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

• UX003 (Drug), also known as recombinant human beta-glucuronidase, rhGUS, Mepsevii ™, vestronidase alfa-vjbk, vestronidase alfa: solution for intravenous infusion

Primary outcomes

• Percent Change From Baseline in uGAG Excretion (LC-MS/MS-DS) at Week 48 [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.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs [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 outcomes

• Change From Baseline Over Time in Standing Height [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.
• Change From Baseline Over Time in Standing Height Z-Score [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.
• Change From Baseline Over Time in Head Circumference [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.
• Change From Baseline Over Time in Head Circumference Z-Score [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.
• Change From Baseline Over Time in Weight [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.
• Post-UX003 Growth Velocity (cm/yr) for Participants With Both Historical Pre-UX003 (Within 2 Years) and Post-UX003 Data [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.
• Change From Pre-Treatment (Within 2 Years) to Post-Treatment Growth Velocity Z-Score [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.
• Change From Baseline Over Time in Liver Measurement [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.
• Change From Baseline Over Time in Spleen Measurement [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.

Sex: All, ages: 1 Day to 5 Years

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.

Participant flow

Outcome results

• Percent Change From Baseline in uGAG Excretion (LC-MS/MS-DS) at Week 48 (Primary), Mean, percent change: UX003 -58.17 +/- 16.915 (p < 0.0001)
• Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, and Discontinuations Due to TEAEs (Primary), Count of participants, Participants: UX003 8
• Change From Baseline Over Time in Standing Height (Secondary), Mean, cm: UX003: eIND ; UX003: Non-eIND 1.94 +/- 1.927
• Change From Baseline Over Time in Standing Height Z-Score (Secondary), Mean, Z-score: UX003: eIND ; UX003: Non-eIND 0.106 +/- 0.4938
• Change From Baseline Over Time in Head Circumference (Secondary), Mean, cm: UX003: eIND ; UX003: Non-eIND 0.36 +/- 0.378
• Change From Baseline Over Time in Head Circumference Z-Score (Secondary), Mean, Z-score: UX003: eIND ; UX003: Non-eIND 0.052 +/- NA
• Change From Baseline Over Time in Weight (Secondary), Mean, kg: UX003: eIND 5.54 +/- NA; UX003: Non-eIND 0.69 +/- 0.626
• Post-UX003 Growth Velocity (cm/yr) for Participants With Both Historical Pre-UX003 (Within 2 Years) and Post-UX003 Data (Secondary), Mean, cm/year: UX003 6.20 +/- 1.954
• Change From Pre-Treatment (Within 2 Years) to Post-Treatment Growth Velocity Z-Score (Secondary), Mean, Z-score: UX003 2.291 +/- 3.3555 (p 0.2655)
• Change From Baseline Over Time in Liver Measurement (Secondary), Mean, cm: UX003: eIND -0.30 +/- NA; UX003: Non-eIND -0.87 +/- 1.873 (p 0.0122)
• Change From Baseline Over Time in Spleen Measurement (Secondary), Mean, cm: UX003: eIND 0.00 +/- NA; UX003: Non-eIND -0.37 +/- 0.624 (p 0.0843)

Adverse events

Time frame: From first dose of study drug until until 30 days after the last dose of study drug (treatment emergent events). Mean (SD) treatment duration was 98.11 (29.02) weeks.

Serious adverse events by term

Other adverse events by term

67 more terms not shown.

• Results publication: Montano AM, Rozdzynska-Swiatkowska A, Jurecka A, Ramirez AN, Zhang L, Marsden D, Wang RY, Harmatz P. Growth patterns in patients with mucopolysaccharidosis VII. Mol Genet Metab Rep. 2023 Jun 26;36:100987. doi: 10.1016/j.ymgmr.2023.100987. eCollection 2023 Sep. PMID 37415957
• Results publication: 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. PMID 35331634
• Results publication: 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. PMID 30467742

• Study Protocol (PDF, 2016-04-07)
• Statistical Analysis Plan (PDF, 2015-12-22)

• Medical Director, Study director, Ultragenyx Pharmaceutical Inc

NIH grants: 2015