UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
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FORM
CURRENT REPORT
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Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
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Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
Item 8.01 Other events
On September 13, 2024, Prelude Therapeutics Incorporated (the "Company") issued a press release announcing the first interim clinical data from its Phase 1 open-label, dose-escalation trial of PRT3789, a novel, highly-selective SMARCA2 degrader. The press release was issued simultaneously with the previously announced oral presentation of an abstract regarding such data at the European Society of Medical Oncology (ESMO) Congress 2024. A copy of the press release is attached as Exhibit 99.1 to this report. Additionally, the Company hosted an investor webcast on September 13, 2024 at 12:00 p.m. EST. A copy of the presentation materials from the investor webcast is attached as Exhibit 99.2 to this report.
In connection with the presentation of the clinical data, the Company has updated its corporate presentation. A copy of the updated corporate presentation is attached as Exhibit 99.3 to this Current Report on Form 8-K and is incorporated herein by reference.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
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SIGNATURE
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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PRELUDE THERAPEUTICS INCORPORATED
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Date: September 13, 2024 |
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/s/ Bryant Lim |
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Bryant Lim |
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Chief Legal Officer, Corporate Secretary, and Interim Chief Financial Officer |
Exhibit 99.1
Prelude Therapeutics’ SMARCA2 Degrader PRT3789 Demonstrated Promising Initial Clinical Activity and Safety Profile in Phase 1 Trial
WILMINGTON, Del., Sep. 13, 2024 (GLOBE NEWSWIRE) – Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, today announced the first interim clinical data from its ongoing Phase 1 open-label, dose-escalation trial of PRT3789, a first-in-class SMARCA2 degrader, highly selective for SMARCA2 and designed to treat cancer patients with a SMARCA4 mutation. The data were presented at the European Society for Medical Oncology (ESMO) Congress 2024 in Barcelona, Spain.
The study investigators reported that, as of the August 5, 2024 data cutoff date (the Cutoff Date), 65 patients were safety evaluable, enrolled and treated. This included 46 efficacy evaluable patients (with a post-baseline scan) with any tumor type harboring any SMARCA4 mutation.
As reported today by the study investigators, PRT3789 was generally well-tolerated through 8 dosing cohorts. Dose escalation continues, now in the 9th dosing cohort. The majority of adverse events reported by investigators have been mild to moderate. A maximum tolerated dose has not yet been identified.
Overall, of the 26 advanced, heavily pre-treated NSCLC or esophageal patients evaluable for efficacy, 7 had tumor shrinkage. RECIST confirmed partial responses (PRs) were observed in 3 patients. Additional patients demonstrated clinical benefit as measured by prolonged stable disease (SD) including one patient on treatment for more than 1 year.
“For cancer patients harboring a SMARCA4 mutation, the disease is particularly aggressive and prognosis with current standard of care is quite poor,” stated Robin Guo, M.D., Memorial Sloan Kettering Cancer Center. “The observation of durable stable disease and tumor regressions in Phase I monotherapy dose escalation, coupled with a tolerable emerging safety profile, is
encouraging. This is what we hope to see with a first-in-class new therapy for a novel target in patients with a high unmet need.”
“We are encouraged by the early clinical activity and emerging safety profile observed to date with PRT3789,” stated Jane Huang, M.D., President and Chief Medical Officer of Prelude. “These data represent initial proof of concept that selective SMARCA2 degradation can yield antitumor activity in certain SMARCA4 mutated cancers.”
Continued Dr. Huang, “Monotherapy dose escalation continues, now at cohort 9 (500mg once weekly) with backfill cohorts continuing to enroll enriched for NSCLC and esophageal cancer patients with Class 1 mutations. We intend to confirm the biologically active dose for PRT3789 as monotherapy by year-end and continue to advance monotherapy and docetaxel combination studies in parallel to best position PRT3789 as a new treatment option for patients suffering from this aggressive type of cancer.”
PRT3789 Interim Phase 1 Results
PRT3789 is currently being evaluated in an ongoing dose-escalation Phase 1 trial in patients with solid tumors harboring any SMARCA4 mutation refractory to standard of care and generally multiple lines of therapy in most patients. As of the Cutoff Date, 65 patients with advanced cancer have been treated at eight dose levels (24 mg QW, 48 mg QW, 80 mg QW, 120 mg QW, 160 mg QW, 212 mg QW, 283 mg QW, 376 mg QW). The median age of these patients is 62 and the median number of prior treatments was 3 (ranging from 1-10). 34 patients (52.3%) presented with a Class 1 (loss of function) SMARCA4 mutation, while 24 patients (36.9%) presented with a Class 2 (missense, VUS) SMARCA4 mutation and 7 (10.8%) had a loss of SMARCA4 protein.
Initial Safety Data
PRT3789 was generally well-tolerated in the 65 patients treated as of the Cutoff Date. Adverse events are reported regardless of attribution to study drug. Adverse events of any grade observed to date consisted of nausea (24.5%), decreased appetite (18.5%), fatigue (18.5%), abdominal pain (16.9%), anemia (16.9%) and constipation (15.4%). No dose limiting toxicities were observed and no study drug-related serious adverse events were reported.
Pharmacokinetic (PK) and Pharmacodynamic (PD) Data
Preliminary PK data was available from 24 mg to 376 mg dose cohorts. A general trend of increases in exposure (Cmax, AUC) with dose was observed. Mean concentrations were observed above SMARCA2 plasma DC50 (21 nM) for approximately 8 hours at the 376 mg dose. No accumulation was observed with repeat dose administration, consistent with the half-life and once-weekly administration. PD effect observed was more prolonged than PK half-life, reaching trough inhibition of 70-75% at higher doses. Increasing doses demonstrated a deeper and more prolonged PD effect. Evaluation of the AUC of PD (SMARCA2 and SMARCA4) demonstrated a dose dependent decrease of SMARCA2 but not SMARCA4, demonstrating the high selectivity of PRT3789.
Analysis of Initial Clinical Activity
As of the Cutoff Date, there were 46 efficacy evaluable patients with a post-baseline scan across all tumor types with any SMARCA4 mutation. Of the 26 advanced, heavily pre-treated NSCLC or esophageal patients who were evaluable for efficacy, 7 had tumor shrinkage. RECIST confirmed partial responses (PRs) were observed in 3 patients (2 esophageal, 1 NSCLC). Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations. Additional patients on study demonstrated clinical benefit as measured by prolonged SD. One patient remains on study having been treated for more than 1 year. Of the 20 patients with tumor types other than NSCLC and esophageal cancer, none demonstrated tumor shrinkage at dose levels studied to date.
Conference Call and Webcast Information
Prelude Therapeutics management team will host a conference call, live webcast with slides and a Q&A on Friday, September 13, 2024 at 12:00 PM ET. A live webcast of the presentation will be available at Events & Presentations - Prelude Therapeutics (preludetx.com) A replay of the webcast will be available shortly after the conclusion of the call at Events & Presentations - Prelude Therapeutics (preludetx.com) and archived on the Company’s website for 60 days following the call.
Interim Phase 1 data selected for Plenary Session at upcoming EORTC-NCI-AACR Symposium
Interim Phase 1 data for PRT3789 was also selected for a Plenary Session oral presentation at the EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics. The presentation titled, “First Clinical Results from a Phase 1 Trial of PRT3789, a First-in-Class SMARCA2 Degrader, in Patients with Advanced Solid Tumors with a SMARCA4 Mutation,” will be presented by Timothy Yap, M.D. from University of Texas MD Anderson Cancer Center. The presentation is scheduled for October 24, 2024 at 10:00 AM CEST (4:00 AM EST) as part of the Proffered Papers: Advancing Patient Care Through Novel Clinical Trials session.
About PRT3789 – A first-in-class, highly selective, intravenous SMARCA2 degrader
PRT3789 is a first-in-class SMARCA2 degrader, highly selective for SMARCA2 and designed to treat patients with a SMARCA4 mutation. Cancer patients whose tumors have SMARCA4 mutations have a poor prognosis and as a result, this is an area of high unmet medical need.
PRT3789 is in Phase 1 clinical development in biomarker selected SMARCA4 mutant patients. Enrollment remains on track, and the Company expects to conclude monotherapy dose escalation in 2024 and identify a recommended Phase 2 dose. In addition, enrollment of patients into back-fill cohorts enriched for NSCLC and SMARCA4 loss-of-function mutations is ongoing, as is enrollment of the docetaxel combination cohort.
Objectives for this first Phase 1 clinical trial are to establish the safety and tolerability profile of PRT3789 as both monotherapy and in combination with docetaxel, evaluate activity, pharmacokinetics and pharmacodynamics and determine a dose and potential indications for advancement into registrational clinical trial(s).
Prelude launched an educational video series focused on the science of SMARCA biology, the discovery of first-in-class, highly selective SMARCA2 degraders and the unmet medical need for patients with SMARCA4 mutated cancer. This series can be found on the Company’s website under Highly Selective SMARCA2 Degraders - Prelude Therapeutics (preludetx.com).
About Prelude Therapeutics
Prelude Therapeutics is a leading precision oncology company developing innovative medicines in areas of high unmet need for cancer patients. Our pipeline is comprised of several novel drug candidates including first-in-class, highly selective IV and oral SMARCA2 degraders, and a potentially best-in-class CDK9 inhibitor. We are also leveraging our expertise in targeted protein degradation to discover, develop and commercialize next generation degrader antibody conjugates (Precision ADCs) with partners. We are on a mission to extend the promise of precision medicine to every cancer patient in need. For more information, visit preludetx.com.
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 for Prelude’s product candidates, the potential safety, efficacy, benefits and addressable market for Prelude’s product candidates, and the expected timeline for concluding the monotherapy dose escalation and identifying the biologically active dose, and expected ongoing work on and development of PRT3789. All statements other than statements of historical fact are statements that could be deemed forward-looking statements. The words “believes,” “anticipates,” “estimates,” “plans,” “expects,” “intends,” “may,” “could,” “should,” “potential,” “likely,” “projects,” “continue,” “will,” “schedule,” and “would” and similar expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These forward-looking statements are predictions based on the Company’s current expectations and projections about future events and various assumptions. 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, 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 Prelude’s Annual Report on Form 10-K for the year ended December 31, 2023, its Quarterly Reports on Form 10-Q and other documents that 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, except as may be required by law.
Investor Contact:
Robert A. Doody, Jr.
Senior Vice President, Investor Relations
Prelude Therapeutics Incorporated
484.639.7235
rdoody@preludetx.com
PRT3789 Phase 1 Interim Clinical Data Update from 2024 ESMO Congress 13 September 2024 Investor Presentation Exhibit 99.2
Forward Looking Statements This presentation contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude’s product candidates, including product candidates that are the subjects of the Company’s collaborations and partnerships, the potential safety, efficacy, benefits and addressable market for Prelude’s product candidates, the expected timeline for clinical trial results for Prelude’s product candidates including its SMARCA2 degrader molecules. Any statements contained herein or provided orally that are not statements of historical fact may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by such terminology as ‘‘believe,’’ ‘‘may,’’ ‘‘will,’’ ‘‘potentially,’’ ‘‘estimate,’’ ‘‘continue,’’ ‘‘anticipate,’’ ‘‘intend,’’ ‘‘could,’’ ‘‘would,’’ ‘‘project,’’ ‘‘plan,’’ ‘‘expect’’ and similar expressions that convey uncertainty of future events or outcomes, although not all forward-looking statements contain these words. Statements, including forward-looking statements, speak only to the date they are provided (unless an earlier date is indicated). This presentation shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction. These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2023 and our Quarterly Reports on Form 10-Q.
Kris Vaddi, Ph.D., CEO Prelude Therapeutics Incorporated Opening Remarks
We are on a mission to extend the promise of precision medicine to every cancer patient in need Select the best modality to precisely target oncogenic mechanisms Strive for first- or best-in-class and anchor to patient unmet need Draw on decades of experience and proven leadership to drive innovation
Developing an Industry Leading Portfolio of SMARCA-Targeted Precision Medicines SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) Oral SMARCA2 Degrader (PRT7732) Precision ADCs with SMARCA2/4 Degrader Payload
Dr. Jane Huang, President & Chief Medical Officer Prelude Therapeutics Incorporated A Phase 1 Trial of PRT3789, a First-in-Class SMARCA2 Degrader in Patients with Advanced Solid Tumors With a SMARCA4 Mutation Guo, R. et. al., ESMO Congress, 13 Sept 2024 PRT3789 Overview and Phase 1 Interim Data
Dr. Timothy Yap, University of Texas MD Anderson Cancer Center Investigator on PRT3789-01: A Phase 1 Trial of PRT3789, a First-in-Class SMARCA2 Degrader in Patients with Advanced Solid Tumors With a SMARCA4 Mutation Expert Perspective on SMARCA4-mutated Cancer
Patients with SMARCA4 mutations are not typically eligible for other targeted therapies Currently treated with standard of care chemotherapy or chemo-immunotherapy Targeting SMARCA4-mutated Cancer By Selectively Degrading SMARCA2 Pancreatic: 3% NSCLC: 10% Esophageal: 8% Gastric: 8% Endometrial: 13% SCLC: 8% Urinary: 9% Colorectal: 6% Dagogo-Jack et al. Journal of Thoracic Oncology. 2020 Foundation Medicine dataset SMARCA4 (BRG1) mutations occur in approximately 5% of all cancers Mutations in the chromatin remodeling complex drive cancer growth and resistance Cancer cells with deleterious SMARCA4 mutations become highly dependent on SMARCA2 for survival Selectively degrading SMARCA2 induces "synthetic lethality" in SMARCA4-deficient cancers
Outcomes for Patients with SMARCA4-mutated NSCLC are Poor with Current Standard of Care Alessi JV, et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2023 Feb 10:S1556-0864(23)00121-1. doi: 10.1016/j.jtho.2023.01.091. PMID: 36775193. Median progression free survival for first-line SMARCA4-mutated NSCLC treated with chemoimmunotherapy is 2.7 months and response rates approximately 22% There is even greater unmet need in second-line and beyond Patients treated with first-line chemoimmunotherapy
PRT3789: A Highly Potent SMARCA2 Degrader with >1000-fold Selectivity Over SMARCA4 Hulse et al. Cancer Res. (2022); 82 (12_Suppl) :3263. AACR 2022: https://preludetx.com/wp-content/uploads/2022/05/Prelude_AACR_Hulse-SMARCA2-FINAL-21Mar2022.pdf Highly selective for SMARCA2 vs SMARCA4 (>1000 fold) and selective across the proteome Preclinical Assay PRT3789 SMARCA2 Degradation (nM) 0.73 Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold Sub-nanomolar SMARCA2 degradation potency in cell lines Anti-tumor activity, including regressions, in SMARCA4 mutant models in vivo PRT3789 Tumor Regression PRT3789 Vehicle Days of Dosing
LOF, loss of function; NSCLC, non-small cell lung cancer PRT3789-01: Study Schema and Enrollment Dose Escalation Cohorts Any Solid Tumor Any SMARCA4 Mutation Evaluable Disease Backfill Cohorts Enriched NSCLC LOF SMARCA4 Mutation Measurable Disease n=2 n=5 n=6 n=8 24 mg n=4 48 mg n=7 80 mg n=5 120 mg n=7 160 mg n=7 212 mg n=5 283 mg n=4 376 mg n=5 500 mg … Phase 1 dose escalation study enrolled patients who had evaluable disease, any solid tumors, and any type of SMARCA4 mutation All patients received PRT3789 intravenously once weekly Patients treated in escalating doses from 24 to 376 mg and backfill cohort patients who had SMARCA4 (Class 1) loss of function mutations Guo, R. et al., ESMO Congress, 13 Sept 2024 Data cutoff: 05 August 2024
65 patients were safety evaluable Primary tumor type was NSCLC (n = 34) patients along with a range of other solid tumors 34 patients had Class 1 loss of function mutations and additional 7 patients had loss of SMARCA4 protein by IHC PRT3789-01: Demographics and Disease Characteristics Guo, R. et al., ESMO Congress, 13 Sept 2024 Characteristics Patients (N=65) Age (years) Median 62.0 Sex, n (%) Male 36 (55.4) Female 29 (44.6) Prior lines of systemic anti-cancer therapy, n Median (min, max) 3 (1, 10) Tumor type, n (%) Non-small cell lung cancer 34 (52.3) Pancreatic cancer 6 (9.2) Breast cancer 4 (6.2) Cholangiocarcinoma 2 (3.1) Colorectal cancer 2 (3.1) Esophageal cancer 2 (3.1) Ovarian cancer 2 (3.1) Other 13 (20.0) Type of SMARCA4 mutation, n (%) Class 1 (loss of function) 34 (52.3) Class 2 (missense, VUS) 24 (36.9) Loss of SMARCA4 protein (BRG1) by IHC 7 (10.8) Data cutoff: 05 August 2024 IHC, immunohistochemistry; VUS, variant of uncertain significance.
PRT3789-01: Patient Disposition As of the data cutoff, 21.5% patients remained on treatment Only one patient discontinued treatment due to an adverse event, considered unrelated to study drug Data cutoff: 05 August 2024 Guo, R. et al., ESMO Congress, 13 Sept 2024
PRT3789-01: Summary of Adverse Events 65 patients were safety evaluable PRT3789 was generally well tolerated; no drug related SAEs or dose limiting toxicities to date Of all adverse events, nausea, decreased appetite and fatigue had the highest incidence Guo, R. et al., ESMO Congress, 13 Sept 2024 Data cutoff: 05 August 2024 Patients receiving at least one dose of PRT3789 ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adverse events, n (%) Patients (N=65) Any adverse event 58 (89.2) Treatment related 37 (56.9) Grade ≥3 adverse event 33 (50.8) Treatment related 3 (4.6) Serious adverse event 19 (29.2) Treatment related 0 Adverse event leading to Dose hold 18 (27.7) Dose reduction 0 Treatment discontinuation 2 (3.1) Death 0 Any dose-limiting toxicity 0 Patients, %
PRT3789-01: Phase 1 Interim PK/PD Findings As expected with a potent degrader, the observed pharmacodynamic effect was more prolonged than pharmacokinetic half-life Increasing doses showed deeper and more prolonged SMARCA2 degradation in the peripheral blood monocytes (PBMCs) of patients PRT3789 showed selective SMARCA2 degradation with minimal observed effect on SMARCA4 levels Preliminary PK data are available from 24mg to 376mg General trend of increases in exposure (Cmax, AUC) with dose were seen Mean concentrations were above SMARCA2 plasma DC50 (21 nM) for approximately 8 hours at 376 mg Mean half-life was 4.7 hours at the 376 mg dose level No accumulation seen with repeat dose administration; consistent with the half-life and once-weekly administration Guo, R. et al., ESMO Congress, 13 Sept 2024 AUC, area under the curve; Cmax, maximum concentration; DC50, half-maximal degradation concentration; PK, pharmacokinetics. C1D8, cycle1 day 8.
PRT3789-01: Phase 1 Interim Clinical Activity Positive correlation observed between tumor shrinkage and a higher level of sustained SMARCA2 degradation Enrollment is now into dose cohort 9 (500 mg QW) Of the 26 NSCLC or esophageal patients with at least one post baseline scan who were evaluable for efficacy, 7 had tumor shrinkage RECIST confirmed partial responses (PRs) were observed in 3 patients (2 esophageal, 1 NSCLC) Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations Tumor shrinkage defined as 5% or greater decrease in sum of longest diameters of target lesions. Guo, R. et al., ESMO Congress, 13 Sept 2024
PRT3789-01: Phase 1 Interim Clinical Activity Guo, R. et al., ESMO Congress, 13 Sept 2024 The median progression free survival for first-line SMARCA4-mutated NSCLC treated with chemo-immunotherapy is 2.7 months1 In this heavily pretreated patient population of SMARCA4-mutated patients, some have demonstrated clinical benefit as measured by prolonged stable disease (SD) and confirmed responses One patient remains on study having been on treatment for more than 1 year 1 Alessi JV, et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2023 Feb 10:S1556-0864(23)00121-1. doi: 10.1016/j.jtho.2023.01.091. PMID: 36775193.
PRT3789-01: Patient Case Study Guo, R. et al., ESMO Congress, 13 Sept 2024 The patient images depicted here are representative of a “classical” patient with SMARCA4 mutations: poorly differentiated, aggressive disease This patient experienced a confirmed PR, with tumor shrinkage in liver lesions and lymph nodes This patient was treated at 283 mg and is ongoing on the trial
PRT3789-01: Key Takeaways Guo, R. et al., ESMO Congress, 13 Sept 2024 These data represent initial proof of concept that selective SMARCA2 degradation can yield anti-tumor activity in certain SMARCA4-mutated cancers
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. LOF = “Loss-of-function”; QW = once weekly; DLT = dose limiting toxicity; NSCLC – non-small cell lung cancer; 2L = second-line What’s Next for PRT3789? ‘3789 Monotherapy Dose Confirmation ‘3789 + KEYTRUDA® ‘3789 Program Priorities: Confirm biologically active dose as monotherapy Further characterize activity in Class 1 (LOF) vs. Class 2 patients at biologically active doses Share initial data on combination with docetaxel Currently enrolling patients in dose escalation cohort 9 (500 mg QW) Backfill cohorts continue to enroll Enriching for NSCLC and esophageal cancer w/ Class I LOF mutations Expecting dose confirmation by YE24 Additional information to be presented at plenary session of Triple Meeting, October 24th, 2024 ‘3789 + Docetaxel Phase 2 pembrolizumab combination trial on track to initiate in 2H 2024 Subject of recent clinical collaboration agreement with Merck Goal is to assess safety and clinical activity in combination Docetaxel combination cohorts continue to enroll Goal is to assess safety and clinical activity in combination Docetaxel is the chemotherapy most often used in 2L+ NSCLC Seeking to improve upon poor outcomes observed with current standard of care
PRT7732: First-in-Class, Highly Selective Oral SMARCA2 Degrader – Phase I Trial Initiated Sub-nanomolar SMARCA2 degradation potency in cell lines Very high selectivity for SMARCA2 over SMARCA4 Good oral bioavailability observed across species supporting once-daily projected human dose Preclinical Assay PRT7732 SMARCA2 Degradation (nM) 0.98 Selectivity: Degradation (SMARCA4 / SMARCA2) >3000 fold Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold ClinicalTrials.gov Identifier: NCT06560645 Patient Population Dose Finding/Expansion PRT7732 Monotherapy SMARCA4-mutated Solid Tumors Backfill Cohorts to Determine Biologically Active Dose and Inform Registration Path Goal: Establish Initial Proof-of-Concept and Identify Biologically Active Dose as Monotherapy
Kris Vaddi, Ph.D., CEO Prelude Therapeutics Incorporated Closing Remarks
Open for Questions Kris Vaddi, PhD Chief Executive Officer Jane Huang M.D. President and Chief Medical Officer Sean Brusky, MBA Chief Business Officer Peggy Scherle, PhD Chief Scientific Officer Bryant Lim, J.D. Chief Legal Officer, Corporate Secretary and Interim CFO
Correlation observed between peripheral blood monocyte (PBMC) and tumor SMARCA2 degradation levels at efficacious doses Increasing doses result in increased reduction in SMARCA2 PD AUC in tumors and were associated with higher efficacy PD Correlates with Efficacy in Preclinical Models In vivo Efficacy Tumor levels from mouse xenograft model and PBMC levels from normal rat after single doses that provide equivalent exposure AUC, area under curve Source: Wang et al. ENA 2023; Data on file SMARCA2 Levels over Time After a Single IV Dose of PRT3789 PD AUC/Efficacy Correlation 50 mg/kg = 243 mg human dose equivalent 75 mg/kg = 365 mg human dose equivalent 100 mg/kg = 487 mg human dose equivalent
Dose Dependent Degradation of SMARCA2, but not SMARCA4 Pharmacodynamic Effect (AUC) Over 1 Week AUC normalized SMARCA2 AUC normalized SMARCA4 Pharmacodynamic Effect (AUC) Over 1 Week SMARCA2 AUC, n 4 4 4 4 9 10 5 3 SMARCA4 AUC, n 3 8 10 5 3
Corporate Presentation September 2024 Exhibit 99.3
Forward Looking Statements This presentation contains “forward-looking” statements within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to, anticipated discovery, preclinical and clinical development activities for Prelude’s product candidates, the potential safety, efficacy, benefits and addressable market for Prelude’s product candidates, the expected timeline for clinical trial results for Prelude’s product candidates including its SMARCA2 degrader molecules. Any statements contained herein or provided orally that are not statements of historical fact may be deemed to be forward-looking statements. In some cases, you can identify forward-looking statements by such terminology as ‘‘believe,’’ ‘‘may,’’ ‘‘will,’’ ‘‘potentially,’’ ‘‘estimate,’’ ‘‘continue,’’ ‘‘anticipate,’’ ‘‘intend,’’ ‘‘could,’’ ‘‘would,’’ ‘‘project,’’ ‘‘plan,’’ ‘‘expect’’ and similar expressions that convey uncertainty of future events or outcomes, although not all forward-looking statements contain these words. Statements, including forward-looking statements, speak only to the date they are provided (unless an earlier date is indicated). This presentation shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or other jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or other jurisdiction. These forward-looking statements are based on the beliefs of our management as well as assumptions made by and information currently available to us. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. If such assumptions do not fully materialize or prove incorrect, the events or circumstances referred to in the forward-looking statements may not occur. We undertake no obligation to update publicly any forward-looking statements for any reason after the date of this presentation to conform these statements to actual results or to changes in our expectations, except as required by law. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. Additional risks and uncertainties that could affect our business are included under the caption “Risk Factors” in our filings with the Securities and Exchange Commission, including our Annual Report on Form 10-K for the year ended December 31, 2023.
We are on a mission to extend the promise of precision medicine to every cancer patient in need Select the best modality to precisely target oncogenic mechanisms Strive for first- or best-in-class and anchor to patient unmet need Draw on decades of experience and proven leadership to drive innovation
Kris Vaddi, PhD Chief Executive Officer Jane Huang M.D. President and Chief Medical Officer Andrew Combs, PhD Chief Chemistry Officer Sean Brusky, MBA Chief Business Officer Peggy Scherle, PhD Chief Scientific Officer Bryant Lim, J.D. Chief Legal Officer, Corporate Secretary and Interim CFO Experienced Leadership Team With Proven Track Records in Precision Oncology
Prelude’s Evolution Strategic Priorities Continue to build SMARCA leadership Generate proof-of-concept data Prepare for global registrational trials Advance SMARCA “Pipeline in a Program” Explore collaborations to accelerate trials and global capabilities ~1 new IND every 12-18 months Successfully advance programs into early clinical development Assembled team to create a highly productive discovery engine Delivered initial wave of first- or potentially best-in-class clinical development candidates: PRMT5i, MCL1i, CDK9i, CDK4/6i, SMARCA2 degraders Continue to grow R&D team while adding key capabilities for future growth Expand global clinical development footprint and capabilities Advance lead clinical development candidates to registrational trials Advancing clinical programs including IV SMARCA2 degrader (PRT3789), oral SMARCA2 degrader (PRT7732) and CDK9 inhibitor (PRT2527) towards PoC Developing SMARCA as ‘Pipeline in Program’ with IV, Oral and ‘Precision ADC’ Approaches 2016 – 2022 2022 – 2025 2025+ Establish Leading Precision Oncology Discovery Engine Expand Development Capabilities, Strategic Focus on SMARCA Advance to Registrational Trials, Demonstrate Value
Prelude’s Precision Medicine Pipeline & Discovery Engine PROGRAM POTENTIAL INDICATIONS DISCOVERY PHASE 1 PHASE 2/3 Lead SMARCA2 Degrader (IV) SMARCA4-mutated NSCLC & other cancers Oral SMARCA2 Degrader SMARCA4-mutated NSCLC & other cancers SMARCA2/4 Precision ADCs* Dose Confirmation by YE2024; Phase 2 Pembrolizumab Combo Trial Start in Q4 2024 UPCOMING MILESTONES Expand SMARCA Portfolio to Address Cancers Without SMARCA4 Mutations Phase I Trial Initiated PRT3789 Next-Gen CDK9 Selective Inhibitor Myeloid and Lymphoid malignancies PRT2527 Interim Phase 1 Data Anticipated in Q4 2024 Discovery Engine Deliver a First- or Best-in-Class New Program Every 12-18 Months Hard-to-treat cancers, “undruggable” targets, high unmet need Precision ADCs* Broad range of cancers (heme & solid tumors) First Program to be Presented at Medical Conference in Q4 2024 Broad range of cancers (heme & solid tumors) * Precision ADCs are the focus of our strategic collaboration with AbCellera PRT7732
Developing an Industry Leading Portfolio of SMARCA-Targeted Precision Medicines SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) Oral SMARCA2 Degrader (PRT7732) Precision ADCs with SMARCA2/4 Degrader Payload
Patients with SMARCA4 mutations are not typically eligible for other targeted therapies Currently treated with standard of care chemotherapy or chemo-immunotherapy Targeting SMARCA4-mutated Cancer By Selectively Degrading SMARCA2 Pancreatic: 3% NSCLC: 10% Esophageal: 8% Gastric: 8% Endometrial: 13% SCLC: 8% Urinary: 9% Colorectal: 6% Dagogo-Jack et al. Journal of Thoracic Oncology. 2020 Foundation Medicine dataset SMARCA4 (BRG1) mutations occur in approximately 5% of all cancers Mutations in the chromatin remodeling complex drive cancer growth and resistance Cancer cells with deleterious SMARCA4 mutations become highly dependent on SMARCA2 for survival Selectively degrading SMARCA2 induces "synthetic lethality" in SMARCA4-deficient cancers
Outcomes for Patients with SMARCA4-mutated NSCLC are Poor with Current Standard of Care Alessi JV, et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2023 Feb 10:S1556-0864(23)00121-1. doi: 10.1016/j.jtho.2023.01.091. PMID: 36775193. Median progression free survival for first-line SMARCA4-mutated NSCLC treated with chemoimmunotherapy is 2.7 months and response rates approximately 22% There is even greater unmet need in second-line and beyond Patients treated with first-line chemoimmunotherapy
PRT3789: A Highly Potent SMARCA2 Degrader with >1000-fold Selectivity Over SMARCA4 Hulse et al. Cancer Res. (2022); 82 (12_Suppl) :3263. AACR 2022: https://preludetx.com/wp-content/uploads/2022/05/Prelude_AACR_Hulse-SMARCA2-FINAL-21Mar2022.pdf Highly selective for SMARCA2 vs SMARCA4 (>1000 fold) and selective across the proteome Preclinical Assay PRT3789 SMARCA2 Degradation (nM) 0.73 Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold Sub-nanomolar SMARCA2 degradation potency in cell lines Anti-tumor activity, including regressions, in SMARCA4 mutant models in vivo PRT3789 Tumor Regression PRT3789 Vehicle Days of Dosing
LOF, loss of function; NSCLC, non-small cell lung cancer PRT3789-01: Study Schema and Enrollment Dose Escalation Cohorts Any Solid Tumor Any SMARCA4 Mutation Evaluable Disease Backfill Cohorts Enriched NSCLC LOF SMARCA4 Mutation Measurable Disease n=2 n=5 n=6 n=8 24 mg n=4 48 mg n=7 80 mg n=5 120 mg n=7 160 mg n=7 212 mg n=5 283 mg n=4 376 mg n=5 500 mg … Phase 1 dose escalation study enrolled patients who had evaluable disease, any solid tumors, and any type of SMARCA4 mutation All patients received PRT3789 intravenously once weekly Patients treated in escalating doses from 24 to 376 mg and backfill cohort patients who had SMARCA4 (Class 1) loss of function mutations Guo, R. et al., ESMO Congress, 13 Sept 2024 Data cutoff: 05 August 2024
65 patients were safety evaluable Primary tumor type was NSCLC (n = 34) patients along with a range of other solid tumors 34 patients had Class 1 loss of function mutations and additional 7 patients had loss of SMARCA4 protein by IHC PRT3789-01: Demographics and Disease Characteristics Guo, R. et al., ESMO Congress, 13 Sept 2024 Characteristics Patients (N=65) Age (years) Median 62.0 Sex, n (%) Male 36 (55.4) Female 29 (44.6) Prior lines of systemic anti-cancer therapy, n Median (min, max) 3 (1, 10) Tumor type, n (%) Non-small cell lung cancer 34 (52.3) Pancreatic cancer 6 (9.2) Breast cancer 4 (6.2) Cholangiocarcinoma 2 (3.1) Colorectal cancer 2 (3.1) Esophageal cancer 2 (3.1) Ovarian cancer 2 (3.1) Other 13 (20.0) Type of SMARCA4 mutation, n (%) Class 1 (loss of function) 34 (52.3) Class 2 (missense, VUS) 24 (36.9) Loss of SMARCA4 protein (BRG1) by IHC 7 (10.8) Data cutoff: 05 August 2024 IHC, immunohistochemistry; VUS, variant of uncertain significance.
PRT3789-01: Patient Disposition As of the data cutoff, 21.5% patients remained on treatment Only one patient discontinued treatment due to an adverse event, considered unrelated to study drug Data cutoff: 05 August 2024 Guo, R. et al., ESMO Congress, 13 Sept 2024
PRT3789-01: Summary of Adverse Events 65 patients were safety evaluable PRT3789 was generally well tolerated; no drug related SAEs or dose limiting toxicities to date Of all adverse events of any grade, nausea, decreased appetite and fatigue had the highest incidence Guo, R. et al., ESMO Congress, 13 Sept 2024 Data cutoff: 05 August 2024 Patients receiving at least one dose of PRT3789 ALT, alanine aminotransferase; AST, aspartate aminotransferase. Adverse events, n (%) Patients (N=65) Any adverse event 58 (89.2) Treatment related 37 (56.9) Grade ≥3 adverse event 33 (50.8) Treatment related 3 (4.6) Serious adverse event 19 (29.2) Treatment related 0 Adverse event leading to Dose hold 18 (27.7) Dose reduction 0 Treatment discontinuation 2 (3.1) Death 0 Any dose-limiting toxicity 0 Patients, %
PRT3789-01: Phase 1 Interim PK/PD Findings As expected with a potent degrader, the observed pharmacodynamic effect is more prolonged than pharmacokinetic half-life Increasing doses show deeper and more prolonged SMARCA2 degradation in the peripheral blood monocytes (PBMCs) of patients PRT3789 showed selective SMARCA2 degradation with minimal observed effect on SMARCA4 levels Preliminary PK data are available from 24mg to 376mg General trend of increases in exposure (Cmax, AUC) with dose were seen Mean concentrations were above SMARCA2 plasma DC50 (21 nM) for approximately 8 hours at 376 mg Mean half-life was 4.7 hours at the 376 mg dose level No accumulation was seen with repeat dose administration; consistent with the half-life and once-weekly administration Guo, R. et al., ESMO Congress, 13 Sept 2024 AUC, area under the curve; Cmax, maximum concentration; DC50, half-maximal degradation concentration; PK, pharmacokinetics. C1D8, cycle1 day 8.
PRT3789-01: Phase 1 Interim Clinical Activity Positive correlation observed between tumor shrinkage and a higher level of sustained SMARCA2 degradation Enrollment is now into dose cohort 9 (500 mg QW) Of the 26 NSCLC or esophageal patients with at least one post baseline scan who were evaluable for efficacy, 7 had tumor shrinkage RECIST confirmed partial responses (PRs) were observed in 3 patients (2 esophageal, 1 NSCLC) Tumor shrinkage was observed in patients with both Class 1 and Class 2 SMARCA4 mutations Tumor shrinkage defined as 5% or greater decrease in sum of longest diameters of target lesions. Guo, R. et al., ESMO Congress, 13 Sept 2024
PRT3789-01: Phase 1 Interim Clinical Activity Guo, R. et al., ESMO Congress, 13 Sept 2024 The median progression free survival for first-line SMARCA4-mutated NSCLC treated with chemo-immunotherapy is 2.7 months1 In this heavily pretreated patient population of SMARCA4-mutated patients, some have demonstrated clinical benefit as measured by prolonged stable disease (SD) and confirmed responses One patient remains on study having been on treatment for more than 1 year 1 Alessi JV, et al. Clinicopathologic and genomic factors impacting efficacy of first-line chemoimmunotherapy in advanced non-small cell lung cancer (NSCLC). J Thorac Oncol. 2023 Feb 10:S1556-0864(23)00121-1. doi: 10.1016/j.jtho.2023.01.091. PMID: 36775193.
PRT3789-01: Patient Case Study Guo, R. et al., ESMO Congress, 13 Sept 2024 The patient images depicted here are representative of a “classical” patient with SMARCA4 mutations: poorly differentiated, aggressive disease This patient experienced a confirmed PR, with tumor shrinkage in liver lesions and lymph nodes This patient was treated at 283 mg and is ongoing on the trial
PRT3789-01: Key Takeaways Guo, R. et al., ESMO Congress, 13 Sept 2024 These data represent initial proof of concept that selective SMARCA2 degradation can yield anti-tumor activity in certain SMARCA4-mutated cancers
KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. LOF = “Loss-of-function”; QW = once weekly; DLT = dose limiting toxicity; NSCLC – non-small cell lung cancer; 2L = second-line What’s Next for PRT3789? ‘3789 Monotherapy Dose Confirmation ‘3789 + KEYTRUDA® ‘3789 Program Priorities: Confirm biologically active dose as monotherapy Further characterize activity in Class 1 (LOF) vs. Class 2 patients at biologically active doses Share initial data on combination with docetaxel Currently enrolling patients in dose escalation cohort 9 (500 mg QW) Backfill cohorts continue to enroll Enriching for NSCLC and esophageal cancer w/ Class I LOF mutations Expecting dose confirmation by YE24 Additional information to be presented at plenary session of Triple Meeting, October 24th, 2024 ‘3789 + Docetaxel Phase 2 pembrolizumab combination trial on track to initiate in 2H 2024 Subject of recent clinical collaboration agreement with Merck Goal is to assess safety and clinical activity in combination Docetaxel combination cohorts continue to enroll Goal is to assess safety and clinical activity in combination Docetaxel is the chemotherapy most often used in 2L+ NSCLC Seeking to improve upon poor outcomes observed with current standard of care
PRT7732: First-in-Class, Highly Selective Oral SMARCA2 Degrader – Phase I Trial Initiated Sub-nanomolar SMARCA2 degradation potency in cell lines Very high selectivity for SMARCA2 over SMARCA4 Good oral bioavailability observed across species supports projected once-daily human dose Assay PRT7732 SMARCA2 Degradation (nM) 0.98 Selectivity: Degradation (SMARCA4 / SMARCA2) >3000 fold Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold ClinicalTrials.gov Identifier: NCT06560645 Patient Population Dose Finding/Expansion PRT7732 Monotherapy SMARCA4-mutated Solid Tumors Backfill Cohorts to Confirm Biologically Active Dose and Inform Registration Path Goal: Establish Initial Proof-of-Concept and Confirm Biologically Active Dose as Monotherapy
Expanding Our Portfolio of SMARCA-Targeted Precision Medicines Precision ADCs with SMARCA2/4 Degrader Payload Cancers with dysregulated SMARCA pathway Independent of SMARCA4 mutation status Initial focus of Prelude/AbCellera collaboration SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) Oral SMARCA2 Degrader (PRT7732)
Together, Prelude and AbCellera Are Creating Novel, First-in-Class Precision ADCs High Unmet Need & Opportunity Potential for Optimized Payload Potential for Optimized Antibody Initial program will link an optimized Prelude SMARCA2/4 dual degrader as a “Precision Payload” to an optimized AbCellera antibody* Prelude’s SMARCA2/4 dual degraders have shown picomolar potency on par with cytotoxics (MMAE) but with potential for a differentiated safety profile Expands the reach of SMARCA degrader technology to cancers without SMARCA4 mutations * Antibody target and tumor type(s) for initial exploration remain undisclosed at this time
Prelude’s SMARCA Portfolio Strategy Addresses a Significant Unmet Need ~195,000 pts/year Up to 19,500 SMARCA4-mutated STAGE IV, FIRST LINE ~130,000 pts/year Up to 13,000 SMARCA4-mutated STAGE IV, SECOND LINE + US & EU5 only (2030 proj.): 1 GlobalData (SEER), Earlier Stage (I-III) includes incidence only, Stage IV includes drug-treated prevalence only, with progression from earlier stages; all three factor-out patients treated with targeted therapies for driver mutations; 2 Datamonitor 2023 Lung Cancer Report; 3 Cerner CancerMpact NSCLC Report 2024 4 Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708. 5 Dagogo-Jack et al. J Thorac Oncol. (2020); 15(5):766-776.; Analysis on File. ~235,000 pts/year Up to 23,500 SMARCA4-mutated EARLIER STAGE (I-III) (Adjuvant / Neo-Adj.) + / Potential Addressable Patient Populations US and EU5 1-5 “Advanced NSCLC” includes patients with Stage IIIB & Stage IV disease1 Excludes patients eligible for other targeted therapy (EGFR, ALK, ROS1, etc.)2 Up to 10% of NSCLC SMARCA4-deficient (includes Class I & II mutations)3,4 Key Assumptions: + / SMARCA4-mutated Cancers Broad Range of Solid Tumors and/or Heme Malignancies TBD based on selected tumors3,4 TBD based on antibody targets / tumor types NSCLC
Highly Selective CDK9 Inhibitor PRT2527
Source: 1) Maiti A et al. Haematologica 2021. https://doi.org/10.3324/haematol.2020.252569 2) Lew TE et al. Blood Advances 2021. https://doi.org/10.1182/bloodadvances.2021005083 Patients with Hematologic Malignancies Refractory to Current Treatments Experience Poor Outcomes After SoC (venetoclax + HMA), AML patients ineligible for intensive therapy have very poor outcomes (mOS of 2.4 months) Double class (BTKi and BCL2i) resistant CLL is another population with high unmet need (mOS of 3-5 months) Median OS 3.6 months (1) AML (2) CLL
CDK9 Inhibition Targets Two Major Validated Pathways (MYC and MCL-1) CDK9 is the primary transcriptional regulator of a major oncogene MYC and an apoptosis inducer MCL-1 Dysregulated pathways involving MYC and MCL-1 drive pathogenesis and resistance in hematologic cancers including lymphoid and myeloid cancers Prior CDK9i therapies have shown significant GI toxicity, likely driven by poor selectivity across the kinome
PRT2527 is a Potent, Highly Selective CDK9 Inhibitor That Depletes MCL-1 and MYC Highly Isoform Selective CDK9 Inhibitor Compound PRT2527 Biochemical* IC50 (nM) CDK9 0.95 Proliferation* IC50 (nM) 18 Plasma* IC50 (nM) 196 Fold Selectivity CDK9 vs Other Isoforms CDK1 73x CDK2 340x CDK3 35x CDK4 250x CDK5 >1000x CDK6 >1000x CDK7 >1000x >100x 10 -100x PRT2527 177 Assays tested 3 Interactions Mapped S-Score(35) = 0.02 PRT2527 Treatment Depletes MCL-1 and MYC Proteins Highly Selective in Kinome pSer2RNAP2 MCL-1 C-MYC C-Cas3 Actin MV4-11 cell line *Internal data; biochemical assay at 1 mM ATP, H929 CTG proliferation assay Presented at ASH 2022; https://preludetx.com/wp-content/uploads/2023/03/ASH-2022_PRT2527-Presentation.pdf
Initial safety and tolerability data for monotherapy dose escalation cohorts in hematologic malignancies Initial assessment of clinical activity in B-cell malignancies as monotherapy Initial clinical data with zanubrutinib from combination cohort *R/R disease following: At least 1 prior systemic therapy for aggressive BCL subtypes, MCL and Richter’s syndrome; At least 2 prior therapies including a BTK inhibitor and venetoclax for CLL. ClinicalTrials.gov Identifier: NCT05665530 Phase 1 Trial of PRT2527 in Hematologic Malignancies is Underway Patient Population* Dose Finding/Expansion Monotherapy PRT2527 Select R/R B-cell, T-cell and myeloid malignancies: Aggressive B-cell lymphoma subtypes, MCL, CLL/SLL including Richter syndrome, AML, and T-cell lymphoma subtypes PRT2527 Combinations What to Expect in Q4 2024 B-cell, T-cell, myeloid malignancies Lymphoid malignancies (combo with zanubrutinib) Myeloid malignancies (combo with venetoclax) Goal: Establish Initial PoC and Identify Mono and/or Combination Recommended Doses for Expansion
Continued Execution Across Strategic Priorities PRT2527 CDK9 Initiate zanubrutinib combination study Initiate myeloid cohort in the existing phase 1 study Complete monotherapy dose escalation in B-cell malignancies Report interim phase 1 clinical results in 2024 PROGRAM Report interim Phase 1 clinical results in 2H 2024 (ESMO) Complete monotherapy escalation and fully enroll backfill cohorts Initiate Phase 2 trial in combination with pembrolizumab PRT3789 Lead IV SMARCA2 Degrader Selective CDK9 Inhibitor PRT2527 Investigational New Drug (IND) authorization from FDA Initiate Phase 1 in patients with SMARCA4 mutations Report interim Phase 1 clinical results PRT7732 Oral SMARCA2 Degrader Discovery Engine Precision ADCs & Other Advance next first-in-class, novel small molecule discovery candidate Advance first SMARCA2/4 Precision ADC in partnership with AbCellera Advance second Precision ADC program in partnership with AbCellera EXPECTED DELIVERABLE MILESTONE Complete YE 2024 Q4 2024 Complete Complete 2025 Complete Complete 2H 2024 Q4 2024 2024 2025 2025 Cash, Cash Equivalents of $179.8 Million as of 6/30/2024
Thank You Contact Us: Robert Doody SVP, Investor Relations rdoody@preludetx.com
Highly Selective SMARCA2 Degrader Program Additional PK/PD Data on PRT3789 Discovery Effort & Oral Degrader Program Preclinical Rationale for Combinations Current Treatment Paradigm & Testing Landscape Precision ADCs CDK9 APPENDIX
Correlation observed between peripheral blood monocyte (PBMC) and tumor SMARCA2 degradation levels at efficacious doses Increasing doses resulted in increased reduction in SMARCA2 PD AUC in tumors and were associated with higher efficacy PD Correlates with Efficacy in Preclinical Models In vivo Efficacy Tumor levels from mouse xenograft model and PBMC levels from normal rat after single doses that provide equivalent and efficacious exposure AUC, area under curve Source: Wang et al. ENA 2023; Data on file SMARCA2 Levels over Time After a Single IV Dose of PRT3789 PD AUC/Efficacy Correlation 50 mg/kg = 243 human dose equivalent 75 mg/kg = 365 mg human dose equivalent 100 mg/kg = 487 mg human dose equivalent
When it Comes to Targeting SMARCA2, Degraders Offer Distinct Advantages Inhibitors Degraders Potency High Selectivity Extended PD Oral Bioavailability X X Early attempts at achieving both potency and selectivity with inhibitor approaches had challenges Inhibitors do not degrade the target and need to be dosed at levels that retain IC90 coverage continuously Degraders demonstrate sustained PD effect as it takes 48-72h for SMARCA2 to resynthesize
Selectively Targeting SMARCA2 Has Been a Significant Challenge for Industry Selective SMARCA2 Inhibition is an Unmet Medicinal Chemistry Challenge Bromodomain Binders Non-selective and inactive in SMARCA4 mutated cancer cells1 ATPase Inhibitors Inhibitors show low selectivity for SMARCA2 in cell proliferation assays (<10 fold2 and ~33 fold3) ATPase domain Prelude’s Targeted Protein Degradation (TPD) Approach SMARCA2 Selective Degradation is possible through differences in ternary complexes and subsequent ubiquitination of unique lysine residues 1 Vangamudi et al, Cancer Res. 2015 (Pfizer); Taylor et al J. Med. Chem 2022 (Genentech) 2 Papillon et al, J. Med. Chem 2018 (Novartis) 3 AACR 2024 (Foghorn/Lilly)
Prelude Scientists Solved the SMARCA2 Selectivity Enigma PRT3789 (IV or SC formulation) PRT7732 (Oral Candidate) Parallel VHL- and CRBN-based SMARCA2 Degrader Programs IV or SC Candidate - VHL-TPDs provided an expedited path to potential clinical development with QW dosing Oral Candidate - CRBN-TPDs provided oral candidates, but required extensive lead optimization with balancing of potency, selectivity and oral PK properties Our lead IV and oral clinical candidates both have sub-nanomolar degradation potencies and very high selectivity (>1000 fold) for SMARCA2 over SMARCA4
Our SMARCA2 Oral Degrader Program Progressed Rapidly and Systematically Confidential Solving for potency, selectivity and oral bioavailability was a challenge PRT7732: Lead Oral Candidate with >3000-fold Selectivity A and B: Two additional structurally distinct oral back-up candidates 0.1 1.0 10 100 1000 SMARCA 2 HeLa HiBit DC50 (nM) PRT7732 SMARCA2 HiBit DC50 & SMARCA4 Selectivity A B *Inactive & weakly potent compounds removed for clarity Program Progression
Tertiary Complex of SMARCA2/ PRT7732/CRBN-DDB1 E3 Ligase PRT7732 binds to the SMARCA2 bromodomain and CRBN/DDB1 E3 ligase complex PRT7732 has been shown to catalyze the polyubiquitination of unique lysine residues expressed only in SMARCA2 and not SMARCA4 Unique conformational bias promotes selective ubiquitination and degradation of SMARCA2 PRT7732: Our Lead Oral SMARCA2 Degrader Source: Shvartsbart, K. Ito et al., AACR Poster, April 2024. Available here: Preclinical Characterization Of PRT7732: A Highly Potent, Selective, And Orally Bioavailable Targeted Protein Degrader Of SMARCA2
PRT7732 is Highly Potent and Orally Bioavailable With Near-Absolute Selectivity for SMARCA2 Near-absolute cellular selectivity for SMARCA2 vs SMARCA4 (>3000 fold) in HiBit cell lines and >1000-fold in cell proliferation assays Sub-nanomolar SMARCA2 degradation potency * Based on highest concentration tested Source: Shvartsbart, K. Ito et al., AACR Poster, April 2024. Available here: Preclinical Characterization Of PRT7732: A Highly Potent, Selective, And Orally Bioavailable Targeted Protein Degrader Of SMARCA2 Good oral bioavailability observed across species supporting once-daily projected human dose Preclinical Assay PRT7732 SMARCA2 Degradation (nM) 0.98 Selectivity: Degradation (SMARCA4 / SMARCA2) >3000 fold Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold*
PRT7732 Has Significant Anti-Tumor Activity in SMARCA4-Deficient Cancer Xenograft Models Daily oral administration of PRT7732 demonstrates anti-tumor activity in SMARCA4-deficient but not SMARCA4 wild type tumors PRT7732 rapidly decreases SMARCA2 protein levels in tumor xenograft models at low doses Preclinical data supported advancing PRT7732 to Phase I with once-daily dosing Source: Shvartsbart, K. Ito et al., AACR Poster, April 2024. Available here: Preclinical Characterization Of PRT7732: A Highly Potent, Selective, And Orally Bioavailable Targeted Protein Degrader Of SMARCA2
PRT3789 Demonstrates Potential for Synergy with Chemotherapy and Apoptosis-Inducing Agents AACR 2022, 2023 BUB1B, CCNA2/B2, CDC25C, CDK1/2, CHEK1/2 FEN1, LIG1, MCM, PCNA, POLA1/2, POLD1/2/3, POLE/2/3 Docetaxel Gemcitabine Several oncogenic gene sets regulated by PRT3789 Supports combination strategies with both cytotoxic and apoptosis-inducing agents (e.g., RAS) In vivo CDX models show strong tumor regression in combination with gemcitabine or docetaxel
PRT7732 Also Shows High Potential for Synergy With Other Common Anti-Cancer Agents Oral daily administration of PRT7732 1 mg/kg in combination with nab-paclitaxel (Abraxane®) induces tumor regression in the NCI-H838 tumor model in mice Source: Shvartsbart, K. Ito et al., AACR Poster, April 2024. Available here: Preclinical Characterization Of PRT7732: A Highly Potent, Selective, And Orally Bioavailable Targeted Protein Degrader Of SMARCA2
SMARCA2 Degraders May Also Help to Potentiate PD1/PDL1 Immunotherapy Confidential Add figure Increased antigen processing “Turning Cold Tumors Hot?” In SMARCA4-deficient cancer cell lines, SMARCA2 degradation… + SMARCA2 Degrader Upregulates antigen processing and presentation machinery Increases cytokine production Promotes T-cell activity and accelerates tumor cell killing Induces presentation of unique MHC-I peptide Increased IFN-γ production Increased T cell activity Anti-PD1 checkpoint blockade
Preclinical Data for PRT3789 Support Rationale for Anti-PD1 Combination Fluorescently labeled tumor cells + PRT3789 + T-cells + T-cells + PRT3789 SMARCA2 Degrader + Anti-PD1 Demonstrates Tumor Regression In Vivo PRT3789 Increases IFN-g Levels in Combination with anti-PD1 In Vitro PRT3789 Upregulates Genes for Antigen Processing and Presentation PRT3789 Promotes T-cell mediated Tumor Cell Killing In Vitro TAP1/2, HLA-A/C/G/F, B2M Anti-PD1 ENA 2023; data on file
Prelude to Initiate Phase 2 Combination Study of PRT3789 + Pembrolizumab in Q4 2024 PRT3789 upregulates genes encoding antigen processing and presentation machinery Trial will explore safety and anti-tumor activity of the combination Preclinical rationale supportive of enhanced efficacy with PRT3789 and anti-PD1 therapy combination KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.
Majority of Advanced NSCLC Patients Currently Treated with Chemoimmunotherapy Advanced NSCLC Diagnosis (Stage IIIB or IV) Actionable Mutation Identified No Actionable Mutation Identified KRAS, MET, ERBB2, BRAF, ROS, RET, Others EGFR ALK ICI +/- Chemo Chemoimmunotherapy PDL1 > 50% PDL1 < 50% Note: Simplified schematic based on current ESMO and NCCN Clinical Practice Guidelines and current clinical experience * Could include combination treatments with bevacizumab, pemetrexed, nab-paclitaxel and others
SMARCA has the Potential to Significantly Expand Precision Medicine for Even More NSCLC Patients Percent of Total Advanced NSCLC Patients Treated (FUTURE STATE) MET, ERBB2, BRAF, ROS, RET, Others EGFR ALK KRAS SMARCA Chemo +/- Immunotherapy Precision Medicines ILLUSTRATIVE Potentially more patients than ALK, MET, BRAF, ROS and RET combined 1 1 Based on mutational prevalence; Source for current relative patient share: Datamonitor 2023 Lung Cancer Report Reinforces need for comprehensive genomic profiling More patients tested = More patients eligible SMARCA4 mutations already included on most commonly used commercial NGS testing panels
Highly Selective SMARCA2 Degrader Program Additional PK/PD Data on PRT3789 Discovery Effort & PRT7732 Preclinical Data Preclinical Rationale for Combinations Current Treatment Paradigm & Testing Landscape Precision ADCs CDK9 APPENDIX
Together, Prelude and AbCellera are Creating Novel, First-in-Class Precision ADCs Multi-year global collaboration to jointly discover, develop and commercialize novel Precision ADCs for up to five programs AbCellera will lead manufacturing activities Prelude will lead clinical development and global commercialization (AbCellera co-promote option) Expertise in chemistry and biology of targeted protein degradation and clinical development capabilities Expertise in antibody discovery, engineering and manufacturing capabilities +
Framework for Precision ADC Differentiation Antibody Differentiation Off-the-shelf / approved mABs Novel, differentiated, highly engineered mABs Payload-Linker Differentiation Broadly cytotoxic (e.g. DM1, MMAE) Traditional ADCs Precision ADCs Current ADCs deliver highly potent cytotoxics to cells expressing selected cell surface antigens Molecularly targeted inhibitor/degrader “Targeted Times Two” Key attributes to optimize : Antigen and Payload dual selectivity to precisely target only desired cancer types Payload potency, selectivity, and half-life to limit off-target toxicities Linker stability / cleavability Additional patient selection factors based on payload characteristics/MOA Key attributes to optimize: Antigen selectivity and binding characteristics Internalization DAR (Drug-Antibody Ratio)
Highly Selective SMARCA2 Degrader Program Additional PK/PD Data on PRT3789 Discovery Effort & PRT7732 Preclinical Data Preclinical Rationale for Combinations Current Treatment Paradigm & Testing Landscape Precision ADCs CDK9 APPENDIX
PRT2527 is Highly Efficacious In Vivo in Models of Hematologic Malignancies Monotherapy Karpas-422 (Double Hit DLBCL) MV4-11 (AML) Combination TMD-8 (ABC DLBCL) OCI-AML3 (VenR AML) Presented at ASH 2022; https://preludetx.com/wp-content/uploads/2023/03/ASH-2022_PRT2527-Presentation.pdf; Data on file
Favorable tolerability with manageable neutropenia and absence of significant gastrointestinal events or hepatotoxicity Dose-dependent downregulation of CDK9 transcriptional targets – MYC and MCL-1 mRNA expression in PBMCs isolated from treated patients 12 mg/m2 QW dosing and higher showed optimal target inhibition Overall safety profile observed in this study supported further development of PRT2527 in hematologic malignancies (NCT05665530) Initial Phase 1 Study of PRT2527 in Solid Tumors Evaluated Both Safety and PK/PD Properties Source: Patel, MR et al., AACR-NCI-EORTC 2023, Poster C164 PRT2527-Associated Inhibition of CDK9 Transcriptional Targets MYC (A), MCL1 (B) in PBMCs Note: The dotted line represents pre-dose baseline levels. ClinicalTrials.gov Identifier: NCT05159518