Safety, Tolerability, and Pharmacokinetics of UX053 in Patients With Glycogen Storage Disease Type III (GSD III)

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

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

Study Overview

• Status: Terminated
• Conditions: Glycogen Storage Disease Type III
• Intervention / Treatment: Biological: UX053; Drug: Antipyretic; Drug: H2 Blocker; Drug: H1 Blocker; Other: Placebo

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).

• Study Type: Interventional
• Enrollment (Actual): 9
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20122
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
• United States
  • California
    • Orange, California, United States, 92868
      • University of California, Irvine
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Rare Disease Research
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • University of Texas, Health Science Center of Houston

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: UX053 Dose Level 1S ->OL-1R; Participants receive a single, peripheral intravenous (IV) infusion of UX053. After completion of the 90-day Follow up Period, participants can enter the open label repeat dose (OL-RD) cohort where they will receive UX053 every 4 weeks (Q4W) for 4 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.	Biological: UX053; mRNA-based biologic; Drug: Antipyretic; participants will receive oral premedication prior to infusion; Other Names: acetaminophen; ibuprofen; paracetamol; Drug: H2 Blocker; participants will receive oral premedication prior to infusion; Other Names: famotidine; Drug: H1 Blocker; participants will receive oral premedication prior to infusion; Other Names: cetirizine
Experimental: UX053 Dose Level 2S->OL-2R; Participants receive a single, peripheral intravenous (IV) infusion of UX053. After completion of the 90-day Follow up Period, participants can enter the open label repeat dose (OL-RD) cohort where they will receive UX053 every 4 weeks (Q4W) for 4 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.	Biological: UX053; mRNA-based biologic; Drug: Antipyretic; participants will receive oral premedication prior to infusion; Other Names: acetaminophen; ibuprofen; paracetamol; Drug: H2 Blocker; participants will receive oral premedication prior to infusion; Other Names: famotidine; Drug: H1 Blocker; participants will receive oral premedication prior to infusion; Other Names: cetirizine
Experimental: UX053 Dose Level 3S->OL-3R; Participants receive a single, peripheral intravenous (IV) infusion of UX053. After completion of the 90-day Follow up Period, participants can enter the open label repeat dose (OL-RD) cohort where they will receive UX053 every 4 weeks (Q4W) for 4 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.	Biological: UX053; mRNA-based biologic; Drug: Antipyretic; participants will receive oral premedication prior to infusion; Other Names: acetaminophen; ibuprofen; paracetamol; Drug: H2 Blocker; participants will receive oral premedication prior to infusion; Other Names: famotidine; Drug: H1 Blocker; participants will receive oral premedication prior to infusion; Other Names: cetirizine
Experimental: UX053 or Placebo Dose Level DB-1R; Participants randomized to receive a single, peripheral IV infusion of UX053 or Placebo every 2 weeks (Q2W) for 5 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.	Biological: UX053; mRNA-based biologic; Drug: Antipyretic; participants will receive oral premedication prior to infusion; Other Names: acetaminophen; ibuprofen; paracetamol; Drug: H2 Blocker; participants will receive oral premedication prior to infusion; Other Names: famotidine; Drug: H1 Blocker; participants will receive oral premedication prior to infusion; Other Names: cetirizine; Other: Placebo; consists of the same components as the formulation buffer for UX053
Experimental: UX053 Dose Level DB-2R; Participants randomized to receive a single, peripheral IV infusion of UX053 or Placebo every 2 weeks (Q2W) for 5 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.	Biological: UX053; mRNA-based biologic; Drug: Antipyretic; participants will receive oral premedication prior to infusion; Other Names: acetaminophen; ibuprofen; paracetamol; Drug: H2 Blocker; participants will receive oral premedication prior to infusion; Other Names: famotidine; Drug: H1 Blocker; participants will receive oral premedication prior to infusion; Other Names: cetirizine; Other: Placebo; consists of the same components as the formulation buffer for UX053
Experimental: UX053 Dose Level DB-3R; Participants randomized to receive a single, peripheral IV infusion of UX053 or Placebo every 2 weeks (Q2W) for 5 doses. Participants will also receive premedication, consisting of oral paracetamol/acetaminophen or ibuprofen, an H2 blocker, and an H1 blocker.	Biological: UX053; mRNA-based biologic; Drug: Antipyretic; participants will receive oral premedication prior to infusion; Other Names: acetaminophen; ibuprofen; paracetamol; Drug: H2 Blocker; participants will receive oral premedication prior to infusion; Other Names: famotidine; Drug: H1 Blocker; participants will receive oral premedication prior to infusion; Other Names: cetirizine; Other: Placebo; consists of the same components as the formulation buffer for UX053

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious TEAEs, Deaths, Discontinuations, and/or Dose Changes	An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. A TEAE is defined as any AE not present prior to the initiation of the drug treatment or any AE already present that worsens in either intensity or frequency following exposure to the drug treatment. An SAE is an AE that meets any of the following criteria in the view of either the Investigator or Ultragenyx: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; disability/Incapacity; congenital anomaly/birth defect not present at screening; other important medical events. Severity of events were graded as mild (grade1), moderate (grade 2), severe (grade 3), life-threatening (grade 4), or death (grade 5).	From first dose of study drug through the end of study (up to Day 90)

Secondary Outcome Measures

Outcome Measure	Time Frame
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)	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
PK of AGL mRNA and the Excipient ATX95: Time to Peak Drug Concentration (Tmax)	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
PK of AGL mRNA and the Excipient ATX95: Total Drug Exposure to the Last Measurable Concentration (AUC0-last)	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
PK of AGL mRNA and the Excipient ATX95: Total Drug Exposure to Infinity (AUC0-inf)	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
PK of AGL mRNA and the Excipient ATX95: Elimination Half-life (t½)	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
PK of AGL mRNA and the Excipient ATX95: Clearance (CL)	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
PK of AGL mRNA and the Excipient ATX95: Volume of Distribution at Steady State (Vss)	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

Collaborators and Investigators

• Sponsor: Ultragenyx Pharmaceutical Inc
• Investigators: Study Director: Medical Director, Ultragenyx Pharmaceutical Inc

Publications and helpful links

Helpful Links

• Ultragenyx Patient Advocacy/GSD III Disease Information

Study record dates

Study Major Dates

• Study Start (Actual): October 18, 2021
• Primary Completion (Actual): March 20, 2023
• Study Completion (Actual): March 20, 2023

Study Registration Dates

• First Submitted: July 26, 2021
• First Submitted That Met QC Criteria: July 26, 2021
• First Posted (Actual): August 4, 2021

Study Record Updates

• Last Update Posted (Actual): April 16, 2024
• Last Update Submitted That Met QC Criteria: April 15, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Genetic Diseases, Inborn; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Disease; Glycogen Storage Disease; Glycogen Storage Disease Type III; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Gastrointestinal Agents; Anti-Ulcer Agents; Anti-Allergic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Histamine H1 Antagonists, Non-Sedating; Histamine H2 Antagonists; Acetaminophen; Cetirizine; Ibuprofen; Famotidine; Antipyretics
• Other Study ID Numbers: UX053-CL101; 2021-000903-19 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No