Moderna, looking beyond vaccines, guides first mRNA protein replacement therapy past early clinical test

Moderna has early clinical evidence that its mRNA technology can treat a rare disease by replacing intracellular proteins. Participants in the phase 1/2 trial experienced a 66% overall relative risk reduction in the frequency of life-threatening events, encouraging the biotech to keep studying the candidate. 

Massachusetts-based Moderna became a household name because of vaccines but, from its early days, has harbored the goal of turning human cells into drug production factories. By hijacking cellular machinery and getting the body to produce therapeutic molecules, Moderna wants to get proteins to intracellular targets and unlock new ways to treat disease. 

The phase 1/2 trial marks the first time a biotech has reported clinical data on an mRNA therapeutic for intracellular protein replacement. In the study, children with propionic acidemia (PA), a rare inherited metabolic disorder, received multiple doses of a lipid nanoparticle-encapsulated dual mRNA therapy.

Moderna’s therapy, mRNA-3927, encodes two subunit proteins, PCCA and PCCB, that form the enzyme that is deficient in patients with PA. By triggering production of the subunit proteins, Moderna could fix the root cause of the disease and prevent the buildup of harmful compounds that cause PA symptoms.

Across the five dose cohorts covered by the data drop (PDF), Moderna saw no dose-limiting toxicities and three drug-related serious adverse events (SAEs). The most severe SAE was grade 3 pancreatitis in one patient. Moderna has now given more than 280 doses of mRNA-3927, with five patients taking the therapy for more than one year, and is forging ahead with the program.

“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. We currently have more than 13 patient-years of experience to date," Kyle Holen, M.D., head of development, therapeutics and oncology at Moderna, said in a statement.

The phase 1/2 has generated early signs of efficacy. Many participants had metabolic decompensation events, which can be life threatening, before starting on mRNA-3927. Participants suffered fewer events after starting on the therapy, with Moderna tracking a 66% overall relative risk reduction across the trial and a 78% reduction in the four cohorts that received mRNA-3927 every two weeks.