Clinical trial NCT03810690: 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
Overall status: WITHDRAWN
Phase: PHASE1
PHASE2
Conditions: Methylmalonic Acidemia (MMA)
Metabolism, Inborn Errors
Lead sponsor: ModernaTX, Inc.
Sponsor class: INDUSTRY
First posted: 2019-01-22
Enrollment: 0
Sex: ALL
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Incidence of treatment-emergent adverse events
timeFrame: Day 1 (initial mRNA-3704 dose) through 52 weeks after final mRNA-3704 dose
measure: Change in plasma methylmalonic acid levels
timeFrame: Week -4 through 36 weeks after initial mRNA-3704 dose
Secondary outcomes:
measure: Maximum observed concentration (Cmax) after administration of mRNA-3704
timeFrame: Baseline through 36 weeks after initial mRNA-3704 dose
measure: Time of Cmax (Tmax)
timeFrame: Baseline through 36 weeks after initial mRNA-3704 dose
measure: Area under the plasma concentration-time curve (AUC)
timeFrame: Baseline through 36 weeks after initial mRNA-3704 dose
measure: Change in plasma 2-methylcitrate levels
timeFrame: Week -4 through 36 weeks after initial mRNA-3704 dose
measure: Measurement of anti-PEG antibodies
timeFrame: Pre-dose through up to 52 weeks after final mRNA-3704 dose
Other outcomes:
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