PRLD Prelude Therapeutics Inc

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Exhibit 99.1

 

Prelude Therapeutics Announces Second Quarter 2023 Financial Results and Provides Corporate Update

Four lead programs on track to deliver clinical data and to inform future development plans.

Recent equity financing extends cash runway into 2026,

enabling advancement of Prelude’s pipeline through critical milestones

WILMINGTON, Del. – (Globe Newswire) August 3, 2023 – Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today reported financial results for the second quarter ended June 30, 2023, and provided a corporate update.

Kris Vaddi, Ph.D., Chief Executive Officer of Prelude stated, “With the recent financing that extended our cash runway into 2026, we are in a strong position to advance our diverse pipeline of potentially best and/or first-in-class compounds to address the needs of patients with certain underserved cancers. Our focus remains on generating critical data for each of our molecules to make key strategic decisions. As disclosed recently, and based on additional data generated in this quarter, PRT2527 (CDK9 inhibitor) and PRT1419 (MCL1 inhibitor) demonstrated differentiated clinical safety profiles and strong target inhibition and are continuing to enroll patients with hematological malignancies, which is where we see the best opportunities for these molecules.”

“Our first-in-class selective SMARCA2 degrader, PRT3789, and next generation CDK4/6 inhibitor, PRT3645, are progressing well in Phase 1 and are on track to reach confirmation doses in the first half of 2024 and by year end 2023, respectively,” added Dr. Vaddi. “Based on meaningful progress made in the first half of the year, we look forward to sharing updates and clarity around strategic prioritization of our pipeline in the coming months.”

Pipeline Updates

PRT2527- CDK9 Inhibitor Program

The Company believes its highly selective CDK9 inhibitor, PRT2527, has the potential to avoid off-target toxicities, achieve substantial clinical activity and become the best-in-class CDK9 inhibitor, making it amenable for combination with other therapies.

PRT2527 has completed a Phase 1 multi-dose escalation study (NCT05159518) in patients with solid tumors. In this trial, PRT2527 was shown to achieve high levels of target inhibition and the potential to be better tolerated than existing CDK9 inhibitors, specifically, manageable neutropenia and an absence of meaningful gastrointestinal events or hepatotoxicity. *

 

*	AACR2023 Poster Presentation

 

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A Phase 1 multi-dose escalation study (NCT05665530) is currently ongoing in hematologic malignancies. Patient recruitment for hematological clinical trials in the US is highly competitive and this trial has recently been expanded to include global sites to support patient recruitment.

The Company’s objective is to establish a biologically active confirmation dose by Q1 2024. As part of this Phase 1 multi-dose escalation trial, the Company intends to expand the Phase 1 clinical trial and evaluate PRT2527 in combination with zanubrutinib.

Potential indications for PRT2527 include aggressive B-cell lymphoma subtypes, mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including Richter syndrome, and T-cell lymphoma subtypes.

The Company intends to provide a program update by year end on the CDK9 inhibitor program and present initial results at a future scientific meeting.

PRT1419- MCL1 Inhibitor Program

PRT1419 is a potent and selective MCL1 inhibitor. With its optimized PK/PD profile, the Company believes PRT1419 has the potential to achieve greater target engagement and provide patients with better clinical outcomes as well as improved safety and tolerability, as compared to other MCL1 inhibitors in development.

PRT1419 has completed a Phase 1 multi-dose escalation study (NCT04837677) in patients with solid tumors. In this study, PRT1419 demonstrated an acceptable safety and tolerability profile in patients with advanced and metastatic solid tumors. No cardiac toxicity was observed. Pharmacokinetics/pharmacodynamics and safety data in the 80 mg/m2 QW dose cohort support further evaluation of this dose in future studies.

A Phase 1 multi-dose escalation clinical trial of PRT1419 in patients with hematologic malignancies is ongoing (NCT05107856). In this trial, PRT1419 is being evaluated as monotherapy for myeloid malignancies and in combination with azacitidine or venetoclax for patients with relapsed/refractory myeloid or B-cell malignancies.

The Company will provide a clinical update on PRT1419 by year end.

PRT3645- Next Generation CDK4/6 Inhibitor Program

PRT3645 is a highly potent and selective next generation CDK4/6 inhibitor with the potential to provide improved safety and tolerability outcomes and higher, more effective brain and tissue penetration than current CDK4/6 inhibitors.

In preclinical models in vivo, PRT3645 has been shown to be efficacious in multiple cancers as monotherapy as well as when combined with KRAS inhibitors, MEK inhibitors and with a brain penetrant HER2 receptor kinase inhibitor. Additionally, oral administration of PRT3645 has been shown to induce tumor regressions in preclinical models that are resistant to currently approved CDK4/6 inhibitors. Together, these data suggest that PRT3645 may extend the benefit of CDK4/6 inhibition beyond HR+ breast cancer.

 

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A Phase 1 multi-dose escalation clinical trial of PRT3645 (NCT05538572) is underway and the Company expects to reach a biologically active dose confirmation in Q4 2023.

Potential indications for PRT3645 in combination with other therapies, in addition to breast cancer with or without brain metastases, include endometrial, sarcomas, glioblastomas, non-small cell lung cancer, head and neck cancers.

The Company intends to provide a program update by year end and present initial results at a future scientific meeting.

PRT3789- SMARCA2 Targeted Protein Degrader Program

PRT3789 is a first-in-class highly selective degrader of SMARCA2 protein, which along with SMARCA4 controls gene regulation through chromatin remodeling. Cancer cells with SMARCA4 mutations are dependent on SMARCA2 for their growth and survival and selectively degrading SMARCA2 induces cell death in cancer cells while sparing normal cells. PRT3789 is efficacious and well tolerated in preclinical models of SMARCA4 deleted/mutated cancers as monotherapy and in combination with standards of care. The Company believes a selective SMARCA2 degrader has the potential to be of benefit in up to 70,000 US/EU cancer patients with the SMARCA4 mutation.

Patients with SMARCA4 mutations or deletions may have poor clinical outcomes and limited treatment options. Therefore, mutated, or deleted SMARCA4 cancers provides a potential biomarker to select those patients most likely to respond to treatment with a highly selective SMARCA2 degrader.

A Phase 1 multi-dose escalation clinical trial of PRT3789 is ongoing (NCT05639751) in biomarker selected SMARCA4 mutated cancers. The Company intends to evaluate PRT3789 as monotherapy as well as in combination.

The Company intends to provide a program update by year end and expects to reach confirmation dose in the first half of 2024.

SMARCA2- Oral Program

The Company has also recently nominated a new chemical entity as a potent, orally bioavailable and highly selective SMARCA2 degrader candidate (>1000x over SMARCA4) and intends to file an IND early in 2024.

Second Quarter 2023 Financial Results

Cash, Cash Equivalents and Marketable Securities: In May 2023, the Company completed a public offering of common stock, raising gross proceeds of $113.0 million before deducting underwriting discounts, commissions and offering expenses. Net proceeds received, $110.4 million, will be focused on the continued development and expansion of the Company’s product pipeline.

 

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Cash, cash equivalents, and marketable securities as of June 30, 2023, were $255.0 million. Prelude anticipates that its existing cash, cash equivalents and marketable securities will fund the Company’s operations into 2026.

Research and Development (R&D) Expenses: For the second quarter of 2023, R&D expense increased to $25.0 million from $21.3 million for the prior year period. Research and development expenses increased primarily due to the timing of our clinical research programs. We expect our R&D expenses to vary from quarter to quarter, primarily due to the timing of our clinical development activities.

General and Administrative (G&A) Expenses: For the second quarter of 2023, G&A expenses decreased to $7.4 million from $8.2 million for the prior year period. General and administrative expenses decreased reflecting the Company’s careful management of its G&A expenses.

Net Loss: For the three months ended June 30, 2023, net loss was $30.4 million, or $0.54 per share compared to $27.4 million, or $0.58 per share, for the prior year period. Included in the net loss for the quarter ended June 30, 2023, was $6.7 million of non-cash expense related to the impact of expensing share-based payments, including employee stock options, as compared to $6.0 million for the same period in 2022.

About Prelude Therapeutics

Prelude Therapeutics is a clinical-stage precision oncology company developing innovative drug candidates targeting critical cancer cell pathways. The Company’s diverse pipeline is comprised of highly differentiated, potentially best-in-class proprietary small molecule compounds aimed at addressing clinically validated pathways for cancers with selectable underserved patients. Prelude’s pipeline includes four candidates currently in clinical development: PRT1419, a potent, selective inhibitor of MCL1, PRT2527, a potent and highly selective CDK9 inhibitor, PRT3645 a next generation CDK4/6 inhibitor, PRT3789 an IV administered, potent and highly selective SMARCA2 degrader, and a preclinical oral candidate targeting SMARCA2.

For more information, visit our website and follow us on LinkedIn and Twitter.

Cautionary Note Regarding Forward-Looking Statements

This press release 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, the timing and/or announcements relating to the reporting of expected findings for PRT1419, PRT2527, PRT3645, PRT3789, and its preclinical oral SMARCA2 degrader, the potential benefits of Prelude’s product candidates and platform, and the sufficiency of cash and cash equivalents to fund operating expenses and capital expenditures into 2026. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. Although Prelude believes that the expectations reflected in such forward-looking statements are reasonable, Prelude cannot guarantee future events, results, actions, levels of activity, performance or achievements, and the timing and results of biotechnology development and potential regulatory approval is inherently

 

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uncertain. Forward-looking statements are subject to risks and uncertainties that may cause Prelude’s actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties related to Prelude’s ability to advance its product candidates, the receipt and timing of potential regulatory designations, approvals and commercialization of product candidates, clinical trial sites and our ability to enroll eligible patients, supply chain and manufacturing facilities, Prelude’s ability to maintain and recognize the benefits of certain designations received by product candidates, the timing and results of preclinical and clinical trials, Prelude’s ability to fund development activities and achieve development goals, Prelude’s ability to protect intellectual property, and other risks and uncertainties described under the heading “Risk Factors” in documents Prelude files from time to time with the Securities and Exchange Commission. These forward-looking statements speak only as of the date of this press release, and Prelude undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof.

 

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PRELUDE THERAPEUTICS INCORPORATED

STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS

(UNAUDITED)

 

		Three Months Ended June 30,
(in thousands, except share and per share data)		2023				2022
Operating expenses:
Research and development		$	24,966			$	21,310
General and administrative			7,432				8,151
Total operating expenses			32,398				29,461
Loss from operations			(32,398	)			(29,461	)
Other income, net			1,967				2,087
Net loss		$	(30,431	)		$	(27,374	)
Per share information:
Net loss per share of common stock, basic and diluted		$	(0.54	)		$	(0.58	)
Weighted average common shares outstanding, basic and diluted			56,240,491				47,276,684
Comprehensive loss
Net loss		$	(30,431	)		$	(27,374	)
Unrealized (loss) gain on marketable securities, net of tax			(313	)			19
Comprehensive loss		$	(30,744	)		$	(27,355	)

 

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PRELUDE THERAPEUTICS INCORPORATED

BALANCE SHEETS

(UNAUDITED)

 

(in thousands, except share data)		June 30, 2023				December 31, 2022
Assets
Current assets:
Cash and cash equivalents		$	26,446			$	30,605
Marketable securities			228,543				171,123
Prepaid expenses and other current assets			5,221				2,652
Total current assets			260,210				204,380
Restricted cash			4,044				4,044
Property and equipment, net			6,082				4,908
Right-of-use asset			918				1,792
Prepaid expenses and other non-current assets			9,357				5,376
Total assets		$	280,611			$	220,500
Liabilities and stockholders’ equity
Current liabilities:
Accounts payable		$	5,585			$	6,777
Accrued expenses and other current liabilities			8,667				13,093
Operating lease liability			938				1,832
Total current liabilities			15,190				21,702
Other liabilities			3,361				3,361
Total liabilities			18,551				25,063
Commitments (Note 8)
Stockholders’ equity:
Voting common stock, $0.0001 par value: 487,149,741 shares authorized; 41,958,456 and 36,496,994 shares issued and outstanding at June 30, 2023 and December 31, 2022, respectively			4				4
Non-voting common stock, $0.0001 par value: 12,850,259 shares authorized; 12,850,259 and 11,402,037 shares issued and outstanding at June 30, 2023 and December 31, 2022, respectively			1				1
Additional paid-in capital			655,473				531,682
Accumulated other comprehensive loss			(711	)			(1,692	)
Accumulated deficit			(392,707	)			(334,558	)
Total stockholders’ equity			262,060				195,437
Total liabilities and stockholders’ equity		$	280,611			$	220,500

 

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Investor Contact:

Lindsey Trickett

Vice President, Investor Relations

240.543.7970

ltrickett@preludetx.com

Media Contact:

Helen Shik

Shik Communications

617.510.4373

Helen@ShikCommuncations.com

 

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Corporate Presentation July 2023 Exhibit 99.2

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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, present data and clinical results or updates, and to obtain regulatory approvals for PRT1419, PRT2527, PRT3645, PRT3789, our oral SMARCA2 candidate 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 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).  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, 2022.

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Prelude Therapeutics: Aiming to Deliver Precision Medicines to Patients with Cancer Large Commercial Opportunities Diversified Pipeline Exceptional Team Well Capitalized Powerful R&D Engine

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Prelude Discovery and Development Engine R&D ENGINE  DIFFERENTIATED PROGRAMS APPROACH CDK9 MCL1 SMARCA2 CDK4/6 Target Mechanisms that drive meaningful benefit in patients with cancer Discover Optimized molecules that overcome the limitations of current treatments  Translate  Science into meaningful treatments for patients Internal Discovery Engine Clinical Development Expertise

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Differentiated Programs with Transformative Potential for Patients with Cancer  Potentially Best-in-Class Selectivity Potential to avoid off-target toxicity and higher clinical activity Potent and Selective Degrader Potential to address major unmet need in biomarker-selected patients Optimized PK Profile Potential for maximal target engagement and improved cardiac safety Highly Selective CDK4 Bias Potential for high tissue and brain penetration and better combinability CDK9 MCL1 SMARCA2 CDK4/6 Powerful Discovery Engine expected to generate new INDs every 12-18 months

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PROGRAM CANCER INDICATIONS  DISCOVERY PHASE 1   PHASE 2/3                                                                         AREAS OF CLINICAL FOCUS CDK9 PRT2527 Selected solid and hematologic malignancies CLL, Lymphoma MCL1 PRT1419 Selected hematologic malignancies  and solid tumors AML, CLL, Lymphoma CDK4/6 PRT3645 Selected solid tumors Breast Cancer, Gliomas, HNSCC, Lung, and Endometrial cancers SMARCA2  PRT3789 (IV) Multiple genomically-  selected cancers SMARCA4 mutated NSCLC and Other cancers SMARCA2  (Oral) Multiple genomically-  selected cancers SMARCA4 mutated NSCLC and Other cancers New Programs (Multiple targets) Selected solid and hematologic malignancies Solid Tumors  Heme Malignancies Prelude Precision Oncology Pipeline: Diversified and Differentiated

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Driving The Programs to Key Milestones and Value Creation PRT2527 PRT1419 PRT3645 SMARCA2 CDK9 MCL1 Next Generation CDK4/6 Present solid tumor data at AACR 2023 RP2D in solid tumors in early-2023 Present clinical update in 2H 2023 Confirmation dose in hematological malignancies in Q1 2024 Present solid tumor data at AACR 2023 RP2D in hematological malignancies in 2H 2023 Present clinical update for hematological malignancies in 2H Present program update in 2H 2023 Confirmation dose in Q4 2023 PROGRAM MILESTONES Initiate Phase 1 in 1Q Expected to provide program update 2H 2023 Confirmation dose in 1H 2024 PRT3789

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PRT2527 CDK9 Inhibitor

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CDK9 Inhibition: Targeting Cancer by Regulating Oncogene Expression CDK9 regulates expression of several oncogenes that drive cancer cell growth and resistance (i.e. MYC, MYB, MCL1) Non-selective CDK9 inhibitors have demonstrated clinical activity in multiple tumor types but poor tolerability Improving the selectivity of CDK9 inhibitors may translate to better activity and safety profile SUPER ENHANCER RNA Pol II TSS MYC & MYB TARGET GENES mRNA CDK9

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PRT2527: Potent and Highly Selective CDK9 Inhibitor Compound AZD4573 KB0742 VIP152** PRT2527 Biochemical* IC50 (nM) CDK9 1.9 483 16 0.95 Proliferation* IC50 (nM) 11 915 84 18 Plasma* IC50 (nM) 192 1056 923 196 Fold Selectivity CDK9 vs Other Isoforms CDK1 23x >20x 371x 73x CDK2 35x >20x 147x 340x CDK3 2x >20x 37x 35x CDK4 53x >20x 38x 250x CDK5 37x >20x >600x >1000x CDK6 79x >20x 296x >1000x CDK7 150x >20x >600x >1000x Highly Selective, ATP Competitive CDK9 Inhibitor >100x100-10x<10x *Internal data; biochemical assay at 1 mM ATP, H929 CTG proliferation assay; **VIP151 was formerly BAY151 and licensed to Vincerx by Bayer

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CDK9 inhibitor: PRT2527 Phase 1 Dose-Escalation Study in Advanced Solid Tumors Phase 1 dose escalation study of PRT2527 is ongoing and enrolling the following tumor types Selected sarcomas displaying a gene fusion Castrate resistant prostate cancer HR+ HER2- breast cancer Non-small cell lung cancer Solid tumors with MYC amplification In the 18 patients treated in dose escalation, PRT2527 was generally well tolerated with manageable neutropenia and absence of significant gastrointestinal events or hepatotoxicity The 15 m/mg2 QW dose of PRT2527 was selected for further evaluation in a dose-confirmation cohort Dose-dependent inhibition of CDK9 transcription targets observed in PBMCs HR+ Hormone receptor positive; HER2- Human epidermal growth factor negative ClinicalTrials.gov Identifier: NCT05159518 Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2023/04/Henry_2527-01_AACR-CT173-poster_23MAR23.pdf Timepoint Mean fold change ± SEM in MYC mRNA expression in PBMCs relative to pre-dose Pre-dose 2 hours post dose 4 hours post dose 1 hour post dose 0.8 0.6 0.0 1.0 1.4 1.6 1.2 0.4 0.2 A 3 mg/m2 QW (n=3) 6 mg/m2 QW (n=3) 12 mg/m2 QW (n=3) 15 mg/m2 QW (n=4) 18 mg/m2 QW (n=4) Pre-dose 2 hours post dose 4 hours post dose 1 hour post dose 0.8 0.6 0.0 1.0 1.4 1.6 1.2 0.4 0.2 Timepoint Mean fold change ± SEM in MCL-1 mRNA expression in PBMCs relative to pre-dose B 3 mg/m2 QW (n=3) 6 mg/m2 QW (n=3) 12 mg/m2 QW (n=3) 15 mg/m2 QW (n=4) 18 mg/m2 QW (n=4)

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CDK9 Inhibitor: PRT2527 Phase 1 Studies in Solid Tumors and Hematologic Malignancies PRT2527 Solid Tumors N=18 PRT2527 MYC Amplified or Overexpressed Solid Tumors, Prostate Cancer N=15 Solid Tumors Dose dependent increases in drug concentrations and target engagement observed in Phase 1 Clinical MYC and MCL1 depletion to levels consistent with tumor regression in preclinical models Generally well tolerated Dose Confirmation Dose Escalation PRT2527 Monotherapy Aggressive B cell lymphomas (multiple types), follicular lymphoma, CLL/SLL/Richters, MCL PRT2527 N=30 Hematologic Malignancies ASH 2022 preclinical oral presentation CDK9 as a target externally validated in aggressive lymphoma and other heme malignancies Dose Confirmation Dose Escalation ClinicalTrials.gov Identifier: NCT05159518 Solid Tumor data at AACR 2023  Present clinical update in 2H 2023  Confirmation dose in hematological malignancies in Q1 2024 ClinicalTrials.gov Identifier: NCT05665530

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CDK9 Inhibitor Differentiation and Market Opportunity Potential for Improved Safety Based on Best-in-Class Kinome Selectivity PRT2527 is designed to be a highly potent CDK9 inhibitor with best-in-class kinome selectivity compared to competitor compounds Designed to have an optimized PK profile to maximize therapeutic window Highly active in pre-clinical models at well-tolerated doses High levels of inhibition of CDK9 dependent genes in Phase 1  Market Opportunity CDK9 inhibitors in lymphomas, including CLL, Mantle cell and DLBCL may address areas of high unmet need CDK9 MCL1 SMARCA2 CDK4/6

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PRT2527: Broad Potential to Address areas of High Unmet Need 1. SEER Cancer Stat Facts: https://seer.cancer.gov/statfacts/html/clyl.html;  2. Gena Kanas, et. al. Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe 3. CancerMPact® Treatment Architecture, Non-Hodgkin US, 4. CancerMPact® Treatment Architecture, Chronic Lymphocytic Leukeimia, US, 5. CLL Patient Based Forecast, Datamonitor Healthcare  Broad Opportunity: ~125K patients treated annually(US): CLL, MCL and DLBCL1,2,3,4,5 Limited Treatment Options: >50% of High Risk CLL, MCL and DLBCL patients are refractory/relapsed within 1 year after 2L Treatment 2,3

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PRT1419  MCL1 Inhibitor

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MCL1 inhibition: Targeting Cancer Cell Survival MCL1 is a member of the BCL2 family of inhibitors of apoptosis Emerged as a resistance mechanism to the BCL2 inhibitor Venetoclax Prolonged depletion of MCL1 is undesirable and may be associated with cardiac toxicity Optimizing the PK profile of an MCL1 inhibitor may maximize the therapeutic window Mechanism

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PRT1419 is Potent MCL1 Inhibitor with Demonstrated Preclinical Activity as Monotherapy and in Combination Monotherapy Combination Robust monotherapy activity also seen in models of DLBCL & MM Proliferation IC50 (nM) Whole Blood IC50 (nM) AMG176 150 1800 AZD5991 31 320 MIK665 4.5 430 PRT1419 80 210 Prelude compounds are competitive inhibitors of BIM binding

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PRT1419: Not Observed to Cause Cardiac Injury in Preclinical Toxicology Studies Doses: 0.3, 1, 3 and 6 mg/m2; once weekly Linear increases in exposure No troponin elevations observed at any doses, even high dose which covered EC90 for 24h No histopathological evidence of cardiac injury Pharmacokinetics Pharmacodynamics PRT1419 Module 2.6 IND: Tox Written Summary

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MCL-1 inhibitor: PRT1419  Phase 1 Dose-Escalation Study in Advanced Solid Tumors PRT1419 demonstrated acceptable safety and tolerability in patients with advanced metastatic solid tumors, with the most common TRAEs of nausea, vomiting and diarrhea Neutropenia was deemed to be dose related No cardiac toxicity was observed Induction of activated-BAX and cleaved caspase-3 was observed at 80 and 120 mg/m2: QW PRT1419, suggesting optimal  MCL-1 inhibition Upregulation of MCL1 is a mechanism of resistance to BCL2 inhibition, particularly in CLL and AML; Strong preclinical hypothesis in heme Phase 1 Target Engagement Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2023/04/Falchook_1419-02_AACR-CT172-poster-23MAR23.pdf

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MCL1 inhibitor: PRT1419 Phase 1 Study in Hematologic Malignancies PRT1419 Monotherapy AML/MDS/CMML CLL/SLL FL/MZL/MCL N=24-30 PRT1419 Combination PRT1419+Aza: AML/MDS/CMML PRT1419+Ven: AML/MDS/CMML PRT1419+Ven: MCL N=24-30 Dose Confirmation Dose Escalation ClinicalTrials.gov Identifier: NCT05107856 RP2D in hematological malignancies in 2H 2023 Present clinical update for hematological malignancies in 2H 2023

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MCL1 Inhibitor Differentiation and Market Opportunity Designed to have PK Profile to Achieve Desired Target Engagement MCL1 CDK9 SMARCA2 CDK4/6 PRT1419 is designed to be a highly potent and selective MCL1 inhibitor Designed to have a PK profile with high clearance to provide desired target engagement with improved safety No cardiotoxicity or troponin changes in GLP preclinical studies at doses exceeding those required for efficacy  No evidence of cardiotoxicity in the solid tumor Phase 1 at the recommended Phase 2 dose Market Opportunity AML, CLL and MCL patients need additional treatment options PRT1419 Module 2.6 IND: Tox Written Summary

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PRT1419:  MCL1 Inhibitor Offers Potential Benefit for Patients with Poor Outcomes 22 Broad Opportunity: ~95K patients treated annually(US):   CLL, AML, MDS 1,2,3,4 Outcomes for relapsed / refractory patients are poor: >50% of CLL, High Risk MDS and Unfit AML patients are refractory/relapsed within 1 year after second relapse2,3,4 1. SEER Cancer Stat Facts: Chronic Lymphocytic Leukemia. National Cancer Institute. Bethesda, MD, https://seer.cancer.gov/statfacts/html/clyl.html; 2. CancerMPact® Treatment Architecture, Non-Hodgkin US May 2022 3, CancerMPact® Treatment Architecture, Chronic Lymphocytic Leukeimia, US May 2022 4. CancerMPact® Treatment Architecture, MDS, US., August 2022 * MDS number represents annual incident patients, treated patient number may be higher.

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PRT3645 Next Generation CDK4/6 Inhibitor

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Next Generation CDK4/6 Inhibition: Targeting Cancer Through Cell Cycle Regulation Mechanism Validated mechanism with approval of Next Generation CDK4/6 inhibitors in HR+ breast cancer Resistance mechanism to other inhibitors of the RAS and HER2 pathways, including KRAS G12C Inability of current inhibitors to penetrate the blood-brain barrier (BBB) Next generation CDK4/6 inhibitor with improved tolerability and tissue penetrance could translate into activity in areas of unmet need beyond HR+ breast cancer Sequential use of Next Generation CDK4/6 inhibitors in breast cancer may also improve outcomes ASCO 2022 reference:  A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. and See AACR 2023; https://preludetx.com/wp-content/uploads/2023/04/Zou_CDK46_AACR-2023_Poster-5973_04APR23.pdf

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PRT3645 – Designed to be a Highly Selective Next Generation CDK4/6 Inhibitor Bias towards CDK4 over CDK6 Compound Palbociclib Abemaciclib PRT3645 Biochemical* IC50 (nM) CDK4 25 5 3 Proliferation* IC50 (nM) 52 70 47 Phospho-Rb* IC50 (nM) 28 30 16 Fold Selectivity CDK4 vs Other Isoforms CDK6 1x 6x 5x CDK1 >500x >500x >500x CDK2 >500x 173x >500x CDK3 >500x 212x >500x CDK5 >500x >500x >500x CDK7 >500x >500x >500x CDK9 209x 59x >500x >500x 500-50x 50-5x<2x *Internal data; biochemical assay at 1 mM ATP, MCF7 CTG proliferation assay; MCF7 pRB Highly Selective, ATP Competitive

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PRT3645: Next Generation CDK4/6 inhibitor Improved Tissue Penetration and Favorable Activity in Preclinical Models PRT3645 demonstrated higher brain penetration than approved CDK4/6 inhibitors PRT3645 showed favorable activity in vivo as monotherapy and in combination U87 glioblastoma model MCF7 breast cancer model Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2022/05/Prelude_AACR_Juvekar-CDK4-FINAL-28Mar2022.pdf

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Potential for Novel Combinations to Extend the Reach of CDK4/6 Inhibition Beyond ER+ Breast Cancer H2122 NSCLC Model DFBM-355 PDX model of ER+/HER2+ Breast Cancer PRT3645 observed to enhance the activity of KRAS G12C inhibitor in NSCLC models and with HER2 kinase inhibitor in ER+/HER2+ BC models Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2023/04/Zou_CDK46_AACR-2023_Poster-5973_04APR23.pdf

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Next Generation CDK4/6 Inhibitor: PRT3645 Phase 1 Study in Solid Tumors A potentially differentiated and highly brain penetrant Next Generation CDK4/6 inhibitor Potential to extend the reach of CDK4/6 inhibition beyond HR+ breast cancers, for which the first generation CDK4/6 inhibitors were approved PRT3645 Biomarker enriched patients with select tumor types including sarcomas, mesothelioma, gliomas, head and neck cancers and non-small cell lung cancer, in addition to breast cancer with or without brain metastases Dose Escalation and Confirmation ClinicalTrials.gov Identifier: NCT05538572 Present program update in 2H 2023 Confirmation dose in Q4 2023

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Next Generation CDK4/6 Inhibitor Differentiation and Market Opportunity Deep Tissue Penetration with Potential for Activity in Areas of Unmet Need  PRT3645 has potential to be a highly potent and selective Next Generation CDK4/6 inhibitor Designed for deep tissue penetration including brain penetrance Designed for improved metabolic profile to allow for combination treatment in diseases beyond breast cancer Favorable toxicity in preclinical GLP studies with potential for improved tolerability in the clinic Market Opportunity: Breast cancer patients may benefit from sequential CDK4/6 inhibitors treatment There are estimated to be 65,000 breast cancer patients treated with CDK4/6 inhibitors in 2023 in the U.S. Other solid tumors (lung cancer, glioma, HER2+ breast cancer) may demonstrate activity in combination  MCL1 CDK9 SMARCA2 CDK4/6 PRT3645 Module 2.6 IND PK written summary; ASCO 2022 reference:  A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial. and See AACR 2023; https://preludetx.com/wp-content/uploads/2023/04/Zou_CDK46_AACR-2023_Poster-5973_04APR23.pdf

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PR3789 SMARCA2 Degrader

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Targeting SMARCA2 (BRM): Leveraging Synthetic Lethality The chromatin remodeling (SWI/SNF) complex is frequently mutated in cancer making it a potential therapeutic target Activation of the SWI/SNF complex requires either SMARCA4 (BRG1) or SMARCA2 (BRM) 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 Mechanism

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Indication Any SMARCA4 Mutation1,2,3 NSCLC 10.0% Esophageal​ 8.0% Gastric​ (stomach adeno) 8.3% Skin (invasive and in situ melanoma)* 21.0% Endometrial​ (uterine corpus) 13.3% Squamous cell​ lung 7.7% Urinary (bladder)​ 9.0% Colorectal 6.0% Pancreatic 2.9% Melanoma​ (invasive) 8.7% SMARCA4 Mutations in NSCLC: An Opportunity with No Approved Therapies SMARCA4 Prevalence across selected Solid Tumors 1.cBioPortal; FoundationCore;  2.SMARCA4 LOF mutations included homozygous missense, hotspot mutations with LOF, and damaging mutations;  3.SEER 2022; Globocan;  * Source: American Cancer Society – Cancer Facts & Figures 2022 Fernando et al. Nature Communications 2020 SMARCA4 Mutation – A Potentially Novel Biomarker for NSCLC Targets for Approved Drugs

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PRT3789: Potent and Selective SMARCA2 Degrader with In Vivo Activity Robust Tumor Growth Inhibition of SMARCA4 mutated but not WT Xenograft Significant Degradation of SMARCA2 Protein but not SMARCA4 in Preclinical Models SMARCA4 mutant SMARCA4 WT PRT3789 PRT3789 Vehicle Low Dose Mid Dose High Dose SMARCA2 SMARCA4 LAMIN B1 SMARCA2 SMARCA4 LAMIN B1 Male Female Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2023/04/Hulse_SMARCA2_AACR-2023_Poster-6270_04APR23.pdf Presented at AACR 2022; https://preludetx.com/wp-content/uploads/2022/05/Prelude_AACR_Hulse-SMARCA2-FINAL-21Mar2022.pdf

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SMARCA2 Degrader: PRT3789 Phase 1 Study in Solid Tumors SMARCA2 inhibition has the greatest potential in patients with SMARCA4 deficient cancers, including approximately 10% of all non-small cell lung cancers SMARCA2 degradation to be evaluated in Phase 1 Study population: advanced, recurrent, or metastatic disease, with loss of SMARCA4 due to truncating mutation and/or deletion Biomarker selected by local NGS or IHC in tumor tissue or blood HR+ and HER2-negative or HR+ and HER2+breast cancer Recurrent GBM (IDH wild type) or CDKN2A/B homozygous deleted IDH-mutant astrocytoma KRAS-mutant NSCLC CDK pathway alternation in any of the following tumor types: malignant mesothelioma, HPV-negative HNSCC (including oral cavity, oropharynx, hypopharynx, and larynx), sarcoma, or NSCLC ClinicalTrials.gov Identifier: NCT05538572 PRT3789 Solid Tumors with loss of SMARCA4 Backfill: up to 10 participants with a minimum of 6 NSCLC participants with loss of SMARCA4 Dose Escalation and Confirmation Expected to provide program update 2H 2023 Confirmation dose in 1H 2024 ClinicalTrials.gov Identifier: NCT05639751

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Selective Orally Bioavailable SMARCA2 Degrader Program PRT5506 - Preclinical Lead to Demonstrate Proof-of-Concept Robust Tumor Growth Inhibition of SMARCA4 Mutated Xenograft with Oral Dosing Potent and Highly Selective SMARCA2 Degradation In Vitro SMARCA2 DC50 1 nM SMARCA4 DC50 54 nM Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2023/05/Ito_SMARCA2_AACR-2023_Poster_6277_01MAY23_CORRECTION.pdf

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SMARCA2 Differentiation and Market Opportunity Potential First-in-Class SMARCA2 (BRM) Targeted Protein Degrader PRT3789 is a potential first-in-class SMARCA2 Degrader Potentially potent and selective SMARCA2 targeted protein degrader approach We believe SMARCA2 selectivity may provide a favorable toxicity profile Observed favorable efficacy in SMARCA4 mutant preclinical models, we believe provides path for patient selection strategy in the clinic Market Opportunity:   70,000 patients with SMARCA4 mutation in the US/EU5 SMARCA2 CDK4/6 MCL1 CDK9

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PRT3789: Large Pan-Tumor Unmet Need in Patients with SMARCA4 Mutation Broad Opportunity: Improvement vs SoC: Most common 2L mNSCLC regimen offers minimal benefit and significant toxicity 4 SMARCA 4 Degrader offers: First in Class Treatment Option in patients with no approved drugs mPFS ~ 4.5 months docetaxel + ramucirumab NSCLC ~40% 1. Fernando, T.M., Piskol, R., Bainer, R. et al. Functional characterization of SMARCA4 variants identified by targeted exome-sequencing of 131,668 cancer patients..https://doi.org/10.1038/s41467-020-19402-8; 2. https://www.mycancergenome.org/content/gene/smarca4/ 3. US SEER Database 4. CancerMPact® Treatment Architecture, NSCLC – Non Driver Mutation. CRC ~18% Urinary ~13% Distribution of Patients with SMARCA4 mutation by Tumor, based on study of ~130k patients1,2,3

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Prelude Therapeutics:  Key Takeaways We expect our cash, cash equivalents and marketable securities as of June 30, 2023 will enable us to fund operating expenses and capital expenditure requirements into 2026 Potentially first-in-class SMARCA2 degrader program with a potentially significant lead over competitors and offers transformational potential for the company Opportunity to drive programs to key inflection points in the next 12 – 24 months Emerging clinical data on CDK9 and MCL-1 programs demonstrated the potential for class-leading opportunities Deep clinical pipeline with unique and potentially best-in-class or first-in-class molecules

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Experienced Management Team: Proven Track Records Andrew Combs, PhD Executive Vice President and Head of Chemistry Peggy Scherle, PhD Chief Scientific Officer Jane Huang M.D. President and Chief Medical Officer Kris Vaddi, PhD Founder & Chief Executive Officer Laurent Chardonnet, MBA Chief Financial Officer Bryant Lim, J.D. Chief Legal Officer and Corporate Secretary

v3.23.2

Document and Entity Information	Aug. 03, 2023
Cover [Abstract]
Entity Registrant Name	Prelude Therapeutics Inc
Amendment Flag	false
Entity Central Index Key	0001678660
Document Type	8-K
Document Period End Date	Aug. 03, 2023
Entity Incorporation State Country Code	DE
Entity File Number	001-39527
Entity Tax Identification Number	81-1384762
Entity Address, Address Line One	200 Powder Mill Road
Entity Address, City or Town	Wilmington
Entity Address, State or Province	DE
Entity Address, Postal Zip Code	19803
City Area Code	(302)
Local Phone Number	467-1280
Written Communications	false
Soliciting Material	false
Pre Commencement Tender Offer	false
Pre Commencement Issuer Tender Offer	false
Security 12b Title	Common Stock, $0.0001 par value per share
Trading Symbol	PRLD
Security Exchange Name	NASDAQ
Entity Emerging Growth Company	true
Entity Ex Transition Period	false

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