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A focus on CDK9 means Prelude Therapeutics now considers its MCL-1 inhibitor, called PRT1419, to be surplus to requirements. Increasingly confident in the potential of its SMARCA2 degrader and a CDK9 inhibitor to treat cancers, Prelude Therapeutics is scrapping the other half of its clinical pipeline. The company’s “top priority” is now to generate initial proof-of-concept data for PRT3789, a first-in-class highly selective degrader of the SMARCA2 protein, Chief Medical Officer and President Jane Huang, M.D., said in a third-quarter earnings release. The biotech hopes the drug will one day benefit the about 70,000 patients in the U.S. and Europe who have cancers with the SMARCA4 mutation. AbCellera appears to have bought into the idea. As part of its earnings announcement, Prelude also disclosed that the two biotechs have signed a multiyear collaboration to develop and commercialize cancer drugs for up to five programs. The first of these programs will comprise antibody-drug conjugates involving a SMARCA degrader. Alongside this work, Prelude will be pushing its own SMARCA2 degrader through a phase 1 trial in patients with biomarker-selected SMARCA4-mutated cancer with a readout expected next year. “Provided these results are as we expect, we anticipate advancing the compound into a registrational phase 2/3 trial thereafter,” Huang said. The Wilmington, Delaware-based biotech also plans to file an IND with the FDA next year to get an oral SMARCA2 degrader into the clinic. The company’s remaining bandwidth will be on its CDK9 inhibitor, dubbed PRT2527. Prelude had been “encouraged by the emerging data in both solid and hematological cancers” from a recently completed phase 1 trial, Huang said. “These data demonstrate that our highly targeted compound has been generally safe and well-tolerated with a strong inhibition of the pathway required for efficacy in preclinical models and is well-differentiated from other CDK9 inhibitors,” the CMO added. Prelude’s ambition is for PRT2527 to become the most advanced CDK9 inhibitor for patients with B-cell malignancies and acute myeloid leukemia, with clinical proof-of-concept data on the candidate as a monotherapy and in combinations expected next year. The focus on CDK9 means Prelude now considers its MCL-1 inhibitor, called PRT1419, to be surplus to requirements, despite having recently completed a phase 1 dose-escalation study in hematological malignancies. “Based on the potential to address the intended patient populations with the CDK9 inhibitor, which potently inhibits MCL-1, Prelude has made a decision to prioritize its CDK9 inhibitor over PRT1419,” the company explained. The CDK4/6 inhibitor PRT3645 is in a similar position. Despite phase 1 dose-escalation data showing levels of drug in the plasma are reaching the amount needed for efficacy, the company is ending work on the program and will instead seek out potential partners. “We made significant progress in the third quarter with our four clinical-stage molecules and, as planned, conducted a rigorous assessment of each program,” CEO Kris Vaddi, Ph.D., said in the earnings release. “Based on this assessment, we are prioritizing our resources on our first-in-class SMARCA2 degrader molecules, IV and oral, and our potential best-in-class CDK9 inhibitor program,” Vaddi added. “We are confident that these two programs represent compelling opportunities for demonstrating clinical proof-of-concept in 2024, for advancing into potential phase 2/3 registration studies, and for becoming important new medicines.” Prelude appears to have the financial fuel to see its near-stage ambitions bear fruit. The biotech ended September with $230.5 million in cash and equivalents, which it expects to fund operations into 2026.

Eight abstracts presented at AACR 2023 demonstrate progress of the pipeline Cash runway unchanged, supporting operations into the fourth quarter of 2024 WILMINGTON, Del., May 08, 2023 (GLOBE NEWSWIRE) -- Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today reported financial results for the first quarter ended March 31, 2023, and provided an update on recent clinical and development pipeline progress. “Our recent presentations at the 2023 AACR Annual Meeting highlight the meaningful progress we made across our clinical and preclinical pipeline programs. In addition to our clinical presentations on PRT2527 (CDK9 inhibitor) and PRT1419 (MCL-1 Inhibitor) that demonstrated differentiated and potential best-in-class PK/PD profiles of these molecules, our preclinical research demonstrated the promise of our pipeline in addressing unmet patient needs in cancer through combination approaches. Patient enrollment in the phase 1 dose escalation of PRT3789 (first-in-class SMARCA2 selective degrader) is now underway. Our teams are focused on advancing our pipeline to key milestones and we look forward to reporting further updates in the coming months,” said Kris Vaddi, Ph.D., Chief Executive Officer of Prelude. Recent Highlights 2023 AACR Annual Meeting: Prelude participated in the 2023 American Association for Cancer Research Annual Meeting, presenting two clinical and six preclinical poster presentations. Initial safety, pharmacokinetic and pharmacodynamic profiles in solid tumors for both PRT2527 and PRT1419 were presented. Preclinical data for both the Company’s next generation CDK4/6 inhibitor, PRT3645, and the SMARCA2 degrader, PRT3789, in combination with other targeted therapies, demonstrated the combinability of these compounds with standard of care medicines and inform potential clinical development. Program Updates and Upcoming Milestones PRT2527- CDK9 Inhibitor Program PRT2527, Prelude’s potentially best in class CDK9 inhibitor, is completing a solid tumor dose escalation study. In adults with advanced solid tumors, PRT2527 was generally well-tolerated with manageable neutropenia and absence of significant gastrointestinal events or hepatotoxicity. The short half-life of PRT2527 enables acute CDK9 inhibition over a defined period making it potentially suitable for weekly administration without inducing significant toxicity. The observed dose-dependent downregulation of CDK9 transcriptional targets – MYC and MCL-1 mRNA expression in PBMCs isolated from patients treated with PRT2527 –was consistent with the degree of target engagement required for preclinical efficacy. The 15 m/mg2 QW dose of PRT2527 was selected for further evaluation in dose-confirmation cohort. The overall safety pro in this study supports further development of PRT2527 in combination with other targeted therapies, including in hematologic malignancies. The Company is on track to establish a RP2D in hematological malignancies in 2H 2023. PRT1419- MCL1 Inhibitor Program PRT1419 demonstrated an acceptable safety and tolerability pro patients with advanced and 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. Pharmacokinetics/pharmacodynamics and safety data in the 80 mg/m2 QW PRT1419 dose cohort support further evaluation of this dose in future studies. Induction of activated-BAX and cleaved caspase-3 was observed at 80 and 120 mg/m2 QW PRT1419, suggesting successful MCL-1 inhibition. No tumor reductions met response criteria. Further investigation of PRT1419 in patients with hematologic malignancy is ongoing. The Company is on track to determine the RP2D in hematological RP2D and will provide a clinical update at year end. PRT3645-Next Generation CDK4/6 Inhibitor Program Prelude showed that PRT3645 is highly efficacious when combined with KRAS/MEK inhibitors, and with a brain penetrant HER2 receptor kinase inhibitor in in vivo preclinical models. Additionally, oral administration of PRT3645 induces tumor regression in palbociclib-resistant preclinical models. Dose escalation phase of PRT3645 is progressing per plan and the Company expects to provide an update by year end. PRT3789 SMARCA2 Targeted Protein Degrader Program Phase 1 dose escalation of PRT3789 (first-in-class selective SMARCA2 degrader) is ongoing. The Company recently presented preclinical data, showing that SMARCA2 selective degraders demonstrate anti-proliferation activity and promote cell differentiation in a wide range of indications demonstrating activity as monotherapy, as well as in combination with KRAS G12C inhibitors, chemotherapy and other targeted agents. Consistent with the Company’s plans to nominate an orally bioavailable candidate in early 2024, preclinical data at AACR showed that oral administration of multiple internally developed compounds results in significant tumor growth inhibition of SMARCA4-deficient lung cancer xenografts at well-tolerated doses. First Quarter 2023 Financial Results Cash, Cash Equivalents and Marketable Securities: Cash, cash equivalents, and marketable securities as of March 31, 2023, were $172.3 million. Prelude anticipates that its existing cash, cash equivalents and marketable securities will fund the Company’s operations into the fourth quarter of 2024. Research and Development (R&D) Expenses: For the first quarter of 2023, R&D expense decreased to $21.8 million from $22.8 million for the prior year period. Research and development expenses decreased 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 first quarter of 2023, G&A expenses were relatively unchanged as compared to the three months ended March 31, 2022. Net Loss: For the three months ended March 31, 2023, net loss was $27.7 million, or $0.58 per share compared to $29.5 million, or $0.63 per share, for the prior year period. Included in the net loss for the quarter ended March 31, 2023, was $6.3 million of non-cash expense related to the impact of expensing share-based payments, including employee stock options, as compared to $6.8 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, and PRT3789 an IV administered, potent and highly selective SMARCA2 degrader. 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 and PRT3789, 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 the fourth quarter of 2024. 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 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, the impact of the COVID-19 pandemic on Prelude’s business, clinical trial sites, 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. PRELUDE THERAPEUTICS INCORPORATED STATEMENTS OF OPERATIONS AND COMPREHENSIVE LOSS (UNAUDITED) Three Months Ended March 31, (in thousands, except share and per share data) 2023 2022 Operating expenses: Research and development $ 21,834 $ 22,821 General and administrative 7,281 7,467 Total operating expenses 29,115 30,288 Loss from operations (29,115 ) (30,288 ) Other income, net 1,397 823 Net loss $ (27,718 ) $ (29,465 ) Per share information: Net loss per share of common stock, basic and diluted $ (0.58 ) $ (0.63 ) Weighted average common shares outstanding, basic and diluted 47,737,190 47,066,427 Comprehensive loss Net loss $ (27,718 ) $ (29,465 ) Unrealized gain (loss) on marketable securities, net of tax 1,294 (1,602 ) Comprehensive loss $ (26,424 ) $ (31,067 ) PRELUDE THERAPEUTICS INCORPORATED BALANCE SHEETS (UNAUDITED) (in thousands, except share data) March 31, 2023 December 31, 2022 Assets Current assets: Cash and cash equivalents $ 18,201 $ 30,605 Marketable securities 154,054 171,123 Prepaid expenses and other current assets 3,008 2,652 Total current assets 175,263 204,380 Restricted cash 4,044 4,044 Property and equipment, net 5,371 4,908 Right-of-use asset 1,360 1,792 Prepaid expenses and other non-current assets 12,282 5,376 Total assets $ 198,320 $ 220,500 Liabilities and stockholders’ equity Current liabilities: Accounts payable $ 7,082 $ 6,777 Accrued expenses and other current liabilities 11,190 13,093 Operating lease liability 1,390 1,832 Total current liabilities 19,662 21,702 Other liabilities 3,361 3,361 Total liabilities 23,023 25,063 Commitments Stockholders’ equity: Voting common stock, $0.0001 par value: 487,149,741 shares authorized; 36,514,218 and 36,496,994 shares issued and outstanding at March 31, 2023 and December 31, 2022, respectively 4 4 Non-voting common stock, $0.0001 par value: 12,850,259 shares authorized; 11,402,037 and 11,402,037 shares issued and outstanding at March 31, 2023 and December 31, 2022, respectively 1 1 Additional paid-in capital 537,966 531,682 Accumulated other comprehensive loss (398 ) (1,692 ) Accumulated deficit (362,276 ) (334,558 ) Total stockholders’ equity 175,297 195,437 Total liabilities and stockholders’ equity $ 198,320 $ 220,500 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