An Open-Label Phase 1/2 Study to Assess the Safety, Efficacy and Dose of Study Drug UX003 Recombinant Human Beta-glucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)

Study Overview
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Brief Summary
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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.

Official Title
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An Open-Label Phase 1/2 Study to Assess the Safety, Efficacy and Dose of UX003 rhGUS Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)

Conditions
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Mucopolysaccharidosis Type 7

Intervention / Treatment
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* Drug: UX003


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UX003<br>During the initial 14-week treatment period of the study, participants receive 2 mg/kg UX003 every other week (QOW) for 12 weeks. At Week 14, participants continue on UX003 therapy and begin 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 continue 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 elect to continue drug treatment are transitioned to the long-term extension phase, where they are treated with UX003 at 4 mg/kg beginning at Week 74, for up to an additional 168 weeks. | Drug: UX003<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Week 14, Week 22, Week 30, Week 38, Week 72, and end of study (up to Week 132) | 
| 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. | Baseline, Week 14, Week 22, Week 30, Week 38, Week 72, and end of study (up to Week 132) | 
| 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. | up to Week 132 | 
| 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. | 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. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 36 | 
| 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. | Baseline, Week 36 | 
| 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. | 36 Weeks | 
| 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. | Baseline, Week 36 | 
| 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. | Baseline, Week 36 | 
| 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. | Baseline, Week 36 | 
| 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. | Baseline, Week 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidosis type 7, MPS 7, Sly syndrome, enzyme replacement therapy, rare disease, lysosomal storage disease, metabolic disorder