MPS VII, Mucopolysaccharidosis, Mucopolysaccharidosis VII, Sly Syndrome
Conditions
Keywords
MPS 7, Sly Syndrome, MPS VII, Enzyme Replacement Therapy, Rare Disease, Mucopolysaccharidosis Type 7, Lysosomal Storage Disease, Metabolic Disorder
Brief summary
The primary objective of the study is to evaluate the long-term safety of UX003 in subjects with MPS 7.
Detailed description
Participants with MPS 7 who were UX003 treatment-naïve or previously enrolled and treated in a prior clinical study of UX003 (e.g. UX003-CL301 \[NCT02230566\], investigator sponsored trials, expanded access/compassionate use) can enroll into this treatment and extension study provided all eligibility criteria is met for a given participant.
Interventions
DRUGUX003
solution for intravenous (IV) infusion
Sponsors
Ultragenyx Pharmaceutical Inc
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
5 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay or genetic testing. * Willing and able to provide written, signed informed consent or, in the case of subjects 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. * Willing and able to comply with all study procedures. * Sexually active subjects must be willing to use acceptable, highly-effective methods of contraception while participating in the study and for 30 days following the last dose. * Females of childbearing potential must have a negative pregnancy test at Baseline and be willing to have additional pregnancy tests during the study. Females considered not of childbearing potential include those who have not experienced menarche, or have had tubal ligation at least one year prior to completion of the primary study, or have had total hysterectomy. * For UX003 treatment-naïve subjects only, apparent clinical signs of lysosomal storage disease as judged by the Investigator, including at least one of the following: enlarged liver and spleen, joint limitations, airway obstruction or pulmonary problems, limitation of mobility while still ambulatory. * For UX003 treatment-naïve subjects only, elevated urinary glycosaminoglycans (uGAG) excretion at a minimum of 2-fold over normal. * For UX003 treatment-naïve subjects only, aged 5 years and older.
Exclusion criteria
* If enrolled in a prior UX003 clinical study, the subject experienced safety-related event(s) in the prior UX003 clinical study that, in the opinion of the Investigator and sponsor, precludes resuming UX003 treatment. * Undergone a successful bone marrow or stem cell transplant or has any degree of detectable chimaerism with donor cells. * Presence or history of any hypersensitivity to rhGUS or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects. * Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at any time during the study. * Other than the use of UX003, use of any investigational product (drug or device or combination) within 30 days prior to Baseline, or requirement for any investigational agent prior to completion of all scheduled study assessments. * Presence of a condition of such severity and acuity that, in the opinion of the Investigator, warrants immediate surgical intervention or other treatment or may not allow safe study participation. * Concurrent disease or condition, or laboratory abnormality that, in the view of the Investigator, places the subject at high risk of poor treatment compliance or of not completing the study, or would interfere with study participation or introduce additional safety concerns.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | From first dose of study drug until 30 days after the last dose of study drug. Mean duration of UX003 treatment was 100.5 weeks. | An adverse event (AE) is defined as any untoward medical occurrence, whether or not considered drug related. A serious AE is an AE that at any dose, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; or is an important medical event. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death). TEAEs were defined as reported AEs with onset during the treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Baseline (prior to the first dose of study drug in UX003-CL301), Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144 | First morning void urine was evaluated for uGAG concentration and normalized to urinary creatinine concentration. |
Countries
Brazil, Mexico, Portugal, United States
Participant flow
Recruitment details
Participants with mucopolysaccharidosis VII (MPS 7) who were UX003 treatment-naïve or previously enrolled and treated in a prior clinical study of UX003 could enroll into this treatment and extension study provided all eligibility criteria had been met for a given participant.
Pre-assignment details
Ten of 12 participants entered this extension study at study Week 0 with ongoing UX003 treatment for the prior 24 or 48 weeks in study UX003-CL301 \[NCT02230566\]; 2 participants had a large gap between studies (61 weeks between doses).
Participants by arm
| Arm | Count |
|---|---|
| UX003 4 mg/kg UX003 QOW | 12 |
| Total | 12 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Participant Non-Compliance | 1 |
Baseline characteristics
| Characteristic | UX003 |
|---|---|
| Age, Continuous | 16.56 years STANDARD_DEVIATION 5.466 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Other, Not Specified | 3 Participants |
| Race/Ethnicity, Customized White | 9 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 4 Participants |
| Urinary Glycosaminoglycans (uGAG) | 1.54848 g GAG/g creatinine STANDARD_DEVIATION 0.413237 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 12 / 12 |
| serious Total, serious adverse events | 4 / 12 |
Outcome results
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation
An adverse event (AE) is defined as any untoward medical occurrence, whether or not considered drug related. A serious AE is an AE that at any dose, results in any of the following outcomes: death; a life-threatening AE; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions; a congenital anomaly/birth defect; or is an important medical event. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0: Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), Grade 5 (death). TEAEs were defined as reported AEs with onset during the treatment.
Time frame: From first dose of study drug until 30 days after the last dose of study drug. Mean duration of UX003 treatment was 100.5 weeks.
Population: Full Analysis Set: all enrolled participants who received at least one dose of investigational product in this study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs Leading to Study Discontinuation | 0 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs Leading to Death | 0 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs | 12 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Serious TEAEs | 4 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Treatment-Related TEAEs | 9 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Treatment-Related Serious TEAEs | 1 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | Grade 3 or 4 TEAEs | 3 Participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and TEAEs Leading to Discontinuation | TEAEs Leading to Treatment Discontinuation | 0 Participants |
Secondary
Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate)
First morning void urine was evaluated for uGAG concentration and normalized to urinary creatinine concentration.
Time frame: Baseline (prior to the first dose of study drug in UX003-CL301), Weeks 0, 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132, 144
Population: Full Analysis Set: all enrolled participants who received at least one dose of investigational product in this study; participants with an assessment at given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 0 | -62.19 percentage change in uGAG excretion | Standard Deviation 16.133 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 12 | -67.31 percentage change in uGAG excretion | Standard Deviation 13.953 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 24 | -64.03 percentage change in uGAG excretion | Standard Deviation 14.669 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 36 | -60.58 percentage change in uGAG excretion | Standard Deviation 23.552 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 48 | -57.04 percentage change in uGAG excretion | Standard Deviation 23.611 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 60 | -72.25 percentage change in uGAG excretion | Standard Deviation 18.609 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 72 | -78.52 percentage change in uGAG excretion | Standard Deviation 10.367 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 84 | -80.89 percentage change in uGAG excretion | Standard Deviation 10.023 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 96 | -82.39 percentage change in uGAG excretion | Standard Deviation 6.011 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 108 | -82.19 percentage change in uGAG excretion | Standard Deviation 6.551 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 120 | -88.74 percentage change in uGAG excretion | Standard Deviation 4.023 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 132 | -89.22 percentage change in uGAG excretion | Standard Deviation 3.662 |
| UX003 | Percent Change From Baseline Over Time in Urinary Glycosaminoglycan (uGAG) Excretion (Liquid Chromatography-Tandem Mass Spectrometry, Dermatan Sulfate) | Week 144 | -91.62 percentage change in uGAG excretion | Standard Deviation 1.827 |
Comparison: Week 0p-value: <0.000195% CI: [-71.98, -52.59]GEE model
Comparison: Week 12p-value: <0.000195% CI: [-73.49, -60.86]GEE model
Comparison: Week 24p-value: <0.000195% CI: [-71.99, -56.24]GEE model
Comparison: Week 36p-value: <0.000195% CI: [-72.54, -49.06]GEE model
Comparison: Week 48p-value: <0.000195% CI: [-71.87, -43.82]GEE model