Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia

A Global, Phase 1/2, Open Label, Dose Escalation Study to Evaluate the Safety, Pharmacodynamics, and Pharmacokinetics of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency

Study was terminated before the start of dosing due to a business decision and not due to safety or efficacy reasons.

This First-in-Human (FIH) Phase 1/2 study will evaluate mRNA-3704 in patients with methylmalonic acidemia/aciduria (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency between 1 to 18 years of age with elevated plasma methylmalonic acid. The study is designed to characterize baseline biomarker levels followed by assessment of safety, pharmacokinetics, and pharmacodynamics of different doses of mRNA-3704 in patients affected by MMA as part of the Dose Escalation phase. During the Dose Escalation phase, three dose levels of mRNA-3704 are planned to be investigated in this study among patients with MMA due to MUT deficiency: low dose, mid dose, and high dose. An additional cohort to evaluate a fourth dose level may be considered jointly by the independent SMC and the Sponsor. Upon establishment of a dose with acceptable safety and pharmacodynamic activity, additional patients will be enrolled in a Dose Expansion phase to allow for further characterization of the safety and pharmacodynamics of mRNA-3704. Patients in both phases of study will participate in a pre-dosing observational period, followed by a treatment period, and then a follow-up period after withdrawal of treatment.

Baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704

Baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704

Inclusion Criteria: Patients are eligible to be included in the study only if all of the following criteria apply: Confirmed diagnosis of isolated MMA due to MUT deficiency based on the following criteria: Elevated plasma methylmalonic acid concentrations (≥ 100 µmol/L) Presence of normal serum/plasma Vitamin B12 and plasma homocysteine levels Confirmed diagnosis by molecular genetic testing Patient must be ≥ 1 year of age at the time of consent/assent (Inclusion of the first three patients will be restricted to individuals age ≥ 8 years) Exclusion Criteria: Patients are excluded from the study if any of the following criteria apply: Diagnosis of isolated MMA cblA, cblB, or cblD enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria History of organ transplantation Previously received gene therapy for the treatment of MMA. Estimated glomerular filtration rate (GFR) < 30 mL/min/1.73 m2; or patients who receive chronic dialysis