mRNA-3927 for Propionic Acidemia

Recruiting at 42 trial locations

Overseen By Moderna WeCare Team

Age: Any Age

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: ModernaTX, Inc.

Disqualifiers: Organ transplant, Heart failure, others

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

Compensation: Varies

Number of Visits: 58

77 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment, mRNA-3927, for individuals with propionic acidemia (PA), a rare genetic disorder affecting metabolism. The goal is to determine the optimal dose, assess safety, and evaluate its effectiveness in managing PA symptoms. Participants will receive the treatment through IV infusion at specific intervals. Ideal candidates include those with a confirmed PA diagnosis, such as children and infants who have shown signs like difficulty feeding or breathing. As a Phase 1 trial, participants will be among the first to receive this treatment, aiding researchers in understanding its effects in people.

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-3927 is likely to be safe for humans?

Research has shown that mRNA-3927 demonstrates promising safety results from early studies. Participants received doses of mRNA-3927 and underwent safety monitoring over time. The treatment is administered through an IV infusion, injecting it directly into the bloodstream.

Reports indicate that participants generally tolerated the treatment well. Some experienced mild side effects, but no major safety issues emerged. Early data revealed that the treatment successfully reached liver cells, which is crucial for its effectiveness.

Although further studies are necessary to confirm these findings, current data offers a positive outlook on the safety of mRNA-3927 for individuals with propionic acidemia. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for propionic acidemia?

Unlike the standard treatments for propionic acidemia, which often focus on dietary management and supplements, mRNA-3927 is a cutting-edge approach that uses messenger RNA (mRNA) to target the root cause of the condition. Researchers are excited about mRNA-3927 because it aims to provide the body with the instructions to produce the deficient enzyme necessary to break down certain proteins and fats efficiently. This innovative mechanism has the potential to address the underlying metabolic defect, offering a promising alternative to current management strategies.

What evidence suggests that mRNA-3927 might be an effective treatment for propionic acidemia?

Research has shown that mRNA-3927 holds promise for treating propionic acidemia (PA). In this trial, participants will receive mRNA-3927 through an IV infusion. Studies have found that after administration, mRNA-3927 enters liver cells and helps produce an enzyme that people with PA lack. Early data also indicates a decrease in metabolic decompensation events (MDEs), which pose serious health risks for those with PA. Overall, these initial findings are encouraging for anyone considering joining the trial. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for people aged 1 year and older with a genetic confirmation of propionic acidemia (PA). Participants must have had at least one metabolic decompensation event in the past year. They can't join if they have severe heart failure, organ transplants, certain heart rhythm issues, recent COVID-19 vaccination, or poor kidney function.

Inclusion Criteria

I have been diagnosed with PA through genetic testing.

I am 8 years or older and could be one of the first two participants.

In the year before signing up, you have been diagnosed with at least one major depressive episode.

Exclusion Criteria

I received my last COVID-19 vaccine or booster within the last 6 weeks.

Your heart's electrical activity takes longer than normal to reset after each beat.

I have had an organ transplant or plan to have one during the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Predosing Observational Period

Participants undergo observation before receiving the treatment

2 weeks

Dose Optimization (Part 1)

Participants (≥1 year of age) receive mRNA-3927 by IV infusion every 2 or 3 weeks for up to 10 doses to determine optimal dosing

20-30 weeks

10 visits (in-person)

Dose Expansion (Part 2)

Additional participants (≥1 year of age) receive mRNA-3927 by IV infusion every 2 weeks for up to 12 months to further characterize safety and efficacy

12 months

24 visits (in-person)

Infant Evaluation (Part 3)

Infants (<1 year of age) receive mRNA-3927 by IV infusion every 2 weeks for up to 12 months to evaluate safety and efficacy

12 months

24 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• mRNA-3927

Trial Overview The study tests mRNA-3927's safety and effectiveness in treating PA. It has two parts: first to find a safe dose that works (Dose Optimization), then to further assess this dose's efficacy and safety (Dose Expansion) by monitoring biomarkers.

How Is the Trial Designed?

Group I: Part 1 (Dose Optimization), Part 2 (Pivotal Study), and Part 3 (Infants) Experimental Treatment 1 Intervention

Part 1 (Dose Optimization): Participants (≥1 year of age) will receive single dose of mRNA-3927 by intravenous (IV) infusion every 2 weeks (Q2W) or every 3 weeks (Q3W) for up to 10 doses. Part 2 (Pivotal Study): Participants (≥1 year of age) will receive single dose of mRNA-3927 (identified during Dose Optimization Phase) by IV infusion Q2W for up to 26 doses or approximately 12 months. Part 3: Participants (\<1 year of age) will receive single dose of mRNA-3927 (identified during Dose Optimization Phase) by IV infusion Q2W for up to 26 doses or approximately 12 months.

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

Seven novel splicing mutations in the PCCA and PCCB genes were identified in patients with propionic acidemia, primarily among individuals of Central Asian descent, indicating potential founder effects.

Functional analysis of these mutations revealed that they disrupt normal splicing of the propionyl-CoA carboxylase enzyme, leading to a complete absence of normally spliced transcripts, which emphasizes the importance of transcript analysis alongside genomic sequencing for understanding the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New splicing mutations in propionic acidemia. Desviat, LR., Clavero, S., Perez-Cerdá, C., et al.[2020]

A new method has been developed to identify defective genes causing propionic acidemia by using lipid-mediated transient transfection of normal PCCA or PCCB genes into primary fibroblasts.

This approach allows for reliable identification of the specific gene mutation responsible for the enzyme defect, aiding in the mutational analysis of propionyl-CoA carboxylase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transfection screening for defects in the PCCA and PCCB genes encoding propionyl-CoA carboxylase subunits. Rodriguez-Pombo, P., Pérez-Cerdá, C., Desviat, LR., et al.[2019]

A study screening over 130,000 Japanese newborns revealed that the frequency of propionic acidemia is more than ten times higher than previously reported, with many patients exhibiting milder symptoms than the severe form typically associated with the condition.

The research identified a common mutation (Y435C) in the PCCB gene among patients with milder phenotypes, highlighting the importance of recognizing these patients to understand their natural history and the diverse effects of PCCB mutations, including unusual patterns of exon skipping and mRNA absence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Yorifuji, T., Kawai, M., Muroi, J., et al.[2022]

In a study of 11 Chinese patients with propionic acidemia, researchers identified 13 mutations in the PCCA and PCCB genes, including 10 novel mutations, which contribute to the disease's genetic diversity.

The study found no predominant mutation among the patients, indicating a varied mutation spectrum in the Chinese population affected by propionic acidemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Gene mutation analysis in patients with propionic acidemia]. Hu, YH., Han, LS., Ye, J., et al.[2019]

Two mutations in the PCCB gene were identified in a patient with propionic acidemia, highlighting the genetic complexity of this metabolic disorder.

One mutation caused a deletion of an isoleucine residue, while the other resulted in a frameshift and a premature stop codon, indicating that both mutations significantly impair the function of the propionyl-CoA carboxylase enzyme.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two distinct mutations at the same site in the PCCB gene in propionic acidemia. Lamhonwah, AM., Troxel, CE., Schuster, S., et al.[2019]

Citations

1. nature.com nature.com/articles/s41586-024-07266-7

Interim analyses of a first-in-human phase 1/2 mRNA trial ... Together with reductions in MDEs, these data suggest that IV infusion of mRNA-3927 resulted in successful transportation into liver cells, ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04159103

NCT04159103 | Open-Label Study of mRNA-3927 in ... This 3-part, Phase 1/2 study is designed to characterize the safety, tolerability, and pharmacological activity (as assessed by biomarker measurements) and ...

3. genengnews.com genengnews.com/topics/translational-medicine/moderna-reports-phase-i-ii-data-for-propionic-acidemia-mrna-therapy/

Moderna Reports Phase I/II Data for Propionic Acidemia ... The findings indicate that intravenous infusion of mRNA-3927 resulted in successful transport into liver cells and the synthesis of an active ...

4. ddw-online.com ddw-online.com/positive-initial-data-on-first-mrna-therapy-for-propionic-acidemia-23770-202305/

Positive initial data on first mRNA therapy for propionic ... Moderna has reported encouraging interim data from its Phase I/II trial of mRNA-3927, an mRNA therapy for rare metabolic disorder propionic acidemia (PA).

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11184373/

Toward the full potential of mRNA therapeutics - PMC This small study reports interim analyses of a clinical trial for mRNA-3927, an mRNA therapy developed by Moderna for propionic acidemia (PA), a rare heritable ...

6. s29.q4cdn.com s29.q4cdn.com/435878511/files/doc_presentations/2023/May/18/mrna-3927-pa-p101-ia-oral_asgct2023_final.pdf

mRNA-3927 Therapy for Propionic Acidemia: Interim Data ... • Participants receive up to 10 doses of mRNA-3927, then may enter a 2-year safety follow-up period, or continue to receive mRNA-3927 in an ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05130437

NCT05130437 | A Study to Assess the Long-term Safety ... The main purpose of this study is to evaluate the long-term safety of mRNA-3927 administered to participants with propionic acidemia (PA) who have previously ...

8. clinicaltrials.eu clinicaltrials.eu/trial/study-on-the-safety-and-effectiveness-of-mrna-3927-for-patients-with-propionic-acidemia/

Study on the Safety and Effectiveness of mRNA-3927 for ... This study investigates the safety and effectiveness of the gene therapy mRNA-3927 for the treatment of the rare genetic condition, Propionic Acidemia.