Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia
- Conditions
- Metabolism, Inborn ErrorsMethylmalonic Acidemia (MMA)
- Interventions
- Biological: mRNA-3704
- Registration Number
- NCT03810690
- Lead Sponsor
- ModernaTX, Inc.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- WITHDRAWN
- Sex
- All
- Target Recruitment
- Not specified
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)
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Dose Escalation Phase: Dose Level 1 mRNA-3704 mRNA-3704 Dose Escalation Phase: Dose Level 2 mRNA-3704 mRNA-3704 Dose Escalation Phase: Dose Level 3 mRNA-3704 mRNA-3704 Dose Escalation Phase: Dose Level 4 (optional) mRNA-3704 mRNA-3704 Dose Expansion Phase: mRNA-3704 mRNA-3704 -
- Primary Outcome Measures
Name Time Method Change in plasma methylmalonic acid levels Week -4 through 36 weeks after initial mRNA-3704 dose Baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704
Incidence of treatment-emergent adverse events Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose
- Secondary Outcome Measures
Name Time Method Measurement of anti-PEG antibodies Pre-dose through up to 52 weeks after final mRNA-3704 dose Maximum observed concentration (Cmax) after administration of mRNA-3704 Baseline through 36 weeks after initial mRNA-3704 dose Area under the plasma concentration-time curve (AUC) Baseline through 36 weeks after initial mRNA-3704 dose Time of Cmax (Tmax) Baseline through 36 weeks after initial mRNA-3704 dose Change in plasma 2-methylcitrate levels Week -4 through 36 weeks after initial mRNA-3704 dose Baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704