mRNA-3705 for Methylmalonic Acidemia

Recruiting at 14 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests mRNA-3705, a new treatment for individuals with methylmalonic acidemia (MMA) caused by a specific enzyme deficiency. The main goal is to determine the safety of mRNA-3705 and its effects on the body. Participants will receive the treatment via IV every two or three weeks for several months. Suitable candidates must have a confirmed diagnosis of this type of MMA and a normal vitamin B12 level, without any complicating conditions. As a Phase 1, Phase 2 trial, this research aims to understand how the treatment works in people and to measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that mRNA-3705 is likely to be safe for humans?

Research has shown that mRNA-3705, a new treatment for methylmalonic acidemia (MMA), has undergone safety evaluation. Studies in mice indicate that mRNA-3705 is safe and effective over time, increasing protein levels and reducing symptoms without major issues.

In human trials, results have been encouraging. As of August 2023, no deaths or instances required participants to stop taking mRNA-3705 due to safety concerns, suggesting the treatment is generally well-tolerated. However, the study remains ongoing, and participants should discuss any concerns with the study team. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike standard treatments for methylmalonic acidemia (MMA) that often focus on dietary management and vitamin B12 supplementation, mRNA-3705 offers a new approach by using messenger RNA (mRNA) to address the underlying enzyme deficiency. Researchers are excited about mRNA-3705 because it is designed to instruct the body to produce the functional enzyme needed to process certain proteins and fats properly, potentially correcting the metabolic issue at its source. This innovative mechanism of action could lead to more effective management of MMA, offering hope for improved outcomes beyond what current options can achieve.

What evidence suggests that mRNA-3705 might be an effective treatment for methylmalonic acidemia?

Research has shown that mRNA-3705, the investigational treatment in this trial, may help treat methylmalonic acidemia (MMA), a rare genetic disorder. In studies with mice, this treatment increased the amount of a specific liver protein (MMUT) by 2.1 to 3.4 times more than an earlier version of the drug. This suggests that mRNA-3705 could better address the protein shortage causing MMA. These early results are promising, but further research is needed to confirm the drug's effects in humans. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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).

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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]

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]

Citations

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clinicaltrials.gov

clinicaltrials.gov/study/NCT04899310

NCT04899310 | A Study to Assess Safety, ...

This is a study of mRNA-3705 in participants with isolated elevated methylmalonic acid (MMA) due to methylmalonyl-coenzyme A (CoA) mutase (MUT) deficiency.

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trials.modernatx.com

trials.modernatx.com/study/?id=mRNA-3705-P101

A Clinical Trial of a Methylmalonic Acidemia (MMA) Due to ...

The Landmark Study is evaluating whether an investigational treatment, called mRNA-3705, is safe in participants with methylmalonic acidemia (MMA) due to ...

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sciencedirect.com

sciencedirect.com/science/article/abs/pii/S109671922400444X

Improved therapeutic efficacy in two mouse models of ...

mRNA-3705 produced 2.1–3.4-fold higher levels of hepatic MMUT protein expression than the first-generation drug product mRNA-3704 when given at an identical ...

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clinicaltrials.eu

clinicaltrials.eu/trial/study-on-mrna-3705-for-patients-with-methylmalonic-acidemia-due-to-methylmalonyl-coa-mutase-deficiency/

Study on mRNA-3705 for Patients with Methylmalonic ...

The purpose of the study is to evaluate the safety and effectiveness of mRNA-3705 in people with MMA. The study is divided into two parts ...

5.

pubmed.ncbi.nlm.nih.gov

pubmed.ncbi.nlm.nih.gov/39121792/

Improved therapeutic efficacy in two mouse models of ...

mRNA-3705 produced 2.1-3.4-fold higher levels of hepatic MMUT protein expression than the first-generation drug product mRNA-3704 when given at an identical ...

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04899310

NCT04899310 | A Study to Assess Safety, ...

The main goal of the study is to assess safety, pharmacokinetics, and pharmacodynamics of mRNA-3705. Detailed Description. This study comprises 2 parts: Dose ...

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clinicaltrials.eu

clinicaltrials.eu/trial/study-on-long-term-safety-of-mrna-3705-for-patients-with-methylmalonic-acidemia-mma/

Study on Long-Term Safety of mRNA-3705 for Patients with ...

This study evaluates the long-term safety of mRNA-3705 for MMA, monitoring side effects and changes in condition over time, and may include ...

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s29.q4cdn.com

s29.q4cdn.com/435878511/files/doc_downloads/program_detail/2024/06/mma-5-2-24.pdf

Methylmalonic acidemia (MMA) (mRNA-3705)

Safety in mRNA-3705-P101: overall Summary to date. As of August 25, 2023: • No deaths or discontinuations due to safety-related reasons. –One ...