UPDATED: Lack of early efficacy for Translate Bio's mRNA-based cystic fibrosis drug raises some big questions
Looking to bring mRNA therapeutics to cystic fibrosis, Translate Bio revealed its second interim analysis in a Phase I/II study showing their experimental drug to be largely safe and tolerable. But questions remain whether or not the program, dubbed MRT5005, will prove efficacious with a top analyst all but declaring an end to the program.
Translate said that data from 12 patients across three cohorts demonstrate that multiple doses of their inhaled cystic fibrosis treatment suggest the therapy is safe. The mRNA-centric program also appeared safe in an additional cohort with 4 patients in a single-dose cohort.
However, Translate did not observe improvements in lung function in any of the newly reported cohorts, seeing no pattern of increases in ppFEV1 in the multiple-dose cohorts and no increase in the single-dose cohort.
CEO Ron Renaud told Endpoints News he wasn’t concerned about the lack of efficacy because the study was geared toward safety and too small to run a statistical analysis.
“When we set out to do this study, our primary objective here was to determine safety and tolerability. Could we get a messenger RNA across that mucus layer of the lung? And I think we’ve been able to demonstrate that,” Renaud told Endpoints.
Lung function was included in the study as a secondary safety measure, he added, noting that none of the patients saw their lung functions decrease.
In the immediate wake of the news, Translate $TBIO shares sunk about 20% on Wednesday afternoon.
The data readout had been highly anticipated from SVB Leerink analyst Geoffrey Porges, who wrote in January that he was curious about whether MRT5005 could set a precedent for mRNA therapies in diseases where continuous treatment is required. Porges set a benchmark for lung function improvement at a 5% increase in ppFEV1 to validate the program’s therapeutic potential.
That didn’t happen, though, and Porges effectively declared the drug dead early Thursday morning. The best case scenario, he wrote, is a minimum two-year delay to development should the company choose to reformulate the compound.
“To summarize, the trial failed, at least in terms of offering any evidence of efficacy,” Porges wrote to investors.
Renaud is hoping to find more answers when the program moves forward with its next study. Renaud said it’s too early to try to guess what an efficacy study might look like, given that the current trial is still ongoing.
“We do need to understand the efficacy part of this; that is absolutely correct. I would not say anything different there,” Renaud said. “Knowing that we can do this, knowing that we can deliver this to the lung, is a major, major first step. Next part will be trying to figure out how to get systematic efficacy with these programs.”
The results only brought in more negative reactions among analysts. Jeffries’ Eun Yang said Wednesday’s data were “disappointing” and “confusing,” as previously reported results from the single-ascending dose cohort showed a mean ppFEV1 increase of 15.7%. On top of that, Yang pointed to five patients who still had detectable levels of mRNA or fatty particles in their blood, indicating the therapy is getting across the mucus layer and into lung tissue.
Overall, though, Yang expects most of Translate’s future success to come from its infectious disease programs, where it’s partnered with Sanofi to develop an mRNA-based Covid-19 vaccine. Porges agreed with that sentiment, calling the vaccine program unproven but promising.
“We are lowering our probability of success from 40-50% to 20-25% for MRT5005 and delaying development timeline by ~1 year,” Yang wrote.
Translate’s study is expected to have one more interim analysis when all the data are in, which should take place in the second half of this year.
As a whole, Translate is evaluating the candidate in up to 40 patients in the trial, in two portions examining single and multiple ascending doses. The single dose portion originally encompassed levels of 8, 16 and 24 mg, but Renaud said they eventually added a 20 mg dose level and scrapped the 24 mg cohort.
Once Translate reported data from those cohorts back in the summer of 2019, they began testing MRT5005 in the multiple ascending dose cohorts at the 8, 16 and 20 mg levels. In these three cohorts, researchers saw a “generally safe and well tolerated” profile with no serious adverse events, the company said.
All of the side effects were mild to moderate, with three of 12 individuals experiencing fever, chills or headache after the first dose. The symptoms did not recur after the second dose, Translate said.
The final cohort reported Wednesday stems from the single ascending dose portion of the trial at the 20 mg level. Safety here was “generally consistent” with the previously reported cohorts from this portion, though Translate saw one serious side effect occur as a patient developed a pulmonary exacerbation 22 days after being dosed.
There was also one instance of a possible mild to moderate hypersensitivity reaction, but that resolved the next day after the patient received medical treatment.
Translate originally acquired MRT5005 back in late 2016 from Shire before the pharma merged with Takeda. Shire had been working on the mRNA platform since 2008, and at the time Translate took over IND-enabling studies that were underway. Translate first took the program into the clinic in the spring of 2018.