RARE Daily

Moderna Reports Positive Phase 1/2 Interim Data for Therapy to Treat Rare Metabolic Condition

May 22, 2023

Rare Daily Staff

Moderna reported positive interim data from its phase 1/2 trial of mRNA-3927, an experimental mRNA therapy for propionic acidemia, a rare metabolic disorder.

Propionic acidemia (PA) is a serious, inherited condition with significant morbidity and mortality, affecting one in 100,000-150,000 individuals worldwide. PA is caused by pathogenic variants in the propionyl-coenzyme A carboxylase (PCC) alpha or beta subunits (PCCA and PCCB genes), leading to PCC deficiency and a resulting accumulation of toxic metabolites. PA is characterized by recurrent life-threatening metabolic decompensation events (MDEs) and multisystemic complications. Multisystemic complications include neurological manifestations, cardiomyopathy, arrythmias, growth retardation, recurrent pancreatitis, bone marrow suppression, and predisposition to infection. Long-term, insults by toxic metabolites cause complications in various organs, and cognitive outcome is negatively correlated with the number of MDEs.

Moderna’s mRNA-3927 is a novel, IV-administered, lipid nanoparticle-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 ongoing global phase 1/2 clinical trial is a multicenter, open-label study designed to assess the safety, pharmacodynamics, and pharmacokinetics of mRNA-3927 in participants aged 1 year and older with genetically confirmed PA.

The trial utilized a dose-escalation approach to evaluate the intravenous administration of mRNA-3927. Participants who complete the dose optimization 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.

The interim results show mRNA-3927 has 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 treatment emergent adverse events (TEAEs) have occurred. Fifteen participants reported TEAEs, while nine participants experienced drug-related TEAEs. Serious adverse events (SAEs) were reported in eight participants. Most SAEs were related to PA and unrelated to mRNA-3927. Six participants had mild infusion-related (IRR) TEAEs; however, most events occurred at the first doses.

“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,” said Kyle Holen, Moderna’s senior vice president and head of development, therapeutics and oncology. “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.”

Photo: Kyle Holen, Moderna’s senior vice president and head of development, therapeutics and oncology

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