お知らせ • May 21
Wave Life Sciences Ltd. Announces Positive Update on RestorAATion-2 Trial: WVE-006 (GalNAc-RNA Editing) Achieves MZ-Like Phenotype Across Both Biweekly and Monthly Dosing
Wave Life Sciences Ltd. announced updated data from the ongoing RestorAATion-2 trial of WVE-006, its investigational, GalNAc-conjugated, subcutaneously delivered RNA editing oligonucleotide (AIMer) for alpha-1 antitrypsin deficiency (AATD). These data further affirm WVE-006’s potential as a novel therapeutic addressing both lung and liver AATD by generating healthy, wild-type M-AAT, reducing harmful Z-AAT, and restoring the ability to dynamically produce functional AAT protein when needed. Individuals with PiZZ AATD cannot produce healthy, wild-type M-AAT, have unhealthy, mutant Z-AAT aggregates in liver, and cannot dynamically increase AAT, a protein responsible for protecting lungs against ongoing damage. Heterozygous PiMZ individuals have low risk of lung or liver disease and circulating M-AAT levels ranging from 57% to 71% of total (mean=64%), based on analysis of natural history study samples measured with the same assay used in RestorAATion-2. The only approved treatment for AATD is weekly intravenous plasma-derived augmentation therapy, which only addresses lung manifestations and may leave individuals living with AATD at risk if AAT protein levels fall too low during an acute phase response. There are no approved therapies for AATD liver disease. Updated RestorAATion-2 clinical data: RestorAATion-2 is an ongoing open-label Phase 1b/2a trial with three dose cohorts (each n=8), with single and multidose portions. In the multidose portions, individuals receive multiple doses of WVE-006 (200 mg biweekly, 400 mg monthly, 600 mg monthly), over 12 weeks, followed by 12 weeks of follow-up. As of the data cutoff, data is available for the 200 mg (single and multidose), 400 mg (single and multidose), and 600 mg (single dose) cohorts. Circulating M-AAT, Z-AAT, and total (M + Z) AAT protein in the serum were measured by LC-MS/MS assays and reported as mean maximums. Reductions in Z-AAT protein: In PiZZ individuals, Z-AAT aggregates in the liver, where it can result in progressive liver disease. Treatment with WVE-006 led to robust, dose-dependent reductions of circulating, mutant Z-AAT from baseline following a single dose of WVE-006, reaching 47.3% (200 mg), 49.7% (400 mg), and 59.1% (600 mg). There were further reductions in Z-AAT with multiple doses of WVE-006, reaching 70.5% in the 200 mg biweekly dose cohort (seven doses). Reduction of Z-AAT was similar when extending the dosing interval, reaching 67.7% in the 400 mg monthly dose cohort (four doses). Restoration of wild-type M-AAT protein: Individuals with PiZZ AATD cannot produce wild-type M-AAT, the protein responsible for protecting the lungs against ongoing damage. Treatment with WVE-006 led to robust, dose-dependent restoration of wild-type M-AAT protein (canonical M-AAT) as a percentage of total circulating AAT following single doses of WVE-006, reaching 44.4% (200 mg), 48.0% (400 mg), and 52.3% (600 mg). In each single dose cohort, total AAT reached therapeutically relevant levels (200 mg: 12.9 µM; 400 mg: 14.0 µM; 600 mg: 13.0 µM). In the 200 mg multidose cohort, total AAT was 11.9 µM and M-AAT levels reached 64.4% of total AAT, in line with heterozygous MZ individuals with low risk of disease. A similar robust response was also observed when extending the dose interval to monthly (400 mg multidose cohort), where M-AAT levels reached 58.7% of total AAT. Total AAT in the 400 mg multidose cohort reached 13.6 µM. Restoration of dynamic AAT protein: Notably, following treatment with WVE-006, three instances of dynamic and rapid production of AAT protein due to acute phase responses were observed across RestorAATion-2 as indicated by concurrent C-reactive protein (CRP) and AAT elevation. As previously reported, in the 200 mg single dose cohort, one individual produced a significant increase in total AAT (20.6 µM) following an acute phase response related to a kidney stone. In the 400 mg multidose cohort, there were two additional instances of significant increases in AAT (57.8% and 59.8% versus pre-event) following acute phase responses to mild upper respiratory infection (common cold). Additionally, across all available RestorAATion-2 data to date, CRP increases are strongly correlated with increases in AAT (r=0.73, p<0.001, n=19). Convenient dosing and strong safety: Data support monthly subcutaneous dosing, with editing sustained at least three months following the last dose in both the 200 mg and 400 mg multidose cohorts. WVE-006 continues to be well tolerated with a favorable safety profile to date. All adverse events (AEs) were mild to moderate in intensity, and there were no SAEs or clinically meaningful liver function test elevations. Data from the RestorAATion-2 clinical trial were also highlighted earlier today at the American Thoracic Society (ATS) International Conference in an oral presentation by Kenneth R. Chapman, MsC, MD, FRCPC, FACP, FERS, Department of Medicine, University of Toronto. Anticipated upcoming milestones for WVE-006: Wave expects to receive regulatory feedback on a potential accelerated approval pathway mid-2026. Wave expects to share data from the 600 mg (monthly) multidose cohort in the second half of 2026.