MPS IV A
Conditions
Keywords
Mucopolysaccharidosis IV type A, MPS IV 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
Brief summary
This Phase 3 study will evaluate the efficacy and safety of 2.0 mg/kg/week BMN 110 and 2.0 mg/kg/every other week BMN 110 in patients with mucopolysaccharidosis IVA (Morquio A Syndrome). There is currently no standard accepted treatment for MPS IVA other than supportive care. Enzyme replacement therapy (ERT) may be a potential new treatment option for MPS IVA patients. BMN 110 is administered to MPS IVA patients by IV infusion, allowing cellular uptake by the mannose-6-phosphate receptor and transportation to the lysosomes. This enzyme uptake into the lysosomes is hypothesized to promote increased catabolism of keratan sulfate (KS) in tissue macrophages, hyaline cartilage, other connective tissues, and heart valve, and reduce the progressive accumulation of KS which is responsible for the clinical manifestations of the disorders.
Interventions
DRUGBMN 110 Weekly
BMN 110 Weekly: Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours once a week.
DRUGPlacebo
Intravenous infusion of placebo solution at a volume equivalent to that needed for 2.0 mg/kg dose of BMN 110 administered over a period of approximately 4 hours once a week.
DRUGBMN 110 Every Other Week
BMN 110 Every Other Week: Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours every other week and infusions of placebo on alternating weeks.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* At least 5 years of age. * Documented clinical diagnosis of MPS IVA based on clinical signs and symptoms of MPS IVA and documented reduced fibroblast or leukocyte GALNS enzyme activity or genetic testing confirming diagnosis of MPS IVA. * Willing and able to provide written, signed informed consent, or in the case of patients under the age of 18 (or 16 years, depending on the region), 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 any research-related procedures. * Must meet the study entrance requirements for the 6-minute walk test. * Sexually active patients must be willing to use an acceptable method of contraception while participating in the study. * Females of childbearing potential must have a negative pregnancy test at Screening and be willing to have additional pregnancy tests during the study.
Exclusion criteria
* Previous hematopoietic stem cell transplant (HSCT). * Previous treatment with BMN 110. * Has known hypersensitivity to any of the components of BMN 110. * Major surgery within 3 months prior to study entry or planned major surgery during the 24-week treatment period. * Pregnant or breastfeeding at Screening or planning to become pregnant (self or partner) at any time during the study. * Use of any investigational product or investigational medical device within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments. * 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 safety as determined by the Investigator. * 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Baseline to Week 24 |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Baseline to Week 24 |
| Percent Change From Baseline in Urine Keratan Sulfate Normalized for Urine Creatinine | Baseline to Week 24 |
Countries
Argentina, Brazil, Canada, Colombia, Denmark, France, Germany, Italy, Japan, Netherlands, Portugal, Qatar, Saudi Arabia, South Korea, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Intravenous infusion of placebo solution at a volume equivalent to that needed for 2.0 mg/kg dose of BMN 110 administered over a period of approximately 4 hours once a week. | 59 |
| BMN110 2.0 mg/kg/Qow Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours every other week and infusions of placebo on alternating weeks. | 59 |
| BMN110 2.0 mg/kg/Week Intravenous infusion of BMN 110 at a dose of 2.0 mg/kg administered over a period of approximately 4 hours once a week. | 58 |
| Total | 176 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Not Diagnosed w/ Disease | 1 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | BMN110 2.0 mg/kg/Qow | BMN110 2.0 mg/kg/Week | Total |
|---|---|---|---|---|
| Age, Continuous | 15.0 years STANDARD_DEVIATION 11.3 | 15.3 years STANDARD_DEVIATION 10.79 | 13.1 years STANDARD_DEVIATION 8.1 | 14.5 years STANDARD_DEVIATION 10.16 |
| Age, Customized 12 - 18 years | 15 participants | 16 participants | 16 participants | 47 participants |
| Age, Customized >= 19 years | 14 participants | 12 participants | 10 participants | 36 participants |
| Age, Customized 5 - 11 years | 30 participants | 31 participants | 32 participants | 93 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 13 Participants | 16 Participants | 9 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants | 43 Participants | 49 Participants | 138 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Asian | 11 participants | 15 participants | 14 participants | 40 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity, Customized Other | 4 participants | 7 participants | 6 participants | 17 participants |
| Race/Ethnicity, Customized White | 44 participants | 35 participants | 36 participants | 115 participants |
| Region of Enrollment Argentina | 1 participants | 1 participants | 0 participants | 2 participants |
| Region of Enrollment Brazil | 6 participants | 10 participants | 5 participants | 21 participants |
| Region of Enrollment Canada | 4 participants | 5 participants | 5 participants | 14 participants |
| Region of Enrollment Colombia | 2 participants | 2 participants | 2 participants | 6 participants |
| Region of Enrollment Denmark | 0 participants | 0 participants | 1 participants | 1 participants |
| Region of Enrollment France | 7 participants | 5 participants | 8 participants | 20 participants |
| Region of Enrollment Germany | 4 participants | 5 participants | 1 participants | 10 participants |
| Region of Enrollment Italy | 4 participants | 4 participants | 2 participants | 10 participants |
| Region of Enrollment Japan | 0 participants | 4 participants | 2 participants | 6 participants |
| Region of Enrollment Korea, South | 3 participants | 1 participants | 3 participants | 7 participants |
| Region of Enrollment Netherlands | 1 participants | 2 participants | 3 participants | 6 participants |
| Region of Enrollment Portugal | 2 participants | 1 participants | 0 participants | 3 participants |
| Region of Enrollment Qatar | 1 participants | 0 participants | 1 participants | 2 participants |
| Region of Enrollment Saudi Arabia | 2 participants | 1 participants | 4 participants | 7 participants |
| Region of Enrollment Taiwan | 1 participants | 3 participants | 1 participants | 5 participants |
| Region of Enrollment United Kingdom | 9 participants | 4 participants | 10 participants | 23 participants |
| Region of Enrollment United States | 12 participants | 11 participants | 10 participants | 33 participants |
| Sex: Female, Male Female | 32 Participants | 25 Participants | 32 Participants | 89 Participants |
| Sex: Female, Male Male | 27 Participants | 34 Participants | 26 Participants | 87 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 57 / 59 | 59 / 59 | 56 / 58 |
| serious Total, serious adverse events | 2 / 59 | 4 / 59 | 9 / 58 |
Outcome results
Primary
Change From Baseline in Endurance as Measured by the 6-minute Walk Test
Time frame: Baseline to Week 24
Population: Intention to treat (all patients receiving at least one dose of study drug). Two missing outcomes at Week 24 were imputed using method of multiple imputation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Week 24 | 225.4 meters | Standard Deviation 83.22 |
| Placebo | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Baseline | 211.9 meters | Standard Deviation 69.88 |
| Placebo | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Change from Baseline to Week 24 | 13.5 meters | Standard Deviation 50.63 |
| BMN110 2.0 mg/kg/Qow | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Week 24 | 219.9 meters | Standard Deviation 87.6 |
| BMN110 2.0 mg/kg/Qow | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Baseline | 205.7 meters | Standard Deviation 81.19 |
| BMN110 2.0 mg/kg/Qow | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Change from Baseline to Week 24 | 14.2 meters | Standard Deviation 40.82 |
| BMN110 2.0 mg/kg/Week | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Baseline | 203.9 meters | Standard Deviation 76.32 |
| BMN110 2.0 mg/kg/Week | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Change from Baseline to Week 24 | 36.0 meters | Standard Deviation 58.11 |
| BMN110 2.0 mg/kg/Week | Change From Baseline in Endurance as Measured by the 6-minute Walk Test | Week 24 | 240.0 meters | Standard Deviation 86.61 |
p-value: 0.0174ANCOVA
p-value: 0.9542ANCOVA
Secondary
Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test
Time frame: Baseline to Week 24
Population: Intention to treat (all patients receiving at least one dose of study drug). Two missing outcomes at Week 24 were imputed using method of multiple imputation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Change from Baseline to Week 24 | 3.6 stairs/minute | Standard Deviation 8.51 |
| Placebo | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Week 24 | 33.6 stairs/minute | Standard Deviation 18.36 |
| Placebo | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Baseline | 30.0 stairs/minute | Standard Deviation 14.05 |
| BMN110 2.0 mg/kg/Qow | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Change from Baseline to Week 24 | 3.2 stairs/minute | Standard Deviation 10.29 |
| BMN110 2.0 mg/kg/Qow | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Baseline | 27.1 stairs/minute | Standard Deviation 15.8 |
| BMN110 2.0 mg/kg/Qow | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Week 24 | 30.4 stairs/minute | Standard Deviation 17.77 |
| BMN110 2.0 mg/kg/Week | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Week 24 | 34.3 stairs/minute | Standard Deviation 18.7 |
| BMN110 2.0 mg/kg/Week | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Baseline | 29.6 stairs/minute | Standard Deviation 16.44 |
| BMN110 2.0 mg/kg/Week | Change From Baseline in Endurance as Measured by the 3-minute Stair Climb Test | Change from Baseline to Week 24 | 4.7 stairs/minute | Standard Deviation 7.99 |
p-value: 0.4935ANCOVA
p-value: 0.7783ANCOVA
Secondary
Percent Change From Baseline in Urine Keratan Sulfate Normalized for Urine Creatinine
Time frame: Baseline to Week 24
Population: Intention to treat (all patients receiving at least one dose of study drug). Nine missing outcomes at Week 24 were imputed using method of multiple imputation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Urine Keratan Sulfate Normalized for Urine Creatinine | -3.6 percent change | Standard Deviation 27.41 |
| BMN110 2.0 mg/kg/Qow | Percent Change From Baseline in Urine Keratan Sulfate Normalized for Urine Creatinine | -35.3 percent change | Standard Deviation 20.74 |
| BMN110 2.0 mg/kg/Week | Percent Change From Baseline in Urine Keratan Sulfate Normalized for Urine Creatinine | -43.7 percent change | Standard Deviation 22.29 |
p-value: <0.0001ANCOVA
p-value: <0.0001ANCOVA