A Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia

A Global Phase 1/2 Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of mRNA-3705 in Participants With Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency

This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency. The main goal of the study is to assess safety, efficacy, pharmacokinetics, and pharmacodynamics of intravenously (IV)-infused mRNA-3705.

Study Overview

• Status: Terminated
• Conditions: Methylmalonic Acidemia
• Intervention / Treatment: Biological: mRNA-3705; Biological: Placebo

Detailed Description

This study comprises 3 parts and is designed to evaluate multiple doses and dosing intervals of mRNA-3705.

Parts 1 and 3 are designed to characterize the safety, tolerability, and pharmacological activity of mRNA-3705 administered via intravenous infusion to participants with isolated MMA due to MUT deficiency. Part 2 will evaluate the efficacy of mRNA-3705 as assessed by the change in plasma methylmalonic acid levels.

Participants who complete the treatment period in any part of the study, including the end of treatment (EOT) visit, will be offered participation in the mRNA-extension study (mRNA-3705-P101-EXT; NCT05295433) or may transition to the follow-up period of the study. All participants, including those randomized to placebo in Part 2, will receive mRNA-3705 in the extension study.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2R7
      • Stollery Children's Hospital University of Alberta
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• France
  • Paris, France, 75015
    • Hopital Necker - Enfants Malades
• Netherlands
  • Rotterdam, Netherlands, 3015 AA
    • Erasmus MC
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Spain
  • Barakaldo, Spain, 48903
    • Hospital Universitario Cruces
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
• United Kingdom
  • Manchester, United Kingdom, M13 9WL
    • Royal Manchester Children's Hospital
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Medical Center
    • Palo Alto, California, United States, 94304
      • Lucile Packard Children's Hospital at Stanford
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• (Part 1 only) Participant has a body weight of ≥11.0 kilograms at the screening visit.
• Participant has a diagnosis of isolated MMA due to MUT deficiency confirmed by molecular genetic testing.
• Participant has a blood vitamin B12 level equal to or above the lower limit of normal (based on laboratory reference range) confirmed in the screening period.
• Participant or their legally authorized representative is willing and able to provide informed consent and/or assent as mandated by local regulations and is willing and able to comply with study-related assessments.
• Sexually active participants of childbearing or reproductive potential agree to use a highly effective method of contraception, consistent with local regulations, during the study and for 3 months after the last administration of study drug.
• (Part 2 only) Participants with 2 screening MMA levels ≥400 micromolar.
• (Parts 2 and 3 only) Participant is ≥5 years of age at the time of informed consent/assent.

Key Exclusion Criteria:

• Participant has a diagnosis of isolated MMA cofactor adenosyl-cobalamin (cb1A, cb1B, or cb1D) enzymatic subtypes or methylmalonyl-CoA epimerase deficiency or combined MMA with homocystinuria.
• Participant has previously received gene therapy for the treatment of MMA.
• Participant has a history of organ transplantation or planned organ transplantation during the period of study participation.
• Participant has an active, unstable, or clinically significant medical condition not related to MMA or history of noncompliance that, in the investigator's opinion, could potentiate the risk while participating in this study, interfere with the interpretation of study results, or limit the participant's participation in the study. This may include, but is not limited to, history of relevant food or drug allergies; history of cardiovascular, central nervous, gastrointestinal, or infectious disease; history of clinically significant pathology; and/or history of cancer.
• (Part 2 only) Participant has the partial MUT deficiency disease phenotype, as assessed by genotyping, clinical phenotype/presentation, or vitamin B12-responsive MMA.

Note: Additional inclusion/exclusion criteria may apply, per protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: mRNA-3705; Participants in Part 1 will receive a weight-based dose of mRNA-3705, administered IV, once every 2 weeks or once every 3 weeks for up to 10 doses over approximately 40 weeks. Participants in Part 2 and Part 3 will receive mRNA-3705 at the selected dose level and frequency for 3 months.	Biological: mRNA-3705; Sterile liquid for infusion; Other Names: modified mRNA encoding human; methylmalonyl-coenzyme A mutase
Placebo Comparator: Placebo; Participants only in Part 2 will receive placebo at the selected frequency for 3 months.	Biological: Placebo; Sterile liquid for infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Parts 1 and 3: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Study Drug-related TEAEs, Adverse Events of Special Interest (AESIs), Serious Adverse Events (SAEs), and TEAEs Leading to Treatment Discontinuation	Up to 134 weeks
Part 2: Percentage Change in Plasma MMA Levels at Month 3	Baseline, Month 3

Secondary Outcome Measures

Outcome Measure	Time Frame
Parts 1 and 3: Percentage Change in Plasma MMA Level	Baseline up to Week 30
Part 1: Maximum Observed Effect (Emax) for Plasma MMA Measurement after Single and Repeated Administrations of mRNA-3705	Baseline up to Week 30
Part 1: Area Below the Baseline and Above the Response Curve (AUC_Below_B) for Plasma MMA Measurement after Single and Repeated Administrations of mRNA-3705	Baseline up to Week 30
Part 1: Area Under the Curve that is the Area Under the Response Curve Above the Baseline (AUC_Above_B)-AUC_Below_B (AUC_Net_B) for Plasma MMA Measurement after Single and Repeated Administrations of mRNA-3705	Baseline up to Week 30
Parts 1-3: Percentage Change in Plasma 2-Methylcitric Acid (2-MC) Levels	Baseline up to Week 30
Parts 1-3: Maximum Observed Concentration (Cmax) of human Methylmalonyl-Coenzyme A Mutase (hMUT) mRNA-3705	0 (predose) to 264 hours postdose
Parts 1-3: Area Under the Concentration-Time Curve (AUC) of hMUT mRNA-3705	0 (predose) to 264 hours postdose
Parts 1-3: Titer of Anti-Polyethylene Glycol (PEG) Antibodies	0 (predose) to 336 hours postdose
Parts 2 and 3: Titer of Anti-hMUT Antibodies	0 (predose) to 336 hours postdose
Parts 2 and 3: Change from Baseline in Pediatric Quality of Life Inventory (PedsQL) Physical Function Score	Baseline, Month 3
Parts 2 and 3: Annualized Frequency of MMA-related Hospitalizations	Baseline up to Month 3
Parts 2 and 3: Annualized Frequency of Metabolic Decompensation Events	Baseline up to Month 3
Parts 2 and 3: Change from Baseline in PedsQL Total Score	Baseline, Week 47
Parts 2 and 3: Change from Baseline in Investigator Global Assessment of Severity (IGA-S)	Baseline, Week 47
Parts 2 and 3: Change from Baseline in Caregiver-Reported Global Impression of Severity (CrGI-S)	Baseline, Week 47
Parts 2 and 3: Change from Baseline in Investigator Global Assessment of Improvement (IGA-I)	Week 3 (Dose 2), Week 47
Parts 2 and 3: Change from Baseline in Caregiver-Reported Global Impression of Improvement (CrGI-I)	Week 3 (Dose 2), Week 47
Part 2: Number of Participants with TEAEs, SAEs, AESIs, and TEAEs Leading to Treatment Discontinuation	Up to 47 weeks
Part 2: Plasma Concentration of SM-86	0 (predose) to 48 hours postdose

Collaborators and Investigators

• Sponsor: ModernaTX, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2021
• Primary Completion (Actual): April 1, 2026
• Study Completion (Actual): April 1, 2026

Study Registration Dates

• First Submitted: May 19, 2021
• First Submitted That Met QC Criteria: May 19, 2021
• First Posted (Actual): May 24, 2021

Study Record Updates

• Last Update Posted (Actual): May 6, 2026
• Last Update Submitted That Met QC Criteria: May 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Moderna; mRNA; Genetic Diseases; Metabolism, Inborn Errors; mRNA-3705; Isolated Methylmalonic Acidemia; Isolated Methylmalonic Aciduria; Elevated Methylmalonic Acid (MMA)
• Additional Relevant MeSH Terms: Metabolic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Methylmalonic acidemia; Enzymes; Enzymes and Coenzymes; Intramolecular Transferases; Isomerases; Methylmalonyl-CoA Mutase
• Other Study ID Numbers: mRNA-3705-P101; 2022-502492-32-00 (Other Identifier: Clinical Trials Information System (CTIS))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes