Shares of mRNA therapeutics specialist Translate Bio Inc. (NASDAQ:TBIO) fell 30.9% to $17.76 on March 18 over concerns about a new interim analysis of phase I/II data for its cystic fibrosis (CF) candidate, MRT-5005. Several dosing regimens of the inhaled candidate failed to improve a key measure of lung function vs. placebo, in contrast to an earlier readout on other doses tested in the ongoing study, called Restore-CF. Ann Barbier, chief medical officer of the Lexington, Mass.-based company, said her team will need more patient data to fully understand the outcomes. Meanwhile, Translate is talking up its next-generation CF candidate, expected to enter IND-enabling studies later this year.

Though geared toward evaluating safety – a positive quality of the candidate that the first-in-human study continued to affirm – the trial left analysts cold on MRT-5005's prospects in CF, especially as it related to boosting production of the cystic fibrosis transmembrane conductance regulator, or CFTR, protein.

"In the absence of a thesis about where and how the treatment may have broken down (i.e., not produced sufficient CFTR to modify lung function), it is hard to give the company much credit for any value for the program," wrote SVB Leerink analyst Geoffrey Porges, who reduced the firm's price target (PT) for Translate shares to $21 from a prior $33, a move echoed by somewhat smaller PT discounts at Jefferies, Roth Capital Partners and H.C. Wainwright.

That the study was intentionally not powered for efficacy seemed not to affect reaction to the news. Indeed, patient numbers in the study were simply not big enough to address efficacy, said Translate Bio's president and CEO, Ron Renaud, "so I don't think we can draw any hard conclusions right now on efficacy one way or the other."

A different approach

More than 30,000 people in the U.S. live with CF, part of more than 70,000 worldwide, according to the Cystic Fibrosis Foundation. In 2019, global sales of FDA-approved medicines such as Vertex Pharmaceuticals Inc.'s Symdeko (tezacaftor/ivacaftor), Orkambi (lumacaftor/ivacaftor) and Kalydeco (ivacaftor) led the way in terms of revenues generated from the category.

MRT-5005 was designed to be the first clinical-stage mRNA product candidate in the indication to deliver mRNA encoding fully functional CFTR protein to the lung. Furthermore, since currently approved CFTR-modulating therapies are limited to patients with specific genetic mutations, it was expected that inhaled MRT-5005 might be able to meet the needs of people with CF whose disease isn't amenable to those therapies by working directly inside epithelial cells lining the lungs for translation and expression of fully functional CFTR protein.

How much CFTR might have been produced in CF patients who received MRT-5005 in various arms of the trial remained unknown. Translate Bio said Thursday it plans to continue with ongoing and additional translational studies with MRT-5005. But even with potentially fresh insights ahead, analysts were nonplussed, nodding their heads to acknowledge good points of the readout, such as an ongoing lack of immunogenicity markers and a report of detectable levels of mRNA and lipid in the blood of some patients, indicating that MRT-5005 can cross the mucus layer in the lung, while simultaneously seeming to write the candidate off.

For its part, Translate’s team appeared focused on the company’s next-generation CF candidate, which uses new lipid nanoparticles, protein engineering, codon-optimization approaches and manufacturing process enhancements to increase protein production. They’re also pursuing discovery efforts to identify lead product candidates in additional pulmonary diseases, including primary ciliary dyskinesia and pulmonary arterial hypertension, Renaud said.

Despite that work, at least in the near term, investor interest in the company is more focused on its collaboration with Sanofi Pasteur, the global vaccines business of Sanofi SA, to develop infectious disease vaccines using its mRNA technology. Under the terms of that deal, the partners are jointly conducting R&D to advance vaccines targeting up to seven infectious disease pathogens, including SARS-CoV-2 and influenza.

After an evaluation of multiple COVID-19 vaccine candidates in vivo for immunogenicity and neutralizing antibody activity, they selected MRT-5500 as the lead candidate for a vaccine against the virus, which causes COVID-19. And, on March 12, they announced the start of a phase I/II trial, triggering a $25 million milestone payment for Translate. The companies expect interim results from the trial in the third quarter of this year.

An IND filing and trial initiation for the partners' influenza vaccine candidate is expected around midyear.