Positive initial data on first mRNA therapy for propionic acidemia

Lipid nanoparticle mRNA vaccine

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).

The data was presented at the 2023 American Society of Gene & Cell Therapy (ASGCT) Annual Meeting.

The ongoing global Phase I/II clinical trial is a multicentre, open-label study designed to assess the safety, pharmacodynamics, and pharmacokinetics of mRNA-3927 in participants aged one year and older with genetically confirmed PA.

Propionic acidemia is a rare, serious, inherited metabolic disorder with significant morbidity and mortality, affecting one in 100,000-150,000 individuals worldwide. It is caused by pathogenic variants in the propionyl-coenzyme A carboxylase (PCC) α or β subunits, leading to PCC deficiency and subsequent accumulation of toxic metabolites.

Currently, there are no effective therapies for PA that target the underlying root cause of the disease.

mRNA-3927 is a novel, IV-administered, lipid nanoparticle (LNP)-encapsulated dual mRNA therapy that encodes for PCCA and PCCB subunit proteins to restore functional PCC enzyme activity in the liver. By encoding for intracellular proteins, mRNA therapy has a potential role in preventing and treating acute metabolic decompensations.

The Phase I/II clinical trial

The trial utilised a dose-escalation approach to evaluate the intravenous administration of mRNA-3927. Participants who complete the dose optimisation trial (10 doses) are eligible to continue treatment in an open-label extension study.

The primary outcomes of the trial are safety and tolerability, while secondary and exploratory outcomes include pharmacology, evaluation of potential plasma biomarkers, and the frequency and duration of metabolic decompensation events (MDEs).

mRNA-3927 has so far been well-tolerated at the doses administered, with encouraging early signs of dose-dependent pharmacology and potential clinical benefit.

To date, a total of 16 participants have received doses of mRNA-3927 across five dose cohorts. Of these, 11 participants completed the study and enrolled in the open-label extension study, and five participants were treated with mRNA-3927 for over one year.

Following treatment initiation with mRNA-3927, most participants who had reported MDEs in the 12 months prior to dosing had either a lower incidence or no MDEs post-treatment.

No dose-limiting toxicities or study discontinuations due to drug-related TEAEs have occurred. Serious adverse events (SAEs) were reported in eight participants, but most were related to PA and unrelated to mRNA-3927.

“We continue to observe encouraging results with mRNA-3927 as we enter the dose-expansion phase, where we will further assess safety, efficacy, and determine the recommended dose for future clinical studies. This is the first clinical trial reporting results of an mRNA therapeutic for intracellular protein replacement, and we currently have more than 13 patient-years of experience to date,” said Kyle Holen, Moderna’s Senior Vice President and Head of Development, Therapeutics and Oncology.

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