Beyond PARP - Next Generation DDR Therapeutics Q1 2017 Safe Harbor - - PowerPoint PPT Presentation

Beyond PARP - Next Generation DDR Therapeutics

Q1 2017

SIERRA ONCOLOGY

Safe Harbor Statement

2

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

Sierra Oncology

3

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 Development: San Francisco, CA Pro forma Shares (12/31/16): 52.7M* outstanding 59.3M* fully diluted Pro forma Cash on hand (12/31/16): $136.3M*

*includes February 2017 financing (~$27.3M; 21.8M shares) net of underwriting discounts, commissions and offering expenses.

• We are an ambitious oncology drug

development company oriented to registration and commercialization.

• We have a world-class management

team with a proven track record in

• ncology drug development.
• Our two product candidates, SRA737

and SRA141, target the DNA Damage Response (DDR) network, a scientifically validated approach on the leading edge of cancer biology with broad potential across oncology.

• Our DDR program expands beyond

PARP inhibitors, to provide for broader clinical and commercial opportunity.

SIERRA ONCOLOGY

Our Pipeline of ‘Next Generation’ DDR Therapeutics

4

Preclinical Phase 1 Phase 2 Targeting Cell division cycle 7 (Cdc7)

Phase 1 Monotherapy

Adult solid tumors, Currently enrolling

Phase 1 Combination

Adult solid tumors, Currently enrolling Plan to file IND H2 2017

Targeting Checkpoint kinase 1 (Chk1) SRA737 SRA141

SIERRA ONCOLOGY

Our Next Generation DDR Portfolio: SRA737 & SRA141

5

• Highly-selective small molecule inhibitor
• f the serine-threonine kinase

Checkpoint kinase 1 (Chk1).

• Chk1 is a central regulator of the DDR

network and of multiple cell cycle checkpoints.

• Oral bioavailability of SRA737 affords

greater flexibility in dosing strategies compared to IV agents.

• Currently in two Phase 1 clinical trials in

patients with advanced cancer.

• Highly-selective small molecule inhibitor
• f the serine-threonine kinase Cell

division cycle 7 (Cdc7).

• Cdc7 is a key regulator of DNA

replication and the DDR network.

• Broad development scope in solid and

liquid tumors.

• Mono- and combo- therapy development

potential.

• Clinical studies expected to begin by the

end of 2017.

SIERRA ONCOLOGY

Beyond PARP: Our DNA Damage Response (DDR) Program

SIERRA ONCOLOGY

Our DNA is Under Constant Attack

7

• Our DNA is continuously subject to damage through a variety of endogenous and

exogenous mechanisms.

SIERRA ONCOLOGY

The DDR Network Detects & Repairs Damaged DNA

8

• 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

Sierra Oncology’s DDR Program: Expanding Beyond PARP

9

• 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

Burgeoning Scientific Validation for Targeting DDR

10

Focus Issue: DNA Damage Repair June 2016 June 2016

SIERRA ONCOLOGY

Industry Validation of DDR’s Potential in Cancer: PARP Inhibitors Lead The Way

11

May 2016

SIERRA ONCOLOGY

Clinical Proof of Concept for Drugging the DDR: Key Data Summary

12

PARP inhibitor:

• laparib
• 14/16 (88%) response rate in metastatic prostate in a retrospective

analysis of biomarker positive patients with DDR mutations. Wee1 inhibitor: AZD1775

• 2 PRs in SCLC; both patients had mutations in TP53 and RB1, one also

had BRCA1 mutation.

• 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: VX-970

• 4 PRs (17%), 12 SDs (52%) in combination with cisplatin in platinum

resistant or refractory ovarian cancer with no patient selection/enrichment. Chk1/2 inhibitor: LY2606368

• 5/13 PRs (38%) response rate in high grade serous ovarian cancer, non-

BRCA mutated. Chk1/2 inhibitor: AZD7762

• Durable 3+ year CR in combinations with irinotecan in invasive small cell

cancer of the ureter having RAD50 and TP53 mutations. Chk1 inhibitor: GDC-0575

• 1 CR (ongoing >9 months) in sarcoma with lung metastases; 1 PR

(lasted >1 year) in TP53 mutated leiomyosarcoma with extensive metastases; both in combination with low dose gemcitabine.

SIERRA ONCOLOGY

SRA737 Targeting Chk1

SIERRA ONCOLOGY

SRA737: Exemplary Pedigree

14

CRUK/ICR drug discovery track record: Discovered and advanced into the clinic by: Temozolomide for glioblastoma >$1B ww sales* Abiraterone (Zytiga) for advanced prostate cancer >$2B ww sales*

*2016 *2008

SIERRA ONCOLOGY

SRA737: Potential Best-In-Class Characteristics

15

Criterion SRA737 LY2606368 Presentation: Oral i.v. Biochemical IC50: Chk1 1.4 nM ~1 nM Biochemical IC50: Chk2 1850 nM 8 nM Selectivity: Chk1 vs. Chk2 1320x ~10x

10 mg/kg in BALB/c mice

• SRA737 is orally bioavailable, potent, and

highly selective for Chk1 over Chk2.

• SRA737 has an excellent PK

profile, and demonstrates robust efficacy in numerous in vivo cancer models as a single agent and in combination.

HT29 CRC

• SRA737 selectivity:

15/124 kinases at 10 µM ERK8 = 100x All other kinases >200x CDK2 = 2750x CDK1 = 6750x

Cmin

SIERRA ONCOLOGY

Two Key Roles for Chk1: An Important DDR Component

16

• 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

Two Key Roles for Chk1: A Critical Cell Cycle Checkpoint

17

• 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

• ver-reliance on

Chk1, a key S Phase and G2/M checkpoint.

SIERRA ONCOLOGY

SRA737 Targeting Chk1: Striking at an Achilles’ Heel of Cancer

18

• 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

Biology of SRA737 Sensitivity: Exploiting Cancer’s Genetic Alterations

19

• Synthetic lethality due to Chk1 inhibition

has been linked to four major classes of genetic alterations:

• Tumor suppressors

(e.g. TP53, RAD50, etc.)

• Oncogenic drivers

(e.g. MYC, KRAS, etc.)

• Replicative stress

(e.g. ATR, CHEK1, etc.)

• DNA repair mutations

(e.g. BRCA1, BRCA2, FA, etc.)

• Exogenous drivers of DNA damage, like

chemotherapy, are also demonstrated to enhance SRA737 sensitivity.

• Our clinical approach is to select patients

with defined genetic alterations to create synthetic lethal backgrounds for SRA737 therapy.

SIERRA ONCOLOGY

Optimizing Sensitivity to SRA737 in the Clinic

20

• Most studies with DDR agents focus on one enhancer of sensitivity, e.g. defects in

DDR or TP53 mutation, if at all.

• Sierra Oncology’s hypothesis is that optimal sensitivity is achieved by combining

defects: Combining multiple mechanisms known to enhance Chk1 sensitivity could “stack the deck” in favor of clinical activity with SRA737.

(G1/S guardians) (BRCA1/BRCA2/FA)

Oncogenic Driver

(MYC, KRAS) (ATR/CHEK1) (G1/S guardians) (G1/S guardians)

Exogenous Drivers

+/-

+ + +

Chk1: S & G2/M checkpoint reliance Chk1: DDR & replication stress

SIERRA ONCOLOGY

SRA737: Significant Therapeutic Potential Across Oncology

21

Chemotherapy

Combinations with DNA damaging chemotherapy

DDR Combinations

Synergy with other DDR targeting agents to maximize DNA damage

Radiotherapy

Sensitize to ionizing radiation

Immuno-Oncology

DDR targeting agents coupled with immune activation

DDR Monotherapy

Exploit replicative stress and genetic instability for synthetic lethality

SRA737

SIERRA ONCOLOGY

SRA737: Overall Development Strategy

22

I/O Combo Chemotherapy

Gemcitabine and gemcitabine/cisplatin combinations exploit profound potentiating effects of SRA737. Chk1 inhibitor + PARP inhibitor might expand/enhance PARP inhibitor sensitivity. PD-(L)1 combination marries potential driver

• f neoantigen presentation in “double

checkpoint” strategy.

Monotherapy

Exploit synthetic lethality in genetically- defined populations with predicted high sensitivity to SRA737.

PARP Combo

Potential Clinical Opportunities Current Clinical Trials

SIERRA ONCOLOGY

Two Clinical Trials Initiated at Royal Marsden, UK - Current Study Designs

A Phase I Trial of CCT245737 (SRA737) in Patients with Advanced Cancer

ClinicalTrials.gov Identifier: NCT02797964

Estimated Enrollment:

• 40 patients with advanced solid tumors

A Phase I Trial of CCT245737 (SRA737) in Combination with Gemcitabine Plus Cisplatin or Gemcitabine Alone in Patients with Advanced Cancer

ClinicalTrials.gov Identifier: NCT02797977

Estimated enrollment:

• 70 patients with advanced solid tumors

23

• Sierra Oncology assumed ownership of the ongoing SRA737 clinical trials in Jan 2017.
• Formal sponsor transition has now occurred, enabling modifications to the trial designs.
• We have submitted protocol amendments intended to enhance both of these studies,

including to pre-select patients predicted to most likely derive benefit from SRA737 treatment.

SIERRA ONCOLOGY

Genomic Alterations Differ Across Indications: ‘Right Genetics In The Right Patients’

24

• Mutational frequencies (oncogenic drivers; replications stress; DNA repair; tumor

suppressors) differ across indications.

• Certain cancer indications harbor significant genomic instability, and we believe are

promising target indications for therapeutic intervention with SRA737.

• Sierra Oncology’s clinical development strategy: genetically-defined patient

selection in indications predicted to be sensitive to SRA737 inhibition.

Red = most frequently mutated; Green = least frequently mutated Bladder

Ovarian

Squamous NSCLC

Prostate

Colorectal

Head & Neck

Lung Adenocarcinoma

Pancreatic

Cholangiocarcinoma

Invasive Breast

AML

+

SIERRA ONCOLOGY

Proposed Protocol Amendments – Genetic Selection Strategy in Defined Cancers

25

Enroll subjects with a minimum of two types of genetic abnormalities including:

All patients:

• a deleterious mutation in a key tumor

suppressor gene, such as TP53. Plus at least one of the following:

• a loss of function or deleterious mutation in the

DNA damage response pathway such as ATM, BRCA1, BRCA2.

• a genetic indicator of replicative stress, defined

as gain of function or amplification of CHK1 or ATR or other related gene.

• a gain of function mutation or amplification of

an oncogenic driver such as MYC, RAS.

Evaluate cancer indications predicted to have a high prevalence of Chk1- sensitizing genetic aberrations such as:

Monotherapy:

• previously treated metastatic colorectal cancer
• platinum-resistant ovarian cancer
• metastatic castration-resistant prostate cancer
• advanced non-small cell lung cancer
• head and neck squamous cell carcinoma

Combination:

• bladder cancer
• pancreatic cancer

Sierra intends to amend the ongoing clinical trials to include the following patient enrichment strategies:

SIERRA ONCOLOGY

SRA737: Upcoming Milestones

26

Medical conference data 2018 Complete formal CTA transfer Q1 2017 Preliminary ‘Synthetic Lethality’ update ~Y/E 2017 Medical conference data 2018 Complete formal CTA transfer Q1 2017 Preliminary ‘Combination’ update ~Y/E 2017 Chk1i + PARPi preclinical data H2 2017 Chk1i + PD(L)-1 preclinical data H2 2017

Q1 17 Q2 17 Q3 17 Q4 17 Q1 18 Q2 18 Monotherapy Chemo Combo PARP Combo I/O Combo Potential Clinical Opportunities

SIERRA ONCOLOGY

SRA141 Targeting Cdc7

SIERRA ONCOLOGY

SRA141: Selective Small Molecule Targeting Cdc7

28

• SRA141: highly-selective and potent

cell division cycle 7 (Cdc7) inhibitor.

• Cdc7: key regulator of both DNA

replication and DNA damage response.

• Broad development scope in solid and

liquid tumors.

• Mono- and combo- therapy

development potential.

SIERRA ONCOLOGY

Cdc7: Key Function in the DDR Network

29

• Cdc7 activates DNA

replication during S-phase in response to growth promoting signals (e.g. cyclins, Myc, Ras) and stabilizes stalled replication forks during replication stress.

• Stalled replication

forks activate ATR and Chk1 signaling.

• Potential synergies

may be achieved by combining Cdc7, such as with Chk1 inhibition.

SIERRA ONCOLOGY

SRA141: Potential First-In-Class/Best-In-Class Opportunity

30

• Preclinical data and published literature suggest a variety of

indications with potential for response to Cdc7 inhibitors:

• Solid tumors: breast, ovarian, pancreatic, melanoma,

colorectal, uterine, thyroid, etc.

• Hematological malignancies: AML, DLBCL, etc.
• SRA141’s selectivity profile offers possible differentiation and

potential safety and efficacy advantages.

• A biomarker-driven patient selection strategy focusing on

drivers of Cdc7 inhibitor sensitivity may help facilitate clinical trial execution.

• Clinical studies expected to begin by the end of 2017.

SIERRA ONCOLOGY

Advancing Targeted Cancer Therapies

SIERRA ONCOLOGY

Proven Leadership in Oncology Development

32

Nick Glover, PhD President and CEO Barbara Klencke, MD Chief Development Officer Angie You, PhD Chief Business & Strategy Officer and Head of Commercial Sukhi Jagpal, CA, CBV, MBA Chief Financial Officer Mark Kowalski, MD, PhD Chief Medical Officer Keith Anderson, PhD Senior Vice President, Technical Operations Wendy Chapman Senior Vice President, Clinical Operations Diane Gardiner Senior Vice President, Human Resources and Administration Christian Hassig, PhD Senior Vice President, Research Chandra Lovejoy Senior Vice President, Global Regulatory Affairs and Head of Quality Emma McCann Senior Vice President, Program Management Gregg Smith, PhD, MBA Senior Vice President, Preclinical

SIERRA ONCOLOGY

Our DDR Program Expands Beyond PARP

33

We have established a promising portfolio of DDR assets:

• SRA737 and SRA141 target the DNA Damage Response network, a promising

approach to treating cancer based on leading-edge discoveries in cancer biology.

• Our DDR program expands beyond the scope of PARP inhibitors by focusing on

DNA double strand breaks, replication, genomic instability and cell cycle checkpoints.

• The near-term development plan for SRA737, our Chk1 inhibitor, encompasses

synthetic lethality as monotherapy, and in combination with DNA-damaging chemotherapy.

• Two Phase 1 clinical trials with SRA737 are underway; a preliminary update is

anticipated ~Y/E 2017.

• Preclinical research is underway combining SRA737 with other DDR agents (e.g.

PARPi), and in combinations with immuno-oncology.

• SRA141, our Cdc7 inhibitor, is in preclinical development with clinical studies

expected to begin by the end of 2017.