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 multicenter, open-label study is designed to assess safety, dose-response using pharmacokinetic (PK) and pharmacodynamic (PD) measures, and clinical efficacy of BMN 110 in subjects between 5 and 18 years of age, diagnosed with Mucopolysaccharidosis IVA (MPS IVA).
Interventions
DRUGBMN 110
Subjects will receive a weekly 4- to 5-hour intravenous infusion of BMN 110 in 3 consecutive 12-week dosing intervals, using the following regimen: * Weeks 1-12: 0.1 mg/kg/week * Weeks 13-24: 1.0 mg/kg/week * Weeks 25-36: 2.0 mg/kg/week Subjects who complete the 36-week Dose-Escalation Period will have the option to continue drug treatment for an additional 36 to 48 weeks. Subjects continuing on treatment after the Dose-Escalation period will receive weekly 4- to 5-hour intravenous infusions of BMN 110 at a dose of 1.0 mg/kg/week.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Documented history of reduced GALNS activity relative to the normal range of the laboratory performing the assay, or documented result of molecular genetic testing confirming diagnosis of MPS IVA. * Willing and able to provide written, signed informed consent, or in the case of subjects under the age of 16 years, 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. * Between 5 and 18 years of age, inclusive. * Sexually active subjects 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. * Willing to perform all study procedures as physically possible.
Exclusion criteria
* Previous hematopoietic stem cell transplant (HSCT). * Has known hypersensitivity to BMN 110 or its excipients. * 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 that would interfere with study participation or safety, including, but not limited to, symptomatic cervical spine instability. * Any condition that, in the view of the Principal Investigator (PI), places the subject at high risk of poor treatment compliance or of not completing the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Subject Incidence of Treatment Emergent AEs | Entire Study, through week 84 | The primary objective of the study was to evaluate the safety of weekly infusions of BMN 110 administered in escalating doses to subjects with MPS IVA. The safety variable incidence of TEAE is summarized. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in 6MWT | Baseline to Weeks 12, 24, 36, 48, 72 | Change from baseline in meters in 6-minute Walk Test. As a measure of endurance, a 6-minute walk test (6MWT) was performed according to the American Thoracic Society Guidelines. Patients were instructed to walk as far as possible in 6 minutes. |
| Change From Baseline in 3MSCT | Baseline to Weeks 12, 24, 36, 48, 72 | Change from baseline in the 3-minute Stair Climb Test. Patients walked up stairs that have a railing, which could be used for support, for 3 minutes, with the number of stairs climbed recorded. The test result was the number of steps climbed per minute. |
| Percent Change From Baseline in uKS | Baseline to Weeks 12, 24, 36, 72 | Percent Change from baseline in Normalized Urine KS. The percent change was calculated (Week X value - baseline value)/baseline value \*100% |
| Percent Change From Baseline in MVV | Baseline to Weeks 12, 24, 36, 72 | Percent Change from baseline in Maximum Voluntary Ventilation. |
| Percent Change From Baseline in FVC | Baseline to Weeks 12, 24, 36, 72 | Percent Change from baseline in Forced Vital Capacity. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BMN 110 Dose-Escalation Period: | 20 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Weeks 1-12: 0.1 mg/kg/Week | Adverse Event | 1 |
| Weeks 1-12: 0.1 mg/kg/Week | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | BMN 110 |
|---|---|
| Age, Continuous | 8.0 years STANDARD_DEVIATION 2.89 |
| Age, Customized >=10 to <=18 years | 4 participants |
| Age, Customized >=4 to <8 years | 10 participants |
| Age, Customized >=8 to <10 years | 6 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 participants |
| Race/Ethnicity, Customized Asian | 9 participants |
| Race/Ethnicity, Customized Black or African American | 0 participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 participants |
| Race/Ethnicity, Customized Other | 2 participants |
| Race/Ethnicity, Customized White | 9 participants |
| Region of Enrollment United Kingdom | 20 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 20 | 18 / 18 | 16 / 18 | 17 / 18 | 20 / 20 |
| serious Total, serious adverse events | 6 / 20 | 2 / 18 | 8 / 18 | 6 / 18 | 14 / 20 |
Outcome results
Primary
Subject Incidence of Treatment Emergent AEs
The primary objective of the study was to evaluate the safety of weekly infusions of BMN 110 administered in escalating doses to subjects with MPS IVA. The safety variable incidence of TEAE is summarized.
Time frame: Entire Study, through week 84
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Drug-Related AE Causing Permanent StudyDrug Discon | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Death | 0 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | AEs Causing Permanent Study Drug Discont. | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AE Causing Study Discont. | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related SAEs | 2 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AEs | 12 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | StudyDrug-Related SAE Causing Permanent DrugDiscon | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any AEs | 18 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Study Drug-Related SAE Causing Study Discont. | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any SAEs | 6 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Permanent Study Drug Discont. | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any AEs During Infusion | 15 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Study Discontinuation | 1 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any SAEs During Infusion | 5 participants |
| BMN 110 | Subject Incidence of Treatment Emergent AEs | Any AEs Causing Study Discontinuation | 1 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Study Discontinuation | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any AEs Causing Study Discontinuation | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Death | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | AEs Causing Permanent Study Drug Discont. | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs | 2 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Permanent Study Drug Discont. | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AE Causing Study Discont. | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Drug-Related AE Causing Permanent StudyDrug Discon | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related SAEs | 1 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs During Infusion | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | StudyDrug-Related SAE Causing Permanent DrugDiscon | 0 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any AEs During Infusion | 13 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AEs | 10 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any AEs | 18 participants |
| 1.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Study Drug-Related SAE Causing Study Discont. | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AE Causing Study Discont. | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AEs | 7 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs | 8 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related SAEs | 2 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any AEs During Infusion | 10 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs During Infusion | 1 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any AEs Causing Study Discontinuation | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any AEs | 17 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | AEs Causing Permanent Study Drug Discont. | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Drug-Related AE Causing Permanent StudyDrug Discon | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Study Discontinuation | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Permanent Study Drug Discont. | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Study Drug-Related SAE Causing Study Discont. | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | StudyDrug-Related SAE Causing Permanent DrugDiscon | 0 participants |
| 2.0 mg/kg/Week | Subject Incidence of Treatment Emergent AEs | Death | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Study Discontinuation | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AEs | 8 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Drug-Related AE Causing Permanent StudyDrug Discon | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Study Drug-Related SAE Causing Study Discont. | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any AEs During Infusion | 15 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related SAEs | 1 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any SAEs | 6 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Death | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AE Causing Study Discont. | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any AEs | 17 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Permanent Study Drug Discont. | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any AEs Causing Study Discontinuation | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | StudyDrug-Related SAE Causing Permanent DrugDiscon | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | AEs Causing Permanent Study Drug Discont. | 0 participants |
| Continuation Period | Subject Incidence of Treatment Emergent AEs | Any SAEs During Infusion | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | AEs Causing Permanent Study Drug Discont. | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | StudyDrug-Related SAE Causing Permanent DrugDiscon | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Drug-Related AE Causing Permanent StudyDrug Discon | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any AEs During Infusion | 17 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any AEs | 20 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Study Discontinuation | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related SAEs | 4 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any SAEs Causing Permanent Study Drug Discont. | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AEs | 14 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Death | 0 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Study Drug-Related SAE Causing Study Discont. | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any SAEs | 14 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any Study Drug-Related AE Causing Study Discont. | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any AEs Causing Study Discontinuation | 1 participants |
| Entire Study | Subject Incidence of Treatment Emergent AEs | Any SAEs During Infusion | 6 participants |
Secondary
Change From Baseline in 3MSCT
Change from baseline in the 3-minute Stair Climb Test. Patients walked up stairs that have a railing, which could be used for support, for 3 minutes, with the number of stairs climbed recorded. The test result was the number of steps climbed per minute.
Time frame: Baseline to Weeks 12, 24, 36, 48, 72
Population: Intent-to-Treat population (all subjects who enrolled in the study). One patient was developmentally unable to perform the 3MSCT and the test scores were set to missing. The analysis was based on observed cases.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 110 | Change From Baseline in 3MSCT | Week 12 Change from Baseline (n=19) | 0.3 steps/min | Standard Deviation 14.07 |
| BMN 110 | Change From Baseline in 3MSCT | Week 24 Change from Baseline (n=17) | 6.1 steps/min | Standard Deviation 8.66 |
| BMN 110 | Change From Baseline in 3MSCT | Week 36 Change from Baseline (n=17) | 7.8 steps/min | Standard Deviation 13.69 |
| BMN 110 | Change From Baseline in 3MSCT | Week 48 Change from Baseline (n=17) | 9.7 steps/min | Standard Deviation 14.42 |
| BMN 110 | Change From Baseline in 3MSCT | Week 72 Change from Baseline (n=17) | 9.7 steps/min | Standard Deviation 13.91 |
Secondary
Change From Baseline in 6MWT
Change from baseline in meters in 6-minute Walk Test. As a measure of endurance, a 6-minute walk test (6MWT) was performed according to the American Thoracic Society Guidelines. Patients were instructed to walk as far as possible in 6 minutes.
Time frame: Baseline to Weeks 12, 24, 36, 48, 72
Population: Intent-to-Treat population (all subjects who enrolled in the study). Two patients were either physically (score was designated as 0 m) or developmentally (score was set to missing) unable to perform the 6MWT. The analysis was based on observed cases.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 110 | Change From Baseline in 6MWT | Week 12 Change from Baseline (n=19) | -20.7 meters | Standard Deviation 85.95 |
| BMN 110 | Change From Baseline in 6MWT | Week 24 Change from Baseline (n=17) | 16.3 meters | Standard Deviation 71.74 |
| BMN 110 | Change From Baseline in 6MWT | Week 36 Change from Baseline (n=17) | 13.8 meters | Standard Deviation 63.25 |
| BMN 110 | Change From Baseline in 6MWT | Week 48 Change from Baseline (n=17) | -4.8 meters | Standard Deviation 64.7 |
| BMN 110 | Change From Baseline in 6MWT | Week 72 Change from Baseline (n=17) | 4.0 meters | Standard Deviation 87.24 |
Secondary
Percent Change From Baseline in FVC
Percent Change from baseline in Forced Vital Capacity.
Time frame: Baseline to Weeks 12, 24, 36, 72
Population: Intent-to-Treat population (all subjects who enrolled in the study). The analysis was based on observed cases.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 110 | Percent Change From Baseline in FVC | Week 12 Percent Change from Baseline (n=18) | 3.4 percentage of FVC | Standard Deviation 10.85 |
| BMN 110 | Percent Change From Baseline in FVC | Week 24 Percent Change from Baseline (n=16) | 0.2 percentage of FVC | Standard Deviation 16.6 |
| BMN 110 | Percent Change From Baseline in FVC | Week 36 Percent Change from Baseline (n=16) | 10.7 percentage of FVC | Standard Deviation 20.82 |
| BMN 110 | Percent Change From Baseline in FVC | Week 72 Percent Change from Baseline (n=16) | 12.5 percentage of FVC | Standard Deviation 14.88 |
Secondary
Percent Change From Baseline in MVV
Percent Change from baseline in Maximum Voluntary Ventilation.
Time frame: Baseline to Weeks 12, 24, 36, 72
Population: Intent-to-Treat population (all subjects who enrolled in the study). The analysis was based on observed cases.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 110 | Percent Change From Baseline in MVV | Week 12 Percent Change from Baseline (n=14) | 9.9 percentage of MVV | Standard Deviation 21.29 |
| BMN 110 | Percent Change From Baseline in MVV | Week 24 Percent Change from Baseline (n=13) | 11.0 percentage of MVV | Standard Deviation 21.48 |
| BMN 110 | Percent Change From Baseline in MVV | Week 36 Percent Change from Baseline (n=14) | 10.5 percentage of MVV | Standard Deviation 17.43 |
| BMN 110 | Percent Change From Baseline in MVV | Week 72 Percent Change from Baseline (n=14) | 18.4 percentage of MVV | Standard Deviation 20.77 |
Secondary
Percent Change From Baseline in uKS
Percent Change from baseline in Normalized Urine KS. The percent change was calculated (Week X value - baseline value)/baseline value \*100%
Time frame: Baseline to Weeks 12, 24, 36, 72
Population: Intent-to-Treat population (all subjects who enrolled in the study). The analysis was based on observed cases.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 110 | Percent Change From Baseline in uKS | Week 12 Percent Change from Baseline (n=19) | -23.2 percentage of uKS | Standard Deviation 19.04 |
| BMN 110 | Percent Change From Baseline in uKS | Week 24 Percent Change from Baseline (n=18) | -27.9 percentage of uKS | Standard Deviation 17.92 |
| BMN 110 | Percent Change From Baseline in uKS | Week 36 Percent Change from Baseline (n=18) | -40.6 percentage of uKS | Standard Deviation 20.16 |
| BMN 110 | Percent Change From Baseline in uKS | Week 72 Percent Change from Baseline (n=17) | -32.2 percentage of uKS | Standard Deviation 17.1 |