Translate Bio said it is continuing its Phase I/II trial of its inhaled mRNA cystic fibrosis (CF) candidate MRT5005 despite it showing a lack of efficacy in a second interim data analysis—a finding that sent the company’s shares tumbling by about one-third yesterday, and led two analysts to express pessimism about the program’s value in CF.

Translate Bio acknowledged there was no pattern of increases in percent predicted forced expiratory volume in one second (ppFEV1). That finding touched off a stock selloff by investors that sent the company’s shares tumbling 31% in Thursday trading, to $17.76 a share at the close of trading from Wednesday’s closing price of $25.70. While the price is the lowest since November, Translate Bio shares have traded as low as $8.12 a share over the past 12 months.

Translate Bio quickly added that MRT5005 met the primary endpoint of the Phase I/II trial (NCT03375047) by showing safety and tolerability, since repeat dosing was shown to be generally safe and well tolerated with no serious adverse events, and only mild to moderate treatment-emergent adverse events.

The Phase I/II trial remains ongoing, Translate Bio said, adding that it expects to report at a future medical meeting findings from the study that include a daily dosing cohort (4 mg once-daily for five days), and a fourth multiple ascending dose or MAD group (five once-weekly dose of 20 mg), to be added to the study’s three other multiple ascending groups, five once-weekly doses of 8, 12, and 16 mg.

MRT5005 is designed to address the underlying cause of CF regardless of genetic mutation by delivering mRNA encoding fully functional cystic fibrosis transmembrane conductance regulator (CFTR) protein to cells in the lung through nebulization.

“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,” Translate Bio CEO Ronald Renaud said Wednesday in a statement.

Geoffrey C. Porges, MBBS, director of therapeutics research and a senior research analyst at SVB Leerink, was much less sanguine in a research note.

“To summarize, the trial failed, at least in terms of offering any evidence of efficacy,” Porges wrote. “Other than plasma detection, and some fevers, there was no evidence of biological effect of the mRNA, and at this stage the company cannot answer whether the problem is exposure, transcription, dose, degradation, or some other factor.”

Contrast with earlier results

Porges contrasted the MAD efficacy with the positive single-ascending dose (SAD) results seen in some patients that was shared by Translate Bio in the study’s first interim results from the study, announced in July 2019.  At the time, the company reported that in the eight-day period after dosing, the three patients in the 16 mg dose group showed maximal ppFEV1 increases of 11.1%, 13.6%, and 22.2%, for a mean maximum increase from baseline of 15.7% (5.8).

On Wednesday, Translate Bio reported that in the MAD group, five patients—all in the 12 and 16 mg groups—had detectable levels of mRNA and/or lipid nanoparticles in the blood with no signs of accumulation.

In the SAD 20 mg cohort, all three patients receiving MRT5005 had variable but detectable levels of mRNA in the blood at one or more time points, but no patients had detectable levels of lipid in the blood.

“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,” Porges added. “At best it seems that the next step is to take this program back to the drawing board and design an optimized formulation or construct, and then to establish proof-of-concept in an animal or human setting before additional trials are considered. This is likely to be at least a two-year endeavor.”

Porges slashed SVB Leerink’s price target for Translate Bio from $33 a share to $21 a share, saying it was prudent to only value the company’s shares based on the potential of its mRNA vaccines for preventing COVID-19 (MRT5500) and other infectious diseases. Translate Bio is co-developing those vaccines with Sanofi through a collaboration whose value nearly tripled last year into an up-to-$2.3 billion partnership.

Lowering probability of success

Also reducing its price target for Translate Bio was Jefferies, where equity analyst Eun K. Yang, PhD, and three colleagues shrunk their projected 12-month price to $25 a share from $28 a share.

“We are lowering our probability of success from 40–50% to 20–25% for MRT5005 and delaying development timeline by ~1 year,” Yang wrote in a research note. “Though the study was not powered to show efficacy, lack of efficacy signal is confusing.”

“Lack of efficacy signal at multiple doses in lead CF program is disappointing given the encouraging signal at single doses in 2019 (albeit very small patient number),” Yang said. “Now with lowering expectations for CF program, we continue to view its infectious disease (ID) vaccine opportunities with partner SNY [Sanofi] from the platform to be the key value driver.”

Both Yang and Porges stopped short, however, of downgrading their ratings for Translate Bio shares.

Renaud said that the company was evaluating the interim data with findings from its ongoing CF translational research, while also advancing the company’s next-generation CF discovery efforts.

Translate Bio’s pipeline includes a next-generation CF discovery program that, according to the company, has generated preclinical data positive enough to support the planned launch of IND-enabling studies in the second half of 2021.

“We will continue to leverage the internal capabilities that we’ve built over the last 12 to 18 months in pulmonary biology and aerosol sciences as well as the valuable partnerships established with leading academic research teams to optimize further development in our CF programs,” Renaud added.