57 choices. Part 2 corresponds most closely to other typically used pain scales (based on VAS) and for this reason the results from Part 2 are presented here. Change from baseline to Week 12, 24, and 52 in pain intensity. | Baseline, Week 12, 24, and 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidosis IVA Type A, MPS IVA Type A, Mucopolysaccharidosis IVA, MPS IVA, Morquio A Syndrome, Lysosomal Storage Disorder, LSD, N-acetylgalactosamine-6-sulfatase, N-acetylgalactosamine-6-sulfate, sulfatase, galactose-6-sulfatase, GALNS, enzyme replacement therapy, ERT, MOR-008, CPET, MST, muscle strength test, physiological effect