Study of UX003 Recombinant Human Beta-Glucuronidase (rhGUS) Enzyme Replacement Treatment in Mucopolysaccharidosis Type 7, Sly Syndrome (MPS 7) Patients Less Than 5 Years of Age

An Open-label Study of UX003 rhGUS Enzyme Replacement Therapy in MPS 7 Patients Less Than 5 Years Old

The primary objective was to evaluate the effect of UX003 treatment in pediatric MPS VII participants less than 5 years of age on safety, tolerability, and efficacy as determined by the reduction of urinary glycosaminoglycans (uGAG) excretion.

Study Overview

• Status: Completed
• Conditions: Mucopolysaccharidosis; Sly Syndrome; Mucopolysaccharidosis VII; MPS VII
• Intervention / Treatment: Drug: UX003

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 2

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• Portugal
  • Porto, Portugal, 4099-345
    • Centro Hospitalar do Porto
• Spain
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • New York
    • New York, New York, United States, 10038
      • New York University Langone Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 5 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay, or genetic testing.
2. Under 5 years of age at the time of informed consent.
3. Written informed consent of Legally Authorized Representative after the nature of the study has been explained, and prior to any research-related procedures.

Exclusion Criteria:

1. Undergone a successful bone marrow or stem cell transplant or has evidence of any degree of detectable chimaerism with donor cells.
2. Any known hypersensitivity to rhGUS or its excipients that, in the judgment of the Investigator, places the subject at increased risk for adverse effects.
3. Use of any investigational product (drug or device or combination) other than UX003 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.
4. Has a condition of such severity and acuity, in the opinion of the Investigator, which may not allow safe study participation. For patients with hydrops fetalis, the ongoing interventions to manage fluid balance can be continued; if the addition of enzyme replacement therapy (ERT) is considered a fluid-overload risk, the individual should be excluded.
5. 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. Since hydropic patients have a high rate of mortality, the risk of death prior to 1 year of age should not be considered sufficient to exclude the patient from the study for compliance.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UX003; UX003 4 mg/kg every other week (QOW). Initial treatment period 48 weeks. Continuation period up to 240 weeks.	Drug: UX003; solution for intravenous infusion; Other Names: recombinant human beta-glucuronidase; rhGUS; vestronidase alfa; Mepsevii ™; vestronidase alfa-vjbk

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in uGAG Excretion (LC-MS/MS-DS) at Week 48	Liquid chromatography-mass spectrometry/mass spectrometry-dermatan sulfate (LS-MS/MS-DS) method. For the participant previously treated with UX003 under an eIND, percent change from initial baseline was used.	Baseline (Week 0), Week 48
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs	Adverse event (AE): any untoward medical occurrence in a participant, whether or not considered drug related. Serious AE (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.	From first dose of study drug until 30 days after the last dose of study drug. Mean (SD) treatment duration was 98.11 (29.02) weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline Over Time in Standing Height	For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132
Change From Baseline Over Time in Standing Height Z-Score	The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132
Change From Baseline Over Time in Head Circumference	For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132
Change From Baseline Over Time in Head Circumference Z-Score	The Z-score indicates the number of standard deviations away from a reference population (from the CDC growth charts) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 36, 48
Change From Baseline Over Time in Weight	For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132
Post-UX003 Growth Velocity (cm/yr) for Participants With Both Historical Pre-UX003 (Within 2 Years) and Post-UX003 Data	The growth velocity for pre-treatment is based on standing height within 2 years prior to treatment. The growth velocity for post-treatment is based on all standing height data during the study period. For the participant previously treated with UX003 under an eIND, the growth velocity was calculated for pre initial UX003 treatment and post initial UX003 treatment.	Pre-treatment (based on standing height within 2 years prior to treatment), Post-treatment (based on all standing height data during the study period up to 240 weeks)
Change From Pre-Treatment (Within 2 Years) to Post-Treatment Growth Velocity Z-Score	The Z-score indicates the number of standard deviations away from a reference population (based on Tanner's standard [Tanner et al. 1985]) in the same age range and with the same sex. A Z-score of 0 is equal to the mean with negative numbers indicating values lower than the mean and positive values higher. Higher Z-scores indicate a better outcome. The growth velocity for pre-treatment is based on standing height within 2 years prior to treatment. The growth velocity for post-treatment is based on all standing height data during the study period. For the participant previously treated with UX003 under an eIND, the growth velocity was calculated for pre initial UX003 treatment and post initial UX003 treatment.	Pre-treatment (based on standing height within 2 years prior to treatment), Post-treatment (based on all standing height data during the study period up to Week 48)
Change From Baseline Over Time in Liver Measurement	For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 48, 96, 144
Change From Baseline Over Time in Spleen Measurement	For all participants (including the participant previously treated with UX003 under an eIND), the last non-missing study assessment prior to the first dose in this study was used as baseline.	Baseline, Weeks 12, 24, 48, 96, 144

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc

Publications and helpful links

General Publications

• Qi Y, McKeever K, Taylor J, Haller C, Song W, Jones SA, Shi J. Pharmacokinetic and Pharmacodynamic Modeling to Optimize the Dose of Vestronidase Alfa, an Enzyme Replacement Therapy for Treatment of Patients with Mucopolysaccharidosis Type VII: Results from Three Trials. Clin Pharmacokinet. 2019 May;58(5):673-683. doi: 10.1007/s40262-018-0721-y. Erratum In: Clin Pharmacokinet. 2018 Dec 4;:
• Lau HA, Viskochil D, Tanpaiboon P, Lopez AG, Martins E, Taylor J, Malkus B, Zhang L, Jurecka A, Marsden D. Long-term efficacy and safety of vestronidase alfa enzyme replacement therapy in pediatric subjects < 5 years with mucopolysaccharidosis VII. Mol Genet Metab. 2022 May;136(1):28-37. doi: 10.1016/j.ymgme.2022.03.002. Epub 2022 Mar 9.

Study record dates

Study Major Dates

• Study Start (Actual): July 21, 2015
• Primary Completion (Actual): March 26, 2019
• Study Completion (Actual): March 26, 2019

Study Registration Dates

• First Submitted: April 12, 2015
• First Submitted That Met QC Criteria: April 15, 2015
• First Posted (Estimate): April 16, 2015

Study Record Updates

• Last Update Posted (Actual): October 30, 2019
• Last Update Submitted That Met QC Criteria: October 15, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: Enzyme Replacement Therapy; Lysosomal Storage Disease; Rare Disease; MPS 7; Sly Syndrome; MPS VII; Metabolic Disorder; Mucopolysaccharidosis type 7
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Genetic Diseases, Inborn; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Syndrome; Mucopolysaccharidoses; Mucopolysaccharidosis VII
• Other Study ID Numbers: UX003-CL203; 2015-000104-26 (EudraCT Number)