Long-Term Safety of mRNA-3705 for Methylmalonic Acidemia

Recruiting at 8 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

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.

What data supports the effectiveness of the drug mRNA-3705 for treating methylmalonic acidemia?

Research on a similar mRNA treatment showed that it significantly reduced harmful substances in the blood and improved survival and weight gain in mice with methylmalonic acidemia, without causing liver damage or inflammation. ^{1 2 3 4 5}

What safety data exists for mRNA-3705 treatment in humans?

In studies with mice, the mRNA-3705 treatment showed no increase in liver toxicity or inflammation with repeated doses, suggesting it may be safe. However, human safety data is not provided in the available research. ^{1 2 4 5 6}

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

mRNA-3705 is unique because it uses a synthetic messenger RNA (mRNA) to produce the enzyme methylmalonyl-CoA mutase, which is often missing or defective in people with methylmalonic acidemia. Unlike traditional treatments, it is delivered intravenously (through a vein) using lipid nanoparticles, which helps the body produce the necessary enzyme without the risks associated with gene therapy, such as immune reactions or genetic damage. ^{1 2 4 5 7}

What is the purpose of this trial?

The primary objective of this study is to evaluate the long-term safety of mRNA-3705 administered to 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.

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 (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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Neurological outcome of methylmalonic acidaemia. [2019]

2. China pubmed.ncbi.nlm.nih.gov

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

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

Clinical Application of LC-MS/MS in the Follow-Up for Treatment of Children with Methylmalonic Aciduria. [2020]

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

Systemic Messenger RNA Therapy as a Treatment for Methylmalonic Acidemia. [2022]

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

Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. [2019]

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

Neurologic outcome following liver transplantation for methylmalonic aciduria. [2023]

7. India pubmed.ncbi.nlm.nih.gov

Clinical and Molecular Spectrum of Patients with Methylmalonic Acidemia. [2023]