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

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ClinicalTrials.gov Identifier: NCT03810690
Recruitment Status : Not yet recruiting
First Posted : January 21, 2019
Last Update Posted : February 4, 2019
Sponsor:
Information provided by (Responsible Party):
ModernaTX, Inc.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 34 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
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : November 2022
Estimated Study Completion Date : November 2024


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




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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   1 Year to 18 Years   (Child, 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 to ≤ 18 years of age at the time of consent/assent

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03810690


Contacts
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Contact: Moderna Clinical Trials 855-663-6762 clinicaltrials@modernatx.com

Locations
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United States, Massachusetts
Boston Children's Hospital Not yet recruiting
Boston, Massachusetts, United States, 02115
Sponsors and Collaborators
ModernaTX, Inc.

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Responsible Party: ModernaTX, Inc.
ClinicalTrials.gov Identifier: NCT03810690     History of Changes
Other Study ID Numbers: mRNA-3704-P101
First Posted: January 21, 2019    Key Record Dates
Last Update Posted: February 4, 2019
Last Verified: January 2019
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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Acidosis
Metabolism, Inborn Errors
Amino Acid Metabolism, Inborn Errors
Acid-Base Imbalance
Metabolic Diseases
Genetic Diseases, Inborn