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Zenith Capital — Zenith Epigenetics — TNBC Drug Development Summit 2021
22 slides from Zenith Capital's conference presentation, Apr 29, 2021
Slide 1: Phase 1b/2 Combination Study of ZEN-3694 with Talazoparib in TNBC
Phase 1b/2 Combination Study of the BET Inhibitor ZEN-3694 with the PARP Inhibitor Talazoparib for the Treatment of TNBC Patients without germline BRCA1/2 Mutations Eric Campeau, TNBC Drug Development Summit, April 29, 2021
Slide 2: Outline
Outline ➢ Induction of synthetic lethality with PARP and BET inhibitors in DNA repair-competent cancer cells ➢ Design of the ZEN003694-004 clinical trial of ZEN-3694 + talazoparib in non gBRCA1/2m TNBC patients ➢ Results from Dose Escalation and Stage 1 and evidence of clinical activity in non gBRCA
Slide 3: Outline
Outline ➢ Induction of synthetic lethality with PARP and BET inhibitors in DNA repair-competent cancer cells ➢ Design of the ZEN003694-004 clinical trial of ZEN-3694 + talazoparib in non gBRCA1/2m TNBC patients ➢ Results from Dose Escalation and Stage 1 and evidence of clinical activity in non gBRCA
Slide 4: Induction of homologous recombination deficiency by ZEN-3694 and sensitization to PARP inhibitors
Induction of homologous recombination deficiency by ZEN-3694 and sensitization to PARP inhibitors in BRCAwt cells • In breast cancer, only ~20% of patients are eligible to receive a PARPi (germline BRCA1/2 mutant) • Additional clinical activity in advanced breast cancer is currently limited to somat
Slide 5: Outline
Outline ➢ Induction of synthetic lethality with PARP and BET inhibitors in DNA repair-competent cancer cells ➢ Design of the ZEN003694-004 clinical trial of ZEN-3694 + talazoparib in non gBRCA1/2m TNBC patients ➢ Results from Dose Escalation and Stage 1 and evidence of clinical activity in non gBRCA
Slide 6: ZEN-3694 + talazoparib trial design
ZEN-3694 + talazoparib trial design (Phase 2, Pfizer/Zenith collaboration) Patients with advanced TNBC and no germline BRCA1/2 mutations Locally advanced/metastatic TNBC • No germline mutations in BRCA1 and BRCA2 (gBRCA1/2m) (CLIA test) • No prior progression during platinum treatment • No prior exp
Slide 7: Patient baseline characteristics (Dose escalation + Stage 1)
Patient baseline characteristics (Dose escalation + Stage 1) December 2020 Total (n = 32) Age (median years) 56 (28 - 74) ECOG 0 21 (66%) 1 11 (34%) Time from initial breast cancer diagnosis to ZEN-3694 (median mo.) 52.0 (5.0 – 342.0) Duration of last prior treatment (Tx) regimen in metastatic setti
Slide 8: Dose escalation and selection of the recommended phase 2 dose (RP2D)
Dose escalation and selection of the recommended phase 2 dose (RP2D) ZEN-3694 48 mg (QD) 36 mg (QD) 1 mg Dose Escalation Cohort 1 Dose Escalation Cohort 3 (QD) 2/6 patients with DLT (TCP) 0/3 patient with DLT TALAZOPARIB Dose Escalation Cohort 2 0.75 mg 1/6 patient with DLT (TCP) (QD) Dose selected
Slide 9: Common treatment-related adverse events
Common treatment-related adverse events (AEs) DE Cohort 1 DE Cohort 2 DE Cohort 3 Simon Stage 1 Grade 3/4 AEs 48 mg ZEN + 48 mg ZEN + 36 mg ZEN + 48 mg ZEN + Total 1.0 mg Tala 0.75 mg Tala 1.0 mg Tala 0.75 mg Tala n = 32 across all (n = 6) (n = 6) (n = 3) (n = 17) cohorts Any Any Any Any Grade 3/4 G
Slide 10: Manageable thrombocytopenia and maintenance of dose intensity
Manageable thrombocytopenia and maintenance of dose intensity for ZEN-3694 and TALA through first eight cycles ZEN-3694 Average Dose 600 60 Average dose (mg) Starting Dose = 48mg 40 P la te le ts (1 0 0 0 /m l) 400 20 n = 23 n = 19 n = 12 n=2 n=5 n=1 n=3 n=8 0 4 8 12 16 20 24 28 32 Weeks on Study 20
Slide 11: Outline
Outline ➢ Induction of synthetic lethality with PARP and BET inhibitors in DNA repair-competent cancer cells ➢ Design of the ZEN003694-004 clinical trial of ZEN-3694 + talazoparib in non gBRCA1/2m TNBC patients ➢ Results from Dose Escalation and Stage 1 and evidence of clinical activity in non gBRCA
Slide 12: Sustained whole blood target engagement
Sustained whole blood target engagement for > 8 hours Similar exposure-dependent target engagement as prior trials in prostate cancer CCR1 TNBC trial IL1RN compared to pre-dose 1.5 Fold change mRNA compared to pre-dose 1.5 Fold change mRNA 36 mg ZEN003694 1.0 48 mg ZEN003694 1.0 36 mg ZEN00369
Slide 13: % Change in Target Lesions
00 %Change in Target Lesions 4 00 -01 4 7 0 50 100 -100 -50 00 -02 -00 4 0 1 00 -01 -01 (C3 4 2 8 00 -01 -04 (C3) 4 2 8 00 -01 -03 (C3) 4 4 6 00 -01 -04 (C3) 4 2 5 00 -02 -00 (C3) 4 1 7 00 -02 -04 (C3) 4 1 9 00 -01 -01 (C3) 4 6 5 00 -01 -03 (C3) HRR= homologous recombination repair 4 7 4 00 -02 -01
Slide 14: Inhibition of DNA repair and HRR gene expression in tumors
Inhibition of DNA repair and HRR gene expression in tumors from two TNBC patients On-Treatment Significant inhibition of DNA repair (GSEA) in tumors H a llm a r k D N A r e p a ir p t 3 5 a n d 4 2 G O D N A r e p a ir p t 3 5 a n d 4 2 2 .0 Hallmark DNA repair 2 .0 GO DNA repair 1 .5 1 .5 RA D5 1 R
Slide 15: Significant inhibition of oncogenic hallmarks in tumor biopsies
Significant inhibition of oncogenic hallmarks in tumor biopsies On-Treatment (GSEA) Volcano plot (Hallmark MYC V1) Hallmark MYC V1 Hallmark MYC V2 H a llm a r k M Y C V 1 p t 3 5 a n d 4 2 2 .0 CCNA 2 1 .5 -(L O G )p 1 .0 MY C NES: -3.40 NES: -3.1 FDR: <0.0001 0 .5 FDR: <0.0001 0 .0 -5 0 5 lo g F C
Slide 16: Outline
Outline ➢ Induction of synthetic lethality with PARP and BET inhibitors in DNA repair-competent cancer cells ➢ Design of the ZEN003694-004 clinical trial of ZEN-3694 + talazoparib in non gBRCA1/2m TNBC patients ➢ Results from Dose Escalation and Stage 1 and evidence of clinical activity in non gBRCA
Slide 17: Clinical activity of PARP inhibitors in advanced breast cancer
Clinical activity of PARP inhibitors in advanced breast cancer Limited activity in BRCA1/2 wild-type patients BRCA1/2 and PALB2 status Pathway Agent(s) Initial clinical results (advanced breast cancer): MUTANT “WT” ZEN-3694 + TALA ✓ BETi • Limited activity of PARPi outside BRCA1/2m or PALB2m ZEN +
Slide 18: What is the difference from other inhibitors with the same proposed mechanism?
What is the difference from other inhibitors with the same proposed mechanism? • Inhibition of several pathways have been shown to increase sensitivity to PARPi in preclinical models • Mitigated success in the clinic at this time = Inhibition shown to affect RAD51 and/or BRCA1 mRNA or protein levels
Slide 19: BET-dependent mechanism of resistance to PARP inhibitors
BET-dependent mechanism of resistance to PARP inhibitors Single agent PARPi in BRCA wild-type advanced TNBC • PARPi induces DNA damage (PARP trapping) and inhibits DNA repair (BER), replication, and transcription • BET-dependent induction of DNA damage response Epigenetic remodeling Enhancer reprogr
Slide 20: BET-dependent mechanism of resistance to PARP inhibitors
BET-dependent mechanism of resistance to PARP inhibitors Combination of ZEN-3694 + talazoparib in BRCA wild-type advanced TNBC • ZEN-3694 inhibits adaptation to PARPi Epigenetic remodeling • Loss of genomic integrity ZEN-3694 + TALA Enhancer reprogramming • Tumor cell death HRR-competent PARPi s
Slide 21: Summary and conclusions
Summary and conclusions • Combination of ZEN-3694 + TALA demonstrated evidence of anti-tumor activity in previously treated patients with metastatic TNBC without gBRCA1/2 mutations. • The combination is generally well-tolerated. Thrombocytopenia is the most common adverse event and dose- limiting to
Slide 22: Acknowledgements
Acknowledgements Patients and their families Investigators Pfizer Zenith • Philippe Aftimos (Jules Bordet) • Akos Czibere • Sarah Attwell • Valentina Boni (START Madrid) • Yanke Yu • Lisa Bauman • Susan Domchek (UPenn) • Emily Johnson • Ayca Gucalp (MSKCC) • Sanjay Lakhotia • Erika Hamilton (Sarah C
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