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 Other Clinical Studies of mRNA-3705.

The primary objective of this study is to evaluate the long-term **safety** of mRNA-3705 in participants with isolated methylmalonic acidemia (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency, who have previously participated in other clinical studies of mRNA-3705. This is clinically relevant as it aims to ensure the continued safety of mRNA-3705, a potential therapeutic agent, in a population with a rare metabolic disorder, thereby contributing to the understanding of its risk profile over extended use.

Secondary objectives include:

• Evaluating the long-term pharmacodynamic (PD) activity of mRNA-3705 in reducing methylmalonic acid and 2-methylcitric acid levels, which are primary biomarkers.
• Assessing the long-term pharmacokinetic (PK) profile of mRNA encoding hMUT and SM-86.
• Evaluating changes in metabolic decompensation events (MDEs) occurring prior to study enrollment, during treatment, and during the follow-up period.
• Quantifying healthcare resource utilization (HCRU) over time.
• Evaluating the disease impact on missed school and workdays.
• Assessing the presence or development of anti-PEG and anti-hMUT antibodies.
• Characterizing and evaluating patient-centered outcome assessments in participants with MMA over long-term treatment with mRNA-3705.
• Evaluating MMA-related hospitalizations and urgent healthcare visits.

The clinical trial involves a total of **15 participants** diagnosed with isolated **methylmalonic acidemia (MMA)** due to methylmalonyl-coenzyme A mutase (MUT) deficiency. The study population includes both male and female subjects, with an age range that encompasses children and adolescents. Participants were selected based on their previous involvement in clinical studies of mRNA-3705, specifically those who completed the assigned dose regimen or are eligible for early transition due to interruptions caused by COVID-19 vaccination. The trial includes a vulnerable population, indicating that special considerations are in place to ensure the safety and ethical treatment of participants. The study does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria emphasize the completion of prior study protocols and the ability to provide informed consent, either by the participant or their legally authorized representative.

The clinical trial is designed as a **Phase 1/2**, global, open-label, extension study to evaluate the long-term safety and clinical activity of **mRNA-3705** in participants with isolated **methylmalonic acidemia** (MMA) due to methylmalonyl-coenzyme A mutase (MUT) deficiency. The trial aims to assess the safety profile of mRNA-3705 in individuals who have previously participated in other clinical studies involving this investigational product. The study is expected to commence recruitment on August 8, 2023, and is estimated to conclude by January 15, 2029.

Participants will be involved in the study for an extended period, with the trial duration spanning several years. The study will include multiple visits, starting with an inclusion (screening) visit to confirm eligibility based on criteria such as completion of prior mRNA-3705 studies or eligibility for early transition due to missed doses related to COVID-19 vaccination. Follow-up visits will be conducted to monitor the incidence of treatment-emergent adverse events (AEs) and to evaluate secondary endpoints, including changes in blood methylmalonic acid levels, mRNA levels, and healthcare resource utilization. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted.

Participants are expected to remain in the study for its entire duration unless specific conditions necessitate early termination. Such conditions may include the occurrence of significant adverse events or the participant's inability to comply with study-related assessments. The trial's methodology ensures rigorous monitoring and data collection to achieve its primary and secondary objectives, contributing valuable insights into the long-term safety and efficacy of mRNA-3705 in treating MMA.

The clinical trial involves the administration of **mRNA-3705**, an advanced therapy investigational product. This product is a lipid nanoparticle (LNP)-encapsulated modified mRNA encoding human methylmalonyl-coenzyme A mutase containing a polymorphism at position 671. It is administered via intravenous infusion. The investigational product is designed to evaluate its long-term safety and clinical activity in participants with methylmalonic acidemia (MMA) who have previously participated in other clinical studies of mRNA-3705.

**Diphenhydramine Hydrochloride** is used as an auxiliary treatment in the trial. It is provided in tablet form and administered orally. This chemical-origin antihistamine is used to manage allergic reactions that may occur during the study.

**Fexofenadine Hydrochloride** is another antihistamine included in the study. It is available as film-coated tablets for oral use. This chemical-origin medication is used to prevent or treat allergic symptoms in participants.

**Sodium Chloride Solution 0.9%** serves as a diluent in the trial. It is administered intravenously in the form of a solution for injection. This chemical-origin solution is used to maintain fluid balance and as a vehicle for other medications.

**Paracetamol** is included in multiple forms: orodispersible tablet, tablet, and solution for infusion. It is administered orally or via infusion as an antipyretic to manage fever in participants. The chemical-origin paracetamol is used to ensure participant comfort during the trial.

**Dexamethasone** and **Dexamethasone Phosphate** are corticosteroids used in the study. Both are provided as solutions for injection and administered intravenously. These chemical-origin medications are used to manage inflammation and immune responses during the trial.

**Ibuprofen** is included as a non-steroidal anti-inflammatory drug (NSAID) in both oral suspension and tablet forms. It is administered orally to manage pain and inflammation in participants. This chemical-origin medication is used to ensure participant comfort.

**Hydroxyzine Hydrochloride** is another antihistamine used in the trial. It is provided in tablet form for oral use. This chemical-origin medication is used to manage allergic reactions that may occur during the study.

**Cetirizine Dihydrochloride** is included as an antihistamine in both oral solution and film-coated tablet forms. It is administered orally to prevent or treat allergic symptoms in participants. This chemical-origin medication is used to ensure participant comfort.

**Famotidine** is used as an antiacid in the trial. It is provided in tablet form for oral use. This chemical-origin medication is used to manage gastric acid-related symptoms that may occur during the study.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the long-term safety and clinical activity of mRNA-3705, with auxiliary treatments provided to manage potential side effects and ensure participant comfort.

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint focuses on the incidence of treatment-emergent adverse events (AEs). Secondary endpoints include changes in blood methylmalonic acid and 2-methylcitrate (2-MC) levels, which serve as primary biomarkers, from baseline over time during the Treatment and Follow-up Periods. Additionally, pre- and postdose levels of human methylmalonyl-CoA mutase (hMUT) mRNA and SM-86 will be measured over time in the Treatment Period.

Further secondary endpoints involve evaluating changes in metabolic decompensation events (MDEs) both pretreatment and posttreatment, including annualized MDE rate and duration. The incidence and duration of healthcare resource utilization (HCRU) visits, as well as the annualized frequency of methylmalonic acidemia (MMA)-related hospitalizations and healthcare visits, will also be assessed. The impact of the disease on missed school and workdays will be monitored, alongside the incidence and titers of anti-polyethylene glycol (anti-PEG) and anti-hMUT antibodies during the Treatment and Follow-up Periods.

Patient-reported outcomes will be evaluated using the Pediatric Quality of Life Inventory (PedsQL™) and the PedsQL Family Impact Module™ (v4.0), with changes measured over time in the Treatment and Follow-up Periods. Additional assessments include changes in the Methylmalonic Acidemia Patient Assessment Questionnaire-Patient Symptom Score (MMAPAQ-PSS), Clinical Global Impression-Severity (CrGI-S), Clinical Global Impression-Improvement (CrGI-I), Investigator Global Assessment-Improvement (IGA-I), Investigator Global Assessment-Severity (IGA-S), and the EQ-5D-5L/Y.