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

Trial ID: 2022-502492-32-00
Protocol: mRNA-3705-P101
Sponsor: Moderna Inc.

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Diseases & Conditions

Methylmalonic acidaemia

Objectives

The primary objective of this study is to evaluate the **safety** and **tolerability** of mRNA-3705 when administered intravenously to participants with **Isolated Methylmalonic Acidemia** due to Methylmalonyl-CoA Mutase Deficiency. This is clinically relevant as it aims to ensure that the treatment is safe for patients, which is a critical step before assessing its therapeutic efficacy.

The secondary objectives include:

Characterizing the pharmacodynamic (PD) response to mRNA-3705 by measuring changes in blood methylmalonic acid levels after single and repeated administrations.
Assessing changes in blood 2-methylcitrate levels and the pharmacokinetics (PK) of human MUT mRNA.
Evaluating the presence and formation of anti-polyethylene glycol (PEG) antibodies and anti-hMUT antibodies.
In Part II, the study will further evaluate the efficacy of mRNA-3705 by assessing MMA-related hospitalizations, prescribed protein intake, and patient-centered outcomes related to signs, symptoms, quality of life, and overall assessment.
Additionally, the safety and tolerability of mRNA-3705 will be evaluated, along with the characterization of repeated-dose PK and assessment of SM-86 exposure after single and repeated doses.

Participants

The clinical trial involves a total of **33 participants** diagnosed with **Isolated Methylmalonic Acidemia Due to Methylmalonyl-CoA Mutase Deficiency**. The study population includes both male and female subjects, with an age range starting from **1 year** and above. Participants were selected based on specific criteria, including a confirmed diagnosis through molecular genetic testing and a body weight of at least **11.0 kg**. The trial includes individuals with a blood vitamin B12 level at or above the lower limit of normal, with considerations for those with elevated levels due to supplementation. Participants are required to comply with study-related assessments and, if of reproductive potential, agree to use effective contraception. The trial population is considered vulnerable, and the study aims to evaluate the safety, tolerability, and efficacy of mRNA-3705 administered intravenously. Lifestyle factors such as diet and physical activity are not specified, but participants must have parameters indicating the clinical severity of MMA. The selection process ensures that the participants are representative of the target population for this condition.

Plans and Procedures

The clinical trial is a **Phase 1/2, open-label, dose optimization study** designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of **mRNA-3705** in participants with **Isolated Methylmalonic Acidemia** due to **Methylmalonyl-CoA Mutase Deficiency**. The trial is structured to include two parts: Part I focuses on assessing the safety and tolerability of mRNA-3705 administered intravenously, while Part II evaluates the efficacy of the treatment by comparing the frequency of metabolic decompensation events (MDEs) with the standard of care. The study is expected to run from July 2021 to May 2027, with participant involvement lasting up to 12 months.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, body weight, and genetic diagnosis. The screening visit will also ensure that participants have a blood vitamin B12 level within the normal range. Following successful screening, participants will receive mRNA-3705 through intravenous injection, with follow-up visits scheduled to monitor safety, tolerability, and pharmacokinetic parameters. These visits will include assessments of blood methylmalonic acid levels and other relevant biomarkers. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of the treatment's impact on the participant's condition.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. Such conditions include the occurrence of treatment-emergent adverse events (TEAEs) that lead to discontinuation, or if the participant withdraws consent. The primary endpoints of the study include the incidence and severity of TEAEs, while secondary endpoints focus on changes in blood methylmalonic acid levels and other pharmacodynamic and pharmacokinetic parameters. The study aims to provide valuable insights into the potential of mRNA-3705 as a therapeutic option for this rare metabolic disorder.

Treatment

The clinical trial involves the administration of **mRNA-3705**, an experimental medication designed for participants with isolated **Methylmalonic Acidemia** due to **Methylmalonyl-CoA Mutase Deficiency**. The active substance in mRNA-3705 is a **modified mRNA encoding human methylmalonyl-coenzyme A mutase**, which contains a polymorphism at position 671. This investigational product is formulated as an **injection** and is delivered via the **intravenous** route. The administration of mRNA-3705 is encapsulated within lipid nanoparticles (LNPs) to facilitate delivery. The study is structured to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of mRNA-3705, with a focus on dose optimization. The frequency of administration is determined by the study protocol, and participant compliance is monitored throughout the trial.

In addition to the experimental treatment, the study includes a comparison with **standard-of-care therapy**. This non-experimental treatment serves as a comparator to assess the efficacy of mRNA-3705 in reducing the frequency of metabolic decompensation events (MDEs) in participants. The standard-of-care therapy is administered according to established medical guidelines for managing Methylmalonic Acidemia. Compliance with the standard-of-care regimen is also monitored to ensure accurate comparison with the investigational product.

Efficacy

The efficacy of mRNA-3705 in the clinical trial will be assessed primarily by evaluating the **annualized frequency of metabolic decompensation events (MDEs)** after 12 months of treatment, as compared with the standard of care. Secondary efficacy endpoints include changes in blood methylmalonic acid levels and the annualized frequency of hospitalizations related to methylmalonic acidemia (MMA) after 12 months of treatment. Additionally, changes from baseline in prescribed protein intake, measured in grams per kilogram per day and as a percentage of the recommended dietary allowance (RDA), will be evaluated. Patient-reported outcomes will be assessed using the Pediatric Quality of Life Inventory (PedsQL™) and the PedsQL™ Family Impact Module, as well as the Methylmalonic Acidemia Patient Assessment Questionnaire-Patient Symptom Score (MMAPAQ-PSS) and Investigator Global Assessment-Improvement (IGA-I) and Severity (IGA-S) scores.

These efficacy parameters will be measured at specified timepoints throughout the study, including baseline and after 12 months of treatment. The collection and analysis of these parameters will involve validated scales and laboratory tests to ensure accuracy and reliability. The trial is designed to provide comprehensive data on the efficacy of mRNA-3705 in improving clinical outcomes for participants with isolated methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency.

Inclusion and Exclusion Criteria

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Inclusion Criteria

(Part 1 only) Participant is ≥1 year of age at the time of informed consent/assent. 2. (Part 1 only) Participant has a body weight of ≥11.0 kg at the Screening Visit. 3. Participant has a diagnosis of isolated MMA due to MUT deficiency confirmed by molecular genetic testing (see guidance in Section 8.1.2 for participants <23.3 kg). 4. 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. 5. 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. 6. 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. 7. (Part 1 only) Participants with parameters that indicate MMA clinical severity as described in Section 10.2.2. 8. (Part 2 only) Participants with 2 screening methylmalonic acid levels ≥400 μM, as described in Section 8.1.2. 9. (Parts 2& 3 only) Participant is ≥5 years of age at the time of informed consent/assent.

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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. 2. Participant has any individual laboratory abnormalities achieving exclusionary thresholds defined in Table 16. 3. Participant has previously received gene therapy for the treatment of MMA. 4. Participant has an eGFR <30 mL/min/1.73 m2, as estimated by the Schwartz formula for participants <18 years of age (Schwartz et al 2009), or by the Chronic Kidney Disease Epidemiology Collaboration creatinine-based formula for participants ≥18 years of age (Inker et al 2021), or receives long-term dialysis. 5. Participant has a corrected QT interval >480 ms using Bazett’s correction. 6. For participants of reproductive potential, the participant has a positive pregnancy test at the Screening Visit. 7. Participant is pregnant or breastfeeding. 8. Participant has a history of organ transplantation or planned organ transplantation during the period of study participation. 9. Participant has a history of hypersensitivity to any components of the study drug. 10. Participant has a history of hypersensitivity or contraindication to acetaminophen/paracetamol and/or ibuprofen or H1/H2 receptor blockers. 11. Participation in another clinical study of another investigational agent within 30 days before study entry or within 5 elimination half-lives of the investigational agent, whichever is longer. 12. Participant has undergone a major surgical procedure within 30 days before the Screening Visit (excludes central line, port, or feeding tube placement). 13. Participant has new uses or adjusted dosage of antibiotic therapy used to reduce propionate production within 2 weeks before first dose of study drug. 14. Any participant with a new or adjusted dosage of antibiotics may enter the Treatment Period after 2 weeks of stable antibiotic regimen. 14. This criterion has been removed and integrated into Exclusion Criterion 13 in Protocol Amendment 9. 15. 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. 16. Participant has received COVID-19 vaccination (generally 2 doses or a booster) within 28 days prior to first study drug administration. 17.This criterion has been removed in Protocol Amendment 10. 18. Participant has a history of anaphylaxis/anaphylactoid reaction or severe hypersensitivity with infusions. 19. This criterion has been removed in Protocol Amendment 9. 20. (Part 2 only) Participant has the mut- disease phenotype, as assessed by genotyping, clinical phenotype/presentation, or Vitamin B12-responsive MMA.