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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: 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 three months ended September 30, 2021 and in our upcoming Annual Report on Form 10-K for the year ended December 31, 2021. 2
Prelude Therapeutics: Vision Build a fully integrated oncology company
on the foundation of drug discovery excellence to deliver novel precision cancer medicines to underserved patients 3
Experienced Management Team: Proven Track Records Board of Directors
Paul Friedman, MD Founding member CEO Former CEO Mardi Dier CFO Laurent Chardonnet Former CFO, Kris Vaddi, PhD Deborah Morosini, MD, MSW Chief Financial Officer CBO Executive Vice President Founder & and Chief of Clinical Affairs Chief Executive
Victor Sandor, MD Officer Former CMO David Bonita, MD General Partner Julian C. Baker Managing Member Baker Brothers Investments Kris Vaddi, PhD Naveen Babbar, PhD Founder & Peggy Scherle, PhD Andrew Combs, PhD Chief Executive Officer Senior
Vice President of Chief Scientific Officer Executive Vice President Translation Medicine and Head of Chemistry Martin Babler Former CEO 4
Prelude Therapeutics: Key Reasons to Invest Internal Effective Focused
Strong Well Discovery R&D Clinical Execution Capitalized Engine Approach Development Seamless ~$320M cash Driving to go/no Scientists with Proprietary integration & marketable go' decisions with proven track diversified between
biology securities a sense of records pipeline and chemistry (9/30/21) urgency 5
Precision Oncology: Targeting Clinically Relevant Pathways SMARCA2
TARGET PRMT5 MCL1 CDK9 (BRM) mRNA Splicing & Transcriptional Synthetic Apoptosis MOA DNA Repair Regulation Lethality Spliceosome Venetoclax SMARCA4 (BRG1) MYC Amplified SELECTABLE Mutations, Resistance Mutations PATIENTS HRD+ CANCERS Glioma,
Myeloid, Sarcoma, Prostate, NSCLC, Endometrial AML, MDS, CLL Solid Tumors AML 6
Current Pipeline: Diversified and Growing PHASE 1 PHASE 1 PHASE 2/3
PROGRAM CANCER INDICATIONS IND ENABLING ESCALATION EXPANSION REGISTRATION PRT543 Solid Tumors, Myeloid Cancers (PRMT5) IDH+ High Grade Glioma, PRT811 Uveal Melanoma (Brain Penetrant PRMT5) PRT1419 AML, MDS, CLL (MCL1) PRT2527 Sarcoma, Prostate, AML
(CDK9) PRT-SCA2 NSCLC, Endometrial (SMARCA2) PRT-K4 Solid Tumors (Kinase) 7
2022 Goals: Aggressive with Clear Deliverables PRMT5 MCL1 CDK9 SMARCA
(BRM) PRT543/PRT811 PRT1419 PRT2527 PRT-SCA2 Complete dose Complete Establish RP2D escalation expansion phases File IND for both molecules Demonstrate Establish safety, safety in target Demonstrate PoC combination with engagement, and in one or more
venetoclax / RP2D indications azacitidine Demonstrate PoC 8
PRMT5 Program PRT543 PRT811
PRMT5 Pathway Drives Oncogenesis and Resistance PRMT5 PRMT5
catalyzes symmetric arginine dimethylation (sDMA) of protein substrates SYMMETRIC including histones, transcription factors, and DIMETHYLATION spliceosome proteins Dimethylated substrates of PRMT5 control key TUMOR CELL oncogenic and
resistance mechanisms Mechanism Spliceosome Proteins DNA Repair PRMT5 inhibition is highly efficacious in models with mutations in DNA repair or mRNA-splicing pathways in preclinical models Transcription Factors Drug Resistance PRMT5
inhibition can be leveraged to target Histones Proliferation genetically selected patient populations in the clinic 10
Differentiated PRMT5 Inhibitors PRT543 PRT811 Highly selective
and potent oral candidates PRT811 is highly differentiated in the class with high brain penetration potential Applicability in Both Solid Tumors and Heme Strong scientific rationale and robust preclinical activity across broad range
of cancers Early clinical signals in multiple cancer types Potential Best-In-Class Optimized PK Profile PRMT5 Inhibitors High oral bioavailability and optimal half-life to maximize therapeutic window Differentiated safety and
clinical activity profile Potential Rapid Path to Market Potential for accelerated approval pathway Opportunity in multiple cancer types 11
PRMT5: Phase 1 Data Will Drive Phase 2/3 Indication Selection PRMT5
Part 1 Part 2 Dose Escalation Expansion Cohorts COMPLETED ONGOING RECOMMENDED EXPANSION DOSES Adenoid Cystic Carcinoma (N40) PRT543 PRT543 45 mg 5x/wk Homologous Recombination Deficient (HRD+) (solid tumors) Solid Tumors (N40) 35 mg 5x/wk
(hematologic malignancies) Splicing mutated Solid and Myeloid Malignancies (N~40) PRT811 Uveal Melanoma PRT811 600 mg QD High Grade Gliomas SOLID TUMORS, GBM, MYELOID MALIGNANCIES 12
PRT543 and PRT811 Demonstrate Desirable PK and PD Properties PRMT5
Dose-Dependent Increases in Cmax and AUC Dose-dependent Inhibition of Serum sDMA 500 400 300 200 PRT543 100 0 PRT811 13 Data presented at 2021 AACR-NCI-EORTC Annual Meeting. serum sDMA (ng/ml) Mean SEM Baseline 22.5 mg BIW 45 mg
BIW 35 mg 5X 25 mg QD 35 mg QD 45 mg 5X 50 mg QD
PRMT5 Phase 1: Key Takeaways and Next Steps PRMT5 FAVORABLE DESIRABLE
PK & PRELIMINARY NEXT STEPS SAFETY PROFILE PD PROFILES CLINICAL ACTIVITY PRT543 and PRT811 well Dose-dependent increase Objective responses in Complete expansion tolerated in exposure solid tumors phases for both molecules IWG anemia benefit in
Demonstrate PoC in one or Favorable safety properties High levels of target inhibition myeloid malignancies more indications Low incidence of PRT811 demonstrated Anti-tumor activity observed in dose-limiting toxicities at best-in-class profile with
relapsed/refractory patients expansion doses wide therapeutic window with target biomarker profile 14
MCL1 Program PRT1419
MCL1: Targeting Cancer Cell Survival MCL1 MCL1 is a member of
family inhibitors of apoptosis (BCL2); often overexpressed in cancers BCL2 family is clinically validated - Venetoclax approved for lymphoid and myeloid malignancies Mechanism MCL1 is a bypass and resistance mechanism for
Venetoclax and multiple TKIs Challenging medicinal chemistry target that requires disruption of protein-protein interaction 16
MCL1 Inhibitor PRT1419 Potent and selective No
cardiotoxicity signal in GLP-toxicology studies Targeting Selected Heme and Solid Cancers Robust activity in preclinical models with once weekly dosing Potential combination strategy with Venetoclax and/or HMAs in Hematological
malignancies Differentiated Clinical- Stage MCL1 Inhibitor Optimized PK Profile Maximizes Therapeutic Window Candidate Higher clearance built in to achieve desirable duration of target inhibition Optimal physicochemical properties
Potential Rapid Path to Market Venetoclax-resistant cancers offer opportunity for accelerated approval 17 17
MCL1: Phase 1 Overview MCL1 Dose Expansion Phase 1 Dose Escalation Dose
Escalation Combination Combination (Ven + Aza) Monotherapy (mg/m2) 1419 VEN+ AZA R/R AML/MDS 1419 + AZA R/R AML/MDS 1H 2022 2H 2022 1H 2023 18 18
CDK9 Program PRT2527
CDK9: Targeting Cancer Through Transcriptional Regulation CDK9
CDK9 phosphorylates RNA Pol II and regulates transcription SUPER ENHANCER uper nhancer Regulates expression of several immediate early genes driving oncogenesis and resistance (i.e. MYC, MYB, MCL1) F F F MYC & MYB Mechanism
Non-selective CDK9 inhibitors have demonstrated TARGET GENES arget enes D clinical activity in multiple tumor types but poor tolerability TSS Lack of selectivity and potency vs other mRNA R ol mR CDK9s is believed to contribute to low RNA Pol
II therapeutic window 20
PRT2527 CDK9 Inhibitor Most selective in the class vs CDK
family and across the kinome Low nanomolar potency in blocking tumor cell proliferation Targeting Selected Heme and Solid Cancers Robust activity in preclinical models at well-tolerated doses Enhanced sensitivity in tumors
that are MYC-dependent Potential Best-in-Class Provides patient selection strategy in clinic Selectivity and Potency Optimized PK Profile Higher clearance built in to maximize therapeutic window
Robust Activity in Preclinical Models at Well-Tolerated Doses Sustained
Regressions at CDK9 Well-Tolerated Doses in Vivo in both Heme Sustained Regression at Well-Tolerated Doses In Vivo in both and Solid Tumor Models Heme and Solid Tumor Models 7 NSCLC PDX MV4-11 (AML) (MYC Amplified) 6 800 1500 Vehicle 800 AZD 700
PRT2527 5 700 600 600 1000 500 4 500 400 400 300 3 300 Vehicle control 500 200 Vehicle control 200 PRT2527 30 mg/kg, 2 100 79% PRT2527 iv BID (q2h), QW 100 0 96% 0 0 0 5 10 15 20 25 30 35 1 8 11 14 17 20 23 0 5 10 15 20 25 30 35 Days of Dosing Days
post inoculation Days of Dosing 22 3 Tumor Volume (mm ) 3 Tumor Volume +/- SEM (mm ) 3 Tumor Volume +/- SEM (mm )
CDK9: Clinical Overview Phase 1 Dose Escalation (Bayesian Design)
ONGOING Phase 2 With Recommended Dose From Completed Phase 1 Trial (TARGET 1H 2023) MYC-Dependent Solid Tumors (NSCLC, Prostate) Sarcoma MYC-dependent solid tumors Hematologic Malignancies Hematologic Malignancies 23
SMARCA2 (BRM) Program PRT-SCA2
Targeting SMARCA2 (BRM): Leveraging Synthetic Lethality SMARCA2
The chromatin remodeling (SWI/SNF) complex is frequently mutated in cancer making it a potential therapeutic target Activity of the SWI/SNF complex requires either SMARCA4 (BRG1) or SMARCA2 (BRM) Mechanism Loss of SMARCA4 (BRG1)
through mutation leads to dependency on SMARCA2 (BRM) Subsets of solid tumors express SMARCA4 (BRG1) mutations Selectively inhibiting SMARCA2 (BRM) offers an attractive approach to target SMARCA4 (BRG1) mutant tumors 25
Achieving SMARCA2 Selectivity Through Degrader Approach SMARCA2
SMARCA2 selectively over highly homologous SMARCA4 isoform has been a challenging SMALL MOLECULE DEGRADER medical chemistry problem with traditional small molecule approaches E3 LIGASE PROTEASOME Target Protein Degradation (TPD) of SMARCA2
selectively over SMARCA4 is possible through differences in ternary complexes Mechanism Prelude scientists identified the molecular basis for TARGET achieving high degree of selectivity for SMARCA2 PROTEIN over SMARCA4 UBIQUITINATED
Lead molecules from multiple chemical scaffolds TARGET PROTEIN with sub-nanomolar potency and selectivity have been discovered Mullard A. Nat Rev Drug Discov. 2019 26
PRT-SCA2: Potent and Selective SMARCA2 Degrader with In Vivo Activity
SMARCA2 Highly Selective for SMARCA2 Highly Selective for SMARCA2 Prelude SMARCA2 Degraders Replicate Degradation In Vitro Degradation In Vivo Genetic Synthetic Lethality PRT007(nM): DMSO 0.1 1.0 10 100 1000 Hours after dosing NCI-H1693 NCI-H838 Veh
8h 24h SMARCA2 HT1080 SM4 KO SMARCA4 In vitro Actin Calu-6 NCI-H520 HT1080 WT 27 SM4 WT SM4-del
PRT-SCA2: Potent and Selective SMARCA2 Degrader with In Vivo Activity
SMARCA2 Robust Tumor Growth Inhibition of SMARCA4 mutated but not WT Xenograft Vehicle 1800 600 Vehicle PRT-SCA2 1600 PRT-SCA2 1400 1200 400 1000 SMARCA4 mutant SMARCA4 WT 800 600 200 400 200 0 0 0 2 4 6 8 10 12 14 0 4 8 12 16 20 24 28 Days of
dosing Days of dosing 28 3 Tumor volume (mm ) 3 Calu-6 tumor volume (mm )
SMARCA2: Degrader Program Overview SMARCA2 Candidate molecule(s)
identified Phase 1 Dose Escalation IND enabling studies initiated TARGET 1Q 2023 IND Enabling Studies IND Filing 2H 2022 SMARCA4-MUTATED NSCLC AND OTHER TUMOR TYPES 29
2022 Goals: Aggressive with Clear Deliverables PRMT5 MCL1 CDK9 SMARCA
(BRM) PRT543/PRT811 PRT1419 PRT2527 PRT-SCA2 Complete dose Complete Establish RP2D escalation expansion phases File IND for both molecules Demonstrate Establish safety, safety in target Demonstrate PoC combination with engagement, and in one or more
venetoclax / RP2D indications azacitidine Demonstrate PoC 31
Prelude Therapeutics: Key Reasons to Invest Internal Effective Focused
Strong Well Discovery R&D Clinical Execution Capitalized Engine Approach Development Seamless ~$320M cash Driving to go/no Scientists with Proprietary integration & marketable go' decisions with proven track diversified between
biology securities a sense of records pipeline and chemistry (9/30/21) urgency 32