Wave Life Sciences announces updated data from RestorAATion-2 trial of WVE-006

Wave Life Sciences (WVE) announced updated data from the ongoing RestorAATion-2 trial of WVE-006, its investigational, GalNAc-conjugated, subcutaneously delivered RNA editing oligonucleotide for alpha-1 antitrypsin deficiency. The company said 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 Pi*ZZ 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 Pi*MZ individuals have low risk of lung or liver disease and circulating M-AAT levels ranging from 57% to 71% of total, based on analysis of natural history study samples measured with the same assay used in RestorAATion-2. RestorAATion-2 is an ongoing open-label Phase 1b/2a trial with three dose cohorts, with single and multidose portions. In the multidose portions, individuals receive multiple doses of WVE-006, over 12 weeks, followed by 12 weeks of follow-up. As of the data cutoff, data is available for the 200 mg, 400 mg, and 600 mg cohorts. Circulating M-AAT, Z-AAT, and total AAT protein in the serum were measured by LC-MS/MS assays and reported as mean maximums. circulating, mutant Z-AAT from baseline following a single dose of WVE-006, reaching 47.3%, 49.7%, and 59.1%. There were further reductions in Z-AAT with multiple doses of WVE-006, reaching 70.5% in the 200 mg biweekly dose cohort. Reduction of Z-AAT was similar when extending the dosing interval, reaching 67.7% in the 400 mg monthly dose cohort. Individuals with Pi*ZZ 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 as a percentage of total circulating AAT following single doses of WVE-006, reaching 44.4%, 48%, and 52.3%. In each single dose cohort, total AAT reached therapeutically relevant levels. In the 200 mg multidose cohort, total AAT was 11.9 microM 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, where M-AAT levels reached 58.7% of total AAT. Total AAT in the 400 mg multidose cohort reached 13.6 microM. 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 and AAT elevation. As previously reported, in the 200 mg single dose cohort, one individual produced a significant increase in total AAT 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 following acute phase responses to mild upper respiratory infection. Additionally, across all available RestorAATion-2 data to date, CRP increases are strongly correlated with increases in AAT. 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 were mild to moderate in intensity, and there were no SAEs or clinically meaningful liver function test elevations.