It is just as well that Translate Bio has a Covid-19 vaccine collaboration with Sanofi, otherwise it might today be facing an existential crisis. This is because its lead asset, an inhaled mRNA against cystic fibrosis, appears biologically inert.
Data released after market close yesterday from a second interim analysis of the phase I/II Restore-CF trial of the project in question, MRT5005, showed absolutely no efficacy. This is a big disappointment given the signals of lung function improvement reported at the first interim, and Translate stock opened off 30% this morning.
Perhaps the most ominous sign is that the company could offer no explanation for two such disparate results from the same trial. Perhaps the first signals were mere chance, and Translate’s technology is simply incapable of delivering mRNA to its target.
Detected in blood
MRT5005 seeks to deliver, through nebulisation, mRNA encoding a fully functional CFTR protein to lung epithelial cells. In the latest cut of the study data the mRNA was detected in the blood of several patients, Translate said, but there is no indication as to whether this was encoding what it was meant to, or indeed whether it was exerting its activity specifically in the lungs.
Back in mid-2019 the mood was upbeat. The first 16 patients in Restore-CF had received single 8mg, 16mg or 24mg MRT5005 doses, or placebo, and the two highest doses prompted increases from baseline in ppFEV1 (percent predicted forced expiratory volume in one second) above those seen with placebo.
The 16mg dose seemed especially efficacious, and perhaps the lack of a dose response was a red flag. Either way, Translate added 20mg to the single-dose part of the trial, and proceeded with an 8-20mg multiple-dose part, which enrolled another 14 subjects.
Yesterday’s revelation concerned the 20mg dose, comprising three new subjects plus one extra placebo recipient, and 12 in the multiple-dose part; the two remaining subjects had discontinued owing to a Covid-19-related site closure and a febrile reaction.
Among this new cohort there was no observed pattern of increases in ppFEV1, Translate admitted.
The next generation
The group is not giving up, and now wants to switch attention to a next-generation inhaled CFTR mRNA asset that might use a better lipid nanoparticle or a more efficiently read transcript. However, this is in preclinical trials, and will not yield human data until 2023 at the earliest.
Given that until yesterday Translate was the most advanced mRNA player in cystic fibrosis the competition will pay close attention. Arrowhead hopes this year to report preliminary FEV1 data from a phase I/II trial of ARO-ENaC, an inhaled ENaC RNAi therapeutic, for instance.
Meanwhile, Ionis has reported promising phase I data with IONIS-ENAC-2.5Rx, an inhaled ENaC antisense oligonucleotide. 4D Molecular Therapeutics’ 4D-710, an inhaled vector delivering a microCFTR transgene, is to start clinical trials in the second half.
If in inhaled therapeutics Translate now faces a protracted period of radio silence, it does at least have the Sanofi-partnered Covid-19 vaccine MRT5500, which started a 415-strong phase I/II trial this month. Interim data are expected in the third quarter.
While this puts the partners woefully behind the Covid-19 vaccine frontrunners, the readout is now Translate’s most important catalyst.