Beyond PARP - Next Generation DDR Therapeutics Q1 2017
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
Sierra Oncology A clinical-stage drug development • We are an ambitious oncology drug company advancing next generation development company oriented to DNA Damage Response (DDR) registration and commercialization. therapeutics for the treatment of • We have a world-class management patients with cancer. team with a proven track record in oncology drug development. NASDAQ: SRRA • Our two product candidates, SRA737 and SRA141, target the DNA Damage Headquarters: Vancouver, BC Response (DDR) network, a Development: San Francisco, CA scientifically validated approach on Pro forma Shares (12/31/16): the leading edge of cancer biology 52.7M* outstanding with broad potential across oncology. 59.3M* fully diluted • Our DDR program expands beyond Pro forma Cash on hand (12/31/16): PARP inhibitors, to provide for broader $136.3M* clinical and commercial opportunity. *includes February 2017 financing (~$27.3M; 21.8M shares) net of underwriting discounts, commissions and offering expenses. SIERRA ONCOLOGY 3
Our Pipeline of ‘Next Generation’ DDR Therapeutics Preclinical Phase 1 Phase 2 SRA737 Targeting Checkpoint kinase 1 (Chk1) Phase 1 Monotherapy Adult solid tumors, Currently enrolling Phase 1 Combination Adult solid tumors, Currently enrolling SRA141 Targeting Cell division cycle 7 (Cdc7) Plan to file IND H2 2017 4 SIERRA ONCOLOGY
Our Next Generation DDR Portfolio: SRA737 & SRA141 • Highly-selective small molecule inhibitor • Highly-selective small molecule inhibitor of the serine-threonine kinase Cell of the serine-threonine kinase division cycle 7 (Cdc7). Checkpoint kinase 1 (Chk1). • Cdc7 is a key regulator of DNA • Chk1 is a central regulator of the DDR replication and the DDR network. network and of multiple cell cycle checkpoints. • Broad development scope in solid and liquid tumors. • Oral bioavailability of SRA737 affords greater flexibility in dosing strategies • Mono- and combo- therapy development compared to IV agents. potential. • Currently in two Phase 1 clinical trials in • Clinical studies expected to begin by the patients with advanced cancer. end of 2017. SIERRA ONCOLOGY 5
Beyond PARP: Our DNA Damage Response (DDR) Program SIERRA ONCOLOGY
Our DNA is Under Constant Attack • Our DNA is continuously subject to damage through a variety of endogenous and exogenous mechanisms. SIERRA ONCOLOGY 7
The DDR Network Detects & Repairs Damaged DNA • The DDR network is a system of cellular pathways that monitor and repair DNA damage to maintain genomic integrity throughout the cell cycle. • The DDR network comprises cell cycle checkpoints, which temporarily inhibit cellular replication to repair damaged DNA. SIERRA ONCOLOGY 8
Sierra Oncology’s DDR Program: Expanding Beyond PARP • PARP inhibitors are intended to prevent the repair of DNA single strand breaks. • Our DDR program expands beyond the scope of PARP inhibitors. • We focus on impeding the repair of DNA double strand breaks, the most deleterious form of DNA damage, as well as by striking at targets that control DNA replication and cell cycle progression. SIERRA ONCOLOGY 9
Burgeoning Scientific Validation for Targeting DDR Focus Issue: DNA Damage Repair June 2016 June 2016 SIERRA ONCOLOGY 10
Industry Validation of DDR’s Potential in Cancer: PARP Inhibitors Lead The Way May 2016 SIERRA ONCOLOGY 11
Clinical Proof of Concept for Drugging the DDR: Key Data Summary PARP inhibitor: • 14/16 (88%) response rate in metastatic prostate in a retrospective olaparib analysis of biomarker positive patients with DDR mutations. • 2 PRs in SCLC; both patients had mutations in TP53 and RB1 , one also Wee1 inhibitor: had BRCA1 mutation. AZD1775 • 2 PRs in monotherapy: 1 PR head-and-neck had BRCA mutation, 1 PR in ovarian had BRCA mutation. • 27% PR rate in combo with carboplatin in TP53 mutated ovarian cancer refractory/resistant to carboplatin + paclitaxel. ATR inhibitor: • 4 PRs (17%), 12 SDs (52%) in combination with cisplatin in platinum resistant or refractory ovarian cancer with no patient VX-970 selection/enrichment. • 5/13 PRs (38%) response rate in high grade serous ovarian cancer, non- Chk1/2 inhibitor: BRCA mutated. LY2606368 • Durable 3+ year CR in combinations with irinotecan in invasive small cell Chk1/2 inhibitor: cancer of the ureter having RAD50 and TP53 mutations. AZD7762 • 1 CR (ongoing >9 months) in sarcoma with lung metastases; 1 PR Chk1 inhibitor: (lasted >1 year) in TP53 mutated leiomyosarcoma with extensive GDC-0575 metastases; both in combination with low dose gemcitabine. SIERRA ONCOLOGY 12
SRA737 Targeting Chk1 SIERRA ONCOLOGY
SRA737: Exemplary Pedigree Discovered and advanced into the clinic by: CRUK/ICR drug discovery track record: Abiraterone (Zytiga) for advanced prostate cancer >$2B ww sales* *2016 Temozolomide for glioblastoma >$1B ww sales* *2008 SIERRA ONCOLOGY 14
SRA737: Potential Best-In-Class Characteristics Criterion SRA737 LY2606368 Presentation: i.v. Oral Biochemical IC 50 : Chk1 ~1 nM 1.4 nM Biochemical IC 50 : Chk2 1850 nM 8 nM 10 mg/kg in BALB/c mice Selectivity: Chk1 vs. Chk2 1320x ~10x HT29 CRC • SRA737 is orally bioavailable, potent, and highly selective for Chk1 over Chk2. • SRA737 selectivity: 15/124 kinases at 10 µM ERK8 = 100x All other kinases >200x • SRA737 has an excellent PK CDK2 = 2750x profile, and demonstrates robust CDK1 = 6750x efficacy in numerous in vivo cancer models as a single agent and in combination. Cmin SIERRA ONCOLOGY 15
Two Key Roles for Chk1: An Important DDR Component • DNA damage can be resolved by several complementary mechanisms that are activated by DNA damage sensing factors. • Homologous recombination repair (HRR) is an error-free repair process employed in response to double strand breaks and collapsed replication forks. • One of Chk1’s functions is as a critical component of the HRR machinery. SIERRA ONCOLOGY 16
Two Key Roles for Chk1: A Critical Cell Cycle Checkpoint • Replication stress induced by oncogenic drivers (e.g. MYC and RAS) combined with loss of function in tumor suppressors (e.g. TP53 and ATM) results in persistent DNA damage and genomic instability. • Cancer cells tolerate genomic instability and elevated DNA damage due to an over-reliance on Chk1, a key S Phase and G2/M checkpoint . SIERRA ONCOLOGY 17
SRA737 Targeting Chk1: Striking at an Achilles’ Heel of Cancer • Synthetic lethality may be achieved in these genetically mutated cancer cells by inhibiting Chk1, a critical remaining component of the DDR network that is now essential to replication. • With Chk1 inhibited by SRA737, tumor cells are expected to proceed through the S Phase and G2/M checkpoints, leading to mitotic catastrophe resulting in cell death. SIERRA ONCOLOGY 18
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