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

Study Overview
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Brief Summary
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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
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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).

Official Title
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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

Conditions
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Glycogen Storage Disease Type III

Intervention / Treatment
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* Biological: UX053
* Other: Placebo
* Drug: Antipyretic
* Drug: H2 Blocker
* Drug: H1 Blocker


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: UX053 Dose Level 1S ->OL-1R<br>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<br>* mRNA-based biologic<br>Drug: Antipyretic<br>* participants will receive oral premedication prior to infusion<br>* Other names: ibuprofen;Drug: H2 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: famotidine;Drug: H1 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: cetirizine;|
| Experimental: UX053 Dose Level 2S->OL-2R<br>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<br>* mRNA-based biologic<br>Drug: Antipyretic<br>* participants will receive oral premedication prior to infusion<br>* Other names: ibuprofen;Drug: H2 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: famotidine;Drug: H1 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: cetirizine;|
| Experimental: UX053 Dose Level 3S->OL-3R<br>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<br>* mRNA-based biologic<br>Drug: Antipyretic<br>* participants will receive oral premedication prior to infusion<br>* Other names: ibuprofen;Drug: H2 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: famotidine;Drug: H1 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: cetirizine;|
| Experimental: UX053 or Placebo Dose Level DB-1R<br>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<br>* mRNA-based biologic<br>Other: Placebo<br>* consists of the same components as the formulation buffer for UX053<br>Drug: Antipyretic<br>* participants will receive oral premedication prior to infusion<br>* Other names: ibuprofen;Drug: H2 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: famotidine;Drug: H1 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: cetirizine;|
| Experimental: UX053 Dose Level DB-2R<br>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<br>* mRNA-based biologic<br>Other: Placebo<br>* consists of the same components as the formulation buffer for UX053<br>Drug: Antipyretic<br>* participants will receive oral premedication prior to infusion<br>* Other names: ibuprofen;Drug: H2 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: famotidine;Drug: H1 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: cetirizine;|
| Experimental: UX053 Dose Level DB-3R<br>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<br>* mRNA-based biologic<br>Other: Placebo<br>* consists of the same components as the formulation buffer for UX053<br>Drug: Antipyretic<br>* participants will receive oral premedication prior to infusion<br>* Other names: ibuprofen;Drug: H2 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: famotidine;Drug: H1 Blocker<br>* participants will receive oral premedication prior to infusion<br>* Other names: cetirizine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of treatment-emergent adverse events (TEAEs), serious TEAEs, and related TEAEs in the SAD and RD Periods |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK parameters of AGL mRNA: time of maximum observed concentration (Tmax) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: maximum concentration (Cmax) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: area under the concentration-time curve (AUC) from time 0 to the last measurable concentration (AUClast) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: AUC from time 0 to infinity (AUCinf) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: AUC from time 0 to end of dosing period (AUCtau; RD cohorts only) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: accumulation ratio (calculated as AUC after repeat dose / AUC after a single dose; RAUC; RD cohorts only) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: time of last measurable concentration (Tlast) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: half life (T1/2) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: clearance (CL) |  | From pre-infusion up to Day 28 | 
| PK parameters of AGL mRNA: volume of distribution in a steady state (Vss) |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: Tmax |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: Cmax |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: AUClast |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: AUCinf |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: AUCtau; RD cohorts only |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: accumulation ratio (calculated as AUC after repeat dose / AUC after a single dose; RAUC; RD cohorts only) |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: Tlast |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: T1/2 |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: CL |  | From pre-infusion up to Day 28 | 
| PK parameters of ATX95: Vss |  | From pre-infusion up to Day 28 |