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

ModernaTX, Inc.

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Conditions

Methylmalonic Acidemia (MMA)Metabolism, Inborn Errors

Eligibility

Sex: ALLMin age: 1 Year

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Incidence of treatment-emergent adverse events

Time frame: Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose

Change in plasma methylmalonic acid levels

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

Time frame: Week -4 through 36 weeks after initial mRNA-3704 dose

Secondary Outcomes

Maximum observed concentration (Cmax) after administration of mRNA-3704

Time frame: Baseline through 36 weeks after initial mRNA-3704 dose

Time of Cmax (Tmax)

Time frame: Baseline through 36 weeks after initial mRNA-3704 dose

Area under the plasma concentration-time curve (AUC)

Time frame: Baseline through 36 weeks after initial mRNA-3704 dose

Change in plasma 2-methylcitrate levels

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

Time frame: Week -4 through 36 weeks after initial mRNA-3704 dose

Measurement of anti-PEG antibodies

Time frame: Pre-dose through up to 52 weeks after final mRNA-3704 dose

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

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes