RestorAATion-2: WVE-006 Achieves Durable Serum AAT Protein Production in AATD

Wave Life Sciences has announced positive data from the 200 mg single and multidose and 400 mg single dose cohorts of the ongoing phase 1b/2a RestorAATion-2 study evaluating WVE-006 as a treatment for alpha-1 antitrypsin deficiency (AATD).1

According to a September 3, 2025, press release from the Company, WVE-006 achieved durable production of serum AAT protein at levels associated with a reduced risk of AATD liver and lung diseases following repeat 200 mg doses. While data from the 400 mg multidose cohort are not expected until 1Q 2026, single dose 400 mg data showed achievement of 12.8 µM total AAT and 5.3 µM M-AAT.1

“Wave’s clinical trial provides 2 important findings. First, RNA editing resulted in the endogenous production of M protein in ZZ individuals. Second, serendipitously the study observed that the stress of a kidney stone was associated with marked upregulation of M protein production. This suggests that RNA editing has the potential to restore, at least in part, both endogenous M protein production and its normal regulation in AATD. These results are extremely exciting,” Stephen Rennard, MD, a professor of medicine in the division of pulmonary, critical care and sleep medicine at the University of Nebraska Medical Center, said in a statement.1

A GalNAc-conjugated, subcutaneously delivered A-to-I RNA editing oligonucleotide, WVE-006 was developed with Wave’s best-in-class oligonucleotide chemistry platform. By correcting the single RNA base mutation that causes most AATD cases with the Pi*ZZ genotype, WVE-006 is designed to deliver a comprehensive treatment approach for AATD by increasing circulating levels of wild-type AAT protein and reducing mutant protein aggregation in the liver, simultaneously addressing both the lung and liver manifestations of the disease.1

RestorAATion-2 is an ongoing phase 1b/2a open label study designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of WVE-006 in individuals with AATD who have the homozygous Pi*ZZ mutation. The trial includes both single ascending dose and multiple ascending dose portions.1

In October 2024, Wave announced positive proof-of-mechanism data from RestorAATion-2 representing the first-ever clinical demonstration of RNA editing in humans and are from the first single-dose 200 mg cohort in RestorAATion-2, including the first 2 patients with Pi*ZZ AATD to reach day 57.2

As described in the release from Wave, in cohort 1 (200 mg; n = 8), participants received a single subcutaneous dose of WVE-006 and then received 7 subcutaneous doses administered every other week under the multidose protocol. Data were also reported for the single dose portion of cohort 2 (400 mg; n = 8).1

In the 200 mg multidose cohort, total AAT reached therapeutically relevant levels of 11.9 micromolar (µM). Wild-type M-AAT increased from below the level of quantitation at baseline to 7.2 µM, which was significantly increased from levels achieved during the single dose portion of the cohort (4.8 µM; P = .012). Additionally, M-AAT levels reached 64.4% of total AAT, and mutant Z-AAT protein declined from baseline by 60.3%. M-AAT levels were durable and sustained at >50% of total AAT for ≥ 2 months following the last dose. Increases in neutrophil elastase inhibition from baseline were confirmed with production of functional M-AAT.1

Of note, following a single 200 mg dose of WVE-006, a total AAT level of 20.6 µM, including a M-AAT level of 10.3 µM, was observed in one individual during an acute phase response due to a kidney stone, demonstrating that treatment with WVE-006 enables endogenous regulation and dynamic increased secretion of AAT protein during an acute phase response as indicated by a concurrent C-reactive protein elevation.1

In the 200 mg single dose cohort, total AAT reached 12.9 µM, M-AAT increased to 4.8µM, and Z protein decreased by 47.3%. Excluding the individual with an acute phase response, total AAT reached 11.8 µM, M-AAT increased to 4.0 µM, and Z protein decreased by 48.8%.1

A single 400 mg dose of WVE-006 resulted in achievement of total AAT of 12.8 µM and M-AAT of 5.3 µM. Circulating serum M-AAT levels reached 47.2% of total AAT and Z-AAT decreased by 49% versus baseline.1

Data from both the 200 mg and 400 mg (single dose only) cohorts support a monthly or less frequent subcutaneous dosing regimen. Dosing is ongoing in the 400 mg multidose cohort with a monthly dosing regimen, for which Wave expects to deliver data in the first quarter of 2026.1

All adverse events were mild to moderate in intensity, and there were no SAEs or discontinuations.1

“Today’s data represent a significant clinical milestone for individuals living with AATD, as well as the field of RNA editing, with WVE-006 enabling the dynamic generation of wild-type M-AAT protein when needed… Collectively, our data highlight WVE-006’s potential to provide a transformative treatment option for people living with AATD,” said Paul Bolno, MD, MBA, President and Chief Executive Officer at Wave Life Sciences.1 “Today’s update reinforces the strength of our platform as we continue to advance additional wholly owned editing programs toward the clinic. We look forward to sharing more about these at our Research Day this fall.”

References

1. Wave Life Sciences. Wave Life Sciences Announces Positive Update from Ongoing RestorAATion-2 Trial of WVE-006 in Alpha-1 Antitrypsin Deficiency. September 3, 2025. Accessed September 3, 2025. https://ir.wavelifesciences.com/news-releases/news-release-details/wave-life-sciences-announces-positive-update-ongoing

2. Brooks A. First-Ever Human RNA Editing Achieved in RestorAATion-2 Trial of WVE-006 for AATD. HCPLive. October 16, 2024. Accessed September 3, 2025. https://www.hcplive.com/view/first-ever-human-rna-editing-achieved-restoraation-2-trial-wve-006-aatd