Wave Life Sciences (Nasdaq: WVE), based in Cambridge, Massachusetts, reported updated data from its Phase Ib/IIa WVE-006 RestorAATion-2 trial showing that its GalNAc-RNA editing therapy restored wild-type M-AAT to levels consistent with the heterozygous MZ phenotype in adults with homozygous Pi*ZZ alpha-1 antitrypsin deficiency, with effects maintained under both biweekly and monthly dosing schedules. The data, presented at the American Thoracic Society International Conference, also showed that treated patients retained the capacity for dynamic AAT upregulation during acute phase responses — a feature absent in the approved alpha-1 antitrypsin deficiency treatment landscape.
The RestorAATion-2 trial (NCT06405633) is an ongoing Phase Ib/IIa open-label study evaluating WVE-006 in adults with AATD carrying the homozygous Pi*ZZ mutation, across single and multiple ascending dose cohorts of eight patients each.
WVE-006 is a GalNAc-conjugated, subcutaneously administered A-to-I RNA editing oligonucleotide — described by Wave as an AIMer — designed to correct the single-base RNA mutation responsible for the Pi*ZZ genotype. Rather than silencing the mutant allele or supplementing protein exogenously, the molecule is intended to redirect translation toward wild-type M-AAT while simultaneously reducing the hepatotoxic Z-AAT isoform. This positions Wave Life Sciences AATD program as mechanistically distinct from the only currently approved intervention, which is weekly intravenous plasma-derived augmentation therapy that addresses lung disease only and has no effect on liver pathology.
Key results from the WVE-006 RestorAATion-2 trial
In the 200 mg biweekly multidose cohort, seven doses over 12 weeks produced mean maximum M-AAT levels of 64.4% of total circulating AAT, with total AAT reaching 11.9 µM. That M-AAT fraction sits within the reference range observed in heterozygous Pi*MZ individuals — 57% to 71%, mean 64% — who carry low risk of lung or liver disease. The 400 mg monthly multidose cohort, receiving four doses over the same period, produced M-AAT at 58.7% of total AAT and total AAT of 13.6 µM, indicating that extending the dosing interval to monthly did not substantially diminish the pharmacodynamic response.
Z-AAT reduction followed a dose-dependent pattern. Single doses reduced circulating Z-AAT by 47.3%, 49.7%, and 59.1% at the 200 mg, 400 mg, and 600 mg dose levels respectively. With multiple doses, reductions reached 70.5% in the biweekly cohort and 67.7% in the monthly cohort. Z-AAT accumulation in the liver is the primary driver of progressive hepatic fibrosis in Pi*ZZ individuals, and no approved therapy currently addresses this component of disease.
A separate observation reinforced the functional relevance of the pharmacodynamic signal. Across the trial, three patients mounted elevated AAT responses during acute phase reactions — one following a kidney stone event, producing total AAT of 20.6 µM, and two following mild upper respiratory infections in the 400 mg multidose cohort, with AAT increases of 57.8% and 59.8% above pre-event levels. The correlation between C-reactive protein and AAT elevation across all available data reached r=0.73 (p < 0.001, n=19), suggesting preservation of dynamic acute phase responsiveness. This dynamic upregulation capacity is not replicated by augmentation therapy, which delivers a fixed exogenous protein load irrespective of physiological demand.
Editing durability extended at least three months after the last dose in both multidose cohorts, supporting the feasibility of infrequent subcutaneous dosing as a practical alpha-1 antitrypsin deficiency treatment approach.
On safety, all adverse events were mild to moderate in intensity. No serious adverse events were reported, and there were no clinically meaningful elevations in liver function tests across any cohort to date.