Wave Life Sciences Aligns With FDA on Registrational Path for RNA Editing Therapy WVE-006 in AATD

Wave Life Sciences announced on Oct. 1, 2026, that it has reached alignment with FDA on key aspects of the registrational pathway for WVE-006, an investigational GalNAc-conjugated RNA editing oligonucleotide for alpha-1 antitrypsin deficiency (AATD). Following its meeting with the agency, the company is planning a single 2-year registrational trial designed to support potential full approval. The trial will include a 1-year interim analysis that could support accelerated approval based on AATD biomarkers.¹

What did FDA agree to?

According to Wave, FDA supports the use of the company's current liquid chromatography-mass spectrometry (LC-MS) assay to measure wild-type M-AAT and mutant Z-AAT protein in the WVE-006 registrational program.¹ The company stated that the planned design offers a path to full approval without the need for a separate confirmatory trial.¹ The release does not specify the trial's enrollment target, primary end points, or which AATD biomarkers will form the basis of the interim analysis.

What is AATD?

AATD is an inherited disorder caused by variants in the SERPINA1 gene. The gene provides instructions for alpha-1 antitrypsin (AAT), a protein that protects the body, especially the lungs, from the enzyme neutrophil elastase.² The Z allele produces very little AAT, and abnormal AAT can also accumulate in and damage the liver. Individuals with two copies of the Z allele (Pi*ZZ) are at high risk for both emphysema and AATD-associated liver disease.² Wave estimates that approximately 200,000 people in the United States and Europe are homozygous for the Z allele.¹

According to Wave, the current standard of care, IV augmentation therapy, may leave patients with depleted AAT levels during lung exacerbations and does not address the risk of liver disease.¹

How does WVE-006 work?

WVE-006 is a subcutaneously delivered adenosine-to-inosine (A-to-I) RNA editing oligonucleotide, which Wave calls an AIMer. It was developed using the company's oligonucleotide chemistry platform.¹ By correcting the single RNA base mutation associated with the Pi*ZZ genotype, WVE-006 is designed to do three things: produce healthy wild-type M-AAT, decrease mutant Z-AAT aggregates in the liver, and dynamically increase AAT levels.¹ Because the correction happens at the RNA level, the approach does not modify genomic DNA.

What has RestorAATion-2 shown so far?

WVE-006 is being evaluated in RestorAATion-2, an ongoing open-label phase 1b/2a trial in individuals with the homozygous Pi*ZZ mutation.¹ In previously reported data released in May 2026, the 200 mg biweekly multidose cohort reached a total AAT of 11.9 µM. M-AAT made up 64.4% of total AAT in that cohort, and Z-AAT was reduced by approximately 71%.³ In the 400 mg monthly multidose cohort, total AAT reached 13.6 µM and M-AAT reached 58.7% of total AAT, with a 67.7% reduction in Z-AAT. Editing was sustained for at least 3 months following the last dose in both multidose cohorts.³

According to the Oct. 1 release, WVE-006 continues to be generally safe and well tolerated, with no liver toxicities.¹ These results are pharmacodynamic protein measurements from a small, open-label study. Whether they translate into clinical lung and liver outcomes has not yet been established.

Where does RNA editing fit in rare disease development?

Wave is one of several developers applying RNA-level approaches to genetic disease. In a 2025 video interview with BioPharm International®, Ram Aiyar, PhD, chief executive officer and president of Korro Bio, explained why rare genetic diseases are a natural starting point for such therapies. "You have rare genetic diseases, where you understand the genetic cause of a disease and you can go in and fix it, whether changing DNA or modifying RNA or actually coming on top of something else, these are indications and diseases that biotechs can actually work on," Aiyar said.

What happens next?

Planning is underway for the 2-year registrational trial.¹ Wave expects to share data from the 600 mg monthly multidose cohort of RestorAATion-2 in the fourth quarter of 2026.¹

References

1. Wave Life Sciences. Wave Life Sciences Announces FDA Feedback Supports Registrational Pathway for WVE-006 (RNA Editing) in AATD. Press release. Published October 1, 2026. Accessed October 1, 2026.
2. MedlinePlus Genetics. Alpha-1 antitrypsin deficiency. Accessed October 2026.
3. Wave Life Sciences. Wave Life Sciences Announces Positive Update on RestorAATion-2 Trial: WVE-006 (GalNAc-RNA Editing) Achieves MZ-Like Phenotype Across Both Biweekly and Monthly Dosing. Press release. Published May 18, 2026. Accessed October 1, 2026.