MRT5005 is designed to treat CF by delivering messenger RNA (mRNA) with instructions for cells to produce a working CF transmembrane conductance regulator (CFTR) protein — the protein defective in CF patients.
“Based on the first and second interim analyses, we believe we have a achieved a safety profile that supports repeat dosing of inhaled mRNA and further advancement of the pulmonary platform for chronic dosing,” Ann Barbier, MD, PhD, chief medical officer of Translate Bio, said in a press release.
In its first, single ascending dose (SAD) phase, CF patients in this trial were given a single administration of MRT5005 at three different doses. In its second, multiple ascending dose (MAD) phase, participants received MRT5005 once a week, for five weeks, at different doses.
Interim data from that first part showed that a single dose of MRT5005 could improve lung function and was generally well-tolerated by patients.
Now the company announced results from a newly added dose to the SAD group (20 mg), and data from the MAD groups.
For its SAD part, the trial enrolled 16 CF patients who were randomized to either a placebo or MRT5005 at dose levels of 8, 16, 20 or 24 mg. Of these 16 people, 15 had at least one copy of the F508del mutation, the most common CFTR mutation.
The 8, 16 and 24 mg dose groups were already shown to be safe, and the new 20 mg group followed a similar profile. Most treatment-emergent adverse events (TEAEs) were mild to moderate. One patient had an apparent hypersensitivity reaction that resolved with medical treatment, and one serious adverse event, a pulmonary exacerbation, was reported.
ppFEV1, a test to assess lung function, showed no notable increases. Further analysis showed that single dosing did not provoke an immune response.
For its MAD phase, 14 patients received five once-weekly doses of MRT5005 at 8, 12, and 16 mg. In total, 12 patients received all five doses. Ten of these 14 people had at least one copy of the F508del mutation.
Lung function was measured by ppFEV1 before and after each dose, as well as on the day after administration. Testing continued one, two, and four weeks after the last dose, with no increases in ppFEV1 detected. As in the SAD part of the trial, repeat dosing with MRT5005 did not produce an immune response of concern.
Overall, the safety profile of the MAD groups was consistent with that seen in those treated in the trial’s SAD part. No serious adverse events were reported, with the most common being cough and headache. All TEAEs were considered mild to moderate.
“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.
“Our patient communities are of the utmost importance to us, and we are committed to advancing mRNA therapeutics for CF and other pulmonary diseases. This is the first step in an area with significant potential and we look forward to sharing more as we advance our development programs,” Renaud added.
Translate Bio expects to release new results from an additional MAD dose group (20 mg), and a 4 mg once-daily for five days group at a future medical conference.
RESTORE-CF is ongoing and, according to its page, still recruiting eligible adults with CF at multiple sites across the U.S. Study site and contact information is available here.
This trial is being conducted in collaboration with the Cystic Fibrosis Foundation Therapeutics Development Network and the Emily’s Entourage Patient Registry.
Ongoing research at Translate Bio aims to optimize mRNA-based therapies for CF, and include a next-generation candidate in addition to MRT5005, the company announced.
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