Next Generation DDR Therapeutics Q2 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’s Management Team: 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 3 SIERRA ONCOLOGY
Sierra Oncology: Next Generation DDR Therapeutics 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 Shares (03/31/18) : We are an ambitious oncology drug development company oriented to 74.3M outstanding registration and commercialization. 84.5M fully diluted Cash and cash equivalents (03/31/18) : $133.8M We have a highly experienced management team with a proven track record in oncology drug development. 4 SIERRA ONCOLOGY
Our Pipeline Of ‘Next Generation’ DDR Therapeutics: Preclinical Phase 1 Phase 2 Targeting Checkpoint Monotherapy (Six Indications) kinase 1 Target N=120 (20x6) Low Dose Gemcitabine Combination (Four Indications) Target N=80 (20x4) PARPi Combination (Prostate) Study expected to be initiated Q4 2018 I/O Combination Study expected to be submitted Q4 2018 Targeting Cell division cycle 7 kinase Monotherapy (Colorectal) IND expected to be submitted H2 2018 5 SIERRA ONCOLOGY
SRA737: Our Chk1 Inhibitor Program 6 SIERRA ONCOLOGY
Introduction: The DNA Damage Response Network Replication Cell Oxygen Viral Chemotherapy stress metabolism radicals Radiation infection 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 7 SIERRA ONCOLOGY
Replication Stress: 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 – A Hallmark of Cancer 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 HPV Checkpoint High RS Oncogenic drivers Depleted replication building results in: blocks e.g. Dysregulation of replication, transcription/ replication collision e.g. Chemotherapy induced CCNE1 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
Replication Stress: Chk1 Is A Master Regulator Of Replication Stress DNA Damage Response Cell Cycle 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 10 SIERRA ONCOLOGY
High Replication Stress Cancer Cells: Chk1 Inhibition Drives 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
SRA737 Background: Potentially Superior Chk1 Inhibitor Profile • SRA737’s potency, selectivity and oral bioavailability could SRA737 @ 100nM potentially enable a superior efficacy and safety profile. Criterion SRA737 Prexasertib GDC-0575 Stage of Ph1/2 Ph2 Ph1/2 development: Oral Presentation: i.v. Oral Cmin Biochemical IC 50 : 1.4 nM ~1 nM 1.2 nM 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. 12 SIERRA ONCOLOGY
SRA737-01: Monotherapy Development Strategy 13 SIERRA ONCOLOGY
SRA737-01 Monotherapy – Dose Escalation: Encouraging First-in-human Phase 1 Experience In our view, a safe, well tolerated, potent, selective, orally-administered Chk1i represents the optimal asset profile for further advancement, both as monotherapy and in a variety of combination settings. • PK has been broadly dose-linear; very good exposures achieved. • SRA737 appears to have a wide therapeutic window, as predicted from preclinical and toxicological modelling. • Majority of reported AEs are Grade 1 or Grade 2 in severity. • Most commonly observed AEs (≥20%; all reported causalities) are fatigue and GI events (diarrhea, nausea, vomiting). • Dose escalation complete; dose optimization in progress. • Safety data reinforce that SRA737 has a differentiated and improved toxicity profile versus Lilly’s prexasertib, the most advanced Chk1i development candidate. • These data support a potential best-in-class profile for SRA737. (As reported Feb. 27, 2018; Data cut-off Feb. 1, 2018; N = 31) 14 SIERRA ONCOLOGY
Replication Stress: Patient Selection Algorithm For High RS Cancers Genetic selection: Two or more mutations, from any class* Multiple genetic drivers of RS increases overall level Defective DNA damage Cell cycle dysregulation of genomic instability, repair and associated reliance TP53 Defective on Chk1 G1 / S BRCA 1/2 HPV Checkpoint Chk1 Results in high RS Replicative Stress Oncogenic drivers Cell Response Genomic Instability Death MYC CCNE1 ATR Chk1i leads to excessive genomic instability resulting in cancer cell death *Illustrative genes depicted. e.g. TP53 + MYC ; TP53 + ATR , etc. 15 SIERRA ONCOLOGY
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