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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03810690
Recruitment Status : Withdrawn (Study was terminated before the start of dosing due to a business decision and not due to safety or efficacy reasons.)
First Posted : January 22, 2019
Last Update Posted : November 13, 2020
Sponsor:
Information provided by (Responsible Party):
ModernaTX, Inc.

Study Description
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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.


Condition or disease Intervention/treatment Phase
Methylmalonic Acidemia (MMA) Metabolism, Inborn Errors Biological: mRNA-3704 Phase 1 Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : May 28, 2019
Actual Primary Completion Date : August 18, 2020
Actual Study Completion Date : August 18, 2020

Resource links provided by the National Library of Medicine


Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Incidence of treatment-emergent adverse events [ Time Frame: Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose ]
  2. Change in plasma methylmalonic acid levels [ Time Frame: 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


Secondary Outcome Measures :
  1. Maximum observed concentration (Cmax) after administration of mRNA-3704 [ Time Frame: Baseline through 36 weeks after initial mRNA-3704 dose ]
  2. Time of Cmax (Tmax) [ Time Frame: Baseline through 36 weeks after initial mRNA-3704 dose ]
  3. Area under the plasma concentration-time curve (AUC) [ Time Frame: Baseline through 36 weeks after initial mRNA-3704 dose ]
  4. Change in plasma 2-methylcitrate levels [ Time Frame: 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

  5. Measurement of anti-PEG antibodies [ Time Frame: Pre-dose through up to 52 weeks after final mRNA-3704 dose ]

Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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No Contacts or Locations Provided
More Information
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Responsible Party: ModernaTX, Inc.
ClinicalTrials.gov Identifier: NCT03810690    
Other Study ID Numbers: mRNA-3704-P101
First Posted: January 22, 2019    Key Record Dates
Last Update Posted: November 13, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Metabolism, Inborn Errors
Amino Acid Metabolism, Inborn Errors
Metabolic Diseases
Genetic Diseases, Inborn