Wave Life Sciences reported updated Phase 1b/2a data showing its RNA editing therapy WVE-006 reduced toxic Z-AAT protein and restored functional M-AAT production in alpha-1 antitrypsin deficiency, supporting potential treatment of both lung and liver disease.
Written By: Samiksha Jadhav, BPharm
Reviewed By: Pharmacally Editorial Team
Wave Life Sciences reported updated Phase 1b/2a data showing its investigational RNA editing therapy WVE-006 reduced toxic mutant protein levels and restored functional alpha-1 antitrypsin (AAT) production in patients with alpha-1 antitrypsin deficiency (AATD), supporting its potential to treat both lung and liver disease.
The data come from the ongoing open-label RestorAATion-2 trial (NCT06405633) evaluating WVE-006, a GalNAc-conjugated RNA editing oligonucleotide administered subcutaneously. The study includes three dose cohorts with single- and multidose regimens. Current results cover the 200 mg and 400 mg single- and multidose cohorts and the 600 mg single-dose cohort.
Alpha-1 antitrypsin deficiency (AATD) is a rare inherited disorder in which patients with the severe Pi*ZZ genotype cannot produce healthy wild-type M-AAT protein and instead accumulate mutant Z-AAT protein in the liver, increasing the risk of emphysema, lung damage, fibrosis, and cirrhosis. Current augmentation therapies help protect the lungs but do not treat the underlying liver disease.
WVE-006 produced dose-dependent reductions in circulating mutant Z-AAT after a single dose, reaching 47.3% at 200 mg, 49.7% at 400 mg, and 59.1% at 600 mg. With repeat dosing, reductions reached 70.5% in the 200 mg biweekly cohort and 67.7% in the 400 mg monthly cohort.
The therapy also restored production of wild-type M-AAT protein. Following single doses, M-AAT represented 44.4% to 52.3% of total circulating AAT, while total AAT levels reached therapeutically relevant concentrations between 12.9 µM and 14.0 µM. In the 200 mg multidose cohort, M-AAT reached 64.4% of total AAT, comparable to levels observed in lower-risk Pi*MZ individuals.
Investigators additionally observed three acute phase responses in which AAT production rapidly increased during inflammatory events, including upper respiratory infections and a kidney stone episode. Across the dataset, increases in C-reactive protein strongly correlated with rises in AAT levels (r=0.73, p<0.001).
Wave said WVE-006 was generally well tolerated, with no serious adverse events or clinically meaningful liver function abnormalities reported to date.
Christopher Wright, MD, PhD, Chief Medical Officer at Wave Life Sciences said the findings support the potential for WVE-006 to provide durable lung and liver protection while avoiding permanent genomic modifications associated with DNA editing approaches.
Wave expects regulatory feedback on a potential accelerated approval pathway in mid-2026 and plans to report multidose data from the 600 mg monthly cohort later this year.
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About the Writer
Samiksha Vikram Jadhav (LinkedIn) is a B. Pharm graduate with a strong academic foundation in pharmaceutical sciences, pharmacology, and drug development. She specializes in pharma market research, with a focused interest in mergers and acquisitions, strategic partnerships, and global pharma and biotech deals. Her work centers on analyzing industry transactions, market positioning, and business strategies, translating complex developments into clear, accurate, and insightful scientific and commercial reporting.