Mucopolysaccharidosis Type 7
Conditions
Keywords
Mucopolysaccharidosis type 7, MPS 7, Sly syndrome, enzyme replacement therapy, rare disease, lysosomal storage disease, metabolic disorder
Brief summary
UX003-CL201 is an open-label Phase 1/2 study to assess the safety, efficacy, and dose of UX003 in MPS 7 patients via intravenous (IV) administration every other week (QOW) for 36 weeks with up to an additional 36 weeks from the optional continuation period. Up to 5 participants, who are between 5 and 30 years of age inclusive, will be enrolled and treated with UX003. The initial 12-week treatment period will be followed by a 24-week forced dose titration period to assess the optimal dose. Participants who complete both the initial treatment and forced dose titration periods will continue treatment in a 36- week continuation period.
Interventions
DRUGUX003
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 30 Years
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay or genetic testing confirming diagnosis. * Elevated urinary glycosaminoglycan (uGAG) excretion at a minimum of 2-fold over normal. * Between 5 and 30 years of age, inclusive (approximately 2 subjects between the ages of 20-30 years). * 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. * 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. Females considered not of childbearing potential include those who have had tubal ligation at least one year prior to Screening, or who have had total hysterectomy.
Exclusion criteria
* Has undergone a successful bone marrow or stem cell transplant or has any degree of detectable chimaerism with donor cells. * Any known 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 Screening or planning to become pregnant (self or partner) at any time during the study. * Use of any investigational product (drug or device or combination) within 30 days prior to Screening, or requirement for any investigational agent prior to completion of all scheduled study assessments at any time during the study. * Has a condition of such severity and acuity, in the opinion of the Investigator, that it warrants immediate surgical intervention or other treatment or may not allow safe study participation. * Has a concurrent disease or condition 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 affect safety.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Baseline, Week 14, Week 22, Week 30, Week 38, Week 72, and end of study (up to Week 132) | Percentage change from baseline in the concentration of uGAGs normalized to the urinary creatinine concentration as measured by liquid chromatography-mass spectrometry/mass spectrometry-dermatan sulfate. |
| Percentage Change From Baseline in uGAG Chondroitin Sulfate | Baseline, Week 14, Week 22, Week 30, Week 38, Week 72, and end of study (up to Week 132) | Percentage change from baseline in the concentration of uGAGs normalized to the urinary creatinine concentration as measured by liquid chromatography-mass spectrometry/mass spectrometry-chondroitin sulfate. |
| Number of Participants With Any ≥ 50% Decrease in uGAG | up to Week 132 | Participants with a ≥ 50% decrease in the concentration of uGAGs normalized to the urinary creatinine concentration as measured by liquid chromatography-mass spectrometry/mass spectrometry-dermatan sulfate or chondroitin sulfate. |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | Up to 242 weeks + 30 days. SAEs were recorded beginning at the time the subject signed the informed consent form through 30 days following the last study visit. Non-serious AEs were recorded from the time of informed consent through the last study visit. | Adverse Event (AE): any untoward medical occurrence in a subject, whether or not considered drug related. SAE: an AE or suspected adverse reaction 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. Other important medical events may also, in the opinion of the Investigator, be considered SAEs. An AE was considered a TEAE if it occurred on or after the first dose, and was not present prior to the first dose, or it was present at the first dose but increased in severity during the study. Events recorded as either possibly, probably, or definitely related to treatment were categorized as related. AE severity was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.03. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at Week 36 in Pulmonary Function Testing (Spirometry) | Baseline, Week 36 | The following spirometry tests were administered to participants who did not require invasive ventilatory support or have a tracheostomy in accordance with American Thoracic Society/European Respiratory society (ATS/ERS) guidelines: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum voluntary ventilation in one minute (MVV1). Invasive ventilation is defined as any form of ventilatory support applied with the use of an endotracheal tube. |
| Acceptable Dose as Determined by Total uGAG Excretion Using a Forced Dose Titration Regimen | Week 36 | The choice of the dose of UX003 QOW for the Long-Term Extension Phase was based on a preliminary efficacy analysis at Week 36 prior to all 3 participants completing the Forced-dose Titration Period of the First Phase of the study. |
| Change From Baseline at Week 36 in Shoulder Range of Motion (Goniometry) | Baseline, Week 36 | The maximum passive shoulder range of motion in both flexion and extension will be measured in degrees using a goniometer. |
| Change From Baseline at Week 36 in Growth Velocity for Height and Weight | Baseline, Week 36 | Growth velocity (for males ≤18 years and females ≤15) was calculated from anthropometric measurements and compared with pretreatment growth velocity when available. Z-scores and percentiles were calculated using Centers for Disease Control (CDC) growth chart. |
| Change From Baseline at Week 36 in Six-Minute Walk Test (6MWT) | Baseline, Week 36 | The total distance walked (meters) in a 6-minute period was measured once each test day. The test was conducted using a pre-measured walking course according to administration guidelines established by the American Thoracic Society (ATS 2002). Participants who could not walk could omit this test. |
| Percent of Predicted Normal Distance Walked | 36 Weeks | The percent of predicted normal distance walked (based on published normative data) in the total distance walked in a six-minute period. |
| Change From Baseline at Week 36 in the 3-Minute Stair Climb Test (3MSCT) | Baseline, Week 36 | The number of stairs climbed within a 3-minute period was assessed once each test day using available hospital stairs. Participants who could not climb stairs could omit this test. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| UX003 During the initial 14-week treatment period of the study, participants received 2 mg/kg UX003 QOW for 12 weeks. At Week 14, participants continued on UX003 therapy and began a forced dose titration period for an additional 24 weeks at the dose sequence of 1, 4, and 2 mg/kg UX003 QOW as follows: 1 mg/kg UX003 for 8 weeks beginning on Week 14; then 4 mg/kg UX003 for 8 weeks beginning on Week 22; then 2 mg/kg UX003 for 8 weeks beginning on Week 30. Following the 24 week forced dose titration period, participants who continued on treatment (continuation period) received 2 mg/kg UX003 QOW beginning at Week 38 for up to an additional 36 weeks.
After the first phase of the study, participants who elected to continue drug treatment were transitioned to the long-term extension phase, where they were treated with UX003 at 4 mg/kg beginning at Week 74, for up to an additional 168 weeks. | 3 |
| Total | 3 |
Baseline characteristics
| Characteristic | UX003 |
|---|---|
| Age, Customized Adults (18-64 years) | 1 Participants |
| Age, Customized Children (2-11 years) | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
Number of Participants With Any ≥ 50% Decrease in uGAG
Participants with a ≥ 50% decrease in the concentration of uGAGs normalized to the urinary creatinine concentration as measured by liquid chromatography-mass spectrometry/mass spectrometry-dermatan sulfate or chondroitin sulfate.
Time frame: up to Week 132
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| UX003 | Number of Participants With Any ≥ 50% Decrease in uGAG | 3 Participants |
Primary
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations
Adverse Event (AE): any untoward medical occurrence in a subject, whether or not considered drug related. SAE: an AE or suspected adverse reaction 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. Other important medical events may also, in the opinion of the Investigator, be considered SAEs. An AE was considered a TEAE if it occurred on or after the first dose, and was not present prior to the first dose, or it was present at the first dose but increased in severity during the study. Events recorded as either possibly, probably, or definitely related to treatment were categorized as related. AE severity was graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events, Version 4.03.
Time frame: Up to 242 weeks + 30 days. SAEs were recorded beginning at the time the subject signed the informed consent form through 30 days following the last study visit. Non-serious AEs were recorded from the time of informed consent through the last study visit.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | SAE | 2 participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | Grade 3 or 4 TEAE | 2 participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | TEAE leading to treatment discontinuation | 1 participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | Any TEAE | 3 participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | Treatment-related TEAE | 2 participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | TEAE leading to study discontinuation | 0 participants |
| UX003 | Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Study/Treatment Discontinuations | Fatal TEAE | 0 participants |
Primary
Percentage Change From Baseline in uGAG Chondroitin Sulfate
Percentage change from baseline in the concentration of uGAGs normalized to the urinary creatinine concentration as measured by liquid chromatography-mass spectrometry/mass spectrometry-chondroitin sulfate.
Time frame: Baseline, Week 14, Week 22, Week 30, Week 38, Week 72, and end of study (up to Week 132)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| UX003 | Percentage Change From Baseline in uGAG Chondroitin Sulfate | Forced dose titration-Week 22 | -47.58 percentage change | Standard Deviation 3.958 |
| UX003 | Percentage Change From Baseline in uGAG Chondroitin Sulfate | Forced dose titration-Week 30 | -60.78 percentage change | Standard Deviation 7.207 |
| UX003 | Percentage Change From Baseline in uGAG Chondroitin Sulfate | Forced dose titration-Week 38 | -52.08 percentage change | Standard Deviation 13.298 |
| UX003 | Percentage Change From Baseline in uGAG Chondroitin Sulfate | Initial treatment-Week 14 | -52.5 percentage change | Standard Deviation 13.726 |
| UX003 | Percentage Change From Baseline in uGAG Chondroitin Sulfate | Continuation-Week 72 | -56.96 percentage change | Standard Deviation 13.379 |
| UX003 | Percentage Change From Baseline in uGAG Chondroitin Sulfate | Long term extension-end of study | -30.83 percentage change | Standard Deviation 40.794 |
Primary
Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate
Percentage change from baseline in the concentration of uGAGs normalized to the urinary creatinine concentration as measured by liquid chromatography-mass spectrometry/mass spectrometry-dermatan sulfate.
Time frame: Baseline, Week 14, Week 22, Week 30, Week 38, Week 72, and end of study (up to Week 132)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| UX003 | Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Initial treatment-Week 14 | -50.41 percentage change | Standard Deviation 7.895 |
| UX003 | Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Forced dose titration-Week 22 | -38.94 percentage change | Standard Deviation 7.137 |
| UX003 | Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Forced dose titration-Week 30 | -63.49 percentage change | Standard Deviation 6.889 |
| UX003 | Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Forced dose titration-Week 38 | -51.82 percentage change | Standard Deviation 9.033 |
| UX003 | Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Continuation-Week 72 | -54.2 percentage change | Standard Deviation 8.442 |
| UX003 | Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate | Long term extension-end of study | -34.44 percentage change | Standard Deviation 48.56 |
Secondary
Acceptable Dose as Determined by Total uGAG Excretion Using a Forced Dose Titration Regimen
The choice of the dose of UX003 QOW for the Long-Term Extension Phase was based on a preliminary efficacy analysis at Week 36 prior to all 3 participants completing the Forced-dose Titration Period of the First Phase of the study.
Time frame: Week 36
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| UX003 | Acceptable Dose as Determined by Total uGAG Excretion Using a Forced Dose Titration Regimen | 4 mg/kg |
Secondary
Change From Baseline at Week 36 in Growth Velocity for Height and Weight
Growth velocity (for males ≤18 years and females ≤15) was calculated from anthropometric measurements and compared with pretreatment growth velocity when available. Z-scores and percentiles were calculated using Centers for Disease Control (CDC) growth chart.
Time frame: Baseline, Week 36
Population: Summary analyses for all 3 participants combined are not available. Due to the very small number of participants, formal statistical analyses were not performed; and data were presented per participant, which has the potential for participant re-identification given the rarity of disease and the very small population size.
Secondary
Change From Baseline at Week 36 in Pulmonary Function Testing (Spirometry)
The following spirometry tests were administered to participants who did not require invasive ventilatory support or have a tracheostomy in accordance with American Thoracic Society/European Respiratory society (ATS/ERS) guidelines: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), maximum voluntary ventilation in one minute (MVV1). Invasive ventilation is defined as any form of ventilatory support applied with the use of an endotracheal tube.
Time frame: Baseline, Week 36
Population: Summary analyses for all 3 participants are not available due to the very small number of participants; and while data were collected for 1 participant, they are not being reported due to confidentiality issues.
Secondary
Change From Baseline at Week 36 in Shoulder Range of Motion (Goniometry)
The maximum passive shoulder range of motion in both flexion and extension will be measured in degrees using a goniometer.
Time frame: Baseline, Week 36
Population: Summary analyses for all 3 participants are not available due to the very small number of participants; and while data were collected for 1 participant, they are not being reported due to confidentiality issues.
Secondary
Change From Baseline at Week 36 in Six-Minute Walk Test (6MWT)
The total distance walked (meters) in a 6-minute period was measured once each test day. The test was conducted using a pre-measured walking course according to administration guidelines established by the American Thoracic Society (ATS 2002). Participants who could not walk could omit this test.
Time frame: Baseline, Week 36
Population: Summary analyses for all 3 participants are not available due to the very small number of participants; and while data were collected for 1 participant, they are not being reported due to confidentiality issues.
Secondary
Change From Baseline at Week 36 in the 3-Minute Stair Climb Test (3MSCT)
The number of stairs climbed within a 3-minute period was assessed once each test day using available hospital stairs. Participants who could not climb stairs could omit this test.
Time frame: Baseline, Week 36
Population: Summary analyses for all 3 participants are not available due to the very small number of participants; and while data were collected for 1 participant, they are not being reported due to confidentiality issues.
Secondary
Percent of Predicted Normal Distance Walked
The percent of predicted normal distance walked (based on published normative data) in the total distance walked in a six-minute period.
Time frame: 36 Weeks
Population: Summary analyses for all 3 participants are not available due to the very small number of participants; and while data were collected for 1 participant, they are not being reported due to confidentiality issues.