UX003-CL301

Ultragenyx Pharmaceutical Inc

60 Leveroni Court, Novato, United States, 94949

Robert Hostutler, Sr. Clinical Program Manager, Clinical Operations, 1 4154838148, rhostutler@ultragenyx.com

Christine Haller, MD, VP, Drug Safety and Pharmacovigilance, 1 4154838937, challer@ultragenyx.com

Yes

No

No

Final

04 May 2016

No

Yes

04 May 2016

No

In the European Union (EU) and rest of world, efficacy of UX003 in mucopolysaccharidosis VII MPS VII subjects is determined by the percent reduction of urinary glycosaminoglycan (uGAG) excretion after 24 weeks of treatment relative to the pre-treatment baseline. In the United States (US) only, efficacy of UX003 in MPS VII subjects is based on the totality of the clinical data on a per subject basis.

The trial was designed, conducted, recorded, and reported in accordance with the principles established by the 18th World Medical Association General Assembly (Helsinki, 1964) and subsequent amendments and clarifications adopted by the General Assemblies. The investigators made every effort to ensure that the study was conducted in full conformance with Helsinki principles, International Council for Harmonization (ICH) Good Clinical Practice (GCP) guidelines, current Food and Drug Administration (FDA) regulations, EU Clinical Trial Directive 2001/20/EC, and local ethical and regulatory requirements. Each investigator was thoroughly familiar with the appropriate administration and potential risks of administration of the study drug, as described in the protocol and Investigator’s Brochure, prior to the initiation of the study. The method of obtaining and documenting informed consent and the contents of the informed consent form (ICF) complied with ICH GCP guidelines, the requirements of 21 CFR Part 50, “Protection of Human Subjects,” the Health Insurance Portability and Accountability Act regulations, and all other applicable regulatory requirements. Investigators were responsible for preparing the ICF and submitting it to the Sponsor for approval prior to submission to the Institutional Review Board (IRB). All ICFs were written in regional language and contained the minimum elements for consent as mandated by the ICH guidelines. An IRB-approved ICF was provided by the Sponsor prior to initiation of the study. Investigators obtained signed written informed consent from each potential study subject prior to the conduct of any study procedures and after the methods, objectives, requirements, and potential risks of the study were fully explained to each potential subject. Consent for participation could be withdrawn at any time for any reason by the subject.

02 Dec 2014

Yes

Yes

United States: 12

12

0

0

0

0

0

4

5

3

0

0

Overall trial (overall period)

Randomised - controlled

The study was conducted as a randomized, double-blind, blind start, single crossover, placebo-controlled study. Double-blind conditions were established so that neither the sponsor, subject, or site personnel involved in study conduct knew the identity of a subject’s treatment.

Yes

UX003

Solution for infusion

Intravenous use

UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

UX003

Solution for infusion

Intravenous use

UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

Placebo

Solution for infusion

Intravenous use

A placebo consisting of the UX003 formulation buffer (without rhGUS) will be administered IV QOW to Groups B-D over a period of approximately 4 hours during the respective placebo treatment portion of the Blinded Period.

Placebo

Solution for infusion

Intravenous use

A placebo consisting of the UX003 formulation buffer (without rhGUS) will be administered IV QOW to Groups B-D over a period of approximately 4 hours during the respective placebo treatment portion of the Blinded Period.

UX003

Solution for infusion

Intravenous use

UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

UX003

Solution for infusion

Intravenous use

UX003 is a sterile liquid buffered saline formulation of recombinant human betaglucuronidase (rhGUS) at a concentration of 2 mg/mL filled to allow the withdrawal of a 5.0 mL deliverable volume and supplied in a 10 mL glass vial. Dosage of UX003 is 4 mg/kg body weight administered QOW by slow intravenous (IV) infusion over a period of approximately 4 hours.

Placebo

Solution for infusion

Intravenous use

A placebo consisting of the UX003 formulation buffer (without rhGUS) will be administered IV QOW to Groups B-D over a period of approximately 4 hours during the respective placebo treatment portion of the Blinded Period.

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

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

Subjects received placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study, based on the blind-start design.

UX003 Active Treatment

Subjects received 4 mg/kg UX003 QOW per group assignment (based on the blind-start design) and were dosed through Week 46. All groups received a minimum of 24 weeks of treatment with UX003.

UX003 4 mg/kg

Subjects were randomized 1:1:1:1 to 1 of 4 treatment sequence groups to either start treatment with 4 mg/kg UX003 (Group A), or placebo for the first 8 weeks (Group B), 16 weeks (Group C) or 24 weeks (Group D) of the study and cross over to 4 mg/kg UX003. Subjects were dosed QOW through Week 46. All groups received a minimum of 24 weeks of treatment with 4 mg/kg UX003 QOW.

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 subject basis.

Primary

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

MDRI score, calculated as the total response score at UX003 Treatment Week 24 across 6 domains: 6-Minute Walk Test, forced vital capacity predicted value, shoulder flexion, visual acuity, and Bruininks-Oseretsky Test of Motor Proficiency fine motor and gross motor capacity. For each domain, a minimally important difference (MID) was prespecified. Changes from before treatment (baseline) to 24 weeks after treatment in each domain variable were scored against pre-specified MIDs. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) An improvement or decline ≥ MID was scored either as a +1 or -1, respectively, and a change <MID was scored as 0. The integration of benefit occurred by summing the responses (-1, +1, 0) across all 6 domain variables to derive the MDRI score, with a range of -6 (greatest possible decline) to +6 (greatest possible improvement).

Secondary

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

The total distance walked (in meters) in a 6-minute period was measured. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from Baseline indicates improvement. Change from baseline in 6MWT was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.

Secondary

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

Spirometry was administered to subjects who did not require invasive ventilatory support or have a tracheostomy and measured percentage of predicted FVC. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) No GEE analysis was performed for FVC due to the limitation of the sample size.

Secondary

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

Spirometry was administered to subjects who did not require invasive ventilatory support or have a tracheostomy to measure MVV. The percent predicted values were calculated after testing using published normative data. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.)

Secondary

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

Goniometry was used to measure (in degrees) the maximum passive shoulder range of motion in both flexion and extension. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in shoulder flexion left was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had nonmissing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.

Secondary

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

Visual acuity was measured (corrected and uncorrected) using a standard eye chart and recorded for each eye independently. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. The change in the number of lines from pre-treatment baseline to 24 weeks of treatment was evaluated. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) A positive change from baseline indicates improvement. Change from baseline in uncorrected visual acuity was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had non-missing baseline and at least one post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.

Secondary

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

BOT-2 was administered to evaluate treatment-related changes in 4 domains assessing both fine and gross motor function: balance (score 0 to 37), fine motor precision (score 0 to 41), manual dexterity (score 0 to 45), and running speed/agility (score 0 to 52). Higher scores indicate more motor proficiency; a positive change from baseline indicates improvement. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in BOT-2 was analyzed by GEE modeling based on observed data. The GEE model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.

Secondary

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

The PedsQL 18-item scale is comprised of 3 dimensions: general fatigue (6 items), sleep/rest fatigue (6 items) and cognitive fatigue (6 items). Each item has a 5-point Likert response scale that is reverse scored and transformed to a 0 to 100 scale with higher scores indicating less fatigue. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) Change from baseline in PedsQL total fatigue score was analyzed by GEE modeling based on observed data. The GEE model included all subjects who had non-missing baseline and ≥1 post-baseline value during the 24 weeks of UX003 treatment. The model included baseline value, and the UX003 treatment week as a categorical variable. The covariance structure within subjects was assumed to be exchangeable.

Secondary

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

Percentage of subjects who were ICR responders based on MID criteria at Week 24. At the Randomization visit, the physician queried the subject or parent/caregiver about signs and symptoms of MPS VII that interfered most with the subject’s daily life. Answers were mapped to an appropriate clinical outcome measure (e.g., difficulty walking could map to the 6MWT; breathing problems to FVC). The clinical outcome ranked with the highest impact on daily life that could be reliably completed by the subject and met a threshold level of impairment was selected as the ICR for that subject. ICR response was assessed based on a positive change (according to pre-specified MID criteria) of each subject’s ICR. Agresti–Coull confidence interval with nominal coverage ≥ 95%.

Secondary

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

The 3 most impactful clinical problems as reported by the subject/parent/caregiver during the Clinical Problem Evaluation were scored on a Likert scale from 1 (very little problem) to 7 (an extreme amount) at randomization and post-randomization visits. At post-randomization visits, each clinical problem was again scored for impact on daily activities. Total scores ranged from 3 to 21; lower scores reflect less impact on daily life. Baseline was defined as the last assessment prior to or on the date of cross-over to active treatment with UX003. (This provides the valid assessment, as placebo effect would be subtracted from the treatment effect estimate providing a more conservative assessment of the true treatment effect.) The change from baseline up to UX003 Treatment Week 24 were analyzed by GEE modeling, including baseline value, and the post-UX003 initiation treatment week as a categorical variable. The covariance structure within subjects is assumed to be exchangeable.

Secondary

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

Safety information was collected for all subjects who received any study drug from signing the informed consent form through 30 days after last dose of study drug. Mean treatment duration for UX003 was 36.0 weeks, and for placebo was 15.8 weeks.

Treatment-emergent adverse events (TEAEs) are presented. Given that the study has only has 12 subjects, and a by arm/group analysis would include no more than 3 subjects per arm/group, the TEAE summary was planned to present data by treatment only.

19.0

Placebo

UX003 Active Treatment