Wave Life Sciences Announces First-Ever Therapeutic RNA Editing in Humans Achieved in RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency

Wave Life Sciences Ltd. recently announced positive proof-of-mechanism data from the ongoing Phase 1b/2a RestorAATion-2 study of WVE-006 in alpha-1 antitrypsin deficiency (AATD). WVE-006 is a GalNAc-conjugated, subcutaneously delivered, A-to-I RNA editing oligonucleotide (AIMer) that was developed with Wave’s best-in-class oligonucleotide chemistry platform. It is uniquely designed to address AATD-related lung disease, liver disease, or both.

Today’s proof-of-mechanism data are the first-ever clinical demonstration of RNA editing in humans. These data are from the first single dose cohort (200 mg) in RestorAATion-2 and include the first two patients with “ZZ” AATD (Pi*ZZ AATD) to reach day 57. Individuals with Pi*ZZ AATD do not naturally produce wild-type alpha-1 antitrypsin (M-AAT) protein; therefore, the presence of M-AAT protein is confirmation of successful editing of mutant Z-AAT mRNA. Additionally, restoring 50% M-AAT would be consistent with the heterozygous “MZ” genotype with low risk of AATD lung and liver disease.

Circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT. Increases in neutrophil elastase inhibition from baseline were consistent with production of functional M-AAT. Mean total AAT protein increased from below the level of quantification at baseline to 10.8 micromolar at day 15, meeting the level that has been the basis for regulatory approval for AAT augmentation therapies. Increases in total AAT from baseline and M-AAT protein were observed as early as day 3 and through day 57.

WVE-006 has been well-tolerated with a favorable safety profile to date. All adverse events in RestorAATion-2, as well as in the ongoing RestorAATion-1 trial of healthy volunteers, are mild to moderate, with no Serious Adverse Events reported. The RestorAATion-2 trial is ongoing and Wave expects to share multidose data in 2025.

“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. It also unlocks and derisks Wave’s RNA editing platform, in light of the continued strong clinical translation of our proprietary best-in-class chemistry, including PN, stereochemistry and our N3U AIMer modification,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences. “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. These initial data, alongside WVE-006’s durability and convenient subcutaneous administration, are all supportive of a best-in-class profile for WVE-006 relative to other editors and in the broader AATD space. These data also increase our confidence in our wholly owned pipeline, including our HD, DMD and obesity programs, as well as our next RNA editing targets. We look forward to introducing the next RNA editing programs, as well as providing an update on our INHBE GalNAc-siRNA program in obesity, at our Research Day on October 30.”

There are an estimated 200,000 individuals living with AATD in the US and Europe who are homozygous for the SERPINA1 Z mutation. Treatment options are currently limited to weekly IV augmentation therapy for lung disease only (representing over $1.4 billion in worldwide sales in 2023). There are no approved therapies to address AATD liver disease, which ultimately requires many individuals living with AATD to undergo liver transplantation.

GSK has the exclusive global license for WVE-006. Development and commercialization responsibilities will transfer to GSK after Wave completes the RestorAATion-2 study. In total, Wave is eligible for up to $525 million in milestones, as well as tiered royalties on net sales, for WVE-006.

Wave Life Sciences (Nasdaq: WVE) is a biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health. Wave’s RNA medicines platform, PRISM®, combines multiple modalities, chemistry innovation and deep insights in human genetics to deliver scientific breakthroughs that treat both rare and prevalent disorders. Its toolkit of RNA-targeting modalities includes editing, splicing, RNA interference and antisense silencing, providing Wave with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology. Wave’s diversified pipeline includes clinical programs in Duchenne muscular dystrophy, Alpha-1 antitrypsin deficiency and Huntington’s disease, as well as a preclinical program in obesity. Driven by the calling to “Reimagine Possible”, Wave is leading the charge toward a world in which human potential is no longer hindered by the burden of disease. Wave is headquartered in Cambridge, MA. For more information, visit www.wavelifesciences.com.