An Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in the mRNA-3705-P101 Study

Study Overview
=================
Brief Summary
-----------------
The primary objective of this study is to evaluate the long-term safety of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency who have previously participated in Study mRNA-3705-P101 (NCT04899310).

Detailed Description
-----------------
Participants with isolated MMA due to MUT deficiency who were previously enrolled in the mRNA-3705-P101 (NCT04899310) study will have the option to enroll into this extension study provided all eligibility criteria have been met. The study will include 2 periods: 1) Treatment Period and 2) Follow-up Period (up to 2 years after the last dose of study drug). Treatment Period will continue unless one of the following occurs: mRNA-3705 receives marketing approval and reimbursement in the country of origin of the participant, the participant discontinues study drug, the participant is no longer receiving clinical benefit (in the opinion of the Investigator), or Sponsor discontinues the development of mRNA-3705.

Official Title
-----------------
A Phase 1/2, Global, Open-Label, Extension Study to Evaluate the Long-Term Safety and Clinical Activity of mRNA-3705 in Participants Previously Enrolled in the mRNA-3705-P101 Study

Conditions
-----------------
Methylmalonic Acidemia

Intervention / Treatment
-----------------
* Drug: mRNA-3705


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Completed the mRNA-3705-P101 assigned dose regimen treatment time period or is eligible for early transition to this study because they missed more than 3 consecutive doses of study drug due to coronavirus disease 2019 (COVID-19) vaccination during the mRNA-3705-P101 study. Completed the End of treatment (EOT) Visit in Study mRNA-3705-P101 within 10 days of first dose of mRNA-3705 in the current study. Exclusion Criteria: Not expected to receive clinical benefit from continued mRNA-3705 administration, in the opinion of the Investigator. Any clinical or laboratory abnormality or medical condition that, at the discretion of the Investigator, may put the individual at increased risk by participating in this study. History of liver and/or kidney transplant. NOTE: Other inclusion and exclusion criteria may apply.

Ages Eligible for Study
-----------------
Minimum Age: 1 Year

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mRNA-3705<br>Participants will receive mRNA-3705 at the same dose levels at the same dosing interval (every 2 weeks [q2W], every 3 weeks [q3W], or every 4 weeks [q4W]) last received in the mRNA-3705-P101 study, unless the Sponsor recommends modification. | Drug: mRNA-3705<br>* A sterile liquid for injection<br>* Other names: methylmalonyl-coenzyme A mutase;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) |  | Baseline up to follow-up period (up to 8 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Methylmalonic Acid and 2-Methylcitric Acid (2-MC) Levels (Primary Biomarkers) From Baseline up to 8 Years |  | Baseline, Year 8 | 
| Pre- and Postdose Human Methylmalonyl-Coenzyme A Mutase (hMUT) mRNA and SM-86 Levels |  | Baseline up to 6 years | 
| Number of Clinically Significant Events | Clinically significant event is defined as a composite of the following: - Hospitalization (excluding hospitalizations for chronic diseases not related to MMA or elective hospitalizations for conditions not related to MMA); Emergency room visits; and Emergency interventions outside of healthcare settings to prevent an metabolic decompensation event (MDE) (sick-day diets and fluid resuscitation at home). | Baseline up to 8 years | 
| Number of MDEs |  | Baseline up to 8 years | 
| Number of Healthcare Resource Utilization Visits |  | Baseline up to 8 years | 
| Change in Disease Impact on Missed School and Workdays From Baseline up to 8 Years |  | Baseline, Year 8 | 
| Number of Anti-Polyethylene Glycol (PEG) and Anti-hMUT Antibodies |  | Baseline up to 8 years | 
| Change in Health-Related Quality of Life (HRQoL) as Measured Using the Pediatric Quality of Life Inventory (PedsQL™) at Month 3 up to 8 Years |  | Month 3, Year 8 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Isolated Methylmalonic acidemia, Isolated methylmalonic aciduria, Elevated methylmalonic acid (MMA), Metabolism, Inborn Errors, Genetic Diseases, Moderna, mRNA, mRNA-3705