PRESAGE CIVO: A NOVEL PLATFORM FOR PRECISION ONCOLOGY & DRUG DEVELOPMENT

Transcription

1 PRESAGE : A NOVEL PLATFORM FOR PRECISION ONCOLOGY & DRUG DEVELOPMENT DECEMBER 2017 Presage Biosciences, Inc All rights reserved. Presage Proprietary Biosciences, information. Inc All rights reserved. Proprietary information.

2 THE TUMOR MICROENVIRONMENT: MANY INTERACTIONS CTL Cancer 2

3 PREDICTING RESPONSES OF COMPLEX SYSTEMS IS DIFFICULT Genomics = Precision medicine? BCR-ABL, EGFR, BRAF SHIVA 741 tumor samples screened Functional 40% with alterations precision that could cancer be matched with a targeted agent No difference in PFS between matched and physicians choice medicine approaches are needed to COMPLEMENT genomics NCI-MATCH 2000 tumors screened 789 (39%) with actionable genetic alterations (to 1 of 10 treatments arms) 83 (4.2%) enrolled in a genotype-matched trial Clinical response not reported 3

4 A toxicity-sparing, 6 1 trackable way 8 to test 7 multiple anti-cancer 2 agents 56 simultaneously and 1 8 directly in a patient s tumor Tumor Response

5 DRUG DEVELOPMENT PLATFORM Microinjection Tumor Response 5 > 100 IHC Readouts Proliferation/Viability Cell metabolism Cancer pathway activity Immune infiltrate TME Image Analysis

6 PLATFORM PAPER PUBLISHED APRIL 2015 is: Predictive Scalable Clinically Feasible 6

7 CLEAR AND DEFINED DRUG RESPONSES IN CANINE SOFT TISSUE SARCOMAS Canine soft tissue sarcoma Gemcitabine Docetaxel 3 4 Doxorubicin 7 Frazier, Bertout, et al. Cancer Research 2017

8 DETECTS CANCER CELL & IMMUNE DRUG RESPONSES CD3/GrB/DAPI Docetaxel Doxorubicin 8 T-cells (CD3)

9 WHAT S BEEN DONE, WHERE WE RE HEADING Evaluated in thousands of mice, 81 canine patients with cancer, and 6 human subjects. 8 patents issued and 6 peer-reviewed publications Potential for CDx development in the future Currently focusing on Phase 0 assessment of partner assets De novo FDA approval will be sought to broaden access. Study of investigational agents is currently possible under collaborator s IND. 9

10 PHASE 0 OPPORTUNITY Biological insights and early human data to inform go/no go decisions Captures drug, tumor, immune infiltrate and microenvironment interactions in the context that matters the human patient Enables assessment of Pre-IND drug efficacy in Phase 0 setting ~12 months earlier minimal toxicology and CMC package vs full IND package for Phase 1 study First Phase 0 clinical study with a Pre-IND candidate set for initiation - Fall 2018! (Top) Macrophage infiltration and polarization and (Bottom) T- cell recruitment in a canine patient with STS 10

11 HUMAN SARCOMA STUDY Primary Objective Assess feasibility - Demonstrate local and quantifiable responses Secondary Objectives - Determine extent of patient discomfort - Determine inter- and intra- tumor variability of local responses Exploratory Objective - Comparison of response to clinical outcome 11

12 LOGISTICS/HAND-OFFS ESTABLISHED PHARMACY(DEVICE LOADING) TO ONCOLOGIST - No device failures. - Loading was easier than anticipated by the pharmacy staff. - Time = 45 minutes. 12

13 SURGERY TO PATHOLOGY No adverse events, no inflammation of site 13

14 MULTI-DRUG ANALYSIS IN HUMAN SARCOMA PATIENTS Gem Gem DNA damage Apoptosis Macrophage Doxorubicin Dox Dtx DNA damage Apoptosis Macrophage Gemcitabine 14 Localized responses match historic responses to same drugs in the STS clinic

15 DOXORUBICIN INDUCED STAT- 3 PHOSPHORYLATION STAT-3 signaling promotes an immunosuppressive microenvironment p-stat3 15

16 LIVE CELLS AT DOX SITE INDICATES MECHANISMS OF CANCER CELL RESISTANCE IN PLAY Doxorubicin 16

17 POTENTIAL MECHANISMS OF RESISTANCE & RATIONAL COMBINATION HYPOTHESES BCL-2 MCL-1 MAPK pathway mtor pathway BCL-2 p4ebp1 (mtor pathway) MCL-1 perk (pmapk) 17

18 IS THIS DRIVEN BY PDGFR ACTIVATION? Lartruvo perk 18

19 ENRICHMENT OF PDGFα R PHOSPHORYLATION AT DOX SITE ppdgfαr 19

20 DOX + LARTRUVO: EXTENDED SURVIVAL Lartruvo 20

21 COMBINATION ASSESSMENT 21

22 CDK9 INHIBITOR VORUCICLIB REPRESSES MCL1 AND SYNERGIZES WITH VENETOCLAX DLBCL xenograft study 22

23 PREDICT SYSTEMIC RESPONSE Tumor growth inhibition Survival analysis p < 0.01 combo vs single agents U2932 ABC DLBCL model 23

24 VORUCICLIB OUT-LICENSED TO MEI 24

25 - POISED TO EVALUATE INVESTIGATIONAL AGENTS IN THE HUMAN CLINIC Technical Engineering/Manufacturing Regulatory Clinical Research Network DNA damage 25

26 NEW DEVELOPMENT: 2.0 FOR IMMUNO-ONCOLOGY Sustained-release micro-inserts Bar-coded by color Durable exposure to capture adaptiveimmune responses 5x 50x DRUG CD8/CD3/FTM Potential to assess dozens of single agent & combination responses in a single tumor 26

27 THANK YOU! 27

28 BACKUP SLIDES 28

29 PRECISION ONCOLOGY : ID OF DOXORUBICIN SENSITIVE AND RESISTANT TUMORS Each dot represents an individual patient Representative examples of patient tumors classified as drug sensitive, and drug resistant Yellow (γh2ax, proxy for drug distribution) top Orange (vimentin, loss of sarcoma cells, biomarker of response) - bottom 29 Frazier et al., Cancer Research, 2017

30 PS (AUTOPHAGY INHIBITOR) INDUCES CONVERSION TO RESPONDER SUBTYPE Distribution Response Doxorubicin + PS-1001 Doxorubicin 30

31 PS PROMOTED A PRO- IMMUNE MICROENVIRONMENT Autophagy inhibition Macrophage response T lymphocyte response 31 Macrophages skewed towards M1

32 BEYOND SMALL MOLECULES Antibodies (Rituxan) LNP-Nucleic acids CD20 GFP 32

33 : HIGH CONCENTRATION/LOW VOLUME DELIVERY Multi-site low volume/high concentration delivery effectively creates a drug-depot like effect without the need for drug reformulation While the core of the depot diminishes with time, drug exposure in the surrounding tissue remains relatively constant 33

34 MICROENVIRONMENT INFLUENCES DRUG EFFICACY Target Drug Apoptosis Hypoxia 34 Presage Biosciences, Inc All rights reserved. Proprietary information.

35 ANALYZER PROVIDES CELL QUANTITATION Drug Response Curves Pathway engagement Apoptosis 11 Presage Biosciences, Inc All rights reserved. Proprietary information.

36 CAN DIFFERENTIATE SENSITIVE VS. RESISTANT TUMORS Chemonaive Chemoexposed Klinghoffer et al., Science Translational Medicine, 22 Apr Presage Biosciences, Inc All rights reserved. Proprietary information.

37 & SYSTEMIC RESPONSE CORRELATE Tumor volume (mm 3 ) Ramos Chemo-naive Vehicle Doxorubicin Res-Ramos Chemo-exposed Vehicle Doxorubicin Vehicle Vincristine Cyclophosphamide Vincristine Cyclophosphamide Doxorubicin Cyclophosphamide Vincristine Tumor volume (mm 3 ) Vincristine Vehicle Doxorubicin Cyclophosphamide Days Days 37 Klinghoffer et al., Science Translational Medicine, 22 Apr 2015 Presage Biosciences, Inc All rights reserved. Proprietary information.

38 DOXORUBICIN IMPACTS EXPRESSION OF PD- L1 PDL-1 PDL-1 38

39 ASSAYS TO INTERROGATE STING Control R484 cgamp DMXAA A20 syngeneic lymphoma ptbk-1 39

40 ASSAYS TO INTERROGATE STING Control R484 cgamp DMXAA A20 syngeneic lymphoma pirf-3 40

41 FUNCTIONAL BIOMATERIAL CARRIER SYSTEM FOR IMMUNOMODULATING CARGO 20G size implant Fluorescent Tracking Marker and Drug loaded microimplant IN- VIVO DRUG RELEASE BY DIFFUSION AND DEGRADATION 0 hr 74 hr DRUG CD8/CD3/FTM 5x 50x 100 vs. vehicle Cumulative Release (%) Time (days) 10 CD8/CD3/FTM 41 free drug in matrix microsphere encapsulated drug

42 STING PANEL PHOSPHO-TBK1 Control R484 cgamp DMXAA 42

43 STING PANEL PHOSPHO-IRF3 Control R484 cgamp DMXAA 43

44 STING PANEL IRF3 NUCLEAR TRANSLOCATION 44

45 STING PANEL IFN-BETA Control R484 cgamp DMXAA 45

46 ISRE-GFP:DEVELOPMENT OF SYNGENEIC REPORTER LINES (UPDATE) Interferon Stimulated Response Element GFP reporter IFN-responsive clones identified for expansion Untreated + IFNα IFNß ISRE 8x Clonal 4T1 cells 46