A Global, Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants with Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency

Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency

Part I: Incidence and severity of TEAEs, including study drug–related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation., Part II: Percentage change in plasma methylmalonic acid levels at 3 months of treatment in participants treated with mRNA-3705 compared to placebo., Part III: Incidence and severity of TEAEs, including study drug-related and not related TEAEs, AESIs, SAEs, and TEAEs leading to treatment discontinuation.

Part I: - Percentage change in plasma methylmalonic acid levels from baseline (pretreatment) to postdose levels measured after single and repeated administrations of mRNA-3705. - Estimation of PD parameters after single and repeated administrations of mRNA-3705, including AUC_Below_B, AUC_Net_B, and Emax - Percentage change in plasma 2-MC levels from baseline (pretreatment) to levels measured after single and repeated administrations of mRNA-3705., Part I (continuation): - Estimation of hMUT mRNA PK parameters including, but not limited to, Cmax, Tmax, AUC, t½, CL, Vz and Vss. - Presence and titers of anti-PEG antibodies., Part II: - Estimation of PK parameters of hMUT (anti-hMUT) mRNAs including, but not limited to, Cmax, Tmax, AUC, t½, CL, and Vz. - Measurement of SM-86 after single and repeated dosing., Part II(continuation): - Percentage change in plasma 2-MC at 3 months of treatment in participants treated with mRNA-3705 compared to placebo. - Change from baseline in PedsQL™ Physical Function score at 3 months of treatment in participants treated with mRNA-3705 compared to placebo. - Annualized frequency of MMA -related hospitalizations up until 3 months of treatment. - Annualized frequency of MDEs up until 3 months of treatment, both overall and by severity., Part II(continuation): - Change in: − PedsQL™ Total Score from baseline(pretreatment) − IGA-S and CrGI-S from baseline(pretreatment) − IGA-I and CrGI-I from the Dose 2 visit - Incidence and severity of TEAEs. - Incidence and severity of SAEs. - Incidence and severity of AESIs (eg, IRR and hypersensitivity). - Incidence and severity of TEAEs leading to treatment discontinuation. - Presence and titers of antibodies against PEG (anti-PEG) and hMUT (anti-hMUT)., Part III: - Percentage change in plasma methylmalonicacid levels at 3 months of treatment - Percentage change in plasma 2-MC levels at 3months of treatment - Estimation of hMUT mRNA PK parametersincluding, but not limited to, Cmax, Tmax, AUC, t½, CL, and Vz - Change from Baseline in PedsQL™ PhysicalFunction score at 3 months of treatment - Annualized frequency of MMA-relatedhospitalizations up until 3 months of treatment, Part III: - Annualized frequency of MDEs up until 3months of treatment, both overall and by severity - Change in: − PedsQL™ Total Score from baseline(pretreatment). − IGA-S and CrGI-S from baseline(pretreatment). − IGA-I and CrGI-I from the Dose 2 visit - Presence and titers of antibodies against PEG(anti-PEG) and hMUT (anti-hMUT)

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