Enanta Pharmaceuticals, Inc. · NASDAQ:ENTA

Enanta Pharmaceuticals — Discovery on Target: New Antivirals Conference 2022

21 slides from Enanta Pharmaceuticals's conference presentation, Oct 19, 2022

  1. Slide 1: EDP-323, a Small Molecule L-Protein Inhibitor in Development Against Respiratory Syncytial Virus

    EDP-323, a Small Molecule L-Protein Inhibitor in Development Against Respiratory Syncytial Virus M. H. J. Rhodin, N. V. McAllister, N. Bisht, R. E. Levene, J. S. Gibbons, A. Balakrishnan, J. Yu, A. A. Szymaniak, K. P. McGrath, T. J. Mann, I. J. Kim, B. Ludeke, R. Fearns, Y. S. Or, and B. Goodwin Dis

  2. Slide 2: Disclosures

    Disclosures: Authors M. H. J. Rhodin, N. V. McAllister, N. Bisht, R. E. Levene, J. S. Gibbons, A. Balakrishnan, J. Yu, A. A. Szymaniak, K. P. McGrath, T. J. Mann, I. J. Kim, Y. S. Or, and B. Goodwin are employees of Enanta Pharmaceuticals Work performed in the Fearns lab was funded under a sponsored

  3. Slide 3: Our Therapeutic Focus

    EDP-938 RSV N Inhibitor EDP-323 EDP-235 RSV L Inhibitor 3CLpro Inhibitor Our Therapeutic Focus RSV hMPV COVID-19 Leveraging our core strength in Hepatitis C to become a leader in oral treatments for viral infections and liver diseases Several new therapeutic areas with goal of building multiple appr

  4. Slide 4: Respiratory Syncytial Virus (RSV)

    Respiratory Syncytial Virus (RSV) RSV is a (-)ssRNA non-segmented virus with a genome size of roughly 15 kb. It has 10 genes which code for 11 proteins. • Causes ~25 million acute respiratory tract infections annually in children worldwide, with common re-infections in adults • Leading cause of hosp

  5. Slide 5: RSV Life Cycle and Antiviral Targets

    RSV Life Cycle and Antiviral Targets Monoclonal Ab Fusion Inhibitors L Inhibitors N Inhibitors EDP-323 A non-nuc EDP-938 RdRp Inhibitor © 2022 Enanta Pharmaceuticals, Inc. | 5

  6. Slide 6: EDP-323 Displays Potent Antiviral Activity In Vitro

    EDP-323 Displays Potent Antiviral Activity In Vitro EDP-323 Antiviral Activity: EC50/90 [nM] EDP-323 Activity vs Clinical Isolates EC50/90 [nM] Cell Type Virus Readout Virus Isolate EC50 EC90 EC50 EC90 80189 0.33 0.45 CPE 0.44 0.52 RSV-A Long Tracy 0.36 0.61 RT-qPCR 0.84 1.10 79365 0.28 0.45 CPE 0.4

  7. Slide 7: EDP-323's Potency is Resilient to Increases in Viral Load

    EDP-323’s Potency is Resilient to Increases in Viral Load Viral Load Effect on EDP-323 Activity EDP-323 Activity vs Viral Load 11 55 00 MO M O II RSV-A Long MOI 0 ..0 01 EC50 [nM] EC90 [nM] 0 1 t e d C e lls lls H ee aa llth 10 0.70 1.30 0 ..0 03 th 11 00 00 0 3 Viral 3 0.47 0.53 0 ..1 0 1 c te Load

  8. Slide 8: EDP-323 Maintains In Vitro Efficacy Post-Infection in 2D Cell Culture

    EDP-323 Maintains In Vitro Efficacy Post-Infection in 2D Cell Culture Time of Compound MOI: 0.1 Addition MOI: 3 Time of Addition: CPE % Cell Health (vs cells only) % Cell Health (vs cells only) EC50 [nM] ToA (hpi) MOI: 0.1 MOI: 3 CPE 0h 0.36 0.7 8h 0.28 0.76 24 h 0.42 0.76 32 h 0.84 0.97 48 h 1.2 >8

  9. Slide 9: EDP-323 Maintains In Vitro Efficacy Post-Infection in 3D Cell Culture

    EDP-323 Maintains In Vitro Efficacy Post-Infection in 3D Cell Culture 3D pHAEC-ALI Culture primary human airway epithelium cells grown at an air-liquid interface MatTek EC50 0.16 nM 0.18 nM Ciliated apical surface - Infect at apical Mucociliary epithelium surface Microporous membrane - EDP-323 added

  10. Slide 10: Imaging of 3D pHAEC-ALI Culture Highlights EDP-323's ability to Reduce Viral Infection

    Imaging of 3D pHAEC-ALI Culture Highlights EDP-323’s ability to Reduce Viral Infection Untreated Sample +10 nM EDP-323 Apical Cross Section DAPI View RSV N RSV F Top-down Z- Stack View Assay Conditions: EpiAirway 3D pHAEC-ALI infected with RSV-A Long at 3.1 x 104 PFU and treated with EDP-323 or vehi

  11. Slide 11: EDP-323 Resistance Mapping Indicates Binding to Capping Domain of RdRp

    EDP-323 Resistance Mapping Indicates Binding to Capping Domain of RdRp 1 968 1460 1815 1890 2165 N RNA dependent RNA polymerase Domain Capping Domain Connector Domain MTase CTD C R E D P -3 2 3 P a s s a g e H is to r y EDP-323 Cross Resistance Profiling 10000 I392L, L1372V, L1372V, WT L1372V, C1388

  12. Slide 12: EDP-323 Resistance Mapping Indicates Binding to Capping Domain of RdRp

    EDP-323 Resistance Mapping Indicates Binding to Capping Domain of RdRp 1 968 1460 1815 1890 2165 N RNA dependent RNA polymerase Domain Capping Domain Connector Domain MTase CTD C R E D P -3 2 3 P a s s a g e H is to r y EDP-323 Cross Resistance Profiling 10000 I392L, L1372V, L1372V, WT L1372V, C1388

  13. Slide 13: EDP-323 Directly Inhibits L Protein Function

    EDP-323 Directly Inhibits L Protein Function Biochemical Assay Inhibition of RSV L/P RdRp Activity by EDP-323 Pyrophosphate detection by enzyme-coupled luminescence assay IC50 14 nM RSV Proteins: L, P (18 µg/mL) + tr-25 RNA (2 µM) + 1-thio-ATP (100 μM) + C/G/UTP (0.03 μM) • EDP-323 directly interfer

  14. Slide 14: EDP-323 Directly Inhibits L Protein Function

    EDP-323 Directly Inhibits L Protein Function Minigenome Cellular Assays M2-1 P Transfect + or - EDP-323 N L BSR-T7 cells Quantify RNA species Leader (transcription) or trailer (replication) RNA RNA Transcription Inhibition RNA Replication Inhibition IC50 IC50 1.2 nM 0.31 nM © 2022 Enanta Pharmaceuti

  15. Slide 15: EDP-323 Protects RSV-Infected Mice in a Dose-Dependent Manner

    EDP-323 Protects RSV-Infected Mice in a Dose-Dependent Manner EDP-323: 50 / 150 / 400 mg/kg EDP-323 Antiviral Activity: EC50/90 [nM] Cells Virus Readout EC50 EC90 N = 12 RSV-A2 RT-qPCR 1.00 4.10 BALB/c Lung /EDP-323 RSV-A Long RT-qPCR 1.20 5.30 cohort RSV-A Long RT-qPCR 0.16 0.27 3D pHAEC ALI Cultur

  16. Slide 16: EDP-323 Therapeutically Protects RSV-Infected Mice

    EDP-323 Therapeutically Protects RSV-Infected Mice 400 mg/kg N = 12 /EDP-323 cohort Lung Weights Lung Titers: Viral RNA (qPCR) Lung Titers: Live Virus (Plaque Assay) Log10 PFU/ Gram Tissue Copy # / Gram Tissue Lung Weight (mg) Ribavirin = 275 ± 25 mg ***p < 0.001 versus vehicle. LoD is 1.8 log10 PFU

  17. Slide 17: EDP-323 Impairs Viral-Induced Cytokine Responses in Mice

    EDP-323 Impairs Viral-Induced Cytokine Responses in Mice Serum Biomarker Levels Fold Over Naïve • EDP-323 inhibits RSV-induced increases in pro-inflammatory cytokine biomarkers © 2022 Enanta Pharmaceuticals, Inc. | 17

  18. Slide 18: EDP-323 Reduces Viral-Induced Pathology in Mice

    EDP-323 Reduces Viral-Induced Pathology in Mice INF Mouse Lung Mean Inflammatory Cell Infiltrate Scores Mouse Lung Mean Histopathology Scores • All EDP-323 cohorts significantly reduced viral-induced pathology vs vehicle treated infected animals ***p<0.001, **p<0.01 by one one-way ANOVA followed by

  19. Slide 19: EDP-323, A Potent L-Protein Inhibitor for the Treatment of RSV

    EDP-323, A Potent L-Protein Inhibitor for the Treatment of RSV EDP-323… • is a non-nucleoside inhibitor of the RSV RdRp protein inhibiting both viral replication and transcription • is active against both RSV-A and RSV-B subtypes with low picomolar EC50s in multiple primary human cell culture system

  20. Slide 20: Acknowledgements

    Acknowledgements Enanta Pharmaceuticals, Inc.’s RSV Team: • Chemistry: Yat Sun Or, In Jong Kim, Jianming Yu, Adam Szymaniak, Kevin McGrath, Tyler Mann • Virology: Nicole McAllister, Nalini Bisht, Rachel Levene, Joyce Sweeney Gibbons, Nathan Manalo, Bryan Goodwin • DMPK: Lijuan Jiang, Indy Zhang • Bi

  21. Slide 21: Questions?

    Thank you! Questions? © 2022 Enanta Pharmaceuticals, Inc. | 21

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