Moderna announced the preliminary results of a Phase I/II dose optimization and extension study to assess the efficacy and safety of mRNA-3927, an investigational mRNA treatment for propionic acidemia. Mutations in subunits of the mitochondrial enzyme propionyl-coenzyme (PCC) cause this devastating, rare metabolic disease in infants. 

This is the first clinical trial to report on the results of an mRNA therapeutic for intracellular protein replacement in an extremely rare disease with a significant unmet need for treatment options. The current recommendations for treating propionic acidemia are bleak and state that survival is the most crucial result, followed by health-related quality of life.

The findings indicate that intravenous infusion of mRNA-3927 resulted in successful transport into liver cells and the synthesis of an active form of PCC, as well as a reduction in life-threatening metabolic decompensation events (MDEs) in 70% of patients. These preliminary findings are encouraging and suggest that mRNA-3927 may have clinical benefits for propionic acidemia patients.

The research article, “Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidaemia,” was published in Nature.

Fighting for survival

Propionic acidemia is a rare disorder caused by defects in the PCC α or β (PCCA or PCCB) subunits, which comprise the PCC mitochondrial enzyme. PCC plays critical roles in the catabolism of certain amino acids and cholesterol, as well as the beta-oxidation of fatty acids, and deficiencies in PCC cause toxic metabolites to accumulate, resulting in recurring, life-threatening MDEs.

Patients with propionic acidemia frequently develop progressive encephalopathy, which causes lethargy, seizures, decreased arousal, and coma and can be disabling or fatal if not treated quickly. Propionic acidemia can result in growth retardation, neurological symptoms, cardiomyopathy, arrhythmias, recurrent pancreatitis, bone marrow suppression, and an increased susceptibility to infection.

Patients with propionic acidemia have the option of undergoing liver transplantation, which can lead to metabolic stability. However, the chances of surgical complications and the need for lifelong immunosuppression mean that any benefit in metabolic stability from the transplant must be balanced with these risks.

MDEs meet their mRNA match

Patients with genetically confirmed propionic acidemia, aged one year and up, were the subjects of the ongoing worldwide Phase I/II clinical trial that tested mRNA-3927, a dual mRNA therapy encoding PCCA and PCCB. 

More than 340 intravenous doses of mRNA-3927 had been administered to 16 participants as of the data cut on May 31, 2023. Two individuals withdrew from the study, while two others still receive treatment in the dose-optimization trial; all other participants are extending their treatment.

Except for two individuals who reported MDEs during the pretreatment period, all participants in this interim analysis showed a decrease in the number of MDEs. During treatment in the dose-optimization trial, the relative risk of MDEs decreased by 70%.

All dose switches occurred in the extension study, with doses increased to levels that were considered safe and therapeutic in the dose-optimization study, with the exception of one participant who had a dose decrease due to a serious adverse event (grade 3 pancreatitis and increased lipase) during the dose-optimization study’s treatment period. The individual whose dosage was reduced had a flare-up of pancreatitis that occurred frequently, most often due to viral infections.

Participants are still being evaluated as this study progresses. The study’s dose-expansion phase will begin once the analysis has determined the ideal therapeutic dose.

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