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Wave Life Sciences Announces First-Ever Therapeutic RNA Editing in Humans Achieved in RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency
Achieved proof-of-mechanism for Wave’s RNA editing platform; restoring levels of wild-type (edited) M-AAT that are consistent with the heterozygous “MZ” genotype with low risk of AATD lung and liver disease
A single subcutaneous dose of WVE-006 in the first two patients with homozygous “ZZ” AATD resulted in mean plasma total AAT levels of ~11 micromolar, with mean wild-type M-AAT representing more than 60% of total AAT; durable editing with M-AAT protein observed through 57 days
Wave expects to share multidose data from the RestorAATion-2 trial in 2025
Annual Research Day on
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
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
About Wave Life Sciences
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, our understanding of the anticipated therapeutic benefit of WVE-006 as a therapy for AATD and our estimates of the AATD patient population that may benefit from WVE-006; our plans and estimated timing to share multidose data from the RestorAATion-2 trial; our understanding of the mRNA being generated by WVE-006; our expectations that M-AAT levels may to continue to increase with repeat dosing; our understanding of the safety profile of WVE-006; potential milestone payments that we may earn for WVE-006; and the potential benefits of our RNA editing platform and our proprietary best-in-class chemistry, including PN, stereochemistry and our N3U AIMer modification. The words “may,” “will,” “could,” “would,” “should,” “expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,” “predict,” “project,” “potential,” “continue,” “target” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Any forward-looking statements in this press release are based on management's current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release and actual results may differ materially from those indicated by these forward-looking statements as a result of these risks, uncertainties and important factors, including, without limitation, the risks and uncertainties described in the section entitled “Risk Factors” in Wave’s most recent Annual Report on Form 10-K filed with the
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Source: Wave Life Sciences USA, Inc.