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Modified Messenger Ribonucleic Acid Encoding Human Propionyl-Coenzyme A Carboxylase Alpha And Beta Subunits Encapsulated Into Lipid Nanoparticles

This article discusses clinical trials investigating the use of mRNA-3927, a novel drug designed to treat Propionic Acidemia (PA). PA is a rare genetic disorder that affects the body’s ability to break down certain proteins and fats. The drug, developed by Moderna, uses modified messenger RNA encapsulated in lipid nanoparticles to potentially address the underlying cause of PA. These trials aim to assess the safety, effectiveness, and optimal dosing of mRNA-3927 in patients with PA, offering hope for a new treatment option for this challenging condition.

Table of Contents

What is mRNA-3927?

mRNA-3927 is an innovative medication being developed to treat Propionic Acidemia (PA), a rare genetic disorder[1]. This drug is classified as an advanced therapy and specifically as a gene therapy. It consists of modified messenger RNA (mRNA) that encodes for two important proteins: the alpha and beta subunits of an enzyme called propionyl-CoA carboxylase (PCC). These mRNA molecules are packaged into tiny lipid nanoparticles for delivery into the body[1].

Propionic Acidemia: The Target Condition

Propionic Acidemia (PA) is a rare inherited metabolic disorder. People with PA have a deficiency in the PCC enzyme, which is crucial for breaking down certain proteins and fats. This deficiency can lead to a buildup of harmful substances in the body, causing serious health problems[1].

How mRNA-3927 Works

mRNA-3927 aims to address the root cause of PA by providing the body with instructions to produce the missing PCC enzyme. Here’s how it works:

  1. The modified mRNA is delivered into cells via lipid nanoparticles.
  2. Once inside the cells, the mRNA provides instructions to produce the alpha and beta subunits of the PCC enzyme.
  3. The cells then assemble these subunits to form functional PCC enzymes.
  4. These newly produced enzymes can help break down proteins and fats properly, potentially reducing the buildup of harmful substances.

This approach is innovative because it doesn’t permanently alter the patient’s DNA but instead provides temporary instructions for the body to produce the needed enzyme[1].

Clinical Trial Overview

A clinical trial is currently underway to evaluate the safety and effectiveness of mRNA-3927 in patients with Propionic Acidemia. This trial is a global, Phase 1/2, open-label study designed to optimize the dose of the medication[1].

The main objectives of the trial are:

  • To evaluate the safety and tolerability of mRNA-3927
  • To assess how well mRNA-3927 works in reducing the frequency of metabolic decompensation events (MDEs), which are serious health crises that can occur in PA patients
  • To study how the body processes the drug (pharmacokinetics) and how the drug affects the body (pharmacodynamics)

Eligibility Criteria

The trial has specific criteria for who can participate. Some key inclusion criteria are:

  • Participants must be at least 1 year old (or at least 8 years old for the first two participants)
  • Have a confirmed diagnosis of PA based on genetic testing
  • For Part 2 of the study, participants must have had at least one documented MDE in the 12 months before joining the study

There are also several exclusion criteria, such as certain medical conditions or previous treatments that would prevent participation[1].

Study Design

The study is divided into two main parts:

Part 1: Dose Optimization

This part aims to find the best dose and dosing schedule for mRNA-3927. Up to 43 participants will receive multiple doses of the drug over 20 to 40 weeks. The drug is given through an intravenous infusion (directly into a vein) every 2 to 4 weeks[1].

Part 2: Dose Expansion

In this part, up to 15 additional participants will receive the optimal dose determined in Part 1 for about 12 months. The main goal is to further evaluate the drug’s effectiveness and safety[1].

Potential Benefits

If successful, mRNA-3927 could potentially offer several benefits for PA patients:

  • Reduction in the frequency of metabolic decompensation events
  • Improved ability to tolerate protein in the diet
  • Better quality of life
  • Reduced need for hospitalizations

However, it’s important to note that these potential benefits are still being studied and are not guaranteed[1].

Safety Considerations

As with any new treatment, safety is a top priority. The study will closely monitor participants for any side effects or adverse reactions. Some specific safety measures include:

  • Regular check-ups and blood tests
  • Monitoring for allergic reactions or infusion-related reactions
  • Checking for the development of antibodies against the treatment
  • Long-term follow-up to assess any delayed effects

Participants will be followed for up to 2 years after treatment to ensure long-term safety[1].

Aspect Details
Drug Name mRNA-3927
Condition Treated Propionic Acidemia (PA)
Drug Mechanism Modified mRNA encoding PCC alpha and beta subunits, encapsulated in lipid nanoparticles
Trial Structure Phase 1/2, open-label, dose optimization study
Trial Parts Part 1: Dose Optimization (up to 43 participants)
Part 2: Dose Expansion (up to 15 additional participants)
Primary Objectives Part 1: Safety and tolerability
Part 2: Efficacy in reducing metabolic decompensation events
Administration Intravenous infusion, every 2-4 weeks
Dosing Starting dose: 0.3 mg/kg every 3 weeks
Maximum dose: 2 mg/kg
Follow-up Period Part 1: 2 years
Part 2: 6 months

FAQ

  • What is mRNA-3927 and how does it work? mRNA-3927 is a drug that contains modified messenger RNA encoding for the alpha and beta subunits of propionyl-CoA carboxylase (PCC), an enzyme deficient in patients with Propionic Acidemia. The mRNA is encapsulated in lipid nanoparticles to help deliver it to cells. Once inside the cells, the mRNA instructs them to produce the missing enzyme, potentially addressing the underlying cause of the disease.
  • Who can participate in these clinical trials? The trials are open to patients with a confirmed diagnosis of Propionic Acidemia based on molecular genetic testing. Participants must be at least 8 years old for the first two participants in Part 1, and at least 1 year old for subsequent participants. There are specific inclusion and exclusion criteria, such as certain medical conditions or previous treatments, that determine eligibility.
  • What are the main objectives of the clinical trials? The main objectives are to evaluate the safety and tolerability of mRNA-3927 in Part 1, and to assess its efficacy in reducing the frequency of metabolic decompensation events (MDEs) compared to standard care in Part 2. The trials also aim to characterize the pharmacodynamics and pharmacokinetics of the drug.
  • How is the drug administered in the trials? mRNA-3927 is administered through intravenous infusion over 1 to 6 hours. In Part 1, participants receive up to 10 doses of the study drug every 2 to 4 weeks. The starting dose is 0.3 mg/kg every 3 weeks, with a maximum dose of 2 mg/kg. In Part 2, participants receive the optimal dose determined in Part 1 for approximately 12 months.
  • What happens after the treatment period in the clinical trials? After the treatment period, there is a follow-up period to gather safety information and ongoing data about the participant's Propionic Acidemia. In Part 1, the follow-up period lasts 2 years, while in Part 2, it lasts 6 months. These follow-up visits are conducted in an outpatient setting.

Ongoing Clinical Trials on Modified Messenger Ribonucleic Acid Encoding Human Propionyl-Coenzyme A Carboxylase Alpha And Beta Subunits Encapsulated Into Lipid Nanoparticles

  • A study to evaluate the long-term safety and effectiveness of mRNA-3927 in patients with Propionic Acidemia

    Recruiting

    1 1 1
    Investigated drugs:
    France The Netherlands Spain

  • Study on the Safety and Effectiveness of mRNA-3927 for Patients with Propionic Acidemia

    Recruiting

    2 1 1 1
    Investigated drugs:
    France Italy The Netherlands Spain

Glossary

  • Propionic Acidemia (PA): A rare genetic disorder that affects the body's ability to break down certain proteins and fats, leading to a buildup of toxic substances in the blood.
  • mRNA-3927: A drug containing modified messenger RNA encoding for propionyl-CoA carboxylase alpha and beta subunits, encapsulated in lipid nanoparticles, designed to treat Propionic Acidemia.
  • Lipid Nanoparticles (LNP): Tiny particles made of fats that are used to encapsulate and deliver the mRNA in mRNA-3927 to cells in the body.
  • Metabolic Decompensation Event (MDE): A serious complication in Propionic Acidemia where the body's metabolism becomes imbalanced, potentially leading to hospitalization.
  • Pharmacodynamics (PD): The study of how a drug affects the body, including its mechanism of action and the body's response to the drug.
  • Pharmacokinetics (PK): The study of how the body processes a drug, including its absorption, distribution, metabolism, and excretion.
  • 2-MC and 3-HP: Biomarkers (2-methylcitrate and 3-hydroxypropionate) measured in the blood to assess the effectiveness of mRNA-3927 treatment.
  • Propionyl-CoA Carboxylase (PCC): An enzyme deficient in patients with Propionic Acidemia, which is targeted by mRNA-3927 therapy.
  • Adverse Event (AE): Any unfavorable medical occurrence in a patient during a clinical trial, which may or may not be related to the study drug.
  • Serious Adverse Event (SAE): An adverse event that results in death, is life-threatening, requires hospitalization, or causes significant disability.

References

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