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

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)

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.

Study Overview

• Status: Terminated
• Conditions: Morquio A Syndrome; MPS IVA; Mucopolysaccharidosis IVA
• Intervention / Treatment: Drug: BMN 110; Drug: BMN 110

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
  • Ontario
    • Toronto, Ontario, Canada
  • Quebec
    • Montreal, Quebec, Canada
    • Sherbrook, Quebec, Canada
• Germany
  • Hamburg, Germany
• United Kingdom
  • Manchester, United Kingdom
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom
• United States
  • California
    • Oakland, California, United States
  • Illinois
    • Chicago, Illinois, United States
  • New York
    • New York, New York, United States
  • Texas
    • Houston, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BMN 110 Weekly at 2.0 mg/kg/week	Drug: BMN 110; 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.; Other Names: ERT; N-acetylgalactosamine-6-sulfatase; galactose-6-sulfatase; GALNS; enzyme replacement therapy; N-acetylgalactosamine-6-sulfate; sulfatase; elosulfase alfa; Drug: BMN 110; 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.; Other Names: ERT; N-acetylgalactosamine-6-sulfatase; galactose-6-sulfatase; GALNS; enzyme replacement therapy; N-acetylgalactosamine-6-sulfate; sulfatase; elosulfase alfa
Experimental: BMN 110 Weekly at 4.0 mg/kg/week	Drug: BMN 110; 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.; Other Names: ERT; N-acetylgalactosamine-6-sulfatase; galactose-6-sulfatase; GALNS; enzyme replacement therapy; N-acetylgalactosamine-6-sulfate; sulfatase; elosulfase alfa; Drug: BMN 110; 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.; Other Names: ERT; N-acetylgalactosamine-6-sulfatase; galactose-6-sulfatase; GALNS; enzyme replacement therapy; N-acetylgalactosamine-6-sulfate; sulfatase; elosulfase alfa

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Adam Shaywitz, MD PhD, BioMarin Pharmaceutical

Publications and helpful links

General Publications

• Berger KI, Burton BK, Lewis GD, Tarnopolsky M, Harmatz PR, Mitchell JJ, Muschol N, Jones SA, Sutton VR, Pastores GM, Lau H, Sparkes R, Shaywitz AJ. Cardiopulmonary Exercise Testing Reflects Improved Exercise Capacity in Response to Treatment in Morquio A Patients: Results of a 52-Week Pilot Study of Two Different Doses of Elosulfase Alfa. JIMD Rep. 2018;42:9-17. doi: 10.1007/8904_2017_70. Epub 2017 Nov 21.

Study record dates

Study Major Dates

• Study Start: April 1, 2012
• Primary Completion (Actual): November 1, 2014
• Study Completion (Actual): November 1, 2014

Study Registration Dates

• First Submitted: May 24, 2012
• First Submitted That Met QC Criteria: May 29, 2012
• First Posted (Estimate): May 31, 2012

Study Record Updates

• Last Update Posted (Estimate): February 1, 2016
• Last Update Submitted That Met QC Criteria: December 24, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: enzyme replacement therapy; Lysosomal Storage Disorder; GALNS; CPET; Mucopolysaccharidosis IVA; MPS IVA; Morquio A Syndrome; LSD; N-acetylgalactosamine-6-sulfatase; galactose-6-sulfatase; ERT; MST; Mucopolysaccharidosis IVA Type A; MPS IVA Type A; N-acetylgalactosamine-6-sulfate; sulfatase; MOR-008; muscle strength test; physiological effect
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Syndrome; Mucopolysaccharidoses; Mucopolysaccharidosis IV
• Other Study ID Numbers: MOR-008