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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Methylmalonic Acidemia (MMA), Metabolism, Inborn Errors

Intervention / Treatment
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* Biological: mRNA-3704


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 1 Year

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: Dose Escalation Phase: Dose Level 1<br>mRNA-3704 | Biological: mRNA-3704<br>* mRNA-3704 dispersion for intravenous (IV) infusion<br>|
| Experimental: Dose Escalation Phase: Dose Level 2<br>mRNA-3704 | Biological: mRNA-3704<br>* mRNA-3704 dispersion for intravenous (IV) infusion<br>|
| Experimental: Dose Escalation Phase: Dose Level 3<br>mRNA-3704 | Biological: mRNA-3704<br>* mRNA-3704 dispersion for intravenous (IV) infusion<br>|
| Experimental: Dose Escalation Phase: Dose Level 4 (optional)<br>mRNA-3704 | Biological: mRNA-3704<br>* mRNA-3704 dispersion for intravenous (IV) infusion<br>|
| Experimental: Dose Expansion Phase: mRNA-3704<br> | Biological: mRNA-3704<br>* mRNA-3704 dispersion for intravenous (IV) infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events |  | 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 | Week -4 through 36 weeks after initial mRNA-3704 dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum observed concentration (Cmax) after administration of mRNA-3704 |  | Baseline through 36 weeks after initial mRNA-3704 dose | 
| Time of Cmax (Tmax) |  | 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 | 
| Change in plasma 2-methylcitrate levels | Baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704 | Week -4 through 36 weeks after initial mRNA-3704 dose | 
| Measurement of anti-PEG antibodies |  | Pre-dose through up to 52 weeks after final mRNA-3704 dose |