Wave Life Sciences Achieves First Human Therapeutic RNA Editing in Alpha-1 Antitrypsin Deficiency Trial

Wave Life Sciences Ltd. has announced groundbreaking proof-of-mechanism data from its Phase 1b/2a RestorAATion-2 study of WVE-006, an RNA editing oligonucleotide designed to treat alpha-1 antitrypsin deficiency (AATD). This innovative treatment utilizes Wave's advanced oligonucleotide chemistry platform and is administered subcutaneously.

The recent data presents the first clinical evidence of RNA editing in humans. It comes from the initial single-dose cohort of 200 mg and involves the first two patients with the "ZZ" genotype of AATD, followed through to day 57. These individuals naturally lack the wild-type alpha-1 antitrypsin (M-AAT) protein, so the detection of M-AAT protein confirms successful editing of mutant Z-AAT mRNA. Achieving a restoration level of 50% M-AAT is equated with a heterozygous “MZ” genotype, which carries a lower risk of AATD-related lung and liver diseases.

The study revealed that on day 15, circulating wild-type M-AAT protein levels in the plasma reached an average of 6.9 micromolar, making up more than 60% of the total AAT. Increases in neutrophil elastase inhibition from baseline were observed, indicating functional M-AAT production. Total AAT protein levels rose from below quantifiable levels at baseline to 10.8 micromolar by day 15, aligning with the levels targeted for regulatory approval of AAT augmentation therapies. These increases in total AAT and M-AAT were noted as early as day 3 and persisted through day 57.

WVE-006 has shown a favorable safety profile and has been well-tolerated thus far. All adverse events reported in the RestorAATion-2 study and the ongoing RestorAATion-1 trial involving healthy volunteers have been mild to moderate, with no serious adverse events recorded. The study is ongoing, with multidose data expected to be shared in 2025.

Paul Bolno, MD, MBA, President and CEO of Wave Life Sciences, emphasized the significance of achieving the first therapeutic RNA editing in humans. He highlighted that the level of mRNA editing observed with a single dose has exceeded expectations. The durability of WVE-006 and its convenient subcutaneous administration support its potential as a best-in-class treatment for AATD. These findings also bolster confidence in Wave's other programs, including those for Huntington’s disease, Duchenne muscular dystrophy, and obesity.

Alpha-1 antitrypsin deficiency affects approximately 200,000 individuals in the US and Europe with the SERPINA1 Z mutation. Current treatments are limited to weekly intravenous augmentation therapy for lung disease and do not address AATD liver disease, which often necessitates liver transplantation.

GSK holds the exclusive global license for WVE-006 and will take over development and commercialization responsibilities following the completion of the RestorAATion-2 study. Wave Life Sciences stands to receive up to $525 million in milestone payments, along with tiered royalties on net sales of WVE-006.

Wave Life Sciences is a biotechnology company dedicated to harnessing the power of RNA medicines to transform human health. The company's innovative platform, PRISM®, integrates various RNA-targeting modalities, chemistry advancements, and insights into human genetics to develop treatments for both rare and common disorders. Wave's diverse pipeline includes programs for Duchenne muscular dystrophy, alpha-1 antitrypsin deficiency, Huntington’s disease, and a preclinical program in obesity.

Wave Life Sciences is headquartered in Cambridge, MA.