Translate Bio Reports Results from Trial of mRNA Therapy for Cystic Fibrosis

Rare Daily Staff

Translate Bio reported results from the second interim analysis from a first-in-human phase 1/2 clinical trial of its experimental inhaled mRNA therapeutic MRT5005 in patients with cystic fibrosis was generally safe and well tolerated but showed no improved in lung function.

Cystic fibrosis (CF) is a rare, life-shortening genetic disease caused by mutations in the CFTR gene that lead to a defective or missing cystic fibrosis transmembrane conductance regulator (CFTR) protein. There are approximately 2,000 known mutations in the CFTR gene, some of which lead to CF by creating non-working or too few CFTR proteins at the cell surface that results in poor flow of salt and water into and out of the cell in a number of organs. In the lungs, this leads to the buildup of abnormally thick, sticky mucus that can cause chronic lung infections and progressive lung damage in many patients that eventually leads to death. The median age of death is in the early 30s.

MRT5005 is the first inhaled mRNA therapeutic with delivery to the lungs, designed to address the underlying cause of cystic fibrosis, regardless of genetic mutation. It delivers mRNA encoding fully functional cystic fibrosis CFTR protein to cells in the lung through nebulization.

The topline findings from the analysis of the multiple-ascending dose portion (five once-weekly doses of 8, 12 and 16 mg) through one-month follow-up post treatment of the clinical trial found that repeat dosing of MRT5005 was generally safe and well tolerated with no serious adverse events, the primary outcome measure.

Transient mild to moderate symptoms of a febrile reaction such as fever, headache and chills occurred in three patients after the first dose of MRT5005 and did not recur with subsequent dosing in the two patients who continued dosing; the third patient discontinued due to the febrile reaction.

Percent predicted forced expiratory volume in 1 second (ppFEV1), a measure of lung function, was assessed as a safety measure at pre-defined time points throughout the trial with no pattern of increases in ppFEV1.

The randomized, double-blind, placebo-controlled phase 1/2 clinical trial of MRT5005 is designed to enroll at least 40 adult patients with CF who have two Class I and/or Class II mutations. The primary endpoint of the trial is safety and tolerability of single and multiple escalating doses of MRT5005 administered by nebulization. Percent predicted forced expiratory volume in one second (ppFEV1) is also measured at pre-defined time points throughout the trial. The trial is being conducted in collaboration with the Cystic Fibrosis Foundation Therapeutics Development Network and the Emily’s Entourage Patient Registry.

The CF trial is ongoing, and Translate Bio plans to report the findings from the clinical trial, including an additional multiple-ascending dose group (20 mg) and a daily dosing cohort (4 mg once-daily for 5 days), at a future medical meeting.

In spite of no demonstration of efficacy yet, Translate Bio plans to continue with ongoing and additional translational studies with MRT5005 and its next-generation CF candidate to support and optimize future clinical development, including research into dosing, formulation and nebulization. The company’s next-generation CF discovery program has generated positive preclinical data supporting planned initiation of investigational new drug (IND)-enabling studies in the second half of 2021.

“This is the first time messenger RNA encoding CFTR has been administered to patients with cystic fibrosis through inhaled repeat doses, and I believe, this represents an important building block in our pioneering efforts to develop transformative mRNA therapeutics,” said Ronald Renaud, CEO of Translate Bio. “We are evaluating learnings from this trial along with findings from our ongoing CF translational research, while also advancing our next-generation CF discovery efforts.”

Photo: Ronald Renaud, CEO of Translate Bio