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

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 Overview

• Status: Withdrawn
• Conditions: Metabolism, Inborn Errors; Methylmalonic Acidemia (MMA)
• Intervention / Treatment: Biological: mRNA-3704

• Study Type: Interventional
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation Phase: Dose Level 1; mRNA-3704	Biological: mRNA-3704; mRNA-3704 dispersion for intravenous (IV) infusion
Experimental: Dose Escalation Phase: Dose Level 2; mRNA-3704	Biological: mRNA-3704; mRNA-3704 dispersion for intravenous (IV) infusion
Experimental: Dose Escalation Phase: Dose Level 3; mRNA-3704	Biological: mRNA-3704; mRNA-3704 dispersion for intravenous (IV) infusion
Experimental: Dose Escalation Phase: Dose Level 4 (optional); mRNA-3704	Biological: mRNA-3704; mRNA-3704 dispersion for intravenous (IV) infusion
Experimental: Dose Expansion Phase: mRNA-3704	Biological: mRNA-3704; mRNA-3704 dispersion for intravenous (IV) infusion

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: ModernaTX, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): May 28, 2019
• Primary Completion (Actual): August 18, 2020
• Study Completion (Actual): August 18, 2020

Study Registration Dates

• First Submitted: January 14, 2019
• First Submitted That Met QC Criteria: January 16, 2019
• First Posted (Actual): January 22, 2019

Study Record Updates

• Last Update Posted (Actual): November 13, 2020
• Last Update Submitted That Met QC Criteria: November 10, 2020
• Last Verified: November 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Amino Acid Metabolism, Inborn Errors
• Other Study ID Numbers: mRNA-3704-P101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No