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

Methylmalonic Acidemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04899310
• Other study ID #: mRNA-3705-P101
• Secondary ID: 2020-004980-24
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: August 6, 2021
• Est. completion date: August 1, 2028

Study information

• Verified date: April 2024
• Source: ModernaTX, Inc.
• Contact: Moderna Clinical Trials Support Center
• Phone: 1-877-777-7187
• Email: clinicaltrials[@]modernatx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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, pharmacokinetics, and pharmacodynamics of mRNA-3705.

Description:

This study comprises 2 parts: Dose Optimization part (Part 1) followed by a Dose Expansion part (Part 2). The study is designed to evaluate multiple doses and dosing intervals of mRNA-3705.

In both parts, after confirmation of eligibility, participants will enter an Observation Period (48 to 72 hours pre-dose) in Part 1 and 24 hours before dose 1 in Part 2), followed by the Treatment Period. Participants who complete the Treatment Period, including the End of Treatment (EOT) Visit, are offered participation in the mRNA-3705 extension study. If the participant chooses to participate and meets eligibility criteria, they will be enrolled in the extension study; otherwise, they will transition to the follow-up part of the study (approximately 2-year follow-up in Part 1 and 6-months follow-up in Part 2).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 63
• Est. completion date: August 1, 2028
• Est. primary completion date: August 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year and older

Eligibility

Key Inclusion Criteria:

• Participant has a body weight of =11.0 kilograms (kg) 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. For those participants found to have an elevated blood vitamin B12 level, the participant may enter if, in the opinion of the Investigator, the cause of the elevation is secondary to B12 supplementation.

• 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 females of childbearing potential and sexually active males of reproductive potential agree to use a highly-effective method of contraception during the study and for 3 months after the last administration of study drug.

• (Part 2 only) At least 1 documented MDE in the 12-month period before consent.

Key Exclusion Criteria:

• Participant has a diagnosis of isolated MMA 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) History of hepatitis B (known positive hepatitis B surface antigen [HbsAg]), hepatitis C virus (HCV), or HIV (positive HIV1/HIV-2 antibodies). Participants with a past or resolved hepatitis virus B (HBV) infection (defined as the presence of hepatitis B core antibody and absence of HbsAg) are eligible. Participants with history of positive results for HCV antibody are eligible only if polymerase chain reaction is negative for HCV RNA.

Related Conditions & MeSH terms

• Acidosis
• Amino Acid Metabolism, Inborn Errors
• Methylmalonic Acidemia

Intervention

Biological:
• mRNA-3705
A sterile liquid for injection

Locations

Country	Name	City	State
Australia	Royal Children's Hospital Melbourne	Parkville	Victoria
Australia	Children's Hospital at Westmead	Westmead	New South Wales
Canada	Stollery Children's Hospital University of Alberta	Edmonton	Alberta
Canada	Hospital For Sick Children	Toronto	Ontario
France	Hôpital Necker - Enfants Malades	Paris
Netherlands	Erasmus MC	Rotterdam
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Spain	Hospital Universitario Cruces	Barakaldo
Spain	Hospital Sant Joan de Deu - PIN	Esplugues de Llobregat	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Spain	CHUS - H. Clinico U. de Santiago	Santiago de Compostela
Spain	Hospital Universitario Virgen del Rocio - PPDS	Sevilla
United Kingdom	Birmingham Children's Hospital NHS Foundation Trust	Birmingham
United Kingdom	Royal Manchester Childrens Hospital	Manchester
United States	UCLA Medical Center	Los Angeles	California
United States	Lucile Packard Children's Hospital at Stanford	Palo Alto	California
United States	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
ModernaTX, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Part 1: Number of Participants with Treatment-Emergent Adverse Events (TEAEs), Study Drug-related TEAES, Serious Adverse Events (SAEs), and TEAEs Leading to Treatment Discontinuation		Up to 144 weeks
Primary	Part 2: Annualized Frequency of Metabolic Decompensation Events (MDEs)		Baseline up to Week 52
Secondary	Change in Blood Methylmalonic Acid Level		Baseline up to Week 40
Secondary	Maximum Observed Effect (Emax) for Plasma Methylmalonic Acid Measurement after Single and Repeated Administrations of mRNA-3705		Baseline up to Week 40
Secondary	Area Under the Effect Curve (AUEC) for Plasma Methylmalonic Acid Measurement after Single and Repeated Administrations of mRNA-3705		Baseline up to Week 40
Secondary	Duration of Response for Plasma Methylmalonic Acid Measurement after Single and Repeated Administrations of mRNA-3705		0 (predose) up to 336 hours postdose
Secondary	Change in Blood 2-Methylcitric Acid (2-MC ) Levels		Baseline up to Week 40
Secondary	Maximum Observed Concentration (Cmax) of human Methylmalonyl-Coenzyme A Mutase (hMUT) mRNA-3705		0 (predose) to 336 hours postdose
Secondary	Area Under the Concentration-Time Curve (AUC) of hMUT mRNA-3705		0 (predose) to 336 hours postdose
Secondary	Titer of Anti-Polyethylene Glycol (PEG) Antibodies		0 (predose) to 336 hours postdose