Prelude Therapeutics Incorporated · NASDAQ:PRLD
Prelude Therapeutics — Investor Presentation (September 2024)
53 slides from Prelude Therapeutics's investor presentation, Sep 13, 2024
Slide 1: Corporate Presentation September 2024
Corporate Presentation September 2024 Exhibit 99.3
Slide 2: Forward Looking Statements
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 Pre
Slide 3: Mission to extend precision medicine to every cancer patient in need
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 innovatio
Slide 4: Experienced Leadership Team With Proven Track Records in Precision Oncology
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 Experien
Slide 5: Prelude's Evolution and Strategic Priorities
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 a
Slide 6: Prelude's Precision Medicine Pipeline & Discovery Engine
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
Slide 7: Industry Leading Portfolio of SMARCA-Targeted Precision Medicines
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
Slide 8: Targeting SMARCA4-mutated Cancer By Selectively Degrading SMARCA2
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%
Slide 9: Outcomes for Patients with SMARCA4-mutated NSCLC are Poor with Current Standard of Care
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:
Slide 10: PRT3789: Highly Potent SMARCA2 Degrader with >1000-fold Selectivity
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
Slide 11: PRT3789-01: Study Schema and Enrollment
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
Slide 12: PRT3789-01: Demographics and Disease Characteristics
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
Slide 13: PRT3789-01: Patient Disposition
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
Slide 14: PRT3789-01: Summary of Adverse Events
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, 1
Slide 15: PRT3789-01: Interim PK/PD Findings
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
Slide 16: PRT3789-01: Interim Clinical Activity
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
Slide 17: PRT3789-01: Interim Clinical Activity
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 dem
Slide 18: PRT3789-01: Patient Case Study
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
Slide 19: PRT3789-01: Key Takeaways
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
Slide 20: What's Next for PRT3789?
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 Confirmat
Slide 21: PRT7732: First-in-Class Oral SMARCA2 Degrader – Phase I Trial Initiated
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 SM
Slide 22: Expanding Our Portfolio of SMARCA-Targeted Precision Medicines
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
Slide 23: Prelude and AbCellera Creating Novel Precision ADCs
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 a
Slide 24: SMARCA Portfolio Strategy Addresses a Significant Unmet Need
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
Slide 25: Highly Selective CDK9 Inhibitor PRT2527
Highly Selective CDK9 Inhibitor PRT2527
Slide 26: Patients with Hematologic Malignancies Refractory to Current Treatments Experience Poor Outcomes
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 + H
Slide 27: CDK9 Inhibition Targets Two Major Validated Pathways (MYC and MCL-1)
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 myel
Slide 28: PRT2527 is a Potent, Highly Selective CDK9 Inhibitor
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 C
Slide 29: Phase 1 Trial of PRT2527 in Hematologic Malignancies is Underway
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 the
Slide 30: Continued Execution Across Strategic Priorities
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 clinic
Slide 31: Thank You
Thank You Contact Us: Robert Doody SVP, Investor Relations rdoody@preludetx.com
Slide 32: Appendix
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
Slide 33: PD Correlates with Efficacy in Preclinical Models
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 Effi
Slide 34: Degraders Offer Distinct Advantages for Targeting SMARCA2
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 t
Slide 35: Selectively Targeting SMARCA2 Has Been a Significant Challenge for Industry
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 pro
Slide 36: Prelude Scientists Solved the SMARCA2 Selectivity Enigma
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
Slide 37: Oral SMARCA2 Degrader Program Progressed Rapidly and Systematically
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
Slide 38: Tertiary Complex of SMARCA2/PRT7732/CRBN-DDB1 E3 Ligase
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 selectiv
Slide 39: PRT7732 is Highly Potent and Orally Bioavailable
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 concentratio
Slide 40: PRT7732 Has Significant Anti-Tumor Activity in Xenograft Models
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
Slide 41: PRT3789 Demonstrates Potential for Synergy with Chemotherapy
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 strategi
Slide 42: PRT7732 Shows High Potential for Synergy With Other Anti-Cancer Agents
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. Ava
Slide 43: SMARCA2 Degraders May Help Potentiate PD1/PDL1 Immunotherapy
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 cyt
Slide 44: Preclinical Data for PRT3789 Support Anti-PD1 Combination Rationale
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
Slide 45: Prelude to Initiate Combination Study of PRT3789 + Pembrolizumab in Q4 2024
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
Slide 46: Majority of Advanced NSCLC Patients Treated with Chemoimmunotherapy
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: Si
Slide 47: SMARCA Could Significantly Expand Precision Medicine for More NSCLC Patients
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
Slide 48: Appendix
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
Slide 49: Prelude and AbCellera Creating Novel Precision ADCs
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
Slide 50: Framework for Precision ADC Differentiation
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 ex
Slide 51: Appendix
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
Slide 52: PRT2527 is Highly Efficacious In Vivo in Models of Hematologic Malignancies
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
Slide 53: Initial Phase 1 Study of PRT2527 in Solid Tumors: Safety and PK/PD
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 t
Prelude Therapeutics — Investor Presentation (September 2024) on 6ix