Prelude Therapeutics Incorporated : July 2024 Corporate Presentation

Corporate Presentation

July 2024

Forward Looking Statements

This presentation contains "forward-looking" statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude's product candidates, the potential safety, efficacy, benefits and addressable market for Prelude's product candidates, the expected timeline for proof-of-concept data and clinical trial results for Prelude's product candidates including its SMARCA2 degrader molecules.

Any statements contained herein or provided orally that are not statements of historical fact may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by such terminology as ''believe,'' ''may,'' ''will,'' ''potentially,''

''estimate,'' ''continue,'' ''anticipate,'' ''intend,'' ''could,'' ''would,'' ''project,'' ''plan,'' ''expect'' and similar expressions that convey uncertainty of

future events or outcomes, although not all forward-looking statements contain these words. Statements, including forward-looking statements, speak only to the date they are provided (unless an earlier date is indicated).

Certain data in this presentation are based on cross-study comparisons and are not based on any head-to-head clinical trials. Cross-study comparisons are inherently limited and may suggest misleading similarities or differences. This presentation shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction.

These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward- looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption "Risk Factors" in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2023.

We are on a mission to extend the promise of precision medicine to every cancer patient in need

Strive for first- or best-in-class and anchor to patient unmet need

Select the best modality to precisely target oncogenic mechanisms

Draw on decades of experience and

proven leadership to drive innovation

Prelude's Evolution

2016 - 2022	2022 - 2025	2025+

Establish Leading Precision	Expand Development Capabilities,	Advance to Registrational
Oncology Discovery Engine	Strategic Focus on SMARCA	Trials, Demonstrate Value

Strategic Priorities

• Assembled team to create a highly productive discovery engine
• Delivered first wave of first- or potentially best-in-class clinical development candidates:
• • PRMT5i, MCL1i, CDK9i, CDK4/6i, SMARCA2 degrader
• ~1 new IND every 12-18 months
• Successfully advance programs into early clinical development

• Advancing clinical programs including SMARCA2 degrader (PRT3789) and CDK9 inhibitor (PRT2527) towards PoC
• Developing SMARCA as 'Pipeline in Program' with IV, Oral and 'Precision ADC' Approaches
• Continue to build SMARCA leadership
• Generate proof-of-concept data
• Prepare for global registrational trials

• Continue to grow R&D team while adding key capabilities for future growth
• Expand global clinical development footprint and capabilities
• Advance lead clinical development candidates to registrational trials
• Advance SMARCA "Pipeline in a Program"
• Explore collaborations to accelerate trials and global capabilities

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Experienced Leadership Team With Proven Track Records in Precision Oncology

Kris Vaddi, PhD	Jane Huang M.D.	Peggy Scherle, PhD	Andrew Combs, PhD	Sean Brusky, MBA	Bryant Lim, J.D.
Founder &	President and Chief	Chief Scientific Officer	Chief Chemistry Officer	Chief Business Officer	Chief Legal Officer,
Chief Executive Officer	Medical Officer				Corporate Secretary and
					Interim CFO

Prelude's Precision Medicine Pipeline & Discovery Engine

PROGRAM	POTENTIAL	DISCOVERY	PHASE 1	PHASE 2/3
INDICATIONS
Lead SMARCA2	SMARCA4-mutated	PRT3789
Degrader (IV)	NSCLC & other cancers
Oral SMARCA2	SMARCA4-mutated	PRT7732
Degrader	NSCLC & other cancers
SMARCA2/4	Broad range of cancers
Precision ADCs*	(heme & solid tumors)
Next-Gen CDK9	Myeloid and B-cell	PRT2527
Selective Inhibitor	malignancies
Discovery Engine	Hard-to-treat cancers,
"undruggable" targets,

high unmet need

Precision ADCs*	Broad range of cancers
(heme & solid tumors)

Highly selective, brain-penetrantCDK4-biased inhibitor (PRT3645) available for partnering * Precision ADCs are the focus of our strategic collaboration with AbCellera

UPCOMING MILESTONES

Phase I Initial Proof-of-Concept

Data in 2H 2024

Phase I Start Anticipated in 2H 2024

Expand SMARCA Portfolio to Address Cancers WithoutSMARCA4 Mutations

Phase I Initial Proof-of-Concept

Data in 2H 2024

Deliver a First- or Best-in-Class New Program Every 12-18 Months

Co-Develop Up to 5 Novel

Precision ADCs

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Prelude's First-in-Class, Highly Selective SMARCA2 Degraders

PRT3789 (IV) and PRT7732 (Oral)

Click Here to Access Prelude's Educational Video Series on SMARCA2 Degraders

SMARCA4 Mutations Occur in ~10% of All NSCLC and to Varying Degrees Across Other Cancers

NSCLC: 10%

Esophageal: 8%

Gastric: 8%

Endometrial: 13%

SMARCA4 mutations are mostly non- overlapping with other "druggable" mutations

SCLC: 8%

Colorectal: 6%

Pancreatic: 3%

Urinary: 9%

Over half of SMARCA4 mutations are Class I loss of function / deleterious mutations (>5% of NSCLC)

SMARCA4 mutations are associated with aggressive disease and poor prognosis across a range of cancers

Patients with SMARCA4 mutations are not typically eligible for other targeted therapies

Currently treated with standard of

care chemotherapy or chemo-

immunotherapy

1,Dagogo-Jack et al. Journal of Thoracic Oncology. 2020 Foundation Medicine dataset	8
2 Fernando et al. Nature Communications 2020

Outcomes for Patients with SMARCA4-mutated

NSCLC are Poor with Current Standard of Care

Patients treated with first-line chemoimmunotherapy

Response rates are less than 25% and expected median PFS is less than 3 months in first line setting

Even greater unmet need in 2nd line where fewer effective treatment options are available

Alessi JV, et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced non-small cell lung cancer	9
(NSCLC). J Thorac Oncol. 2023 Feb 10:S1556-0864(23)00121-1. doi: 10.1016/j.jtho.2023.01.091. PMID: 36775193 (attached).

Selective Targeting of SMARCA2 is an Attractive Approach to Treat SMARCA4 Mutated Cancers

SMARCA: SWI/SNF-related,Matrix-associated,Actin-dependent

Regulator of Chromatin, subfamily A.

SMARCA2 is also known as "BRM" SMARCA4 is also known as "BRG "

Mutations in the chromatin remodeling complex drive cancer growth and resistance

Cancer cells with SMARCA4 mutations become highly dependent on SMARCA2 for survival

Selectively degrading SMARCA2 induces "synthetic lethality" in SMARCA4-deficient cancers

High selectivity for SMARCA2 has been challenging because of its high similarity to SMARCA4

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