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

• ClinicalTrials.gov Identifier: NCT02418455
• Recruitment Status: Completed
• First Posted: April 16, 2015
• Results First Posted: October 16, 2019
• Last Update Posted: October 30, 2019
• Sponsor: Ultragenyx Pharmaceutical Inc
• Information provided by (Responsible Party): Ultragenyx Pharmaceutical Inc

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Sly Syndrome; MPS VII; Mucopolysaccharidosis; Mucopolysaccharidosis VII	Drug: UX003	Phase 2

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Study of UX003 rhGUS Enzyme Replacement Therapy in MPS 7 Patients Less Than 5 Years Old
• Actual Study Start Date: July 21, 2015
• Actual Primary Completion Date: March 26, 2019
• Actual Study Completion Date: March 26, 2019

Arms and Interventions

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; Mepsevii ™; vestronidase alfa-vjbk; vestronidase alfa

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in uGAG Excretion (LC-MS/MS-DS) at Week 48 [ Time Frame: Baseline (Week 0), 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.
2. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs [ Time Frame: 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 ]
   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.

Secondary Outcome Measures :

1. Change From Baseline Over Time in Standing Height [ Time Frame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 ]
   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.
2. Change From Baseline Over Time in Standing Height Z-Score [ Time Frame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 ]

   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.

3. Change From Baseline Over Time in Head Circumference [ Time Frame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 ]
   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.
4. Change From Baseline Over Time in Head Circumference Z-Score [ Time Frame: Baseline, Weeks 12, 24, 36, 48 ]

   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.

5. Change From Baseline Over Time in Weight [ Time Frame: Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108, 120, 132 ]
   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.
6. Post-UX003 Growth Velocity (cm/yr) for Participants With Both Historical Pre-UX003 (Within 2 Years) and Post-UX003 Data [ Time Frame: 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) ]
   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.
7. Change From Pre-Treatment (Within 2 Years) to Post-Treatment Growth Velocity Z-Score [ Time Frame: 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) ]

   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.

8. Change From Baseline Over Time in Liver Measurement [ Time Frame: Baseline, Weeks 12, 24, 48, 96, 144 ]
   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.
9. Change From Baseline Over Time in Spleen Measurement [ Time Frame: Baseline, Weeks 12, 24, 48, 96, 144 ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 1 Day to 5 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, District of Columbia

Children's National Health System

Washington, District of Columbia, United States, 20010

United States, New York

New York University Langone Medical Center

New York, New York, United States, 10038

United States, Utah

University of Utah Hospital

Salt Lake City, Utah, United States, 84132

Portugal

Centro Hospitalar do Porto

Porto, Portugal, 4099-345

Spain

Hospital Universitario Virgen Del Rocio

Sevilla, Spain, 41013

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

Investigators

• Study Director: Medical Director; Ultragenyx Pharmaceutical Inc

  Study Documents (Full-Text)

Documents provided by Ultragenyx Pharmaceutical Inc:

Study Protocol  [PDF] April 7, 2016

Statistical Analysis Plan  [PDF] December 22, 2015

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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;:

• Responsible Party: Ultragenyx Pharmaceutical Inc
• ClinicalTrials.gov Identifier: NCT02418455
• Other Study ID Numbers: UX003-CL203; 2015-000104-26 ( EudraCT Number )
• First Posted: April 16, 2015
• Results First Posted: October 16, 2019
• Last Update Posted: October 30, 2019
• Last Verified: October 2019

Keywords provided by Ultragenyx Pharmaceutical Inc:

MPS 7; Sly Syndrome; MPS VII; Enzyme Replacement Therapy; Rare Disease; Mucopolysaccharidosis type 7; Lysosomal Storage Disease; Metabolic Disorder

Additional relevant MeSH terms:

Mucopolysaccharidoses; Mucopolysaccharidosis VII; Syndrome; Disease; Pathologic Processes; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases