false000167866000016786602024-06-122024-06-12
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): June 12, 2024
Prelude Therapeutics Incorporated
(Exact Name of Registrant as Specified in its Charter)
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Delaware |
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001-39527 |
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81-1384762 |
(State or other jurisdiction of
incorporation or organization) |
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(I.R.S. Employer
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175 Innovation Boulevard Wilmington, Delaware |
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19805 |
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Registrant’s telephone number, including area code: (302) 467-1280
Not Applicable
(Former Name or Former Address, if Changed Since Last Report)
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:
☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
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Common Stock, $0.0001 par value per share |
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PRLD |
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Nasdaq Global Select Market |
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 7.01 Regulation FD Disclosure.
The Company has prepared a corporate presentation with information about the Company. A copy of the corporate presentation materials to be used by management is attached as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
On June 12, 2024, the Company will make available to the public an educational video series on SMARCA degraders via a link on the Investor Relations section of the Company's website, investors.preludetx.com. The slides that will accompany the presentation are attached as Exhibit 99.2 to this Current Report on Form 8-K and is incorporated herein by reference.
The information in this Current Report on Form 8-K is being furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section and shall not be deemed to be incorporated by reference into any filing of the Company under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly set forth by specific reference in such filing.
Website addresses are included as inactive textual references only. The information contained on the website referenced herein is not incorporated into this Current Report on Form 8-K. Important information may be disseminated initially or exclusively via the Company’s investor website; investors should consult the site to access this information.
Item 9.01 Financial Statements and Exhibits.
(d) Exhibits
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: June 12, 2024 |
By: |
/s/ Bryant Lim |
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Bryant Lim |
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Chief Legal Officer, Corporate Secretary, and Interim Chief Financial Officer |
Corporate Presentation June 2024
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 proof-of-concept data and 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). 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, 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
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 first wave of first- or potentially best-in-class clinical development candidates: PRMT5i, MCL1i, CDK9i, CDK4/6i, SMARCA2 degrader 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 SMARCA2 degrader (PRT3789) 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
Kris Vaddi, PhD Founder & 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 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* Phase I Initial Proof-of-Concept Data in 2H 2024 UPCOMING MILESTONES Expand SMARCA Portfolio to Address Cancers Without SMARCA4 Mutations Phase I Start Anticipated in 2H 2024 PRT3789 Next-Gen CDK9 Selective Inhibitor Myeloid and B-cell malignancies PRT2527 Phase I Initial Proof-of-Concept Data in 2H 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) Co-Develop Up to 5 Novel Precision ADCs Broad range of cancers (heme & solid tumors) Highly selective, brain-penetrant CDK4-biased inhibitor (PRT3645) available for partnering * Precision ADCs are the focus of our strategic collaboration with AbCellera PRT7732
Prelude’s First-in-Class, Highly Selective SMARCA2 Degraders PRT3789 (IV) and PRT7732 (Oral) Click Here to Access Prelude’s Educational Video Series on SMARCA2 Degraders
Over half of SMARCA4 mutations are Class I loss of function / deleterious mutations (>5% of NSCLC) SMARCA4 mutations are associated with aggressive disease and poor prognosis across a range of cancers Patients with SMARCA4 mutations are not typically eligible for other targeted therapies Currently treated with standard of care chemotherapy or chemo-immunotherapy SMARCA4 Mutations Occur in ~10% of All NSCLC and to Varying Degrees Across Other Cancers Pancreatic: 3% NSCLC: 10% Esophageal: 8% Gastric: 8% Endometrial: 13% SCLC: 8% Urinary: 9% Colorectal: 6% 1,Dagogo-Jack et al. Journal of Thoracic Oncology. 2020 Foundation Medicine dataset 2 Fernando et al. Nature Communications 2020 SMARCA4 mutations are mostly non-overlapping with other “druggable” mutations
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 (attached). Response rates are less than 25% and expected median PFS is less than 3 months in first line setting Even greater unmet need in 2nd line where fewer effective treatment options are available Patients treated with first-line chemoimmunotherapy
Selective Targeting of SMARCA2 is an Attractive Approach to Treat SMARCA4 Mutated Cancers Mutations in the chromatin remodeling complex drive cancer growth and resistance Cancer cells with SMARCA4 mutations become highly dependent on SMARCA2 for survival Selectively degrading SMARCA2 induces "synthetic lethality" in SMARCA4-deficient cancers High selectivity for SMARCA2 has been challenging because of its high similarity to SMARCA4 SMARCA: SWI/SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A. SMARCA2 is also known as “BRM” // SMARCA4 is also known as “BRG1”
PRT3789 Solved the Selectivity Enigma With a >1000 fold Selective Degrader 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 Assay PRT3789 SMARCA2 Degradation (nM) 0.73 Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold Sub-nanomolar SMARCA2 degradation potency and tumor regressions in SMARCA4-mutant PDX models PRT3789 Industry’s first initial clinical proof-of-concept data anticipated in 2024 Phase I dose escalation underway with no dose limiting toxicities observed to date Tumor Regression PRT3789 Vehicle Days of Dosing
Initial safety and tolerability data for monotherapy dose escalation cohorts (any solid tumor with any SMARCA4 mutation) Early look at pharmacokinetic profile and pharmacodynamic effects Initial review of monotherapy clinical activity across different tumor types at escalating doses * Includes any mutation (Class I or Class II), including participants with SMARCA4 loss-of-function mutation ** Backfill cohorts enriched for NSCLC patients and enrollment of SMARCA4 deleterious mutations ClinicalTrials.gov: NCT05639751; ESMO 2023: https://preludetx.com/wp-content/uploads/2023/10/Dagogo-Jack_ESMO-2023_PRT3789-01-TiP-Poster_Final_9Oct2023.pdf PRT3789: Phase 1 Study Underway, Now Enrolling Backfill and Combo Escalation Cohorts Study Population Advanced, recurrent, or metastatic disease in solid tumors with any SMARCA4 mutation* Dose Escalation + Backfill Cohorts Monotherapy PRT3789 Dose Escalation (Initiated 2Q 2023) Combination PRT3789 + docetaxel Dose Escalation (Initiated 1Q 2024) Backfill Cohorts** (Initiated 1Q 2024) + What to Expect in 2H 2024 Goal: Establish Initial PoC and Identify Mono and Combination Recommended Doses for Expansion
Next Steps for Development of PRT3789 and Future Directions Full Phase I Trial Results: 2025 Full safety and tolerability data for monotherapy dose escalation, backfill, and chemotherapy combination cohorts Assessment of PK profile and PD effects to support recommended expansion/Phase 2 dose Assessment of clinical activity and ORR for a lead indication at the RDE/RP2D Engagement with regulators on potential registrational trial pathways Future Directions Further evaluation of potential of PRT3789 in combination with both chemotherapy and immunotherapy Potential for use in earlier lines of therapy and potentially early-stage disease as adjuvant or neo-adjuvant therapy Generate evidence across additional tumor types for patients with SMARCA4 mutations
Expanding Our Portfolio of SMARCA-Targeted Precision Medicines SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) Oral SMARCA2 Degrader (PRT7732) Expands access for advanced NSCLC patients (first-line) Enables use in earlier stage disease (adjuvant / neo-adjuvant) Provides optionality across other SMARCA4-mutated cancers Precision ADCs with SMARCA Degrader Payload
PRT7732: First-in-Class, Highly Selective Oral SMARCA2 Degrader Advancing to Clinic Sub-nanomolar SMARCA2 degradation potency Very high selectivity (>1000 fold*) for SMARCA2 over SMARCA4 Good oral bioavailability across species On track to initiate Phase I testing in 2H 2024 * Based on highest concentration tested in cell proliferation assays 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 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 support 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
Expanding Our Portfolio of SMARCA-Targeted Precision Medicines Precision ADCs with SMARCA Degrader Payload Cancers with dysregulated SMARCA pathway Independent of SMARCA4-mutation status Initial focus of AbCellera collaboration SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) Oral SMARCA2 Degrader (PRT7732)
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 +
Prioritizing Initial Precision ADC Programs Based on Patient Unmet Need and Scientific Rationale 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 ~220,000 pts/year Up to 22,000 SMARCA4-mutated FIRST LINE ~150,000 pts/year Up to 15,000 SMARCA4-mutated SECOND LINE + 1 US & EU5 only: Journal of Thoracic Oncology (US, 2021): https://doi.org/10.1016/j.jtho.2021.01.485; Globocan (EU5); 2 Datamonitor 2023 Lung Cancer Report; Analysis on File 3 Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708. 4 Dagogo-Jack et al. J Thorac Oncol. (2020); 15(5):766-776. ~270,000 pts/year Up to 27,000 SMARCA4-mutated EARLIER STAGE (Adjuvant / Neo-Adj.) + / Potential Addressable Patient Populations US and EU5 1-4 “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 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
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
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 2H 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 initial heme phase 1 clinical results at major medical meeting PROGRAM Initiate docetaxel combination study cohort Report initial Phase 1 clinical results at major medical meeting Complete monotherapy escalation and fully enroll backfill cohorts PRT3789 Lead IV SMARCA2 Degrader Selective CDK9 Inhibitor PRT2527 IND filing Initiate Phase 1 in patients with SMARCA4 mutations 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 DELIVERABLE MILESTONE Complete 2H 2024 Mid-2024 Mid-2024 2H 2024 Complete Complete 2H 2024 2H 2024 2024 2025 2025 Cash, Cash Equivalents of $201.9 Million as of 3/31/2024
Thank You Contact Us: ir@preludetx.com
Highly Selective SMARCA2 Degraders
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 proof-of-concept data and 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). 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, 2023.
There is high unmet need in SMARCA4-mutated NSCLC (up to 10% of patients) These mutations are prevalent across a range of other cancers as well SMARCA2 is a promising new “synthetic lethal” target for these patients Targeting SMARCA2 is very challenging; selectivity over SMARCA4 is critical With PRT3789, our lead SMARCA2 degrader, Prelude scientists solved the selectivity challenge >1000-fold Industry-first clinical data validating this approach is coming soon Prelude’s first-in-class oral SMARCA2 degrader (PRT7732) and Precision ADCs further expand potential impact for patients Learning Objectives
Learning Modules Topic Presenter Advancing Our Understanding of SMARCA Science Dr. Timothy Yap, MDACC Discovery Deep Dive: Targeting SMARCA2 Andrew Combs & Peggy Scherle Clinical Experience with SMARCA4-mutated NSCLC Dr. Adam Schoenfeld, MSKCC Clinical Development Plan and Future Directions Dr. Jane Huang Prelude Portfolio Strategy & Closing Remarks Kris Vaddi
We are on a mission to extend the promise of precision medicine to every cancer patient Follow the science and select the best modality to solve the problem Strive for first- or best-in-class and anchor to patient unmet need Draw on decades of experience and collaboration to drive innovation 5
Our scientific leadership has deep experience in precision oncology Kris Vaddi, PhD Founder & Chief Executive Officer Andrew Combs, PhD Chief Chemistry Officer Peggy Scherle, PhD Chief Scientific Officer Jane Huang M.D. President & Chief Medical Officer Clinical Discovery All trademarks are property of their respective owners
High unmet need in SMARCA4-mutated NSCLC A selective SMARCA2 degrader has the potential to transform outcomes for these patients 1 Response Rate and Survival Data: Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708 2 Second line estimates based on docetaxel label and clinical experience Chemoimmunotherapy1 < 12 months < 25% mOS ORR Chemotherapy2 < 8 months < 15% mOS ORR FIRST LINE SECOND LINE The prognosis for SMARCA4-mutated NSCLC patients is poor
We are developing the industry’s leading SMARCA-targeted pipeline PROGRAM POTENTIAL INDICATIONS DISCOVERY PHASE 1 PHASE 2/3 Lead SMARCA2 Degrader PRT3789 Patients with SMARCA4-deficient advanced NSCLC and other cancers Oral SMARCA2 Degrader PRT7732 Patients with SMARCA4-deficient NSCLC and other cancers SMARCA “Precision ADCs” (aka “DACs”) First Interim Phase I Data in 2H 2024 UPCOMING MILESTONES Expand portfolio to target >90% of cancers without SMARCA4 mutations File IND in 1H 2024; Phase I Start in 2024 + Full pipeline includes programs against other cancer targets in active clinical or preclinical development Solid tumors & heme malignancies not addressed by selective SMARCA2 degraders +
Dr. Timothy Yap, University of Texas MD Anderson Cancer Center Advancing our Understanding of SMARCA Science
Learning Objectives Why has SMARCA garnered such interest as a target for cancer research? What is the function of SMARCA2 and SMARCA4 in healthy cells? How do SMARCA4 mutations and alterations contribute to tumorigenesis? How does selectively targeting SMARCA2 result in cancer cell death? Why has targeting SMARCA2 been so challenging for researchers?
Chromatin Remodeling (CR) is an essential step in DNA replication, repair and gene expression Chromatin Remodeling (CR) Complex (aka SWI/SNF) Unwinds Chromatin ATP-Dependent > 20 Subunits SMARCA: SWI/SNF-related, Matrix-associated, Actin-dependent Regulator of Chromatin, subfamily A.
SMARCA2 and SMARCA4 are highly related, interchangeable ATPase subunits SMARCA2 and SMARCA4 work in a complementary manner Regulate gene expression and cell proliferation Only one or the other is engaged at any given time SMARCA2 is also known as “BRM” SMARCA4 is also known as “BRG1”
More than 20% of all human cancers harbor mutation(s) in at least one of the CR subunits Shain AH, Pollack JR (2013) The Spectrum of SWI/SNF Mutations, Ubiquitous in Human Cancers. PLoS ONE 8(1): e55119 Mutations in the CR complex lead to cancer growth, resistance and poor prognosis Implicated across a wide range of cancers Challenging proteins to target for drug discovery Most frequent * Average frequency of subunit mutation across 18 distinct neoplasms tested CR Complex Mutations* Less frequent Rarely mutated
SMARCA4 mutations occur in ~10% of all NSCLC and to varying degrees across other cancers 1,Dagogo-Jack et al. Journal of Thoracic Oncology. 2020 Foundation Medicine dataset Pancreatic: 3% NSCLC: 10% Esophageal: 8% Gastric: 8% Endometrial: 13% Squamous cell lung: 8% Urinary: 9% Colorectal: 6% Mostly non-overlapping with other “druggable” mutations Types of mutations: Class I (Loss-of-function) Class II (Missense, other)
When SMARCA4 is mutated, tumors become reliant on SMARCA2 for growth and survival SMARCA4-mutated cancers become reliant on SMARCA2 In these cancers, when SMARCA2 is depleted, the CR complex no longer functions Cells can no longer survive and tumors regress “Synthetic Lethality”
Selectively knocking out SMARCA2 induces synthetic lethality in SMARCA4-mutated cancers SMARCA4-mut cancer cells Hoffman GR et al. PNAS (2014); 111 (8): 3128-3133 Vangamudi et al. Cancer Res (2015); 75 (18): 3865-3878. SMARCA4-mut cancer model SMARCA2 gene knockdown shows tumor growth inhibition in SMARCA4-mutated cancers … but NOT in SMARCA4 wild-type cancers SMARCA4 WT cancer cells SMARCA4 WT cancer model
Selective SMARCA2 targeted treatments could have utility treating SMARCA4-mutated cancers Selectively targeting SMARCA2 should induce tumor regression in SMARCA4-mutated cancers In healthy tissue, SMARCA4 should compensate for selectively depleted SMARCA2 If both are depleted, there would likely be adverse effects Selectivity is critical
SMARCA2/4 dual degraders show rapid tumor regressions, but may cause unacceptable toxicity Prelude Data on File. Presented at 6th TPD Summit, 2023 SMARCA2/4 dual degraders showed rapid cell death and tumor regression However, dual degraders also showed toxicity, body weight changes and shorter survival Selectivity is key for a better therapeutic window Rapid cell death and tumor regression … but with unacceptable toxicity in animal models
Achieving SMARCA2 selectivity has been a challenge for industry, until recently Hard to achieve selectivity with inhibitors to the ATPase active site Recent advances in targeted protein degrader technology allows for both potency and selectivity Once “undruggable” target now in human clinical trials
Targeting SMARCA2 represents an important new field of cancer research Mutations in the Chromatin Remodeling (CR) complex drive cancer growth and resistance SMARCA4 mutations are present in up to 10% of all NSCLC and across other cancers Cancer cells with loss of SMARCA4 expression through mutations or alteration are highly dependent on SMARCA2 for survival Selective SMARCA2 degraders have the potential to induce "synthetic lethality" in SMARCA4-mutated cancers Discovering new agents with high selectivity for SMARCA2 is critical Key Takeaways
Andrew Combs, Ph.D. Chief Chemistry Officer Prelude Therapeutics Discovery Deep Dive: Prelude’s Lead SMARCA2 Degrader (PRT3789) Peggy Scherle, Ph.D. Chief Scientific Officer Prelude Therapeutics
Learning Objectives Why has SMARCA2 selectivity been so hard to achieve? How did Prelude succeed? Why are we so excited about the profile and potency of our lead program, PRT3789?
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)
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 ~72h for SMARCA2 to resynthesize
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
PRT3789 Presented at AACR 2023; https://preludetx.com/wp-content/uploads/2023/05/Ito_SMARCA2_AACR-2023_Poster_6277_01MAY23_CORRECTION.pdf Tertiary Complex of SMARCA2/ PRT3789/VHL E3 Ligase Hulse et al. Cancer Res. (2022); 82 (12_Suppl) :3263. PRT3789 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 only SMARCA2 PRT3789: Our Lead SMARCA2 Degrader
PRT3789 is highly potent and highly selective Presented at AACR 2022; https://preludetx.com/wp-content/uploads/2022/05/Prelude_AACR_Hulse-SMARCA2-FINAL-21Mar2022.pdf High selectivity across the proteome Highly selective for SMARCA2 vs SMARCA4 (>1000 fold) Assay PRT3789 SMARCA2 Degradation (nM) 0.73 Selectivity: Cell Proliferation (SMARCA4 / SMARCA2) >1000 fold Sub-nanomolar SMARCA2 degradation potency
PRT3789 induces synthetic lethality in SMARCA4-deficient cancer cells in vitro 1. Data on file. 2. Hulse et al. Cancer Res. (2022); 82 (12_Suppl) :3263. PRT3789 selectively inhibits SMARCA4 deficient cancer cell proliferation in vitro None or limited response in SMARCA4 WT and SMARCA2/4 dual loss cancer cells >1000x selectivity in cell proliferation assays
PRT3789 demonstrates selective tumor regression in vivo 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 PK/PD - Highly Selective for SMARCA2 Degradation SMARCA2 Actin Veh 8h 24h SMARCA4 Hours after dosing Robust Tumor Growth Inhibition of SMARCA4 mutated but not WT Xenograft SMARCA4 WT SMARCA4 mutant
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
SMARCA degraders may also have synergy with and 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
PRT3789 was the industry’s first selective SMARCA2 degrader to enter the clinic SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) Highly potent, selective degrader with once-weekly IV dosing Phase 1 trial underway, advancing well in clinic Generally well tolerated with no dose limiting toxicities observed to date Synergy with chemotherapy and immunotherapy Oral SMARCA2 Degrader (PRT7732)
We solved SMARCA2 selectivity challenge >1000 fold Targeting SMARCA2 has been challenging due to the high homology between SMARCA2 and SMARCA4 We have identified both IV and oral candidates with sub-nanomolar degradation potencies and high selectivity for SMARCA2 over SMARCA4 Our lead program, PRT3789, is the first selective SMARCA2 degrader to enter clinical development Preclinical data for ‘3789 shows significant tumor regression in animal models, favorable safety, and high potential for chemoimmunotherapy synergy Key Takeaways
Andrew Combs, Ph.D. Chief Chemistry Officer Prelude Therapeutics Discovery Deep Dive: Prelude’s Oral SMARCA2 Degrader (PRT7732) Peggy Scherle, Ph.D. Chief Scientific Officer Prelude Therapeutics
Learning Objectives What is the status of our oral SMARCA2 degrader program, and lead oral candidate PRT7732? Where is the science leading us next to further expand the reach of our SMARCA portfolio for patients?
Our SMARCA2 oral degrader program has 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 across species 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 inhibits growth of SMARCA4-deficient tumors but not SMARCA4 WT tumors 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 decreases SMARCA2 protein levels in NCI-H838 tumor tissues
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
Expanding our portfolio of SMARCA-targeted therapeutics SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) SMARCA Degrader-Antibody Conjugates (“DACs”) Oral SMARCA2 Degraders (PRT7732)
Prelude is continuing to lead the field Our lead oral SMARCA2 degrader PRT7732 shows >3000-fold selectivity and a PK/PD profile supporting a low-mg once daily projected human dose PRT7732 is advancing to Phase I in 2H 2024 SMARCA Degrader-Antibody-Conjugates (“DACs”) have potential to dramatically expand the reach of this platform, including patients without SMARCA4 mutations Key Takeaways
Clinical Experience with SMARCA4-mutated NSCLC Dr. Adam Schoenfeld Memorial Sloan Kettering Cancer Center
Learning Objectives How is SMARCA4-mutated advanced NSCLC treated today? What has been our clinical experience in treating these patients? Where would a SMARCA2 degrader fit in clinical practice? How could it change SoC? Where is the unmet need greatest in the treatment of advanced NSCLC?
SMARCA4 mutations occur in ~10% of all NSCLC and to varying degrees across other cancers 1,Dagogo-Jack et al. Journal of Thoracic Oncology. 2020 Foundation Medicine dataset Pancreatic: 3% NSCLC: 10% Esophageal: 8% Gastric: 8% Endometrial: 13% Squamous cell lung: 8% Urinary: 9% Colorectal: 6% Types of mutations: Class I (Loss-of-function) Class II (Missense, other)
SMARCA4 mutations are sometimes concurrent with other driver oncogenes Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708. Most Frequent Co-Occurring Mutations Distribution of SMARCA4 Mutation by Commonly Altered Gene Subgroup
Majority of advanced NSCLC patients are 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 at MSKCC All trademarks are property of their respective owners
SMARCA4-mutated NSCLC patients have significantly worse prognosis 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 (attached).
Impact of SMARCA4 mutations on clinical outcomes for NSCLC patients Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708. Class 1 Alterations* Likely oncogenic/oncogenic variants Key Eligibility: Patients with SMARCA4 alteration on MSK-IMPACT SMARCA4 IHC was performed on all patients with tissue available Retrospective review Patients with SMARCA4 wildtype status used as a comparator group Outcomes: Genomic relationships Protein expression Overall survival Outcomes on ICIs Class 2 Alterations Missense mutations Variants of unknown significance * Class 1 includes chromosomal rearrangements, truncating mutations, and likely oncogenic variants as determined by Oncokb
SMARCA4-mutated NSCLC patients (Class I & II) associated with worse prognosis Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708. OS Among All Patients
Substantial unmet need in the treatment of patients with SMARCA4-mutated NSCLC 1 Response Rate and Survival Data: Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708 2 Second line estimates based on docetaxel label and clinical experience Chemoimmunotherapy1 < 12 months < 25% mOS ORR Chemotherapy2 < 8 months < 15% mOS ORR FIRST LINE SECOND LINE Even greater unmet need in 2nd line where fewer effective treatment options are available Response rates are less than 25% and expected median OS is less than a year
There is high unmet need in NSCLC for patients with SMARCA4 mutations In NSCLC, SMARCA4 mutations are observed in ~10% of cases and are associated with more aggressive and invasive disease and shorter survival The majority of these patients are not eligible for other targeted therapies, and therefore are typically treated with chemoimmunotherapy combinations In patients with metastatic NSCLC, SMARCA4 mutations (both Class I & II) have been associated with poor prognosis when given first-line chemo-immunotherapy The unmet need is even greater in 2L NSCLC where few treatment options are approved Key Takeaways
Clinical Development Plan & Future Directions Jane Huang, M.D., President & Chief Medical Officer
Learning Objectives What is the current clinical development status of our SMARCA portfolio? What is the design of the PRT3789 Phase I trial and what have we learned to date? How are we thinking about the potential for monotherapy and combination approaches? What should we expect to see when interim Phase I data is released later this year? What could the future hold for the development of SMARCA2 degrader therapies over time?
Our first-in-class IV and oral SMARCA2 degrader programs are advancing PROGRAM POTENTIAL INDICATIONS DISCOVERY PHASE 1 PHASE 2/3 Lead SMARCA2 Degrader PRT3789 Patients with SMARCA4-mutated advanced NSCLC and other cancers Oral SMARCA2 Degrader PRT7732 Patients with SMARCA4-mutated NSCLC and other cancers First Interim Phase I Data in 2H 2024 UPCOMING MILESTONES File IND in 1H 2024; Phase I Start in 2H 2024 + + Full pipeline includes programs against other cancer targets in active clinical or preclinical development
What is the design of the PRT3789 Phase 1 trial? ^ Dose Finding: Bayesian Optimal Interval (BOIN) Design Method * any mutation (Class I or Class II), including participants with SMARCA4 loss-of-function mutation due to truncating mutation and/or deletion ClinicalTrials.gov Identifier: NCT05639751; ESMO 2023 Poster: https://preludetx.com/wp-content/uploads/2023/10/Dagogo-Jack_ESMO-2023_PRT3789-01-TiP-Poster_Final_9Oct2023.pdf Study Population Dose Escalation + Backfill Cohorts + Expansion Cohorts Advanced, recurrent, or metastatic disease in solid tumors with any SMARCA4 mutation* Dose level 1 Dose level 2 Dose level 3 Dose level 4 Dose level 5 Dose level 6 Dose level 7 Dose level 8 Monotherapy PRT3789 Dose Escalation^ Dosing PRT3789 IV once weekly for 3 weeks (1 cycle) DLTs assessed during first 21 days of dosing during cycle 1 Criteria to Enroll Backfill Cohorts All participants have cleared the DLT observation period; AND An objective response per RECIST v1.1 has been observed; OR The dose level is safe and biologically effective taking into account safety, PK, and pharmacodynamic data Up to 10 participants in each cohort (minimum of 6 with NSCLC) with a SMARCA4 loss-of-function mutation Backfill Cohorts Backfill cohorts allow for deeper assessment of clinical activity in the 6-8% of advanced NSCLC patients with SMARCA4 loss-of-function mutations
Study expanded to evaluate potential for PRT3789 + docetaxel in combination *any mutation (Class I or Class II), including participants with SMARCA4 loss-of-function mutation due to truncating mutation and/or deletion. ClinicalTrials.gov Identifier: NCT05639751; ESMO 2023 Poster: https://preludetx.com/wp-content/uploads/2023/10/Dagogo-Jack_ESMO-2023_PRT3789-01-TiP-Poster_Final_9Oct2023.pdf Study Population Dose Escalation + Backfill Cohorts + Expansion Cohorts Advanced, recurrent, or metastatic disease in solid tumors with any SMARCA4 mutation* Monotherapy PRT3789 Dose Escalation Combination Therapy PRT3789 + docetaxel Backfill Cohorts + Dosing in combination with docetaxel has commenced
What do we hope to learn from the Phase I study? To evaluate the safety, tolerability, and dose limiting toxicities of PRT3789 and to determine the biologically active dose To evaluate the antitumor activity of PRT3789 To evaluate the pharmacokinetic profile of PRT3789 To evaluate the pharmacodynamic effect of PRT3789
What should we expect to see when data is released later this year? Initial Data Readout: 2H 2024 Full Trial Results and Next Steps: 2025+ Initial safety and tolerability data for monotherapy dose escalation cohorts Initial assessment of clinical activity across different tumor types at the various dosing levels under evaluation Early look at pharmacokinetic profile and pharmacodynamic effects Full safety and tolerability data for monotherapy dose escalation, backfill, and chemotherapy combination cohorts Detailed assessment of clinical activity for all trial participants Detailed PK profile and PD effects including recommended Phase 2 dose Engagement with regulators on potential registrational trial pathways
Future Directions: Expanding the patient impact of selective SMARCA2 degraders 1. SEER 2022; 2. American Cancer Society – Cancer Facts & Figures Generate Evidence Across Additional Tumor Types 3 Generate Evidence in Earlier Stages of NSCLC (Adj. / Neo-Adj.) 2 Stage at Initial Diagnosis Incidence (% of Pts)1,2 Treatment Modalities Stage I / Stage IIA ~20-30% Radiation and/or Resection Adjuvant Tx Stage IIB / Stage IIIA ~20-30% Neo Adj. Tx Resection Adjuvant Tx Stage IIIB/ Stage IV ~40-50% Systemic Treatment Assess Combinations with Chemo, I/O or Other Targeted Therapies 1 SMARCA2 Degrader + Chemotherapy Establish safety and efficacy in combination Improve outcomes, expand utility across multiple lines Immunotherapy Chemoimmunotherapy
Prelude’s first-in-class SMARCA2 degraders are advancing Prelude’s lead SMARCA2 degrader PRT3789 is advancing well in the clinic with no dose limiting toxicities observed to date Initial Phase I data in 2H 2024 will be the industry’s first look at safety and clinical activity for the SMARCA2 targeted approach PRT3789 represents our fastest path to address the high unmet need in advanced NSCLC PRT7732, our first-in-class oral degrader, will advance to Phase I start in 2H 2024 pending IND approval Key Takeaways
Highly Selective SMARCA2 Degraders: Portfolio Strategy & Closing Remarks
What could a highly selective SMARCA2 degrader mean for patients if we get this right? Why develop an IV version, oral versions, and Precision ADCs? What makes this is a strategic portfolio opportunity?
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 Relative future utilization: Datamonitor 2023 Lung Cancer Report; Analysis on File All trademarks are property of their respective owners Reinforces need for comprehensive genomic profiling More patients tested = More patients eligible
What could this mean for patients? 1 Response Rate and Survival Data: Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708 2 Second line estimates based on docetaxel label and clinical experience Chemoimmunotherapy1 < 12 months < 25% mOS ORR Chemotherapy2 < 8 months < 15% mOS ORR FIRST LINE SECOND LINE A selective SMARCA2 degrader has the potential to transform outcomes for these patients The prognosis for SMARCA4-mutated NSCLC patients is poor
Why develop IV degraders, oral degraders, and “Precision ADCs”? SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789, IV) High unmet need supports seeking fastest possible path to approval Establishes proof-of-concept (mono or combo) Solidifies SMARCA as new standard of care SMARCA Degrader-Antibody Conjugates (“DACs”) All cancers depend on chromatin remodeling Independent of SMARCA4-mutation status Initial focus of AbCellera collaboration Oral SMARCA2 Degrader (PRT7732) Expands access for advanced NSCLC patients (first-line) Enables use in earlier stage disease (adjuvant / neo-adjuvant) Provides optionality across other SMARCA4-mutated cancers
What makes this such a strategic portfolio opportunity? ~220,000 pts/year Up to 22,000 SMARCA4-mutated FIRST LINE ~150,000 pts/year Up to 15,000 SMARCA4-mutated SECOND LINE + “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: 1 US & EU5 only: Journal of Thoracic Oncology (US, 2021): https://doi.org/10.1016/j.jtho.2021.01.485; Globocan (EU5); 2 Datamonitor 2023 Lung Cancer Report; Analysis on File 3 Schoenfeld et al. Clin Cancer Res. (2020); 26(21):5701-5708. 4 Dagogo-Jack et al. J Thorac Oncol. (2020); 15(5):766-776. ~270,000 pts/year Up to 27,000 SMARCA4-mutated EARLIER STAGE (Adjuvant / Neo-Adj.) + / Addressable Patient Populations1-4 + / SMARCA4-mutated Solid Tumors and/or Heme Malignancies TBD based on selected tumors3,4 TBD based on antibody targets / tumor types
Key Takeaways We are on a mission to extend the promise of precision medicine to every cancer patient There is high unmet need in SMARCA4-mutated NSCLC (up to 10% of patients) These mutations are prevalent across a range of other cancers as well SMARCA2 is a promising new “synthetic lethal” target for these patients Targeting SMARCA2 is very challenging; selectivity over SMARCA4 is critical With PRT3789, our lead SMARCA2 degrader, Prelude scientists solved the selectivity challenge >1000-fold Industry-first clinical data validating this approach is coming soon Prelude’s first-in-class oral SMARCA2 degrader (PRT7732) and Precision ADCs further expand potential impact for patients
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