A Study of mRNA-3745 in Adult and Pediatric Participants With Glycogen Storage Disease Type 1a (GSD1a)

Study Overview
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Brief Summary
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The main goal of this trial is to evaluate the safety and tolerability of mRNA-3745 via intravenous (IV) administration in adult and pediatric participants with GSD1a.

Detailed Description
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The study includes a single ascending dose (SAD) stage and a multiple ascending dose (MAD) stage. Participants enrolled in the study have the option to continue treatment in a 52-week Extension Period that will assess long-term safety and clinical activity of mRNA-3745 treatment.

Official Title
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A Phase 1/2, Adaptive, Open-label, Single Ascending Dose to Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of mRNA-3745 in Participants With Glycogen Storage Disease Type 1a (GSD1a), Followed by an Open-label Extension

Conditions
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Glycogen Storage Disease

Intervention / Treatment
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* Drug: mRNA-3745


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented GSD1a with confirmation by genetic testing Documented history of ≥1 hypoglycemic event with blood glucose <60 mg/dL (<3.3 mmol/L) and symptoms of hypoglycemia in the absence of acute illness, with at least one such event in the 4 weeks before starting run in (Day -14) Exclusion Criteria: Liver transplant, including hepatocyte cell therapy/transplant Received gene therapy for GSD1a Presence of liver adenoma >5 centimeters (cm) (±10%) in size Participant has a diagnosis of type 1 or type 2 diabetes mellitus Presence of liver adenoma with growth of >2 cm or >5 newly diagnosed liver adenomas, in the previous 2 years Participants with known allergy to magnetic resonance imaging (MRI) contrast can be enrolled and receive MRI without contrast. Participants for whom MRI is contraindicated could be enrolled if an alternative imaging technique can be performed. Note: Additional inclusion/exclusion criteria may apply, per protocol.

Ages Eligible for Study
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Minimum Age: 12 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAD: mRNA-3745<br>Participants will receive a single IV dose of mRNA-3745 on Day 1 in an inpatient setting. Participants that are/have been enrolled in the study and receive an administration of mRNA-3745 may also enroll in one of the MAD cohorts. The next dose must occur at least 21 days after the previous dose. | Drug: mRNA-3745<br>* Sterile frozen liquid dispersion for injection<br>|
| Experimental: MAD: mRNA-3745<br>Participants will receive multiple IV doses of mRNA-3745 on Day 1 in an inpatient setting. Participants will have the option to continue treatment in a 52-week Extension Period. | Drug: mRNA-3745<br>* Sterile frozen liquid dispersion for injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) |  | Baseline up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Not Experiencing Hypoglycemia for up to 12 Hours During Fasting Challenges | Hypoglycemia is defined as blood glucose <60 milligrams (mg)/deciliter (dL) (3.3 millimoles [mmol]/liter [L]) and/or symptoms of hypoglycemia. | Baseline through up to Week 32 | 
| Change From Baseline of Area Under the Effect Curve (AUEC) of Blood Glucose and Lactate During Fasting Challenges |  | Baseline through up to Week 32 | 
| Change From Baseline in Time to Hypoglycemia During Fasting Challenges |  | Baseline through up to Week 32 | 
| Change From Baseline in Maximum Effect (Emax) During Fasting Challenges |  | Baseline through up to Week 32 | 
| SAD only: Maximum Observed Concentration (Cmax) of Messenger Ribonucleic Acid (mRNA) and Lipid Nanoparticle (LNP) |  | Pre-infusion, at mid-infusion, and at the end of infusion (EOI) on Day 1 up to Week 52 | 
| SAD only: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Measurable Concentration (AUC0-t) of mRNA and LNP |  | Pre-infusion, at mid-infusion, and at EOI on Day 1 up to Week 52 | 
| Change From Baseline in Metabolic Biomarkers |  | Baseline through up to Week 32 | 
| MAD only: Maximum Observed Concentration at Steady State (Cmax,ss) of mRNA and LNP |  | Pre-infusion, at mid-infusion, and at the EOI on Day 1 up to Week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Glycogen storage disease type 1a, GSD1a, Von Gierke disease, Glucose metabolism disorder, Genetic disorder, Autosomal recessive disorder, messenger RNA, mRNA, Pediatric