Clinical trial NCT04990388: Safety, Tolerability, and Pharmacokinetics of UX053 in Patients With Glycogen Storage Disease Type III (GSD III)
Official title: A Phase 1/2 First-in-human, Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single Ascending Doses and Repeat Doses of UX053 in Patients With GSD III
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Glycogen Storage Disease Type III
Lead sponsor: Ultragenyx Pharmaceutical Inc
Sponsor class: INDUSTRY
First posted: 2021-08-04
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to evaluate the safety of UX053 in adults with Glycogen Storage Disease Type III (GSD III).

Detailed description: This study is a phase 1/2 first-in-human (FIH), study to evaluate the safety, tolerability, and pharmacokinetic (PK) of a single ascending dose (SAD) and repeat doses (RD) of UX053 in patients with GSD III. The SAD cohorts will be open-label (OL). There will be two types of RD cohorts, an open-label (OL-RD) and a randomized, double-blind (DB), and placebo-controlled (DB-RD).

Eligibility criteria: Key Inclusion Criteria:

* Confirmed diagnosis of GSD III by gene sequencing or enzymatic testing
* Alanine aminotransferase at or below 5 times normal during the three months prior to dosing
* Willing and able to comply with standard dietary management of GSD III

Inclusion Criteria for Participants Rescreening Into OL-RD Cohorts After Treatment with UX053 in SAD Cohort:

* If a significant rise in ALT occurs after the prior dose, ALT should show a decreasing trend toward the subject's baseline value
* Total bilirubin, platelets and international normalized ratio (INR) is within normal limits

Key Exclusion Criteria:

* History of liver transplant or currently awaiting liver transplant
* History of cirrhosis
* Active Hepatitis B or C
* Severe kidney impairment
* History of liver cancer or large liver tumors
* History of any cancer within the past 3 years
* Known history of HIV infection
* Known severe allergy to polyethylene glycol (PEG), polysorbate, or mRNA vaccine
* Heart failure that causes marked limitation in physical activity
* Poorly controlled diabetes
* Poorly controlled hypothyroidism
* Treatment with immunosuppressive medications such as those used to treat chronic autoimmune conditions and solid organ transplants
* Pregnant or nursing, or planning to become pregnant during the study

Exclusion Criteria for Participants Rescreening Into OL-RD Cohorts After Treatment with UX053 in SAD Cohort:

* New or worsening symptoms of liver disease (including new or worsening hepatomegaly) along with any increase in transaminase levels
* Receipt of any blood product administration (eg, packed red blood cells, platelet, FFP) for management of consumptive coagulopathy
* An ALT level that is ≥ 8x ULN and \> 2x the participants baseline value in the absence of an alternative explanation

Note: Additional inclusion/exclusion criteria may apply, per protocol

Primary outcomes:
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, Discontinuations, and/or Dose Changes
timeFrame: From first dose of study drug through the end of study (up to Day 90)
Secondary outcomes:
measure: Pharmacokinetics (PK) of Amylo-α-1,6-glucosidase 4-alpha-glucanotransferase Messenger Ribonucleic Acid (AGL mRNA) and the Excipient ATX95: Maximum Blood/Plasma Concentration (Cmax)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
measure: PK of AGL mRNA and the Excipient ATX95: Time to Peak Drug Concentration (Tmax)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
measure: PK of AGL mRNA and the Excipient ATX95: Total Drug Exposure to the Last Measurable Concentration (AUC0-last)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
measure: PK of AGL mRNA and the Excipient ATX95: Total Drug Exposure to Infinity (AUC0-inf)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
measure: PK of AGL mRNA and the Excipient ATX95: Elimination Half-life (t½)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
measure: PK of AGL mRNA and the Excipient ATX95: Clearance (CL)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
measure: PK of AGL mRNA and the Excipient ATX95: Volume of Distribution at Steady State (Vss)
timeFrame: Pre-infusion; 1, 3, 4, 4.5, 5 hr (± 10 min), 6 hr (± 20 min), 8, 10 hr (± 30 min), 24 hr (± 2 hr), 96, 168 hr (± 24 hr), 336, 504, 672 hr (± 48 hr) post-start of infusion
Other outcomes:
Locations:
city: Orange
country: United States
facility: University of California, Irvine
state: California
city: Atlanta
country: United States
facility: Rare Disease Research
state: Georgia
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Houston
country: United States
facility: University of Texas, Health Science Center of Houston
state: Texas
city: Milan
country: Italy
facility: Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
Study officials:
affiliation: Ultragenyx Pharmaceutical Inc
name: Medical Director
role: STUDY_DIRECTOR
References: