Next Generation DDR Therapeutics Q1 2018
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, cash flows and funding status, 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. 2 SIERRA ONCOLOGY
Sierra Oncology A clinical-stage drug development company advancing next generation DNA Damage Response (DDR) therapeutics for the treatment of patients with cancer. NASDAQ: SRRA Headquarters: Vancouver, BC We are an ambitious oncology drug Shares (09/30/17) : development company oriented to 52.3M outstanding registration and commercialization. 60.0M fully diluted Cash on hand (09/30/17) : $107.8M We have a highly experienced management team with a proven track record in oncology drug development. 3 SIERRA ONCOLOGY
Proven Leadership in Oncology Development Nick Glover, PhD President and CEO Barbara Klencke, MD Chief Development Officer Mark Kowalski, MD, PhD Chief Medical Officer Angie You, PhD Chief Business & Strategy Officer and Head of Commercial Christian Hassig, PhD Chief Scientific Officer Sukhi Jagpal, CA, CBV, MBA Chief Financial Officer 4 SIERRA ONCOLOGY
Our Pipeline of ‘Next Generation’ DDR Therapeutics Preclinical Phase 1 Phase 2 Targeting Checkpoint Monotherapy kinase 1 Five indications; prospective genetic selection Low-Dose Gemcitabine Combination Advanced solid tumors PARPi Combination Potential clinical study in 2018 I/O Combination Potential clinical study in 2018 Targeting Cell division cycle 7 kinase IND enabling studies SIERRA ONCOLOGY 5
SRA737: Our Chk1 Inhibitor Program SIERRA ONCOLOGY
The DNA Damage Response Network Replication Cell Oxygen Viral stress metabolism infection radicals Radiation Chemotherapy ENDOGENOUS EXOGENOUS DNA Damage monitor and detect DNA damage G1 / S Checkpoint Single strand Double strand Stalled replication Cell Cycle breaks breaks forks Base Excision Homologous Recombination G2 / M Repair (BER) Repair (HRR) Checkpoint S Phase Checkpoint trigger DNA repair pause the cell cycle SIERRA ONCOLOGY 7
Pathologic DNA Replication is Fundamental to Cancer “Cancer. . . is a genome that becomes pathologically obsessed with replicating itself. . .” Dr. Siddhartha Mukherjee, Oncologist Pulitzer Prize winning author of The Emperor of All Maladies & The Gene Replication Stress (RS) Hyperproliferation and dysregulated DNA replication result in Replication Stress manifested by stalled replication forks and DNA damage, leading to increased genomic instability, a fundamental hallmark of cancer. 8 SIERRA ONCOLOGY
Replication Stress Drives Genomic Instability Defective DNA damage repair Cell cycle dysregulation e.g. Single strand breaks, e.g. Loss of G1/S double strand breaks TP53 Defective G1 / S BRCA 1/2 Checkpoint HPV High RS Oncogenic drivers Depleted replication building results in: blocks e.g. Dysregulation of replication, transcription/ replication collision e.g. Chemotherapy induced RAS MYC Cancer cell survives with increased mutagenic capacity Excessive genomic instability results in cancer cell death Cell Death Normal Cell Genomic Instability 9 SIERRA ONCOLOGY
Chk1 is a Master Regulator of the Replication Stress DNA Damage Response Cell Cycle Regulation Chk1 pauses the cell cycle to enable Chk1 regulates origin firing to manage replication stress DNA repair Defective Chk1 Chk1 G1 / S Checkpoint Chk1 Chk1 mediates DNA repair via Chk1 stabilizes stalled HRR replication forks Cancer Cell Cycle Chk1 Double strand breaks G2 / M Checkpoint S Phase BRCA 1/2 ATM Checkpoint Chk1 Stalled replication forks Chk1 Chk1 G1/S-defective cancer cells are reliant on HRR = Homologous Recombination Repair Chk1-regulated cell cycle checkpoints SIERRA ONCOLOGY 10
Chk1 Inhibition Drives High-RS Cancer Cells Into Catastrophic Genomic Instability Chk1 Chk1 inhibition results in catastrophic Chk1 Cancer cells are dependent on Chk1 dysregulation of replication, leading to to manage high levels of RS and survive cancer cell death RS increases RS increases genomic instability genomic instability Cancer Cell Replicates Chk1 Chk1 regulates RS Normal Cell Normal Cell Cell Death Genomic Instability Genomic Instability Excessive genomic instability results in cancer cell death 11 SIERRA ONCOLOGY
Chk1i Synthetic Lethality Associated with RS Genes Preclinical and emerging clinical data support that Chk1i sensitivity is associated with genetic backgrounds linked to increasing replication stress Gene Class Biological Rationale Dysregulated Cell Cycle Defective G1/S checkpoint increases reliance on (e.g. TP53 , RAD50 , etc.) remaining Chk1-regulated DNA damage checkpoints Oncogene-induced replication and transcription results Oncogenic Drivers in transcription/replication collisions, dysregulation of (e.g. MYC , KRAS , etc.) replication and dNTP exhaustion, driving RS Mutated DNA repair genes results in excessive DNA DNA Repair Machinery damage, increased RS and increase reliance on Chk1- (e.g. BRCA1 /2, FA, etc.) mediated DNA repair and/or cell cycle functions Replicative Stress Amplification of genes encoding ATR or Chk1 suggests Response greater reliance on Chk1 pathway to accommodate RS ( ATR , CHEK1 ) 12 SIERRA ONCOLOGY
SRA737: Originates from Renowned Drug Discovery Group with Proven Track Record Drug discovery track record: Discovered and advanced into the clinic by: Temozolomide for glioblastoma >$1B ww sales* *2008 Abiraterone (Zytiga) for advanced prostate cancer >$2B ww sales* *2016 13 SIERRA ONCOLOGY
SRA737 – Potentially Superior Chk1 Inhibitor Profile SRA737 @ 100nM • SRA737’s potency, selectivity and oral bioavailability could enable a superior efficacy and safety profile. Criterion SRA737 Prexasertib GDC-0575 Stage of Ph1 Ph2 Ph1 development: Presentation: Oral i.v. Oral Biochemical IC 50 : 1.4 nM ~1 nM 2 nM Cmin Chk1 Biochemical IC 50 : SRA737 selectivity: 1850 nM 8 nM unk Chk2 • 15/124 kinases at 10 µM • ERK8 = 100x Selectivity: 1320x ~10x >30x • All other kinases >200x Chk1 vs. Chk2 • CDK2 = 2750x • CDK1 = 6750x • SRA737 patent protection to 2033+. 14 SIERRA ONCOLOGY
SRA737 Phase 1/2 Monotherapy Synthetic Lethality Trial SIERRA ONCOLOGY
Clinical Validation of Chk1i Monotherapy with Emerging Data for Prexasertib (LY2606368) Lancet Oncology 2018: Tumor Type Efficacy Phase 2 study in high-grade serous HGSOC 33% ORR (8/24) Evaluable ovarian cancer. Heavily pre-treated. (BRCAwt) 32% ORR (6/19) Platinum resistant BRCA wild type (PARP insensitive). 58% DCR (11/19) Platinum resistant Dosed 1 out of every 14 days. Clinical validation of: • the target • genetic selection strategy • monotherapy 16 SIERRA ONCOLOGY
Clinical Validation of Chk1i Monotherapy with Emerging Data for Prexasertib (LY2606368) AACR 2017 Poster: Tumor Type Disease Control Rate (CR+PR+SD) Phase 1b monotherapy expansion HNSCC 60% (28/47): 3 PRs cohort data in advanced head and neck squamous cancers and SCCA 75% (18/24); 1 CR, 4 PRs squamous cell carcinoma of the anus. Dosed 1 out of every 14 days. Patients with favorable responses harbored: • Loss of function mutations in FBXW7 and SCCA Cohort PARK2 , two genes implicated in Cyclin E1 proteolysis. • Mutations and/or germline variants in DDR genes: BRCA1, BRCA2, MRE11A and ATR . Clinical validation of: • the target • genetic selection strategy • monotherapy 17 SIERRA ONCOLOGY
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