Wave Life Sciences has taken a step toward validating a new modality, becoming the first group to report therapeutic RNA editing in humans. The update on the GSK-partnered prospect sent Wave’s share price up 63% to almost $14 despite coinciding with news that Takeda has axed a deal for another asset.
The ongoing phase 1b/2a study is testing WVE-006 in alpha-1 antitrypsin deficiency (AATD). The drug candidate is a GalNAc-conjugated RNA editing oligonucleotide that is designed to correct a mutation in mRNA. The mutation drives misfolding and aggregation of AAT in the liver, a decrease in functional forms of the protein in circulation and the symptoms that make AATD an unmet medical need.
Wave presented data on two patients who received a single 200 mg dose of WVE-006. Neither patient can naturally produce wild-type M-AAT, enabling Wave to use the presence of the protein as evidence that its candidate is successfully editing mRNA.
Circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15. At that time, the wild-type protein accounted for more than 60% of total AAT. Increases were seen at Day 3 and lasted through the cutoff at Day 57. Wave saw increases in the inhibition of neutrophil elastase, an enzyme that AAT defends the lungs against, that it said were consistent with the production of functional protein.
Mean total AAT was below the level of quantification at baseline. By day 15, the level had risen to 10.8 micromolar. Wave said the result meets the level that has been the basis for regulatory approval for AAT augmentation therapies, although it will need to validate the result across more patients to get WVE-006 to market. Work to collect more data is underway, with Wave aiming to share multi-dose data next year.
“The level of mRNA editing we are observing with a single dose exceeded our expectations and we expect M-AAT levels to continue to increase with repeat dosing, based on our preclinical data,” Wave CEO Paul Bolno said in a statement.
GSK paid $170 million to close a deal that included global rights to WVE-006 in 2022. Wave will wrap up the current study of WVE-006 and then hand over to GSK, which is on the hook for up to $525 million in milestones, for further development.
Multiple treatments for AATD that contain plasma-derived human alpha1-proteinase inhibitors are on the market already. However, the limitations of those treatments have led companies including Takeda and Vertex to move AATD candidates into and through clinical development.