Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia
Primary Purpose
Methylmalonic Acidemia (MMA), Metabolism, Inborn Errors
Status
Withdrawn
Phase
Phase 1
Locations
Study Type
Interventional
Intervention
mRNA-3704
Sponsored by
About this trial
This is an interventional treatment trial for Methylmalonic Acidemia (MMA)
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Dose Escalation Phase: Dose Level 1
Dose Escalation Phase: Dose Level 2
Dose Escalation Phase: Dose Level 3
Dose Escalation Phase: Dose Level 4 (optional)
Dose Expansion Phase: mRNA-3704
Arm Description
mRNA-3704
mRNA-3704
mRNA-3704
mRNA-3704
Outcomes
Primary Outcome Measures
Incidence of treatment-emergent adverse events
Change in plasma methylmalonic acid levels
Baseline (pre-dose levels) to post-dose levels measured after single and after repeated administrations of mRNA-3704
Secondary Outcome Measures
Maximum observed concentration (Cmax) after administration of mRNA-3704
Time of Cmax (Tmax)
Area under the plasma concentration-time curve (AUC)
Change in plasma 2-methylcitrate levels
Baseline (pre-dose levels) to levels measured after single and after repeated administrations of mRNA-3704
Measurement of anti-PEG antibodies
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT03810690
Brief Title
Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
November 2020
Overall Recruitment Status
Withdrawn
Why Stopped
Study was terminated before the start of dosing due to a business decision and not due to safety or efficacy reasons.
Study Start Date
May 28, 2019 (Actual)
Primary Completion Date
August 18, 2020 (Actual)
Study Completion Date
August 18, 2020 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ModernaTX, Inc.
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Methylmalonic Acidemia (MMA), Metabolism, Inborn Errors
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
0 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Dose Escalation Phase: Dose Level 1
Arm Type
Experimental
Arm Description
mRNA-3704
Arm Title
Dose Escalation Phase: Dose Level 2
Arm Type
Experimental
Arm Description
mRNA-3704
Arm Title
Dose Escalation Phase: Dose Level 3
Arm Type
Experimental
Arm Description
mRNA-3704
Arm Title
Dose Escalation Phase: Dose Level 4 (optional)
Arm Type
Experimental
Arm Description
mRNA-3704
Arm Title
Dose Expansion Phase: mRNA-3704
Arm Type
Experimental
Intervention Type
Biological
Intervention Name(s)
mRNA-3704
Intervention Description
mRNA-3704 dispersion for intravenous (IV) infusion
Primary Outcome Measure Information:
Title
Incidence of treatment-emergent adverse events
Time Frame
Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose
Title
Change in plasma methylmalonic acid levels
Description
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 Outcome Measure Information:
Title
Maximum observed concentration (Cmax) after administration of mRNA-3704
Time Frame
Baseline through 36 weeks after initial mRNA-3704 dose
Title
Time of Cmax (Tmax)
Time Frame
Baseline through 36 weeks after initial mRNA-3704 dose
Title
Area under the plasma concentration-time curve (AUC)
Time Frame
Baseline through 36 weeks after initial mRNA-3704 dose
Title
Change in plasma 2-methylcitrate levels
Description
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
Title
Measurement of anti-PEG antibodies
Time Frame
Pre-dose through up to 52 weeks after final mRNA-3704 dose
10. Eligibility
Sex
All
Minimum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility Criteria
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
12. IPD Sharing Statement
Plan to Share IPD
No
Learn more about this trial
Open Label Study of mRNA-3704 in Patients With Isolated Methylmalonic Acidemia
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