Prelude Therapeutics Incorporated · NASDAQ:PRLD
Prelude Therapeutics — Technical Presentation (October 2024)
22 slides from Prelude Therapeutics's technical presentation, October 2024
Slide 1: Clinical results from a phase 1 trial of PRT3789, a SMARCA2 degrader
Clinical results from a phase 1 trial of PRT3789, a first-in- class intravenous SMARCA2 degrader, in patients with advanced solid tumors with a SMARCA4 mutation Timothy A Yap,1 Afshin Dowlati,2 Ibiayi Dagogo-Jack,3 Julien Vibert,4 Alexander I Spira,5 Victor Moreno,6 Salman R Punekar,7 Emiliano Calvo
Slide 2: Timothy A Yap conflict of interest disclosures
Timothy A Yap I have the following potential conflict(s) of interest to report: Employment with The University of Texas MD Anderson Cancer Center, where I am Vice President, Head of Clinical Development in the Therapeutics Discovery Division, which has a commercial interest in DDR and other inhibito
Slide 3: SMARCA4 Mutations in NSCLC and Other Solid Tumors
SMARCA4 Mutations in NSCLC and Other Solid Tumors Progression-Free Survival • SMARCA4 is inactivated in a variety of cancers and considered a tumor suppressor1 Median PFS SMARCA4MUT 2.7 Months SMARCA4WT • In NSCLC, SMARCA4 mutations are observed in SMARCA4MUT ~10% of cases, and are associated with m
Slide 4: PRT3789: An Intravenous SMARCA2 Degrader
PRT3789: An Intravenous SMARCA2 Degrader • Highly potent (plasma DC50 = 21 nM) • Selective for SMARCA2 over SMARCA4 • Induces synthetic lethality in various CDX and PDX mouse models of SMARCA4-deficient cancer at well-tolerated doses 1000 Vehicle NSCLC PDX volume (mm3) PRT3789 200 mg/kg sc q3d 800 6
Slide 5: Study Schema and Enrollment
Study Schema and Enrollment PRT3789 Monotherapy Dose-Escalation Cohorts Backfill Cohorts Eligibility criteria PRT3789 900 mg • Any solid tumor n=x n=x • Any SMARCA4 mutation PRT3789 665 mg • Evaluable disease n=x n=x PRT3789 500 mg n=x • PRT3789 dosing is intravenous, weekly n=x • Dose escalation on
Slide 6: Demographics and Disease Characteristics
Demographics and Disease Characteristics PRT3789 Monotherapy Demographics and Disease Characteristics Patients Characteristics (N=65) Age (years) Median 62 Sex, n (%) Male 36 (55.4) Female 29 (44.6) Prior lines of systemic anticancer therapy, n Median (min, max) 3 (1, 10) Tumor type, n (%) Non-small
Slide 7: Summary of Adverse Events
Summary of Adverse Events PRT3789 Monotherapy Most Frequent Adverse Events PRT3789 Monotherapy Adverse Events, n (%) (N=65) Any adverse event 61 (93.8) Treatment related 39 (60.0) Grade ≥3 adverse event 35 (53.8) Treatment related 5 (7.7) Serious adverse event 20 (30.8) Treatment related 0 Adverse e
Slide 8: Change in Tumor Burden in Patients With NSCLC or Esophageal Cancer
Change in Tumor Burden in Patients With NSCLC or Esophageal Cancer Efficacy Evaluable Population with Post-baseline scan * * * * Data cutoff: 23 September 2024. NSCLC, non-small cell lung cancer; SLD, sum of longest diameter. * Confirmed partial response; [1], class 1 mutation; [2], class 2 mutation
Slide 9: Duration of Treatment in Patients With NSCLC or Esophageal Cancer
Duration of Treatment in Patients With NSCLC or Esophageal Cancer Efficacy Evaluable Population # # Data cutoff: 23 September 2024. NSCLC, non-small cell lung cancer; PD, progressive disease; PR, partial response; SD, stable disease. #Patients with esophageal cancer.
Slide 10: Response Rate in NSCLC or Esophageal Cancer, Class 1 Mutations
Response Rate in NSCLC or Esophageal Cancer, Efficacy Evaluable, With Class 1 Mutations Patients With Class 1 SMARCA4 Mutations PRT3789 Doses PRT3789 Doses All Doses Response Rate <283 mg ≥283 mg (n=26) (n=17) (n=9) Objective response rate, n (%) 2 (11.8) 2 (22.2) 4 (15.4) 95% CI 1.5, 36.4 2.8, 60.0
Slide 11: Examples of Responses in NSCLC
Examples of Responses in NSCLC Patient 1 Patient 2 Baseline Week 12 Baseline Week 6 • 72-year-old man with metastatic, poorly differentiated • 72-year-old man with moderately well-differentiated lung carcinoma of the lung with squamous differentiation adenocarcinoma. Metastases to brain and malignan
Slide 12: Example of Responses in Esophageal Cancer
Example of Responses in Esophageal Cancer Patient 3 • 53-year-old man with metastatic, poorly Baseline Week 6 differentiated carcinoma of the esophagus with squamous differentiation • SMARCA4 deletion-frameshift (c2732delG, pG911fs) • Prior therapy included cisplatin-platinum, 5-fluorouracil, pembro
Slide 13: Pharmacokinetics and Pharmacodynamics
Pharmacokinetics and Pharmacodynamics Target Engagement Confirmed by SMARCA2 Reduction Median Concentration Time on C1D1 Pharmacodynamic Effect on SMARCA2 Levels in PBMCs by Dose Median AUC of normalized SMARCA2 (h·nM) Dose (mg) Pharmacodynamic effect is more prolonged than pharmacokinetics Increasi
Slide 14: Target Engagement Confirmed by SMARCA2 Reduction in Tumor Tissue
Target Engagement Confirmed by SMARCA2 Reduction in Tumor Tissue 42-year-old Caucasian male with large cell neuroendocrine cancer PRT3789 120 mg + docetaxel cohort 4012-074 Combo 120mg SMARCA2 levels normalized to C1D1 predose 100 0 - Absent Staining intensity Percent positive cells 1 - Weak0 - Abse
Slide 15: Distribution of SMARCA4 Mutations in Study Patients
Distribution of SMARCA4 Mutations in Study Patients Class I (truncation, frameshift, splice site) and Class II (missense, VUS) SMARCA4 mutations occur across the length of the gene VUS, variant of uncertain significance.
Slide 16: Type of SMARCA4 Mutation and Co-Mutations in Class I Patients
Type of SMARCA4 Mutation and Co-Mutations in Class I Lung and Esophageal Study Patients ^ ^ ^ ^ ^ ^ ^ ^ ^ • Class I SMARCA4 mutations: 42% truncation, 32% frameshift, 13% splice site, 3% deletion • Most common co-mutations: TP53 (77%), CDKN2A (29%), KEAP1 (19%), KRAS (16%), STK11 (13%) Central NGS t
Slide 17: Study Schema and Enrollment
Study Schema and Enrollment Docetaxel + PRT3789 Dose-Escalation Cohorts Backfill Cohorts Eligibility criteria Eligibility criteria • Any solid tumor • Enriched NSCLC • Any SMARCA4 mutation • LOF SMARCA4 mutation • Evaluable disease • Measurable disease PRT3789 900 mg • PRT3789 dosing is intravenous,
Slide 18: Demographics and Disease Characteristics
Demographics and Disease Characteristics Docetaxel + PRT3789 Demographics and Disease Characteristics Patients Characteristics (N=11) Age (years) Median 65 Sex, n (%) Male 8 (72.7) Female 3 (27.3) Prior lines of systemic anticancer therapy, n Median (min, max) 1 (1, 6) Tumor type, n (%) Non-small ce
Slide 19: Adverse Events
Adverse Events Docetaxel + PRT3789 Summary of Adverse Events Most Frequent Adverse Events PRT3789 + Docetaxel Adverse Events, n (%) 40% (N=11) Fatigue 83% Any adverse event 9 (81.8) Neutropenia 20% PRT3789 treatment related 5 (45.5) 50% Docetaxel treatment related 8 (72.7) 20% Diarrhea 33% Grade ≥3
Slide 20: Pharmacokinetics of PRT3789 + Docetaxel
Pharmacokinetics of PRT3789 + Docetaxel Median Concentration Time on C1D1 • Preliminary PK data is available from 6 patients in the 120 mg combination cohort • PRT3789 PK in combination with docetaxel appears to be consistent with monotherapy at 120 mg Mean (SD) of PK PRT3789 parameters Cohort N Cma
Slide 21: Summary and Conclusions
Summary and Conclusions • PRT3789 represents a first-in-class, novel, targeted therapeutic designed to induce synthetic lethality in SMARCA4-deficient cancer, while sparing normal tissue • PRT3789 monotherapy and in combination with docetaxel demonstrated an acceptable safety profile, with no dose-l
Slide 22: Acknowledgments
Acknowledgments • We would like to thank the study patients, families, investigators, coordinators, and health care staff at each study site for participating in study PRT3789-01 • This study is sponsored by Prelude Therapeutics, Incorporated • Medical writing support was provided by Miriam Cohen, P
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