First-Ever Human RNA Editing Achieved in RestorAATion-2 Trial of WVE-006 for AATD

Paul Bolno, MD, MBA

Credit: Wave Life Sciences

Wave Life Sciences has announced positive proof-of-mechanism data from the ongoing phase 1b/2a RestorAATion-2 study of WVE-006 in alpha-1 antitrypsin deficiency (AATD), including both AATD-related lung and liver disease.¹

The data represent the first-ever clinical demonstration of RNA editing in humans and are from the first single-dose cohort (200 mg) in RestorAATion-2, including the first 2 patients with “ZZ” AATD (Pi*ZZ AATD) to reach day 57. Results showed a single subcutaneous dose of WVE-006 in these patients resulted in mean plasma total AAT levels of ~11 micromolar, with mean wild-type M-AAT representing > 60% of total AAT.¹

“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,” Paul Bolno, MD, MBA, president and chief executive officer at Wave Life Sciences, said in a press release.¹ “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.”

A phase 1b/2a open-label study, RestorAATion-2 is designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of WVE-006 in individuals with AATD who have the homozygous Pi*ZZ mutation. The trial includes both single ascending dose and multiple ascending dose portions.²

WVE-006 is a GalNAc-conjugated, subcutaneously delivered, A-to-I RNA editing oligonucleotide (AIMer) designed to correct the single base mutation in messenger RNA (mRNA) coded by the SERPINA1 Z allele, enabling restoration and circulation of functional M-AAT protein. It is uniquely designed to address AATD-related lung disease, liver disease, or both.^1,2

In the study, circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing > 60% of total AAT. Increases in neutrophil elastase inhibition from baseline were consistent with the production of functional M-AAT.¹

Of note, individuals with Pi*ZZ AATD do not naturally produce M-AAT protein, so the presence of M-AAT protein observed in the study is confirmation of successful editing of mutant Z-AAT mRNA. As noted in the press release from Wave, restoring 50% M-AAT would be consistent with the heterozygous “MZ” genotype with a low risk of AATD lung and liver disease.¹

Additionally, study results showed 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. According to the press release, increases in total AAT from baseline and M-AAT protein were observed as early as day 3 and through day 57.¹

To date, WVE-006 has been well tolerated with a favorable safety profile. All adverse events in RestorAATion-2 and the ongoing RestorAATion-1 trial of healthy volunteers have been mild to moderate, with no serious adverse events reported. The RestorAATion-2 trial is ongoing with multidose data expected in 2025.¹

“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,” Bolno said.¹ “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.”

References

1. ^{Wave Life Sciences. Wave Life Sciences Announces First-Ever Therapeutic RNA Editing in Humans Achieved in RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency. October 16, 2024. Accessed October 16, 2024. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-first-ever-therapeutic-rna-editing}
2. ^{Wave Life Sciences. Wave Life Sciences Announces Approval of First Clinical Trial Application for RestorAATion-2 Trial of WVE-006 in Individuals with Alpha-1 Antitrypsin Deficiency (AATD). April 30, 2024. Accessed October 16, 2024. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-approval-first-clinical-trial}