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

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

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

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.

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.

Glycogen storage disease type 1a, GSD1a, Von Gierke disease, Glucose metabolism disorder, Genetic disorder, Autosomal recessive disorder, messenger RNA, mRNA, Pediatric

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.

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.

Hypoglycemia is defined as blood glucose <60 milligrams (mg)/deciliter (dL) (3.3 millimoles [mmol]/liter [L]) and/or symptoms of hypoglycemia.

Change From Baseline of Area Under the Effect Curve (AUEC) of Blood Glucose and Lactate During Fasting Challenges

SAD only: Maximum Observed Concentration (Cmax) of Messenger Ribonucleic Acid (mRNA) and Lipid Nanoparticle (LNP)

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

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.

Cao J, Choi M, Guadagnin E, Soty M, Silva M, Verzieux V, Weisser E, Markel A, Zhuo J, Liang S, Yin L, Frassetto A, Graham AR, Burke K, Ketova T, Mihai C, Zalinger Z, Levy B, Besin G, Wolfrom M, Tran B, Tunkey C, Owen E, Sarkis J, Dousis A, Presnyak V, Pepin C, Zheng W, Ci L, Hard M, Miracco E, Rice L, Nguyen V, Zimmer M, Rajarajacholan U, Finn PF, Mithieux G, Rajas F, Martini PGV, Giangrande PH. mRNA therapy restores euglycemia and prevents liver tumors in murine model of glycogen storage disease. Nat Commun. 2021 May 25;12(1):3090. doi: 10.1038/s41467-021-23318-2.