Corporate January 2021 Presentation Disclaimer This presentation contains "forward-looking" statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995, including

January 2021 Presentation

Disclaimer 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: our plans to develop and commercialize small molecule therapies, our expectations about

timing and ability to commence, enroll or complete clinical studies and to obtain regulatory approvals for PRT543, PRT811, PRT1419, PRT2527 and other candidates in development, the ability of our product candidates to treat various cancers, the

ability to discover additional suitable candidates for regulatory approval, the potential impact of the COVID-19 pandemic and the sufficiency of our cash and cash equivalents to fund our operations. 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). 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 Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission

for the fiscal quarter ended September 30, 2020. 2Disclaimer 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: our plans to develop and commercialize small molecule therapies, our expectations about timing and ability to commence, enroll or complete clinical studies and to obtain regulatory approvals for PRT543, PRT811,

PRT1419, PRT2527 and other candidates in development, the ability of our product candidates to treat various cancers, the ability to discover additional suitable candidates for regulatory approval, the potential impact of the COVID-19 pandemic and

the sufficiency of our cash and cash equivalents to fund our operations. 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). 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 Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission for the fiscal quarter ended September 30, 2020. 2

Prelude Therapeutics Vision Building a patient-focused precision

oncology company Regulatory Strategy Efficient development path with potential for accelerated regulatory approvals Discovery Engine Powered by scientists with proven ability to deliver precision oncology medicines Commercial Approach Rapidly

advancing potentially high value therapy candidates with a commitment to future patient access, awareness, and support Clinical Development Highly selected patient populations & cancers with significant unmet need 3Prelude Therapeutics Vision

Building a patient-focused precision oncology company Regulatory Strategy Efficient development path with potential for accelerated regulatory approvals Discovery Engine Powered by scientists with proven ability to deliver precision oncology

medicines Commercial Approach Rapidly advancing potentially high value therapy candidates with a commitment to future patient access, awareness, and support Clinical Development Highly selected patient populations & cancers with significant

Senior Management & Board of Directors Board of Directors

Experienced. Proven. Focused. Paul Friedman, MD CEO Former CEO Mardi Dier Parsaclisib CFO Former CFO, CBO PhD Andrew Combs PhD MD, PhD Peggy Scherle David Mauro Victor Sandor, MD Chief Medical Officer EVP and Chief Scientific Officer Former Head of

Chemistry CMO Kris Vaddi PhD David Bonita, MD Founder & General Chief Executive Officer Partner Founding Kelvin Neu, MD member Partner Baker Brothers Investments Deborah Morosini MD, MSW Brian Piper MBA Christopher Pierce MBA Kris Vaddi, PhD EVP

and EVP and Chief Financial Officer Founder & Chief Executive Chief of Business Chief of Clinical Affairs Officer Operations 4Senior Management & Board of Directors Board of Directors Experienced. Proven. Focused. Paul Friedman, MD CEO

Former CEO Mardi Dier Parsaclisib CFO Former CFO, CBO PhD Andrew Combs PhD MD, PhD Peggy Scherle David Mauro Victor Sandor, MD Chief Medical Officer EVP and Chief Scientific Officer Former Head of Chemistry CMO Kris Vaddi PhD David Bonita, MD

Founder & General Chief Executive Officer Partner Founding Kelvin Neu, MD member Partner Baker Brothers Investments Deborah Morosini MD, MSW Brian Piper MBA Christopher Pierce MBA Kris Vaddi, PhD EVP and EVP and Chief Financial Officer Founder

& Chief Executive Chief of Business Chief of Clinical Affairs Officer Operations 4

Prelude Therapeutics Corporate Highlights INDs approved in 3 years; 3

clinical stage molecules 3 Pipeline focused on differentiated and validated targets Highly productive target class 1 IND filed each year in 2018, 2019, and 2020 At least 1 additional IND anticipated in 2021 agnostic discovery engine

1 IND planned every 12 - 18 months Multiple wholly owned programs with Lead programs, PRT543 & PRT811 (PRMT5) and PRT1419 (MCL1) target clinically validated mechanisms with fast-to-market potential differentiated product profile

Compelling market opportunities Patient-inspired drug development, regulatory, and commercial strategies to address high unmet need across multiple tumor types Experienced leadership team with Deeply experienced employee base that has worked on

multiple approved targeted agents marquee investors and board members 5Prelude Therapeutics Corporate Highlights INDs approved in 3 years; 3 clinical stage molecules 3 Pipeline focused on differentiated and validated targets Highly productive target

class 1 IND filed each year in 2018, 2019, and 2020 At least 1 additional IND anticipated in 2021 agnostic discovery engine 1 IND planned every 12 - 18 months Multiple wholly owned programs with Lead programs, PRT543

& PRT811 (PRMT5) and PRT1419 (MCL1) target clinically validated mechanisms with fast-to-market potential differentiated product profile Compelling market opportunities Patient-inspired drug development, regulatory, and commercial strategies to

address high unmet need across multiple tumor types Experienced leadership team with Deeply experienced employee base that has worked on multiple approved targeted agents marquee investors and board members 5

Prelude Discovery and Development Approach Target Selection Discovery

Engine Pipeline Methyltransferases Identify target mechanisms Kinases with compelling biological Novel rationale Intervention Points Degraders Leverage our advanced medicinal chemistry capabilities to create Chemical better product Leads

Protein-Protein candidates Interactions Medicinal and Process Chemistry Pursue targets that drive Capabilities Focused Clinical Development cancers with high unmet Rapidly building synthetically complex Optimized for early clinical POC and rapid

need molecules execution of pivotal trials Cancer Biology & Translational Expertise Deep understanding of oncogenic pathways with translational focus 6Prelude Discovery and Development Approach Target Selection Discovery Engine Pipeline

Methyltransferases Identify target mechanisms Kinases with compelling biological Novel rationale Intervention Points Degraders Leverage our advanced medicinal chemistry capabilities to create Chemical better product Leads Protein-Protein candidates

Interactions Medicinal and Process Chemistry Pursue targets that drive Capabilities Focused Clinical Development cancers with high unmet Rapidly building synthetically complex Optimized for early clinical POC and rapid need molecules execution of

pivotal trials Cancer Biology & Translational Expertise Deep understanding of oncogenic pathways with translational focus 6

Prelude Therapeutics Pipeline Discovery/ IND Worldwide Program

Indications Phase 1 Phase 2 Phase 3 Upcoming Milestones Preclinical Enabling Rights Selected Solid Tumors Expansion cohorts (incl. ACC, HRD+) 4Q2020/1H2021 PRT543* Selected Myeloid Data presentation (PRMT5) Malignancies 2H2021 (incl.

MF and MDS) Expansion cohorts PRT811* GBM and CNS Metastatic 1H2021 (Brain Penetrant Cancers Initial clinical data PRMT5) YE2021 Selected Hematological Expansion cohorts PRT1419* Malignancies 2H2021 (MCL1) Selected Solid and

PRT2527 IND 2021 Hematological Malignancies (CDK9) Multiple Genomically PRT-SCA2 IND 2021/2022 Selected Cancers (SMARCA2) - PRT-K4 Solid Tumors IND-enabling 2021 (Kinase) Wholly owned patent portfolio covering composition of

matter and method of * Currently in Phase 1 dose escalation 7 use patents. Prior to any possible extensions, PRT543 has IP coverage into at least H2 2038, while PRT811 and PRT1419 have coverage until at least 2039Prelude Therapeutics Pipeline

Discovery/ IND Worldwide Program Indications Phase 1 Phase 2 Phase 3 Upcoming Milestones Preclinical Enabling Rights Selected Solid Tumors Expansion cohorts (incl. ACC, HRD+) 4Q2020/1H2021 PRT543* Selected Myeloid Data presentation

(PRMT5) Malignancies 2H2021 (incl. MF and MDS) Expansion cohorts PRT811* GBM and CNS Metastatic 1H2021 (Brain Penetrant Cancers Initial clinical data PRMT5) YE2021 Selected Hematological Expansion cohorts PRT1419*

Malignancies 2H2021 (MCL1) Selected Solid and PRT2527 IND 2021 Hematological Malignancies (CDK9) Multiple Genomically PRT-SCA2 IND 2021/2022 Selected Cancers (SMARCA2) - PRT-K4 Solid Tumors IND-enabling 2021 (Kinase) Wholly

owned patent portfolio covering composition of matter and method of * Currently in Phase 1 dose escalation 7 use patents. Prior to any possible extensions, PRT543 has IP coverage into at least H2 2038, while PRT811 and PRT1419 have coverage until at

PRMT5 Programs 8PRMT5 Programs 8

PRMT5 Pathway Drives Oncogenesis and Resistance Regulates transcription

of genes linked to cancer cell growth and proliferation Cell cycle genes Cancer metabolism Tumor suppressors Spliceosome Histones Oncogenes Proliferative signaling Transcription Factors PRMT5 inhibition can be leveraged to potentially treat a 9

broad range of solid tumors and hematologic malignancies PRMT5PRMT5 Pathway Drives Oncogenesis and Resistance Regulates transcription of genes linked to cancer cell growth and proliferation Cell cycle genes Cancer metabolism Tumor suppressors

Spliceosome Histones Oncogenes Proliferative signaling Transcription Factors PRMT5 inhibition can be leveraged to potentially treat a 9 broad range of solid tumors and hematologic malignancies PRMT5

PRMT5 Regulates Drivers of DNA Damage Repair PRMT5 inhibition

suppresses DNA repair gene expression & growth of HRD+ cell lines PRMT5 promotes DNA repair and cell survival 1000 POLD1 BRCA1 100 ATM CHEK2 RAD51 ATR 10 BRCA2 PRMT5 regulates multiple DNA repair genes 1 -4 -3 -2 -1 0 1 2 3 4 PRT543 -

0.25 M 125 MDA-MB-436 100 MDA-MB-468 BRCA1/2 RAD51/51D Ku80 75 50 25 DNA Repair 0 and Cell Survival 0.0001 0.001 0.01 0.1 1 10 PRT543 ( M) PRMT5 inhibition potentially drives synthetic lethality in 10 HRD+ cancers PRMT5 -Log (q-values) 10

Relative cell count (%)PRMT5 Regulates Drivers of DNA Damage Repair PRMT5 inhibition suppresses DNA repair gene expression & growth of HRD+ cell lines PRMT5 promotes DNA repair and cell survival 1000 POLD1 BRCA1 100 ATM CHEK2 RAD51 ATR 10 BRCA2

PRMT5 regulates multiple DNA repair genes 1 -4 -3 -2 -1 0 1 2 3 4 PRT543 - 0.25 M 125 MDA-MB-436 100 MDA-MB-468 BRCA1/2 RAD51/51D Ku80 75 50 25 DNA Repair 0 and Cell Survival 0.0001 0.001 0.01 0.1 1 10 PRT543 ( M) PRMT5 inhibition

potentially drives synthetic lethality in 10 HRD+ cancers PRMT5 -Log (q-values) 10 Relative cell count (%)

PRMT5 Pathway Is Clinically Validated in Multiple Cancers by GSK'595

21% OR and mPFS of 11.2 mos observed with GSK'595 in Adenoid cystic carcinoma (ACC) Highly underserved cancer in which typical OR is <10% and PFS is 4 - 6 mos Objective responses reported in other cancers; currently in dose expansion phase

in multiple tumors PRMT5 Inhibition Demonstrated Objective Responses Confirmed PR in ACC Source: GSK595, ESMO 2019 Siu, Lillian L., et al. Annals of Oncology 30.Supplement_5 (2019): mdz244. ACC offers potential fast-to-market opportunity for 11

Prelude PRMT5 inhibitors PRMT5PRMT5 Pathway Is Clinically Validated in Multiple Cancers by GSK'595 21% OR and mPFS of 11.2 mos observed with GSK'595 in Adenoid cystic carcinoma (ACC) Highly underserved cancer in which typical OR is <10% and PFS

is 4 - 6 mos Objective responses reported in other cancers; currently in dose expansion phase in multiple tumors PRMT5 Inhibition Demonstrated Objective Responses Confirmed PR in ACC Source: GSK595, ESMO 2019 Siu, Lillian L., et al. Annals of

Oncology 30.Supplement_5 (2019): mdz244. ACC offers potential fast-to-market opportunity for 11 Prelude PRMT5 inhibitors PRMT5

Prelude PRMT5 Program Optimized for a well-balanced and differentiated

profile Differentiating Mechanism of Action Potency Selectivity Optimal Chemical Substrate Prelude compounds Space competitive are co-factor (SAM) Inhibitors (GSK) competitive inhibitors ADME Pharmaceutical properties Designed and synthesized

>600 compounds to select 12 PRT543 and PRT811 for advancement PRMT5Prelude PRMT5 Program Optimized for a well-balanced and differentiated profile Differentiating Mechanism of Action Potency Selectivity Optimal Chemical Substrate Prelude compounds

Space competitive are co-factor (SAM) Inhibitors (GSK) competitive inhibitors ADME Pharmaceutical properties Designed and synthesized >600 compounds to select 12 PRT543 and PRT811 for advancement PRMT5

PRT543 - Opportunity for Accelerated Development Path Potential

best-in-class PRMT5 inhibitor Potential Rapid Path to Market Targets Selected Optimized Solid Tumors and PK Profile Phase 1 ongoing Differentiated Heme Malignancies PRMT5 Inhibitor Enrollment began in select High solid tumor expansion Strong oral

bioavailability cohorts in 4Q2020 and expect Highly selective scientific rationale and long half-life to commence in select myeloid malignancies in early Highly potent Clinical PoC for target Differentiated safety 2021 and efficacy profile Potential

for accelerated approval pathway 13 PRMT5PRT543 - Opportunity for Accelerated Development Path Potential best-in-class PRMT5 inhibitor Potential Rapid Path to Market Targets Selected Optimized Solid Tumors and PK Profile Phase 1 ongoing

Differentiated Heme Malignancies PRMT5 Inhibitor Enrollment began in select High solid tumor expansion Strong oral bioavailability cohorts in 4Q2020 and expect Highly selective scientific rationale and long half-life to commence in select myeloid

malignancies in early Highly potent Clinical PoC for target Differentiated safety 2021 and efficacy profile Potential for accelerated approval pathway 13 PRMT5

PRT543 - A Potent, Selective and Oral PRMT5 Inhibitor Candidate

PRT543 is Highly-Selective Dose-Dependent PD Vs 36 methyltransferases in addition to a broad panel of Modulation of sDMA (symmetric dimethylation) is a receptors, transporters and channels direct measure of PRMT5 activity ~50% reduction in plasma

sDMA correlates with efficacy in preclinical models PRT543 demonstrated optimized potency, dose-dependent 14 PD, and selectivity offering best-in-class potential PRMT5PRT543 - A Potent, Selective and Oral PRMT5 Inhibitor Candidate PRT543 is

Highly-Selective Dose-Dependent PD Vs 36 methyltransferases in addition to a broad panel of Modulation of sDMA (symmetric dimethylation) is a receptors, transporters and channels direct measure of PRMT5 activity ~50% reduction in plasma sDMA

correlates with efficacy in preclinical models PRT543 demonstrated optimized potency, dose-dependent 14 PD, and selectivity offering best-in-class potential PRMT5

PRT543 Demonstrated Broad Preclinical Activity JAK2V617F MPN Model

Monotherapy Combination Oral administration of PRT543 as monotherapy and in combination with ruxolitinib led to significant decrease in spleen size in the JAK2VF bone marrow transplant model of MF. Data represent mean SEM. Dotted line

indicates mean spleen weight of WT transplanted mice. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. vehicle by Mann-Whitney U test. Dose-dependent activity as single agent and in combination 15 in heme and solid tumor models PRMT5PRT543

Demonstrated Broad Preclinical Activity JAK2V617F MPN Model Monotherapy Combination Oral administration of PRT543 as monotherapy and in combination with ruxolitinib led to significant decrease in spleen size in the JAK2VF bone marrow transplant

model of MF. Data represent mean SEM. Dotted line indicates mean spleen weight of WT transplanted mice. * P < 0.05, ** P < 0.01, *** P < 0.001 vs. vehicle by Mann-Whitney U test. Dose-dependent activity as single agent and in

combination 15 in heme and solid tumor models PRMT5

PRT543 Phase 1 Clinical Trial as of September 1, 2020 4Q2020 / Early