Wave Life Sciences (WVE) Study update summary

Study background and unmet need

• RestorAATion-2 is a phase I/II trial evaluating WVE-006, an RNA editing therapy for PiZZ alpha-1 antitrypsin deficiency (AATD), a disease with significant unmet need affecting both liver and lung health.

• AATD is caused by the SERPINA1 Z mutation, leading to misfolded Z-AAT protein accumulation in the liver and insufficient protective AAT in the lungs, resulting in progressive organ damage and high morbidity and mortality.

• Only about 10% of the estimated 200,000 PiZZ individuals in the US and Europe are diagnosed, with underdiagnosis due to limited therapeutic options and frequent misidentification as other conditions.

• Current standard of care is weekly IV augmentation therapy for lung disease, which does not address the underlying genetic defect or liver disease and is not reimbursed in many markets outside the U.S.

• AATD significantly impacts quality of life, with high rates of liver fibrosis and frequent exacerbations of lung disease.

Mechanism and therapeutic goals

• WVE-006 is a GalNAc-conjugated, subcutaneously delivered RNA editing oligonucleotide designed to correct the SERPINA1 Z mutation, restoring wild-type M-AAT production and reducing Z-AAT.

• The therapy aims to recapitulate the MZ phenotype (>50% wild-type M-AAT), which is associated with low risk of lung and liver disease, and restore dynamic AAT response during inflammation.

• RNA editing avoids permanent off-target effects and bystander edits seen with DNA editing approaches.

• WVE-006 is designed for convenient, infrequent subcutaneous dosing, potentially monthly or less frequent, supporting self-administration.

Study design and baseline

• RestorAATion-2 is an ongoing open-label, multi-dose, ascending dose Phase 1b/2a trial in PiZZ AATD patients, with cohorts receiving 200 mg biweekly, 400 mg monthly, and ongoing 600 mg monthly dosing.

• Each cohort includes eight participants, with multidose portions spanning 12 weeks of dosing and 12 weeks of follow-up.

• Participants included adults with PiZZ genotype, mild to moderate lung or stable mild liver disease, and similar baseline characteristics across cohorts.