Clinical trial results released by Wave Life Sciences Wednesday appear to provide early validation for the company’s newest drugmaking technology as well as a burgeoning field of genetic medicine, RNA editing.
The data are from just two patients, the first treated in a Wave study of the biotechnology firm’s medicine for an inherited lung and liver disease called alpha-1 antitrypsin deficiency, or AATD. Still, Wave claims the data show convincing evidence its medicine successfully edited the messenger molecules cells use to turn DNA blueprints into proteins.
According to the company, this kind of effect hasn’t before been demonstrated in clinical testing.
“Achieving the first-ever therapeutic RNA editing in humans is a significant milestone for our organization, for our GSK collaboration, and for the entire oligonucleotide field,” said Wave CEO Paul Bolno in a statement.
Wave’s medicine is built from a strand of nucleic acid known as an oligonucleotide. Delivered into the body’s cells via a type of sugar molecule, the oligonucleotide recruits enzymes known as ADAR to change single bases on messenger RNA. This could allow Wave to correct garbled instructions for making proteins in people with genetic diseases like AATD. In theory, it could also sidestep some of the risks inherent to permanently altering DNA with drugmaking approaches like CRISPR gene editing.
The data Wave reported Wednesday indicate that, at least in the first two patients, the company’s treatment worked as intended. Both patients have a form of AATD which means their bodies don’t produce wild-type AAT protein. But, after treatment, researchers measured significant increases in this protein as early as the third day and through about two months of follow-up.
Total AAT protein levels reached, on average, 10.8 micromolars in blood plasma concentration by day 15 after treatment, which Wave said meets the threshold set by regulators for approval of AAT augmentation therapies.
There were no serious side effects and all adverse events in this study, as well as another in healthy volunteers, have been mild to moderate in nature, Wave said.
While preliminary, Wave’s results look to be a step forward for RNA editing, which has recently drawn significant investment from biotech and pharmaceutical companies alike.
Because RNA molecules degrade quickly, the effects of an RNA editing treatment are temporary. Developers claim this will help avoid the risk of long-term harm that might result from wayward snips to DNA via gene editing. They also contend RNA editing allows for more precise tweaking of protein expression and gives them the ability to administer multiple doses.
“It can address a whole bunch of features” associated with DNA editing, said Bolno, in a recent interview with BioPharma Dive.
Wave is one of only two companies, along with privately held Ascidian Therapeutics, with an RNA editing medicine in human trials. Its trial has therefore been closely watched by investors and analysts as a gauge of how well the technology might actually work.
Notably, while the two patients only received a single dose of Wave’s drug, the effects of treatment appeared more potent and durable than analysts had expected. The findings “provide [a] robust demonstration of ADAR RNA editing in humans” as well as “clinical validation” of Wave’s technology, wrote Leerink Partners analyst Joseph Schwartz in a note to clients.
"We view this as both a bar-clearing and, more importantly, enabling event for the ADAR space more broadly," wrote William Blair analyst Myles Minter in a separate investor note.
The results lifted shares of Wave by more than 75% Wednesday morning, pushing its market value above $2 billion. Shares in Korro Bio and ProQR, two other companies investing in RNA editing, rose by even more.
Korro and another firm, the privately held Airna, are also working on RNA editing therapies for AATD. Korro has said it intends to ask regulators by the end of the year to start a trial.
GSK has global rights to Wave’s AATD medicine under a broad partnership the two companies signed in 2022. The British pharma will take the lead on development and commercialization after Wave’s current trial wraps up. Wave could receive up to $525 million in milestone payments from GSK, if all goes well.
Separately, Wave said in a regulatory filing Tuesday that Takeda Pharmaceuticals opted out of a deal to license an RNA medicine it’s developing for Huntington’s disease. Wave is awaiting feedback from regulators on whether it could pursue an accelerated approval of the drug and, in the filing, claimed the program has “generated significant interest from prospective partners.”
