Slide 1: RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD)
RNA Editing for the Treatment of Alpha-1 Antitrypsin Deficiency (AATD) Kenneth R. Chapman, MD, MSc, FRCPC, FACP, FCCP, FERS Director, Asthma & Airway Centre, University Health Network, Professor of Medicine, University of Toronto May 18th, 2026 Presented at ATS, 2026
Slide 2: Disclosures
Disclosures Kenneth R Chapman Consultations Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, GlaxoSmithKline, Grifols, InhibRx, Kamada, Merck Frosst, Novartis, Regeneron, Roche, Sanofi, Takeda Research Grants/Contracts Amgen, AstraZeneca, Bellus, BMS, CSL Behring, Genentech, GlaxoSmithKline, G
Slide 3: Disclosures
Disclosures - Alice M Turner has received grants and/or honoraria from GSK, Takeda, Vertex, CSL Behring, Grifols, Sanofi, Beam, Tessera, Korrobio, AiRNA • Pavel Strnad has received grants and honoraria from Arrowhead Pharmaceuticals, CSL Behring, Grifols Inc, consulting fees or honoraria from AiRNA
Slide 4: AAT protein produced by the liver protects the lung against neutrophil elastase
AAT protein which is predominately produced by the liver protects the lung against neutrophil elastase 4
Slide 5: Pi*ZZ genotype is leading cause of severe AATD
Pi*ZZ genotype is leading cause of severe AATD, predisposing to progressive lung damage, liver damage or both 5 Strnad et al., 2020 N Engl J Med 382:1443-55; Stoller et al., 1993 Alpha-1 Antitrypsin Deficiency GeneReviews
Slide 6: DNA is transcribed into RNA, then translated into alpha-1 antitrypsin protein
DNA is transcribed into RNA, which is then translated into the alpha- 1 antitrypsin protein In patients with AATD, correcting the mutant Z-AAT RNA transcript in the liver can restore the normal protein and address both lung and liver manifestations of the disease 6
Slide 7: Wave RNA editing oligonucleotides direct editing of mRNA by endogenous ADAR
Wave Life Sciences has developed RNA editing oligonucleotides that direct efficient and specific editing of mRNA by endogenous ADAR* enzymes + RNA with Z Disease-causing Wave Compound Wave compound joins ADAR makes RNA is edited Functional, Mutation Mutant & RNA with Z with RNA; recognized single le
Slide 8: WVE-006 designed to replace Z-AAT with M-AAT
WVE-006 is designed to replace Z-AAT with M-AAT, addressing both lung and liver manifestations of AATD RNA editing approach is designed to release M-AAT in the blood, potentially protecting the lungs and reducing the risk of disease in humans 3) Restore functional, 1) Reduce Z-AAT protein 2) Release
Slide 9: RestorAATion-2
RestorAATion-2 9
Slide 10: RestorAATion-2 clinical trial in Pi*ZZ patients ongoing
RestorAATion-2 clinical trial in Pi*ZZ patients ongoing RestorAATion-1: RestorAATion-1: Healthy Healthy Volunteers Volunteers RestorAATion-2: AATD Patients SAD MAD Multi-dosing complete 600 mg SAD Cohort 3 MAD Cohort 3 600 mg 600 mg; Q4W 400 mg SAD Cohort 2 MAD Cohort 2 200 mg 400 mg 400 mg; Q4W 1
Slide 11: Baseline participant characteristics were similar across first two cohorts
Baseline participant characteristics were similar across first two cohorts WVE-006 Key Inclusion Criteria RestorAATion-2 Baseline Participant Characteristics 200 mg 400 mg N=8 N=8 • Pi*ZZ genotype Age at consent (years) (mean (SD)) 51.4 (12.0) 49.4 (18.1) • 18 to 70 years of age Gender, N 8 8 Male 2
Slide 12: Therapeutically relevant levels of total AAT protein with durable editing
Therapeutically relevant levels of total AAT protein with durable editing and M-AAT reaching 64% of total protein in 200 mg cohort Circulating serum total AAT protein Proportion of circulating serum wild-type M-AAT and mutant Z-AAT protein 100 75 Proportion (%) 11.9 Proportion (%) AAT (µM) 50 12.9 2
Slide 13: Consistent M-AAT increase and Z-AAT decrease; MAD enhances effects versus SAD
200 mg cohort: Consistent M-AAT increase and Z-AAT decrease observed, MAD significantly enhances effects versus SAD Increases in neutrophil elastase inhibition from baseline confirmed production of functional M-AAT Increase in M-AAT protein 7.2 Wild-type M-AAT M-AAT (µM) 4.8 Dosing period Follow-up
Slide 14: Restoration of physiological serum AAT production during acute phase response
Restoration of physiological serum AAT production; total AAT reached 20.6 µM during acute phase response Pi*ZZ patients have a reduced capacity to produce AAT protein during an acute phase response Following WVE-006 200 mg single dose, total AAT and M-AAT increased significantly in one patient durin
Slide 15: 400 mg monthly dosing complete with potential for infrequent dosing
400 mg monthly dosing complete with potential for an infrequent dosing regimen 400 mg SAD Cohort As compared to 200 mg SAD Cohort 12.8 µM 5.3 µM • Increases in M-AAT protein Total AAT M-AAT • Greater % of M-AAT protein 47.2% 49.0% • Greater reductions in Z-AAT Circulating Decrease in protein M-AAT Z
Slide 16: WVE-006 continues to be safe and well tolerated
RestorAATion-2: WVE-006 continues to be safe and well tolerated 200 mg SAD 200 mg MAD 400 mg SAD TEAE Category N=8 N=8 N=8 • No SAEs, discontinuations or n (%) n (%) n (%) withdrawals due to TEAEs Any TEAE 6 (75.0) 5 (62.5) 5 (62.5) Mild 2 (25.0) 0 1 (12.5) • All TEAEs were mild to Moderate 4 (50.0)
Slide 17: Summary: Ongoing RestorAATion-2 clinical trial of WVE-006
Summary: Ongoing RestorAATion-2 clinical trial of WVE-006 for alpha-1 antitrypsin deficiency (AATD) Achieved durable production of serum AAT at levels following repeat 200 mg doses of WVE-006 11.9 µM 7.2 µM 64.4% 60.3% Circulating Decrease in Total AAT M-AAT M-AAT Z-AAT 20.6 µM Therapeutically resto
Slide 18: WVE-006: Potential first-in-class, convenient therapy for AATD
WVE-006: Potential first-in-class, convenient therapy for AATD that addresses both liver and lung manifestations of the disease Pi*ZZ genotype is leading cause of severe AATD, predisposing to progressive lung damage, liver damage or both Correcting the mutant Z-AAT RNA transcript in the liver restor
Slide 19: Thank you
Thank you 19