A Phase 3 Study of UX003 Recombinant Human Betaglucuronidase (rhGUS) Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis Type 7 (MPS 7)

NCT02230566 | Completed Phase 3 Results DMC

• 1 other identifier: UX003-CL301
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 4

Brief Summary

The Phase 3 study will use a novel randomized, intra-subject placebo-controlled, single crossover design, referred to as Blind Start, to evaluate the safety and efficacy of UX003. The Blind Start is a novel design whereby participants will be randomized to 1 of 4 groups, each representing a different treatment sequence, and will cross over to UX003 at different pre-defined time points in a blinded manner. All groups will receive a minimum of 24 weeks treatment with 4 mg/kg UX003 every other week (QOW).

Conditions

MPS 7; Sly Syndrome; Mucopolysaccharidosis; MPS VII

Keywords

MPS 7; Sly Syndrome; Mucopolysaccharidosis; MPS VII; Enzyme Replacement Therapy; Mucopolysaccharidosis type 7; rare disease; lysosomal storage disease; metabolic disorder

Outcome Measures

Primary Outcomes (1)

• European Union (EU) and Rest of World: Percentage Change From Baseline in Urinary Glycosaminoglycan (uGAG) Dermatan Sulfate (DS) at UX003 Treatment Week 24

  Baseline was defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect was subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Percent change from baseline in uGAG DS was analyzed by generalized estimating equation (GEE) modeling based on observed data. The GEE model included included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable. In the United States (US), this was considered a secondary outcome measure. Per guidance from the Food and Drug Administration (FDA), no primary efficacy variable was declared in the US. Efficacy was to be based on the totality of the clinical data on a per participant basis.

  Baseline (defined as the average of all assessments prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment

Secondary Outcomes (10)

• Multi-Domain Responder Index (MDRI) Score at UX003 Treatment Week 24

  Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment

• Change From Baseline in 6-Minute Walk Test (6MWT) at UX003 Treatment Week 24

  Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment

• Change From Baseline in Pulmonary Function Testing: Percentage of Predicted Forced Vital Capacity (FVC%Pred) at UX003 Treatment Week 24

  Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment

• Change From Baseline in Pulmonary Function Testing: Maximum Ventilatory Ventilation (MVV) at UX003 Treatment Week 24

  Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment

• Change From Baseline in Shoulder Flexion and Extension Maximum Range of Motion at UX003 Treatment Week 24

  Baseline (defined as the last assessment prior to or on the date of cross-over to active treatment with UX003) to 24 weeks of UX003 study drug treatment

Study Arms (4)

Group A: 4 mg/kg UX003

EXPERIMENTAL

4 mg/kg UX003 QOW through Week 46

Drug: UX003

Group B: 8 Weeks Placebo then 4 mg/kg UX003

EXPERIMENTAL

Placebo QOW for the first 8 weeks followed by 4 mg/kg UX003 QOW through Week 46

Drug: UX003; Other: Placebo

Group C: 16 Weeks Placebo then 4 mg/kg UX003

EXPERIMENTAL

Placebo QOW for the first 16 weeks followed by 4 mg/kg UX003 QOW through Week 46

Drug: UX003; Other: Placebo

Group D: 24 Weeks Placebo then 4 mg/kg UX003

EXPERIMENTAL

Placebo QOW for the first 24 weeks followed by 4 mg/kg UX003 QOW through Week 46

Drug: UX003; Other: Placebo

Interventions

UX003 DRUG

UX003 is a sterile concentrate formulation of rhGUS for intravenous infusion

Also known as: recombinant human beta-glucuronidase, rh-β-glucuronidase, rhGUS

Group A: 4 mg/kg UX003; Group B: 8 Weeks Placebo then 4 mg/kg UX003; Group C: 16 Weeks Placebo then 4 mg/kg UX003; Group D: 24 Weeks Placebo then 4 mg/kg UX003

Placebo OTHER

Placebo consisting of the UX003 formulation buffer (without rhGUS)

Also known as: Reference therapy

Group B: 8 Weeks Placebo then 4 mg/kg UX003; Group C: 16 Weeks Placebo then 4 mg/kg UX003; Group D: 24 Weeks Placebo then 4 mg/kg UX003

Eligibility Criteria

• Age: 5 Years - 35 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Confirmed diagnosis of MPS 7 based on leukocyte or fibroblast glucuronidase enzyme assay or genetic testing.
• Elevated urinary glycosaminoglycan (uGAG) excretion at a minimum of 3-fold over the mean normal for age (at Screening).
• Apparent clinical signs of lysosomal storage disease as judged by the Investigator, including at least one of the following: enlarged liver and spleen, joint limitations, airway obstruction or pulmonary problems, limitation of mobility while still ambulatory.
• Aged 5 - 35 years, inclusive.
• Willing and able to provide written 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 acceptable highly effective methods of contraception while participating in the study and for 30 days following the last dose.
• 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 not experienced menarche, or have had tubal ligation at least one year prior to Screening, or who have had total hysterectomy.
• Naïve to treatment with UX003.

You may not qualify if:

• Undergone a successful bone marrow or stem cell transplant or has any degree of detectable chimaerism with donor cells.
• Major surgery within 3 months prior to study entry or planned major surgery during the study that may not allow safe participation in the study.
• Presence or history of any 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.
• Presence of a condition of such severity and acuity that, in the opinion of the Investigator, warrants immediate surgical intervention or other treatment or may not allow safe participation in the study.
• Concurrent disease or condition, or laboratory abnormality 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 introduce additional safety concerns.

Sponsors & Collaborators

• Ultragenyx Pharmaceutical Inc: lead

Study Sites (4)

Children's Hospital Oakland

Oakland, California, 94609, United States

Location

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

Miami Children's Hospital

Miami, Florida, 33155, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Related Publications (5)

• Wang RY, da Silva Franco JF, Lopez-Valdez J, Martins E, Sutton VR, Whitley CB, Zhang L, Cimms T, Marsden D, Jurecka A, Harmatz P. The long-term safety and efficacy of vestronidase alfa, rhGUS enzyme replacement therapy, in subjects with mucopolysaccharidosis VII. Mol Genet Metab. 2020 Mar;129(3):219-227. doi: 10.1016/j.ymgme.2020.01.003. Epub 2020 Jan 11.

  PMID: 32063397 RESULT

• Harmatz P, Whitley CB, Wang RY, Bauer M, Song W, Haller C, Kakkis E. A novel Blind Start study design to investigate vestronidase alfa for mucopolysaccharidosis VII, an ultra-rare genetic disease. Mol Genet Metab. 2018 Apr;123(4):488-494. doi: 10.1016/j.ymgme.2018.02.006. Epub 2018 Feb 12.

  PMID: 29478819 RESULT

• 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 DERIVED

• Tandon PK, Kakkis ED. The multi-domain responder index: a novel analysis tool to capture a broader assessment of clinical benefit in heterogeneous complex rare diseases. Orphanet J Rare Dis. 2021 Apr 19;16(1):183. doi: 10.1186/s13023-021-01805-5.

  PMID: 33874971 DERIVED

• 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 DERIVED

MeSH Terms

Conditions

Mucopolysaccharidosis VII; Mucopolysaccharidoses; Rare Diseases; Lysosomal Storage Diseases; Metabolic Diseases

Interventions

vestronidase alfa

Condition Hierarchy (Ancestors)

Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Mucinoses; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Nutritional and Metabolic Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Kim Mooney, Associate Director, Patient Advocacy Medical Services
• Organization: Ultragenyx Pharmaceutical Inc

kmooney@ultragenyx.com

408-981-3526

Study Officials

• Paul Harmatz, MD

  UCSF Benioff Children's Hospital Oakland

  PRINCIPAL INVESTIGATOR

• Raymond Wang, MD

  Children's Hospital of Orange County

  PRINCIPAL INVESTIGATOR

• Mislen Bauer, MD

  Nicklaus Children's Hospital f/k/a Miami Children's Hospital

  PRINCIPAL INVESTIGATOR

• Chester Whitley, MD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR
• Expanded Access: Yes

Study Record Dates

• First Submitted: August 22, 2014
• First Posted: September 3, 2014
• Study Start: December 1, 2014
• Primary Completion: May 1, 2016
• Study Completion: May 1, 2016
• Last Updated: July 30, 2020
• Results First Posted: February 19, 2018

Record last verified: 2020-07

Locations

US (4)