Beyond PARP - Next Generation DDR Therapeutics

Transcription

1 Beyond PARP - Next Generation DDR Therapeutics September 19, 2017

2 Safe Harbor Statement Except for statements of historical fact, any information contained in this presentation may be a forward-looking statement that reflects the Company s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances that may cause events or the Company s actual activities or results to differ significantly from those expressed in any forward-looking statement. In some cases, you can identify forward-looking statements by terminology such as may, will, should, plan, predict, expect, estimate, anticipate, intend, goal, strategy, believe, and similar expressions and variations thereof. Forward-looking statements may include statements regarding the Company s business strategy, potential growth opportunities, clinical development activities, the timing and results of preclinical research, clinical trials and potential regulatory approval and commercialization of product candidates. Although the Company believes that the expectations reflected in such forward-looking statements are reasonable, the Company cannot guarantee future events, results, actions, levels of activity, performance or achievements. These forward-looking statements are subject to a number of risks, uncertainties and assumptions, including those described under the heading Risk Factors in documents the Company has filed with the SEC. These forward-looking statements speak only as of the date of this presentation and the Company undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date hereof. Certain information contained in this presentation may be derived from information provided by industry sources. The Company believes such information is accurate and that the sources from which it has been obtained are reliable. However, the Company cannot guarantee the accuracy of, and has not independently verified, such information. Trademarks: The trademarks included herein are the property of the owners thereof and are used for reference purposes only. Such use should not be construed as an endorsement of such products. SIERRA ONCOLOGY 2

3 Our Pipeline of Next Generation DDR Therapeutics Preclinical Phase 1 Phase 2 SRA737 Chk1 Targeting Checkpoint kinase 1 Phase 1 Monotherapy Advanced solid tumors, Currently enrolling Phase 1 Chemotherapy Combination Advanced solid tumors, Currently enrolling NASDAQ: SRRA SRA141 Cdc7 Targeting Cell division cycle 7 Plan to file IND H Headquarters: Vancouver, BC Shares (06/30/17): 52.3M outstanding 60.0M fully diluted Cash on hand (06/30/17): $116.7M SIERRA ONCOLOGY 3

4 Monotherapy Phase 1: Innovative Trial Design to Show Synthetic Lethality Jan 2017: Sierra assumes sponsorship of SRA737 May 2017: Amendment cleared by regulators June 2017: Progress update Early 2018: Preliminary R&D update H2 2018: Medical conference data Continued dose escalation to MTD Fall 2016: CRUK-sponsored Ph1 monotherapy dose escalation initiated (advanced solid tumors) Parallel MTD determination and cohort expansion in genetically-defined patient populations. Continuous daily oral administration. Prospective patient selection using NGS technology + / / Prostate Ovarian Non-Small Cell Lung Head & Neck Colorectal SIERRA ONCOLOGY 4

5 Chemotherapy Combination Phase 1: Leverages Potentiation & Synthetic Lethality Jan 2017: Sierra assumes sponsorship of SRA737 May 2017: Amendment cleared by regulators Early 2018: Preliminary R&D update H2 2018: Medical conference data Low-dose gem combo dose escalation Bladder Fall 2016: CRUK-sponsored Ph1 cis-gem combination dose escalation initiated (advanced solid tumors) Low-dose gemcitabine combination. Intermittent oral dosing following each dose of chemotherapy. Prospective patient selection using NGS technology + / / + Pancreatic SIERRA ONCOLOGY 5

6 Breadth of Development Opportunities Reflected in Sierra s Development Strategy Current Clinical Trials Monotherapy Chemotherapy Combination Exploit synthetic lethality in genetically-defined patient populations across five tumor types that have predicted high sensitivity to SRA737. Exploit profound potentiating effects of SRA737 with low dose gemcitabine plus synthetic lethality in genetically-defined populations in two tumor types. Potential Clinical Opportunities PARP Combo I/O Combo Exploit synergy between SRA737 + PARP inhibitor to expand/enhance PARP inhibitor sensitivity / overcome resistance. Explore PD-(L)1 combination and its potential to drive neoantigen presentation in double checkpoint strategy. SIERRA ONCOLOGY 6

7 DDR Advisory Committee Leading DDR Experts Represented by leading experts in DDR biology, chemistry and medicine; Providing advice on our DDR oriented development programs with a focus on maximizing the potential clinical and commercial deployment of our drug candidates. Eric J. Brown, PhD Associate Professor of Cancer Biology at the Perelman School of Medicine of the University of Pennsylvania. Karlene Cimprich, PhD Vice Chair and Professor of Chemical and Systems Biology at the Stanford University School of Medicine. Alan D. D'Andrea, MD Fuller-American Cancer Society Professor of Radiation Oncology at Harvard Medical School and the Director of the Center for DNA Damage and Repair at the Dana-Farber Cancer Institute. Alan R. Eastman, PhD Professor at the Geisel School of Medicine at Dartmouth and the founding Director of the Molecular Therapeutics Research Program of the Norris Cotton Cancer Center at Dartmouth. Michelle D. Garrett, PhD Professor of Cancer Therapeutics in the School of Biosciences at the University of Kent and Visiting Professor of Cancer Therapeutics at the Institute of Cancer Research, London, UK. Thomas Helleday, PhD The Torsten and Ragnar Söderberg Professor of Translational Medicine and Chemical Biology at Karolinska Institutet, Stockholm, Sweden. Leonard Post, PhD Chief Scientific Officer of Vivace Therapeutics; former CSO of BioMarin Pharmaceuticals. SIERRA ONCOLOGY 7

8 Thomas Helleday, PhD Translational research focused on DNA repair, DNA-damage and novel oncology drug development. First group to demonstrate PARPi with synthetic lethality in BRCA1/2 mutated cancers. Published extensively on the ATR/Chk1 pathway; established Chk1/ATR synthetic lethal relationship. Awarded numerous grants and awards including the Eppendorf-Nature Young European Investigator Award (2005) and European Research Council advanced grants (2010 and 2016). Thomas Helleday, PhD The Torsten and Ragnar Söderberg Professor of Translational Medicine and Chemical Biology at Karolinska Institutet, Stockholm, Sweden. SIERRA ONCOLOGY 8

9 Beyond PARP - Next Generation DDR Therapeutics Thomas Helleday 9/19/2017 9

10 DISCLOSURE: I have the following financial relationships to disclose: Royalty from PARP inhibitor sales Obtaining funding from Helleday Foundation Shareholder in: Oxcia AB Consultant for Sierra Oncology Slides and Opinion expressed here are my own and not that of Sierra Oncology 9/19/

11 DNA repair inhibitors to exploit high DNA damage load in tumours Controlled replication ORI ORI ORI ORI ORI initiation + oncogene Replication stress promotion + Oncogene ORI ORI ORI ORI ORI Oncogene-induced replication stress DNA repair defect progression Hypoxia DNA repair Replication lesion No DNA repair metastasis CELL SURVIVAL Mis-repair gives genetic instability Fatal Replication lesions CELL DEATH DNA repair inhibitor 9/19/

12 Clinical strategies targeting the DDR 9/19/2017 Jackson and Helleday 2016 Science 352:

13 Clinical strategies targeting the DDR Synthetic Lethality 9/19/2017 Jackson and Helleday 2016 Science 352:

14 Clinical strategies targeting the DDR Synthetic Lethality Classical Synthetic Lethality 9/19/2017 Jackson and Helleday 2016 Science 352:

15 Genetic buffering a limitation to effective synthetic lethality No genetic buffering Synthetic lethal 100% 80% A B Survival 60% 40% 20% Therapeutic index A -/- A +/+ 0% [B inhibitor] High genetic buffering Synthetic sick 100% 80% D A C B Survival 60% 40% 20% A -/- A +/+ Therapeutic index 0% [B inhibitor] 9/19/

16 Genetic buffering a limitation to effective synthetic lethality No genetic buffering Synthetic lethal 100% 80% Survival Therapeutic index 60% 40% A B A -/- A o Extensive genetic buffering +/+ 20% few examples of strong SL 0% [B inhibitor] o Cancers High geneticcan buffering change genotype Synthetic sick 100% 80% Therapeutic index o Intra tumour heterogeneity 60% is biopsy representative? D Survival 40% A C B A -/- A +/+ 20% o Predict phenotype from genotype? Microenvironment? 0% [B inhibitor] 9/19/

17 ARID1A ATR/CHK1 inhibitors in classical synthetic lethality ERCC1 HPV+ Williamson et al 2016 Nat Commun. 7: BRCA/FA We need more sequencing of patients!! A smart trial should enrich for patients with mutation!! 9/19/ Mohni et al 2014 Cancer Res. 74(10):

18 Replication stress is a source for endogenous DNA damage in cancer 9/19/ Sørensen and Dobbelstein 2015 Nat Rev Drug Discov. 14:

19 CHK1 inhibitors target cancers with high replication stress Myc-driven lymphoma High levels of CHK1 Improved survival in myc-driven cancer Hoglund et al 2011 Clin Cancer Res; 17(22); Murga 9/19/2017 et al., 2011 Nat Struct Mol Biol. 18(12):

20 CHK1 inhibitors target cancers with high replication stress Myc-driven neuroblastoma 9/19/

21 CHK1 inhibitors target cancers with high replication stress Myc-driven lymphoma but not K-Ras driven pancreatic cancer Mutation context dependent Murga 9/19/2017 et al., 2011 Nat Struct Mol Biol. 18(12):

22 ATR inhibitors target cancers with high replication stress We need clinical biomarker for replication stress!! Nieto-Soler et al 2016 Oncotarget. 7: /19/

23 Replication stress in cancers Sørensen and Dobbelstein 2015 Nat Rev Drug Discov. 14: CHK1i CHK1i normal pre-neoplastic cancer apoptosis 9/19/

24 The treatment history and genomic landscape of a metastatic carcinoma with an extreme outlier response to combination therapy. ATM defective and Rad50 mutation made this patient extremely responsive to CHK1i Hikmat Al-Ahmadie et al. Cancer Discovery 2014;4: /19/

25 Replication stress in cancers Sørensen and Dobbelstein 2015 Nat Rev Drug Discov. 14: CHK1i CHK1i normal pre-neoplastic cancer A apoptosis ATM null Rad50 mut cancer C CHK1i 9/19/

26 Replication stress in cancers Sørensen and Dobbelstein 2015 Nat Rev Drug Discov. 14: CHK1i CHK1i normal pre-neoplastic cancer A apoptosis ATM null Rad50 mut cancer C CHK1i ATRi 9/19/ apoptosis

27 Induced synthetic lethality with ATR-CHK1 combination Sanjiv et al 2016 Cell Research7:428 9/19/

28 Induced synthetic lethality with PARP-CHK1 combination 9/19/

29 Induced synthetic lethality with PARP-CHK1 combination CHK1i 9/19/

30 Induced synthetic lethality with PARP-CHK1 combination 9/19/ Tang et al., 2012 Mol Pharmacol. 82(2):

31 Clinical strategies targeting the DDR 9/19/ Jackson and Helleday 2016 Science 352:1178-9

32 CHK1 inhibitors in potentiating gemcitabine treatment High Gem Dose Infante et al., 2017 Clin Cancer Res; 23(10) May 15 9/19/

33 CHK1 inhibitors in potentiating gemcitabine treatment Mutations? 8/40 benefitted? Infante et al., 2017 Clin Cancer Res; 23(10) May 15 9/19/

34 A phase II study to evaluate LY in combination with gemcitabine in pancreatic cancer patients Laquente 2017 BMC Cancer. 17: /19/

35 Non-BRCA ovarian cancers also respond to olaparib 9/19/ Gelmon KA et al. Lancet Oncol 2011;12(9):

36 Non-BRCA ovarian cancers also respond to olaparib Eligible patients had completed at least two courses of platinum-based chemotherapy Ledermann et al. Lancet Oncol (11): Ledermann et al. N Engl J Med (15): /19/

37 Non-BRCA ovarian cancers also respond to olaparib Eligible patients had completed at least two courses of platinum-based chemotherapy Ledermann et al. Lancet Oncol (11): Ledermann et al. N Engl J Med (15): August LYNPARZA (olaparib) receives additional FDA approval in the US for ovarian cancer New use of LYNPARZA tablets as a maintenance treatment of adult patients with recurrent, epithelial ovarian, fallopian tube or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, regardless of BRCA status AZ update in press release March /19/

38 CHK1 inhibitors in SCLC 9/19/

39 CHK1 and PARP inhibitor Combination in SCLC 9/19/

40 Clinical opportunities with CHK1 inhibitors o MYC driven cancer in monotherapy (Cyc E or other replication stress) o Gem-CHK1 combo (get in early low gem high CHK1) o Targeted combo with ATR/PARP (wee1) inhibitors 9/19/

41 Clinical challenges with CHK1 inhibitors o Biomarker for replication stress o Most exploitable mutation for monotherapy? o Management of toxicity with combination with chemotherapy o Which targeted therapies to combine with CHK1 inhibitor? o IO combo. 9/19/

42 Increasing immunogenicity by targeting the DDR CHK1i cdc7i Improved response to immune checkpoint inhibitors 9/19/ /19/2017 O Connor et al., 2015 Mol Cell 60:547-60

43 Increasing immunogenicity by targeting the DDR +DDR inhibitor Improved response to immune checkpoint inhibitors Liang et al., J Immunol : /19/ /19/2017 O Connor et al., 2015 Mol Cell 60:547-60

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