Presentation: RestorAATion: The First Clinical Program Evaluating an RNA Editing Therapeutic in Humans

RestorAATion: The First Clinical

Program Evaluating an RNA Editing

Therapeutic in Humans

Cynthia Caracta, MD

June 20, 2024

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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Wave is building the leading RNA medicines company, with RNA editing as a core competency

Multi-modal drug discovery and	Differentiated RNA medicines pipeline
development platform

• Therapeutic candidates that optimally address disease biology

• Clinical data updates expected in 2024 from AATD, DMD, HD clinical programs

•	RNA editing, siRNA, splicing, antisense	•	INHBE clinical trial initiation for obesity expected 1Q 2025
•	Best-in-class oligonucleotide chemistry	•	Initiated first-ever clinical trial in RNA editing for AATD

Strategic collaborations	In-house GMP manufacturing	Strong and broad IP
(GSK and Takeda)

Well capitalized with cash runway into 4Q 2025*

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*Cash runway does not include potential future milestones or opt-in payments under GSK and Takeda collaborations AATD: Alpha-1 antitrypsin deficiency, DMD: Duchenne muscular dystrophy, HD: Huntington's disease

Wave's versatile multimodal RNA medicines platform is ideal for capitalizing on new genetic insights in rare and common diseases

Accessing UK Biobank and building proprietary machine learning models to generate unique genetic insights

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Claussnitzer, et al. Nature (2020) 577, 179; King et al. PLoS Genet (2019) 15, e1008489

Wave's A-to-I RNA editing oligonucleotides (AIMers)

 Best-in-class, proprietary chemistry yielding superior potency, distribution, durability

 Efficient and highly specific recruitment of ADAR enzymes

 Uses GalNAc in the liver and free uptake outside liver; avoids LNPs/other complex delivery vehicles

 Leveraging ML, AI, large genetic datasets to identify novel insights, targets, target sites

 First RNA editing clinical candidate will provide proof-of-mechanism for Wave's other AIMer programs

Proof-of-mechanism data from first-ever RNA editing clinical program (RestorAATion) expected in 2024

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LNPs: lipid nanoparticles; ML: Machine learning; AI: artificial intelligence

WVE-006: A first-in-class investigational RNA editing therapeutic for AATD

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AATD may result in lung and liver disease and has limited treatment options

• SERPINA1 Z mutation (E342K) is most common cause of AATD1
• ~200,000 Pi*ZZ patients in US and Europe2
• Augmentation therapy is only treatment option for AATD lung disease and requires weekly IV infusions
• No treatment for AATD liver disease, other than liver transplant
• Average age of diagnosis of AATD lung disease is 46 years3 and average age of adult-onset liver disease is 61 years4

AATD Lung Disease		AATD Liver Disease
•	Emphysema		•	Hepatitis
•	Asthma		•	Fibrosis
•	Bronchitis		•	Cirrhosis
•	Pneumonia		•	HCC
•	Bronchiectasis		•	Liver Failure

Other Complications

• Panniculitis (skin)
• ANCA vasculitis

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1. Greene, C.M., et al., 2016 Nat Rev Dis Primers 2, 16051; 2. Blanco et al., 2017 Int J Chron Obstruct Pulmon Dis 12:561-69; 3. Strnad, et al. 2020 N Engl J Med 382:1443-55; 4. Tanash and Piitulainen 2019 J Gastroenterol 54:541-548

Patient insights highlight burden of AATD

• It's an invisible disease. It seems like it tricks you - I look healthy and then I tell someone I can't help them grab something 20 feet away. That's the disconnect.
• I used to own a salon and with my lungs going bad so quickly, I had to do away with that…I get short winded…I lay around a lot, I'm sick a lot.
• It makes it harder for us to travel and go do things, because I have to be home once a week for my infusions. It's definitely an inconvenience.

• I now have very high elevated liver enzymes and fatty liver just in the last year. I get a lot of pain on that side. They believe it is related to AATD.
• I have back issues, anytime they do a CAT scan or MRI there is always a notation about fatty liver disease and scarring on my liver. I know it's there. I know there's a problem. It's just part of my everyday.

Engaged patient community to inform clinical development plans

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AATD landscape is poised to evolve but most approaches focus on lung or liver disease

Selected Therapeutic Strategies in Development for AATD

Frequency of Lung or Liver Disease of Pi*ZZ Patients at Diagnosis*

• Augmentation therapy (Plasma derived, IV) [Approved]

•	Recombinant Fc-AAT (IV)	Lung Disease		Liver
		61%	20%	Disease	• RNAi (subcutaneous)
•	Inhaled AAT (nebulized)			5%

• Neutrophil elastase inhibitors (oral)

*From Alpha One International Registry (n=3,405)3 (13% reported no disease at diagnosis)

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Despite being a rare disease, AATD market estimated to grow to ~$3B by 2028

AATD Market Overview

Global AATD Market Value (2021 - 2028)1

• AATD market today is estimated at ~$1.3B	$3B
worldwide1 despite limitations of current
treatment					12%
- Market consists entirely of plasma-derived				CAGR
augmentation therapy for AATD-lung disease	$2B
- Augmentation therapy requires weekly IV and is not					Driven by new therapies
reimbursed in some markets					and higher diagnosis rates
• Market expected to grow to ~$3B by 2028	$1B
- Treatment for AATD-liver disease in development
- Opportunity to improve upon treatments for AATD-lung
disease (efficacy, administration)	$0B
- Potential to increase diagnosis (e.g., for liver disease,
2021	2022	2023	2024	2025	2026	2027	2028
through direct-to-consumer genetic testing)

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1. Evaluate Pharma; 2. Lumanity KOL Market Research 2022