mRNA-3705 for Methylmalonic Acidemia

Recruiting at 13 trial locations

Overseen By Moderna WeCare Team

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ModernaTX, Inc.

Disqualifiers: Gene therapy, Organ transplant, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 40 weeks (Part 1), 12 months (Part 2)

63 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

How is the drug mRNA-3705 different from other treatments for methylmalonic acidemia?

mRNA-3705 is a novel treatment that uses messenger RNA (mRNA) technology to address the underlying genetic cause of methylmalonic acidemia, which is different from traditional treatments that mainly focus on managing symptoms. This approach aims to provide a more targeted and potentially effective solution by delivering genetic instructions to produce the missing or defective enzyme in patients. ^{1 2 3 4 5}

What is the purpose of this trial?

This trial is testing mRNA-3705, a treatment that helps the body produce a missing enzyme, in patients with high levels of MMA due to a genetic condition. The goal is to see if it is safe and effective in reducing harmful substance buildup.

Eligibility Criteria

This trial is for individuals with isolated Methylmalonic Acidemia (MMA) due to MUT deficiency, confirmed by genetic testing. Participants must have normal or supplemented vitamin B12 levels, weigh at least 11 kg, and agree to use effective contraception. Excluded are those with organ transplants, other MMA types, prior gene therapy for MMA, significant unrelated medical conditions, or certain infections.

Inclusion Criteria

Your vitamin B12 levels are within the normal range, or if they are high due to taking B12 supplements, you may still be able to participate.

I agree to use effective birth control during and for 3 months after the study.

You have experienced at least 1 major depressive episode in the year before agreeing to take part in the study.

Exclusion Criteria

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.

I have a history of hepatitis B, C, or HIV but meet the specific recovery or negative criteria.

I have had gene therapy for MMA before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Observation

Participants undergo an observation period before dosing

48 to 72 hours (Part 1), 24 hours (Part 2)

Treatment

Participants receive mRNA-3705 intravenously every 2 or 3 weeks for up to 10 doses over approximately 40 weeks in Part 1, and for up to 12 months in Part 2

40 weeks (Part 1), 12 months (Part 2)

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years (Part 1), 6 months (Part 2)

Extension

Participants may opt into the mRNA-3705 extension study after completing the treatment period

Treatment Details

Interventions

• mRNA-3705

Trial Overview The study tests mRNA-3705 in patients with elevated methylmalonic acid from MUT deficiency. It aims to evaluate the safety of the drug as well as how it's processed in the body (pharmacokinetics) and its effect on the disease (pharmacodynamics).

Participant Groups

Group I: mRNA-3705 Experimental Treatment 1 Intervention

Participants in Part 1 will receive a weight based dose of mRNA-3705, administered intravenously (IV), once every 2 weeks (Q2W) or once every 3 weeks (Q3W) for up to 10 doses over approximately 40 weeks. Participants in Part 2 will receive mRNA 3705 at the selected dose level and frequency for up to 12 months.

mRNA-3705 is already approved in United States for the following indications:

Approved in United States as mRNA-3705 for:

Who Is Running the Clinical Trial?

ModernaTX, Inc.

Lead Sponsor

Trials

127

Recruited

66,790,000+

Dr. Stephen Hoge

ModernaTX, Inc.

Chief Medical Officer

MD from Harvard Medical School

Stéphane Bancel

ModernaTX, Inc.

Chief Executive Officer since 2011

MBA from Harvard Business School, MSc in Engineering from École Centrale Paris

Findings from Research

In a study of 12 patients with cblA-type methylmalonic acidemia (MMA), the main symptoms included vomiting, dyspnea, and drowsiness, with 11 patients showing a positive response to vitamin B12 treatment.

After treatment, significant reductions in harmful metabolites were observed, and 66.7% of patients achieved normal development, indicating that early intervention can lead to better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Analysis of 12 cases with methylmalonicacidemia cblA type]. E, H., Han, L., Ye, J., et al.[2020]

This study reports the first three cases of Combined Malonic and Methylmalonic Aciduria (CMAMMA) in China, highlighting the clinical variability of the disease, which can range from asymptomatic to severe symptoms, including anemia and jaundice.

All patients exhibited elevated levels of malonic and methylmalonic acids in their urine, and different genetic variants in the ACSF3 gene were identified, suggesting that CMAMMA can be a benign condition but may lead to severe symptoms under certain triggers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients. Wang, P., Shu, J., Gu, C., et al.[2021]

In a study of 15 Chinese patients with methylmalonic acidemia (MMA), common clinical symptoms included poor feeding, vomiting, lethargy, seizures, and developmental delays, with high levels of propionylcarnitine and methylmalonic acid observed in all patients.

Genetic analysis revealed that most patients had mutations in the MUT and MMACHC genes, with a high mortality rate of seven patients dying within the first year, while those who survived showed varying degrees of growth and developmental challenges despite treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Clinical and variant analysis of 15 patients with methylmalonic acidemia]. Xiong, H., Deng, W., Guo, L., et al.[2020]

In a study of 77 Chinese patients with methylmalonic aciduria, 59.7% had the condition combined with homocystinemia, indicating a higher prevalence of this combination in China compared to other countries.

The clinical outcomes varied widely, with neonatal and infantile onset cases being more severe; however, some patients with combined methylmalonic aciduria and homocystinemia showed significant recovery and normal intelligence, highlighting the importance of early diagnosis and treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and biochemical studies on Chinese patients with methylmalonic aciduria. Yang, Y., Sun, F., Song, J., et al.[2022]

In a study of 1,003 patients with methylmalonic acidemia in China, the most common type was combined methylmalonic acidemia and homocysteinemia, primarily caused by MMACHC mutations, which were found in 94.7% of those with this condition.

Newborn screening was crucial for early diagnosis, leading to better outcomes, as 97.2% of patients diagnosed after onset received treatment, with 45 achieving normal development, highlighting the importance of early intervention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Heterogeneous phenotypes, genotypes, treatment and prevention of 1 003 patients with methylmalonic acidemia in the mainland of China]. Liu, Y., Liu, YP., Zhang, Y., et al.[2019]

References

1. China pubmed.ncbi.nlm.nih.gov

[Analysis of 12 cases with methylmalonicacidemia cblA type]. [2020]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Combined Malonic and Methylmalonic Aciduria Due to ACSF3 Variants Results in Benign Clinical Course in Three Chinese Patients. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Clinical and variant analysis of 15 patients with methylmalonic acidemia]. [2020]

4. United States pubmed.ncbi.nlm.nih.gov

Clinical and biochemical studies on Chinese patients with methylmalonic aciduria. [2022]

5. China pubmed.ncbi.nlm.nih.gov

[Heterogeneous phenotypes, genotypes, treatment and prevention of 1 003 patients with methylmalonic acidemia in the mainland of China]. [2019]