Long-Term Safety of mRNA-3705 for Methylmalonic Acidemia

Recruiting at 10 trial locations

Overseen By Moderna WeCare Team

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ModernaTX, Inc.

Disqualifiers: Liver transplant, Kidney transplant, 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: 2

Duration: Indefinite, until specific conditions are met

63 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the long-term safety of mRNA-3705 for individuals with methylmalonic acidemia (MMA), a rare genetic disorder affecting the breakdown of certain fats and proteins. The focus is on those with MMA due to a specific enzyme deficiency who have already participated in earlier studies of mRNA-3705. Participants should have completed a previous trial with this treatment or missed doses due to COVID-19 vaccination. The trial aims to ensure that continued use of mRNA-3705 remains safe and beneficial over time. As a Phase 1, Phase 2 trial, this research seeks to understand how the treatment works in people and 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 shows that mRNA-3705 appears safe. In earlier studies, participants tolerated it well. These studies involved people with methylmalonic acidemia (MMA), a rare genetic disorder. Researchers closely monitored side effects and changes in the condition, and no serious safety issues emerged.

Additionally, tests on animals showed that mRNA-3705 was safe and effective in mice, leading to higher protein levels and fewer MMA symptoms. While results in animals don't always match human outcomes, they provide helpful early information.

Since mRNA-3705 remains in the early stages of testing, more information is needed. However, ongoing research aims to ensure its safety for long-term use in people with MMA. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for methylmalonic acidemia (MMA) focus on managing symptoms through dietary restrictions and supplements, such as vitamin B12, but they don’t address the root cause. Unlike these standard care options, mRNA-3705 is unique because it uses messenger RNA (mRNA) technology to target the underlying genetic defect causing MMA. By providing instructions to produce the missing or defective enzyme, mRNA-3705 aims to correct the metabolic imbalance at its source. Researchers are excited about this approach because it has the potential to offer a long-term solution, rather than just temporary symptom management.

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

Research has shown that mRNA-3705, the treatment under study in this trial, may help treat methylmalonic acidemia (MMA), a condition caused by a lack of a specific enzyme. In studies with mice, mRNA-3705 increased the levels of an important liver protein, MMUT, by 2.1 to 3.4 times more than an earlier treatment, mRNA-3704. This protein is crucial because it helps the body break down certain amino acids and fats. Higher levels of MMUT might reduce the buildup of harmful acids in people with MMA. Early studies with patients are examining the safety and effectiveness of this treatment, with ongoing research to confirm these results in humans. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for people with Methylmalonic Acidemia who were in a previous study (mRNA-3705-P101). They must have finished the earlier trial or moved to this one because they missed doses due to COVID-19 vaccination.

Inclusion Criteria

I missed doses in a previous study due to COVID-19 vaccination.

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

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

I have had a liver or kidney transplant.

Not expected to receive clinical benefit from continued mRNA-3705 administration, in the opinion of the Investigator

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive mRNA-3705 at the same dose levels and intervals as in previous studies, unless modified by the Sponsor

Indefinite, until specific conditions are met

Every 2 or 3 weeks, depending on previous study protocol

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years after the last dose

Open-label extension

Participants may continue treatment long-term if mRNA-3705 receives market approval and reimbursement

What Are the Treatments Tested in This Trial?

Interventions

• mRNA-3705

Trial Overview

The trial is testing the long-term safety and effectiveness of mRNA-3705, a treatment for those with isolated methylmalonic acidemia caused by MUT deficiency, based on their prior participation in an initial study.

How Is the Trial Designed?

Group I: mRNA-3705 Experimental Treatment 1 Intervention

Participants will receive mRNA-3705 at the same dose levels at the same dosing interval (every 2 weeks \[Q2W\], or every 3 weeks \[Q3W\]) last received in the clinical study of mRNA-3705 in which they initially participated, unless the Sponsor recommends modification.

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

Patients with methylmalonic acidaemia who are cobalamin responsive have a significantly better long-term outcome, with milder disease and no reported deaths, compared to the non-responsive group.

The non-responsive patients, especially those with early onset, face a poor prognosis with higher mortality rates and cognitive challenges, indicating a need for alternative treatments for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurological outcome of methylmalonic acidaemia. Nicolaides, P., Leonard, J., Surtees, R.[2019]

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]

Liver (LT) or liver-kidney transplantation (LKT) for severe methylmalonic acidemia resulted in 100% patient survival and significant reductions in serum MMA levels, indicating effective treatment of the condition.

Post-transplantation, patients showed stabilization or improvement in neurodevelopmental abilities, suggesting that these procedures not only address metabolic issues but also positively impact cognitive development.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. Niemi, AK., Kim, IK., Krueger, CE., et al.[2019]

In a study of 30 patients with Methylmalonic acidemia (MMA), the most common subtype was MMA cblC, and early detection and management were highlighted as crucial for improving patient outcomes.

The study found a 30% mortality rate, particularly in patients with severe early-onset forms of MMA, indicating that the type of molecular defect and the severity of the disease significantly influence prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and Molecular Spectrum of Patients with Methylmalonic Acidemia. Gupta, N., Endrakanti, M., Bhat, M., et al.[2023]

High-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) effectively measures methylmalonic acid (MMA), 2-methylcitric acid (MCA), and homocysteine (Hcy) levels in children with methylmalonic aciduria, providing a reliable method for treatment follow-up.

The study established significant correlations between MMA and MCA levels in dried blood spots and urine, indicating that LC-MS/MS can be a valuable tool for monitoring treatment efficacy, although local reference intervals need to be defined.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Application of LC-MS/MS in the Follow-Up for Treatment of Children with Methylmalonic Aciduria. Wang, Y., Sun, Y., Jiang, T.[2020]

A new therapy using mRNA encoding human methylmalonyl-CoA mutase (hMUT) delivered via lipid nanoparticles significantly reduced plasma methylmalonic acid levels by 75%-85% in mouse models of isolated methylmalonic acidemia/aciduria (MMA).

Repeat intravenous dosing of this mRNA therapy not only lowered harmful metabolites but also improved survival and weight gain in mice without increasing liver toxicity or inflammation, suggesting a safe and effective treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. An, D., Schneller, JL., Frassetto, A., et al.[2022]

Liver and liver/kidney transplantation in six patients with methylmalonic aciduria led to significant improvements in plasma biomarkers and neurocognitive scores, indicating a positive impact on neurological outcomes post-transplant.

Despite some reversible neurological events related to treatment, the study suggests that early transplantation is beneficial due to the high risk of long-term complications and the overall improvement in brain health and function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurologic outcome following liver transplantation for methylmalonic aciduria. Martinelli, D., Catesini, G., Greco, B., et al.[2023]

Citations

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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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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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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 ...

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The primary objective of this study is to evaluate the long-term safety of mRNA-3705 administered to participants with isolated methylmalonic acidemia (MMA)

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This extension study will determine the long-term safety and effectiveness of mRNA-3705, a treatment for Methylmalonic acidemia (MMA), in patients who.