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Investor presentation March 26, 2025 48-Week Results from FORWARD -53 Trial of WVE-N531 in Duchenne Muscular Dystrophy
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2 Forward-looking statements This document contains forward-looking statements. All statements other than statements of historical facts contained in this document, including statements regarding possible or assumed future results of operations, preclinical and clinical studies, business strategies, research and development plans, collaborations and partnerships, regulatory activities and timing thereof, competitive position, potential growth opportunities, use of proceeds and the effects of competition are forward-looking statements. These statements involve known and unknown risks, uncertainties and other important factors that may cause the actual results, performance or achievements of Wave Life Sciences Ltd. (the “Company”) to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. In some cases, you can identify forward-looking statements by terms such as “may, ” “will, ” “should, ” “expect, ” “plan, ” “aim, ” “anticipate, ” “could, ” “intend, ” “target, ” “project, ” “contemplate, ” “believe, ” “estimate, ” “predict, ” “potential” or “continue” or the negative of these terms or other similar expressions. The forward-looking statements in this presentation are only predictions. The Company has based these forward-looking statements largely on its current expectations and projections about future events and financial trends that it believes may affect the Company’s business, financial condition and results of operations. These forward-looking statements speak only as of the date of this presentation and are subject to a number of risks, uncertainties and assumptions, including those listed under Risk Factors in the Company’s Form 10-K and other filings with the SEC, some of which cannot be predicted or quantified and some of which are beyond the Company’s control. The events and circumstances reflected in the Company’s forward-looking statements may not be achieved or occur, and actual results could differ materially from those projected in the forward-looking statements. Moreover, the Company operates in a dynamic industry and economy. New risk factors and uncertainties may emerge from time to time, and it is not possible for management to predict all risk factors and uncertainties that the Company may face. Except as required by applicable law, the Company does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
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3 Today’s agenda FORWARD-53: 48-week clinical trial results Erik Ingelsson, MD, PhD Chief Scientific Officer WVE-N531 next steps and anticipated milestones Paul Bolno, MD, MBA President and CEO Opening remarks and opportunity for WVE-N531 Paul Bolno, MD, MBA President and CEO
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4 Opening remarks and opportunity for WVE -N531 Paul Bolno, MD, MBA President and CEO
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5 CONTINUES OUR COMMITMENT TO REIMAGINE POSSIBLE IN DMD
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6 Duan, D., et al. 2021 Nat Rev Dis Primers; Dumont, N.A., et al. 2015 Nat Med; Muscular Dystrophy Association ~20,000 new cases of DMD annually worldwide DMD is a fatal genetic disorder leading to progressive muscle degeneration • Dystrophin supports stabilizing and repairing muscle fibers and stem cell replenishment & function Healthy muscle • Muscle fibers susceptible to damage • Stem cells and regeneration impaired • Muscle replaced with adipose and fibrous tissue DMD muscle lacking dystrophin Progressive weakness in skeletal muscle leads to decline in motor function and loss of ambulation Progressive muscle deterioration in DMD Urgent need for improved therapeutic options Increasing diaphragm weakness causes respiratory failure Cardiac dysfunction leads to heart failure
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7 Therapeutic strategy in DMD is to achieve broad and consistent delivery of >5% endogenous functional dystrophin to reverse muscle damage Feraudy, Y., et al. 2020 Annals Neurology 89, 280 Slow, stop or reverse loss of function Broad muscle distribution, including heart and diaphragm, and access stem cells Produce endogenous functional dystrophin protein Becker phenotype Delayed loss of ambulation Becker phenotype Loss of ambulation
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8 Kandasamy et al., 2022 Nuc Acids Res doi: 10.1093/nar/gkac018 WVE-N531 for Exon 53 amenable DMD is designed from Wave’s best -in-class oligonucleotide PRISM platform WVE-N531 Unmatched toolkit to access novel biology Data-driven discovery powered by human genetics Foundation in chemistry innovation Best-in-class chemistry Muscle delivery, including to heart and diaphragm Evidence of myogenic stem cell uptake Long tissue half- life to support extended dosing intervals No use of muscle- targeting conjugates
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9 IV: Intravenous; Q2W: Every 2 Weeks; Q4W: Monthly Phase 2 open -label FORWARD -53 trial was designed to evaluate safety, dystrophin expression, longitudinal muscle health and functional outcomes Functional Benefit Muscle Regeneration Dystrophin Production Exon SkippingDelivery Part A: 3 doses 10 mg/kg Q2W n=3 Part B: Biopsies after 24 and 48 weeks of dosing 10 mg/kg Q2W n=11 Extension 10 mg/kg Q4W
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10 ✓ Exon skipping: 53% ✓ Muscle tissue concentration: 42,000 ng/g ✓ Distribution to myofibers and muscle stem cells ✓ Safe and well tolerated, no SAEs SAE: Serious Adverse Event; Q2W: Every 2 Weeks FORWARD-53 enabled longitudinal evaluation of WVE -N531 across essential elements of a disease modifying therapy for DMD Part A 10 mg/kg Q2W x 3 doses (n=3) Functional Benefit Muscle Regeneration Dystrophin Production Exon SkippingDelivery
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11 ✓ Dystrophin consistently above 5% with mean of 9.0% ✓ Safe and well tolerated, no SAEs ✓ Shift to myofiber regeneration ✓ Leading indicators: improvement in serum biomarkers, including CK ✓ With 61-day tissue half-life, profile supports monthly dosing ✓ Exon skipping: 53% ✓ Muscle tissue concentration: 42,000 ng/g ✓ Distribution to myofibers and muscle stem cells ✓ Safe and well tolerated, no SAEs SAE: Serious Adverse Event; Q2W: Every 2 Weeks Right: RNAScope for N531 (red) and immunohistochemistry for PAX7 (brown): a stem cell marker FORWARD-53 enabled longitudinal evaluation of WVE -N531 across essential elements of a disease modifying therapy for DMD Part A 10 mg/kg Q2W x 3 doses (n=3) Part B: Interim at 24 Weeks 10 mg/kg Q2W (n=11) Functional Benefit Muscle Regeneration Dystrophin Production Exon SkippingDelivery WVE-N531 uptake in myogenic stem cells
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12 ✓ Dystrophin consistently above 5% with mean of 9.0% ✓ Safe and well tolerated, no SAEs ✓ Shift to myofiber regeneration ✓ Leading indicators: improvement in serum biomarkers, including CK ✓ With 61-day tissue half-life, profile supports monthly dosing Can we demonstrate these achievements translate to: Improvements in muscle health Improvements in functional outcomes ✓ Exon skipping: 53% ✓ Muscle tissue concentration: 42,000 ng/g ✓ Distribution to myofibers and muscle stem cells ✓ Safe and well tolerated, no SAEs SAE: Serious Adverse Event; Q2W: Every 2 Weeks FORWARD-53 enabled longitudinal evaluation of WVE -N531 across essential elements of a disease modifying therapy for DMD Part A 10 mg/kg Q2W x 3 doses (n=3) Part B: Interim at 24 Weeks 10 mg/kg Q2W (n=11) Objectives for 48 weeks 10 mg/kg Q2W (n=11) Functional Benefit Muscle Regeneration Dystrophin Production Exon SkippingDelivery
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13 NDA filing for accelerated approval with monthly dosing planned for 2026 Today’s update: 48-week data demonstrate WVE -N531’s best-in-class profile for boys amenable to exon 53 skipping Statistically significant and clinically meaningful improvement (3.8s) in Time-to-Rise vs. natural history; functional benefits on other measures including NSAA✓ Statistically significant reductions in muscle fibrosis and CK, driven by decreases in inflammation and necrosis; transition from regenerative to mature muscle Consistent dystrophin expression averaged 7.8% between 24 and 48 weeks, with 88% of boys above 5% dystrophin WVE-N531 remains safe and well-tolerated with no Serious Adverse Events ✓ ✓ ✓ Muscle content-adjusted dystrophin
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14 FORWARD-53: 48-week clinical trial results Erik Ingelsson, MD, PhD Chief Scientific Officer
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15 NSAA: North Star Ambulatory Assessment; TTR: Time to Rise; 10MWR 10-meter walk/run test; 4SC: 4-stair climb Baseline participant characteristics Baseline DMD Participant Characteristics FORWARD-53 population (n=11) Age at consent (years) (mean (SD)) Age 5-7 (n (%)) Age 8-11 (n (%)) 8.1 (2.3) 5 (45) 6 (55) BMI (kg/m2) (mean (SD)) 19.1 (4.0) Years since DMD diagnosis (mean (SD)) 3.9 (2.6) Participants on Oral Steroids (n (%)) Prednisone Deflazacort 11 (100) 4 (36.4) 7 (63.6) Ambulatory (n (%)) 10 (90.9) Functional baselines (n=10 ambulatory) NSAA total score TTR (sec) 10MWR (sec) 4SC (sec) 20.0 6.2 5.5 5.0
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16 TEAE: Treatment emergent adverse event; Data as of February 5, 2025; *One participant had a severe TEAE non-study drug related event of self-limiting, short-lived, viral gastroenteritis No Serious Adverse Events and all drug-related TEAEs were mild to moderate WVE-N531 continues to be safe and well tolerated at 48 weeks TEAE Category WVE-N531 10 mg/kg Q2W n=11 Participants (%) Any TEAE Mild Moderate Severe 11 (100%) 10 (90.9%) 7 (63.6%) 1 (9.1%) Any drug-related TEAE Mild Moderate Severe 4 (36.4%) 4 (36.4%) 1 (9.1%) 0 Any serious TEAE 0 Any TEAE leading to discontinuation 0 Any TEAE leading to death 0
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17 Best-in-class profile: 7.8% average dystrophin expression, consistently exceeding levels associated with milder Becker phenotype Left: week 24 (n=9), among these participants eight had muscle biopsies available for week 48 and average; Dystrophin measured by western blot (AB15277). Dystrophin expression was quantified from two isoforms; MCA: muscle content-adjusted (MHC-normalized dystrophin/(total myofiber area/total area of biopsy section)). Middle: Dystrophin levels were scaled to range between 0 and 1; Pearson correlation (r) is presented; Right: Average between 24 and 48 weeks. Dystrophin expression by western blot stabilized by 24 weeks Week Average 24 48 Mean exon skipping induced 57% (95% CI: 49-65%) 54% (95% CI: 44-65%) 54% (95% CI: 46-63%) Mean MCA dystrophin 9.0% (95% CI: 6.5-11.5%) 6.4% (95% CI: 3.8-9.0%) 7.8% (95% CI: 5.4-10.3%) 88% of boys achieving greater than 5% average dystrophin Consistency at 24 and 48 weeks confirmed with orthogonal assay Participants Average dystrophin protein (%normal) MHC & muscle adj. Week 48 Relative dystrophin levels Week 24 Relative dystrophin levels r=0.89
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18 Cardone et al., 2023 Acta Neuropathol Comm DMD is characterized by a progressive decline in muscle function Damage Inflammation Regeneration Damage Necrosis and inflammation Regeneration to exhaustion Fibrosis Feedback turns off regeneration (fewer stem cells and they are in resting state) Healthy DMD (lack of dystrophin) Fiber maturation Progressive muscle degeneration
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19 H&E-stained sections (20X magnification). Seven paired biopsies available from week 24 and 48 for histopathology. Evidence of reversal of muscle damage across majority of participants Participant number 1 1 2 3 4 765 2 3 4 765 Week 24 Week 48
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20 0 1 2 3 4 5 0 1 2 3 Number participants Week 24 Week 48 0 1 2 3 4 5 0 1 2 3 Number participants 0 1 2 3 4 5 1 2 3 4 Number participants Median muscle inflammation and necrosis scores decreased from 2 to 1 between week 24 and 48 Severity scoring (x-axis) based on Schafer et al., 2018 Toxicol Pathol. Severity scores: 1 = minimal, 2= mild, 3 = moderate, and 4 = marked Inflammation 71% Minimal to mild Necrosis 100% 71% Normal to minimalMinimal to mild Improving muscle inflammation and necrosis to lower (minimal/mild) levels Shift to minimal/mild Shift to minimal 43% Normal to minimal 0 1 2 3 4 5 1 2 3 4 Number participants
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21 Meaningful decreases in inflammatory cytokines with treatment Data are means ± SE Blood vessel Macrophage Pro-inflammatory cytokines activate muscle repair (e.g., MCP-1, IL-6, TGF-β) Anti-inflammatory cytokines dampen inflammation, prevent fibrosis & necrosis Damaged muscle fiber In DMD, muscles are in a perpetual inflammatory state, which promotes muscle degeneration and fibrosis Decrease in MCP-1 and IL-6 suggests reduction in inflammation with treatment Week 24 Week 48 MCP-1 (pg/mL) Week 0 IL-6 (pg/mL) Week 24 Week 48Week 0
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22 *p<0.05, ** p<0.01, ***p<0.001; Data are mean ± SE Left: n=11; right: n=10 (all ambulatory) Decreased CK to levels observed in milder DMD individuals Statistically significant reductions in creatine kinase (CK) as compared to baseline and natural history ~50% CK reduction from baseline at 48 weeks Statistically significant reduction in CK vs. C-PATH Natural History Creatine kinase (U/L) Change in Creatine kinase (U/L) Week Week 0 24 48 ***** *** * *** ***
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23 ~20% change in density of myogenic stem cells at 48 weeks Significant decrease (~48%) in internalized nuclei at 48 weeks Left: NS; Data are mean ± SE (of n = 9); PAX7-positive cells/mm2 quantified using Pax7 immunohistochemistry (IHC) with HALO. Right: Data are mean ± SE (of n=9) (wk 24) and n=8 (wk 48);**p<0.01 (two-tailed Welch’s test); Internalized nuclei quantified using 6 random fields in H&E stained sections Changes to key cell populations in muscle supports muscle maturation, suggesting transition to healthier muscle Progression of regenerative to mature state of muscle tissue 24 48 Time (weeks) 24 weeks 48 weeks 24 weeks 48 weeks Time (weeks) Week 24 Week 48 PAX7 positive cells/mm2 Week 24 Week 48 %Myofibers with internalized nuclei
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24 First evidence of reversal of muscle damage with exon skipping treatment Right: Magnification 5X; fibrosis stained with trichrome stain and analyzed with HALO; ** p<0.01; Data are mean ± SE Mean fibrotic muscle declined 28.6% at 48W Time (weeks) % Fibrotic muscle declined by individual Time (weeks) 24 %Trichrome positive Week 48 showed improved organization and uniformity of myofibers Week 24 Week 48 Participant 1Participant 2 (n = 7) (n = 7) %Trichrome positive tissue 484824
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25 Cardone et al., 2023 Acta Neuropathol Comm WVE-N531 appears to shift dystrophic muscle towards healthy muscle Damage Inflammation Regeneration Damage Necrosis and inflammation Regeneration to exhaustion Fibrosis Feedback turns off regeneration (fewer stem cells and they are in resting state) Healthy DMD (lack of dystrophin) Fiber maturation Inflammatory cytokines (MCP-1 and IL-6) Serum CK Reduced Fibrosis Healthier Muscle Fiber organization and uniformity of myofibers Reduced Necrosis and Inflammation Shift Toward Fiber Maturation Stem cell density Internalized nucleiImpact of WVE-N531 on Muscle Health Functional benefit
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26 Functional assessments: Baseline FORWARD -53 population well matched to natural history cohort WVE-N531 FORWARD-53 (Exon 53) Natural History Cohort PRO-DMD-01 (Exon 53) N 10 18 Age (years) 7.8 7.9 NSAA total score 20.0 20.4 TTR (sec) 6.2 7.4 10MWR (sec) 5.5 6.1 4SC (sec) 5.0 4.6 All boys on stable steroids; Analysis of ambulatory participants NSAA: North Star Ambulatory Assessment; TTR: Time to Rise; 10MWR 10-meter walk/run test; 4SC: 4-stair climb
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27 Statistically significant and clinically meaningful slowing of disease progression as measured by TTR Minimal Clinical Important Difference (MCID) for TTR: 1.4 sec based on method from McDonald 2013; *p<0.05; Data are mean ± SE Mean change in time-to-rise (TTR) Change from baseline in TTR (sec) 3.8 second improvement with WVE-N531 Week Worsening
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28 Treatment with WVE-N531 slowed progression as measured by NSAA NSAA: North Star Ambulatory Assessment; data are mean ± SE Mean change in NSAA Change from baseline in NSAA Total (points) Worsening 1.2 point improvement with WVE-N531 Week
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29 Positive trends on additional functional measures supporting muscle restoration Data are mean ± SE; n=11 Mean change in grip strength from baseline ImprovementStabilization Right Hand GripLeft Hand Grip Grip Strength (kg) Change From Baseline
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30 Investigator feedback supports potential clinical benefit of WVE -N531 “…shown remarkable progress, as they are now able to play football, which was something they previously struggled with. ” “…developed the ability to run in reverse, which is a significant improvement. ” “ …have become more independent in their daily activities. They are now able to jump, run, and even dress themselves without assistance, which marks a clear improvement in their overall mobility and quality of life. ”
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31 WVE-N531 next steps and anticipated milestones Paul Bolno, MD, MBA President and CEO
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32 Regulatory update and exon skipping franchise derisked FORWARD-53 • All participants are enrolled in the ongoing open-label FORWARD-53 extension trial receiving monthly doses of WVE-N531 • Expanding FORWARD-53 to include additional boys on monthly dosing regimen REGULATORY • FDA feedback confirmed that the accelerated approval pathway using dystrophin expression as asurrogate endpoint remains open • Based on FDA feedback and the 48-week data, Wave intends to submit an NDA in 2026 to support accelerated approval of WVE-N531 with monthly dosing • Wave will continue to engage the Agency with the new 48-week data, including functional outcomes, and its planned global confirmatory trial of WVE-N531 EXON SKIPPING FRANCHISE • Expect to submit multiple CTAs for other exon skipping candidates in 2026 • Candidates all use Wave’s best-in-class chemistry; and preclinical data suggest best-in-class exon skipping franchise
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33 Monthly WVE-N531 is expected to offer a differentiated profile that addresses key unmet needs for boys with exon 53 amenable DMD 1. 48 weeks (Vyondys 53); 2. 24 weeks (Viltepso); 3. Based on 48-week data; 4. Evidence of ability to reach heart and diaphragm through preclinical studies (Kandasamy et al., 2022 Nuc Acids Res doi: 10.1093/nar/gkac018) Currently marketed exon 53 skipping therapies under accelerated approval WVE-N531 4 Dystrophin consistency No1 or few2 boys achieve levels above 5% Evidence of ability to reach myogenic stem cells Favorable dosing frequency Weekly Favorable safety profile Favorable evidence of functional benefit (TTR)3 Evidence of disease reversal in muscle Evidence of ability to reach heart and diaphragm
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34 8% 6% 4% 17% Wave DMD portfolio addresses >$2.4 billion opportunity in US alone with potential for expansion Exon 51 Wave portfolio addresses up to 40% of the DMD population • ~40–50% of exon 53, 51, 45 skipping amenable boys remain untreated today • No exon skipping therapies available for exons 44 and 52 • Advantages over gene therapy (endogenous dystrophin, favorable safety) Switches from marketed exon skipping therapies Increasing exon skipping treatment rates Expansion to ex-US markets Multiple drivers of value with Wave portfolio • Monthly dosing, superior dystrophin profile, and improvements in muscle health WVE-N531 Exon 53 8-10% Not Amenable to Skipping Other Exons 44% Exon 45 Exon 44 Exon 52 Exon 51 • Best-in-class exon skipping profile where no exon skipping therapies are available 11-13% Aartsma-Rus, et al. 2009 Hum Mutat
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35 Full list of Wave publications: https://ir.wavelifesciences.com/events-publications/publications HD: mHTT reductions compared to placebo; DMD: Mean muscle-adjusted dystrophin Continued clinical translation sets foundation for multiple near -term milestones Clinical translation Improvements on multiple functional outcomes and muscle health; 7.8% average dystrophin Novel base and sugar chemistry modifications Stereopure oligonucleotides Novel backbone modifications (including PN chemistry) Proprietary PRISM platform Therapeutic modalities Splicing (WVE-N531 for DMD) GalNAc-RNA editing (WVE-006 for AATD) GalNAc-RNAi (WVE-007 for obesity) First ever RNA editing achieved; ~11 µM total AAT protein, >60% (6.9 µM ) M-AAT with single dose 46% allele-selective mHTT silencing; correlation with slowing of caudate atrophy Allele-selective silencing (WVE-003 for HD) 200 mg multidose data and 400 mg single dose data expected in 2025 Clinical data expected 2H 2025 Next steps IND expected 2H 2025 for potentially registrational Phase 2/3 trial Expect to file NDA for WVE-N531 to support accelerated approval and file CTAs for additional exons in 2026
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36 Thank you to the boys, families, clinicians and study site staff who are participating in this study
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37 Q&A