Slide 1: Highly Selective SMARCA2 Degraders
Highly Selective SMARCA2 Degraders
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: Learning Objectives
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 PRT
Slide 4: Learning Modules
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
Slide 5: Mission to extend the promise of precision medicine to every cancer patient
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
Slide 6: Scientific leadership has deep experience in precision oncology
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
Slide 7: High unmet need in SMARCA4-mutated NSCLC
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 Che
Slide 8: Industry's leading SMARCA-targeted pipeline
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 can
Slide 9: Advancing our Understanding of SMARCA Science
Dr. Timothy Yap, University of Texas MD Anderson Cancer Center Advancing our Understanding of SMARCA Science
Slide 10: Learning Objectives
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 t
Slide 11: Chromatin Remodeling is essential for DNA replication, repair and gene expression
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.
Slide 12: SMARCA2 and SMARCA4 are highly related, interchangeable ATPase subunits
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”
Slide 13: More than 20% of human cancers harbor CR subunit mutations
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 acros
Slide 14: SMARCA4 mutations occur in ~10% of all 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% Mostly
Slide 15: Tumors become reliant on SMARCA2 when SMARCA4 is mutated
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”
Slide 16: Knocking out SMARCA2 induces 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
Slide 17: Selective SMARCA2 treatments could treat SMARCA4-mutated cancers
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
Slide 18: Dual degraders show rapid regressions but may cause toxicity
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 survi
Slide 19: SMARCA2 selectivity has been a challenge for industry
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 tria
Slide 20: Key Takeaways
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
Slide 21: Discovery Deep Dive: Lead SMARCA2 Degrader (PRT3789)
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
Slide 22: Learning Objectives
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?
Slide 23: Selectively targeting SMARCA2 has been a significant challenge
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 24: Degraders offer distinct advantages over inhibitors
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 25: 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 26: PRT3789: Our Lead SMARCA2 Degrader
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
Slide 27: PRT3789 is highly potent and highly selective
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
Slide 28: PRT3789 induces synthetic lethality in vitro
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 ca
Slide 29: PRT3789 demonstrates selective tumor regression in vivo
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/
Slide 30: 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 31: Potential synergy with PD1/PDL1 immunotherapy
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 mac
Slide 32: Preclinical data support anti-PD1 combination
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 33: First selective SMARCA2 degrader to enter the clinic
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 obse
Slide 34: Key Takeaways
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, PRT37
Slide 35: Discovery Deep Dive: Oral SMARCA2 Degrader (PRT7732)
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
Slide 36: Learning Objectives
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?
Slide 37: Oral degrader program progressed rapidly and systematically
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
Slide 38: PRT7732: Our Lead Oral SMARCA2 Degrader
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 potent and orally bioavailable with near-absolute selectivity
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 anti-tumor activity in xenograft models
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 Characterizatio
Slide 41: PRT7732 shows potential for synergy with 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 42: Expanding our portfolio of SMARCA-targeted therapeutics
Expanding our portfolio of SMARCA-targeted therapeutics SMARCA - DACs + Lead SMARCA2 Degrader (PRT3789) SMARCA Degrader-Antibody Conjugates (“DACs”) Oral SMARCA2 Degraders (PRT7732)
Slide 43: Key Takeaways
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 e
Slide 44: Clinical Experience with SMARCA4-mutated NSCLC
Clinical Experience with SMARCA4-mutated NSCLC Dr. Adam Schoenfeld Memorial Sloan Kettering Cancer Center
Slide 45: Learning Objectives
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?
Slide 46: SMARCA4 mutations occur in ~10% of all 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 o
Slide 47: SMARCA4 mutations concurrent with other driver oncogenes
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
Slide 48: Most advanced NSCLC patients treated with chemoimmunotherapy
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
Slide 49: SMARCA4-mutated NSCLC patients have worse prognosis
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
Slide 50: Impact of SMARCA4 mutations on clinical outcomes
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 tis
Slide 51: SMARCA4-mutated NSCLC associated with worse prognosis
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
Slide 52: Substantial unmet need in SMARCA4-mutated NSCLC
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 Chemoth
Slide 53: Key Takeaways
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 therefor
Slide 54: Clinical Development Plan & Future Directions
Clinical Development Plan & Future Directions Jane Huang, M.D., President & Chief Medical Officer
Slide 55: Learning Objectives
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
Slide 56: First-in-class IV and oral SMARCA2 degrader programs are advancing
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 ca
Slide 57: Design of the PRT3789 Phase I trial
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; E
Slide 58: Study expanded to evaluate PRT3789 + docetaxel
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.c
Slide 59: What do we hope to learn from the Phase I study?
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 pharmacodynami
Slide 60: What to expect when data is released later this year
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
Slide 61: Future Directions: Expanding patient impact of SMARCA2 degraders
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 (%
Slide 62: Key Takeaways
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 targete
Slide 63: Portfolio Strategy & Closing Remarks
Highly Selective SMARCA2 Degraders: Portfolio Strategy & Closing Remarks
Slide 64: Learning questions on strategic portfolio opportunity
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?
Slide 65: SMARCA could 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 66: What could this mean for patients?
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 S
Slide 67: Why develop IV degraders, oral degraders, and Precision ADCs?
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 Conju
Slide 68: What makes this such a strategic portfolio opportunity?
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
Slide 69: Key Takeaways
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 f
Slide 70: Thank You
@e0® @e®@ ©ee%e ee ee? ee e eee%e eee°e e e@ e oes THANK YOU