First-of-its-kind failure

Sad Setback

MRT5005, an experimental, messenger RNA-based drug candidate from Translate Bio did not improve the lung function of patients with cystic fibrosis (CF) in an early-stage trial, according to an article by Ben Fidler in BioPharma Dive.

The candidate was the first of its kind to reach clinical testing. It was an inhalable therapy designed to use synthetic genetic material to treat the underlying cause of the disease. The safety profile appeared satisfactory, but there was "no pattern of increases" in a key measure of lung function, according to Translate Bio.  CEO Ron Renaud said that the results provide a "data driven foundation" for a next-generation treatment while being a setback for the present time, as well as for the possibility of using mRNA for something other than COVID-19 vaccines.

Fidler said that, “Messenger RNA technology, which uses synthetic, genetic material to teach the body to make helpful proteins, has come of age over the past year. When the coronavirus pandemic took hold in 2020, the technology was uniquely suited to meet the moment, having already shown potential as a new way to quickly design vaccines. The ensuing success of two similar mRNA vaccines from Moderna as well as partners BioNTech and Pfizer validated the technology, and the shots have since been used to protect millions of people around the world from COVID-19.”

Still, the idea of using mRNA to produce therapeutics is not taking hold as quickly, with only a small number of programs for certain diseases in human trials. Translate Bio’s work in cystic fibrosis, which began at Shire several years ago, is further along than other attempts to work with mRNA in therapeutics. Renaud claimed that the company "recognized that we were entering uncharted territory" when clinical testing for MRT5005 began in 2018.

The objective of the Translate program is to spray synthetic mRNA into cells in the lungs of CF patients to get them to produce a key protein known as cystic fibrosisTR. Translate had hoped that it would be a way to treat all CF patients and a better option for critically ill patients than the approach used by Vertex, whose CF drugs “help people who can already make some cystic fibrosisTR protein,” Renaud explained.

However, the approach is especially challenging, because it is difficult to get mRNA into the lungs. Both Moderna and Vertex have worked on a similar effort since 2016 and do not have a candidate close to clinical trials. After creating a second CF alliance in 2020, Vertex chief scientific officer David Altshuler called delivering such treatments "the most significant technological and scientific challenge."

The approach Translate has used is to pack mRNAs into tiny fat bubbles called lipid nanoparticles and  make them into an inhalable mist with a nebulizer. Translate has used that method to make treatments for cystic fibrosis and other lung diseases, including pulmonary arterial hypertension. Early results from a single dose of MRT5005 in cystic fibrosis patients indicated that the drug candidate might be working, but the findings did not hold up in a test of multiple doses.

Translate already has several projects in process through an alliance with Sanofi, including a coronavirus vaccine that began human testing recently.  Translate maintains that researchers found mRNA in the blood of some patients treated with MRT5005, meaning that it was possible to deliver multiple doses of an mRNA drug to the lungs. Translate hopes to refine its approach with the procedure to find a more potent treatment for cystic fibrosis and other diseases.