Targeted Therapeutics for Hematology & Oncology Q4 2018

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 reflectsthe Company’s current views about future events and are subject to risks, uncertainties, assumptions and changes in circumstances thatmay cause events or the Company’s actual activities or results to differ significantly from those expressed in any forward-lookingstatement. 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-lookingstatements may include statements regarding the Company’s business strategy, cash flows and funding status, potential growthopportunities, preclinical and clinical development activities, the timing and results of preclinical research, clinical trials and potentialregulatory approval and commercialization of product candidates. Although the Company believes that the expectations reflected in suchforward-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-lookingstatements 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 believessuch information is accurate and that the sources from which it has been obtained are reliable. However, the Company cannot guaranteethe 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 notbe construed as an endorsement of such products.

SIERRA ONCOLOGY

Sierra Oncology’s Broad Pipeline:Addressing Unmet Medical Needs

momelotinibTARGETING JAK1/2 AND ACVR1

THERAPEUTIC FOCUS

Myelofibrosis

SRA737TARGETING Chk1

SRA141TARGETING Cdc7

THERAPEUTIC FOCUS

High Grade Serous Ovarian Cancer

Squamous & Other Solid Tumors

THERAPEUTIC FOCUS

Colorectal Cancer

DDR Network Programs

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SIERRA ONCOLOGY

momelotinib(MMB)

JAK1/2 AND ACVR1

SRA141TARGETING Cdc7

SRA737TARGETING Chk1

Sierra Oncology:Our Pipeline of Targeted Therapeutics

Product Preclinical Phase 1 Phase 2 Phase 3

-01 Phase 2

-02 Phase 2

PARPi Combination; Prostate Cancer

Additional registration study

Monotherapy; prioritized for HGSOC

Simplify 1

Simplify 2

Myelofibrosis (MF)

Monotherapy; Colorectal Cancer

Low Dose Gemcitabine Combination; prioritized for HGSOC

I/O Combination

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SIERRA ONCOLOGY

Momelotinib: Targeting JAK1, JAK2 and ACVR15

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Robust DataMomelotinib never filed for approval

2x Phase 3 SIMPLIFY studies support efficacy profile

Opportunity2nd line (2L) myelofibrosis = large unmet need market

No approved therapies in 2L MF

AnemiaMF patients = anemic & transfusion dependent (TD)Momelotinib demonstrably improves anemia and TD

3x BenefitOnly agent that impacts all three MF hallmarks:

anemia, spleen and symptoms

RegistrationTotality of data = clear potential path to registration

Strong KOL support for momelotinib

Momelotinib: Key PointsClear Strategy for Large 2L MF Opportunity

SIERRA ONCOLOGY

Myelofibrosis: A Chronic Myeloproliferative Neoplasm (MPN)

Inflammation

Constitutional symptoms

CONSTITUTIONAL SYMPTOMS

Inefficient hematopoiesis

Anemia & transfusion dependency

ANEMIA

Extramedullary hematopoiesis

Splenomegaly

SPLENOMEGALY

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SIERRA ONCOLOGY

• Extramedullary hematopoiesis (EMH) in the spleen and other organs.

• Progressive bone marrow fibrosis due to inflammation.• Decreased erythropoiesis.

45% transfusion dependent

46% splenomegaly

34% constitutional

symptoms

64% anemia

Myelofibrosis: The Three Hallmarks of a Progressive Disease

ANEMIA

SPLENOMEGALY

CONSTITUTIONAL SYMPTOMS

• Anemia, chronic inflammation, and splenomegaly lead to constitutional symptoms.

Tefferi A, et al. Mayo Clin Proc. 2012;87:25-33.

>1 Year After Diagnosis:

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SIERRA ONCOLOGY

Myelofibrosis:Unmet Medical Needs

• Only one agent approved – ruxolitinib for 1L MF.• Ruxolitinib (Jakafi®) addresses ~70% 1L patients.• Average time on ruxolitinib (RUX): ~245 days*.• Projected global market for RUX >$2B.• RUX only addresses spleen and symptom issues.• Anemia not addressed by RUX.

Initial Treatment:

• Physicians need more choices after RUX.• Optimal MF therapeutic would address anemia,

spleen and symptoms.• Treating anemia and transfusion dependency

remain significant unmet medical needs.

Unmet Medical Needs:

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average time on ruxolitinib

Truven

days~245

*Truven proprietary analysis

SIERRA ONCOLOGY

Momelotinib: Inhibits JAK1, JAK2 and ACVR1Controls All Three Facets of Myelofibrosis

JAK2

ACVR1JAK1HepcidinImpaired

Erythropoiesis

JAK-STAT-Driven Clonal

Myeloproliferation

Aberrant Cytokine

Production and Immune

Dysregulation

SPLENOMEGALY

CONSTITUTIONAL SYMPTOMS

ANEMIA

INHIBITS

INHIBITS

INHIBITS

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momelotinib

SIERRA ONCOLOGY

Momelotinib:Key Facts & Figures

>20Phase 1, 2 & 3 studies

>1,200subjects dosed with

momelotinib

>550MF patients treated

>7years on treatment for

several patients

Momelotinib is uniquely positioned to provide a spectrum of robust benefits in MF – spleen, symptoms & anemia.

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SIERRA ONCOLOGY

Myelofibrosis:The Challenge of Anemia

“Anemia is major area of unmet need. That’s one of the major problems… a quarter of the patients at the beginning may require transfusions, and after one year of therapy almost half of the patients already require transfusion. Anemia and transfusion dependency are important prognostic factors.”

Srdan Verstovsek, MD, PhDProfessor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, Houston.

Unmet Medical Needs In Myelofibrosis - KOL Presentation, October 17, 2018

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SIERRA ONCOLOGY

Myelofibrosis:Anemia: Critical Prognostic Factor in MF

No anemia Median survival 7.9 years

Mild anemia Median survival 4.9 years

Moderate anemia Median survival 3.4 years

Severe anemia Median survival 2.1 years

Surv

ival

Years

0

0

2

4

6

8

10

5 10 15 20 25 30 35

Nicolosi et al; Leukemia 2018.

Baseline Anemia:Mild = Hgb ≥ 10 g/dl but below lower limit of normalModerate = Hgb between 8 g/dl and <10 g/dl; Severe = Hgb <8 g/dl or transfusion dependent.

P<0.0001

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SIERRA ONCOLOGY

Myelofibrosis: Pathways To Anemia in Myelofibrosis

BONE MARROW FIBROSIS INFLAMMATION JAK THERAPYHEPCIDIN

Displacement of marrow erythropoietic tissue by

fibrosis

Extramedullary hematopoiesis &

splenomegaly

Pro-inflammatory cytokine profile

ANEMIA

Inadequate extramedullary

erythropoiesis & RBC sequestration

Impaired erythroiddifferentiation

JAK inhibitor therapy induced

myelosuppression

Impairment of iron metabolism

Elevated hepcidin

Activated ACVR1Alterations in bone marrow

cytokine expression

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SIERRA ONCOLOGY

15

15

Plasma ironnormalization

Hepcidin

Erythroblast precursors Hgb Accumulation Reticulocytes RBCs

Plasma irondeficiency

Fe2+

Momelotinib:Reducing Hepcidin Restores RBC Production

Hepcidin

Momelotinib–mediated plasma iron elevation leads to stimulation of erythropoiesis and RBC production.

Vs.

SIERRA ONCOLOGY

Myelofibrosis:Post-Ruxolitinib: The Key Opinion Leader View

Srdan Verstovsek, MD, PhDProfessor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.

“Momelotinib… unlike any other JAK inhibitor, can benefit patients to a great extent on all three aspects.”

Unmet Medical Needs In Myelofibrosis KOL Presentation, October 17, 2018Analyst CallASH, December 3, 2018

“Ruxolitinib may control the signs and symptoms of the disease for some time… but it doesn’t prevent progression.”

“Three quarters of the patients would be candidates… for a second line therapy.”

“The majority of patients… need another agent to salvage their quality of life, to control spleen, symptoms, and to improve the anemia, if possible.”

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“The leading cause of loss of response that has been published is anemia.”

SIERRA ONCOLOGY

MMB Benefit

Convert TD patients to TIReduce transfusionsIncrease hemoglobin

Improve constitutional symptoms

Maintain maximal/stable spleen response.

• Sierra is currently reviewing and mining the robust body of existing clinical data generated by Gilead.

• Planning for near-term regulatory interactions to determine registration path and requirements for a likely additional Phase 3 study in 2L setting.

• Focus on 2L anemic & transfusion dependent patients, major unmet need in MF.

• Registration plan clarity projected for H1 2019.

Momelotinib Registration Strategy:Addressing 2L Medical Needs

2L Development Strategy

SPLENOMEGALYCONSTITUTIONAL SYMPTOMS ANEMIA

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SIERRA ONCOLOGY

Completed Phase 3 Studies with Momelotinib:SIMPLIFY-1 & SIMPLIFY-2

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Goal: Non-InferiorityMMB: N=215RUX: N=217

Primary endpoint:• Splenic response rate

Secondary endpoints:• Total symptom score• Effects on RBC

transfusion requirements

Goal: SuperiorityMMB: N=104 BAT: N=52

Primary endpoint:• Splenic response rate

Secondary endpoints:• Total symptom score • Effects on RBC

transfusion requirements

2L Population: anemic or thrombocytopenic subjects previously treated with RUX.

1L Population: previously untreated with JAKi.

Simplify 2

Simplify 1

RBC transfusions on RUX = 64%RUX dose adjustment for:

thrombocytopenia = 21%anemia/hematoma = 35%

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JAK NaïveDouble-blind,

N=432

Momelotinib 200 mg QD

Ruxolitinib20 mg BID

Momelotinib 200 mg QD

1:1

rand

omiz

atio

n

Double-blind treatment Open label LTFU

Year 7Day 1 Week 24

Primary Endpoint

JAK Exposed

Open label, N=156

Momelotinib 200 mg QD Momelotinib

200 mg QD

2:1

rand

omiz

atio

n

Randomized treatment Extension LTFU

Year 7Day 1 Week 24

Primary Endpoint

90% = RUX/RUX+

Best available therapy

Best available therapy

SIERRA ONCOLOGY

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies:Maintenance of Transfusion Independence

vs. 21% BAT

of patients wereTI at week 24

on momelotinib.

43%

Simplify 2PREVENTS

TRANSFUSIONS

TD: Transfusion DependentTI: Transfusion Independent

Simplify 1

66%Statistically significant

TI rate (p < 0.001).

vs. 49% RUX

PREVENTSTRANSFUSIONS

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SIERRA ONCOLOGY

46.6%49.1%

≥ 12 WEEK TRANSFUSION

INDEPENDENCE RATE

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≥ 12 WEEK TRANSFUSION

INDEPENDENCE RATE

Simplify 2Simplify 1

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies:Transfusion Dependent to Independent (12W)

• Data from Sierra’s post-hoc analyses of SIMPLIFY-1 & SIMPLIFY-2 studies.

SIERRA ONCOLOGY

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies: Hemoglobin Improvement After MMB Crossover

Simplify 1

9

10

11

12

13Open-Label PhaseDouble-Blind Phase

MomelotinibRuxolitinib

Baseline

BL 12 24 36 48 60 72 84

HG

B (g

/dL)

All patients on MMB

Weeks

21

Crossover

SIERRA ONCOLOGY

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies: Non-Inferior H2H Activity on Splenomegaly

Momelotinib statistically non-inferior to RUX on spleen (p=0.011).

Only JAKi shown equivalent to ruxolitinibfor splenic response in 1L.

26.5% SRRSimplify 1

vs. 29% RUX

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SRR: Splenic Response Rate

SIERRA ONCOLOGY

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies: Pronounced Activity on Symptoms

Statistically significant symptom response (p < 0.001).

momelotinib compared to BAT (~90% ruxolitinib) in second line patients.

26.2% TSSSimplify 2

vs. 5.9% Best Available Treatment (BAT)

TSS: Total Symptom Score23

SIERRA ONCOLOGY

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies:Clinically Comparable H2H Symptom Benefit

Both momelotinib and ruxolitinib substantially improved all symptoms relative to baseline in a clinically comparable manner*.

Med

ian

Base

line

and

Med

ian

Wee

k 24

4-W

eek

Aver

age

Sym

ptom

Sco

re

Baseline

Week 24

AbDiscomfort

Itching BonePain

Night Sweats

EarlySatiety

Pain UnderLeft Ribs

Tiredness

10

9

8

7

6

5

4

3

2

1

0

MMB

RUX

Simplify 1

*Momelotinib marginally missed Total Symptom Score (TSS) non-inferiority to RUX in SIMPLIFY-1: 28.4% vs. 42.2% (Noninferior Proportion Difference 0.00 (-0.08, 0.08)). Mean & Median Baseline TSS higher in momelotinib arm vs. RUX. No stratification for baseline symptoms in SIMPLIFY-1. 24

absent

worst20

19

18

17

16

15

Base

line

TSS

MeanMedian

MMB arm: More symptomatic at baseline

SIERRA ONCOLOGY

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies:Noteworthy Survival Post-RUX vs. Historical Controls

vs. 7-14 months*

momelotinib compared to historical controls in post-ruxolitinib treated patients.

28 months mOSSimplify 2

*Mehra et al 2016 Blood 128(22):4769; Newberry et al, 2017 Blood 130(9):1125-1131 25

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Simplify 1

SIMPLIFY-1 & SIMPLIFY-2 Phase 3 Studies:Anemia is a Reported Toxicity of Ruxolitinib

Simplify 1Anemia rate 14% momelotinib vs.

38%ruxolitinib

6% momelotinib vs.

23%≥ Grade 3 anemia rate

ruxolitinib

~3-4x higher rates of anemia for RUX

SIERRA ONCOLOGY

Momelotinib:Unique Profile Delivers All Three Benefits

Momelotinib (MMB) Ruxolitinib (RUX) Fedratinib (FED) Pacritinib (PAC)

Status in Myelofibrosis

Phase 3(2x completed P3s; P2 translational biology)

Approved(intermediate / high-risk; platelets ≥50 × 103/dL)

Post-Phase 3(P3 safety & efficacy

study; NDA TBD)

Phase 2(P3 trial requested by FDA; EU MAA refiled)

Targets JAK1, JAK2, ACVR1 JAK1, JAK2 JAK2, FLT3 JAK2, FLT3

Splenic Response

Symptom Benefit

Anemia Benefit

Toxicity: Anemia & Thrombocytopenia LOW HIGH HIGH HIGH

• Only JAKi to consistently demonstrate a broad ability to address the needs of MF patients• Momelotinib has robust anemia, spleen, and symptom benefits.

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SIERRA ONCOLOGY

Myelofibrosis:Momelotinib 2L Market Opportunity*

45-50kpatients living with MF in EU and US

~70%

>70%of INT-2/HIGH MF

patients have anemia

receive 1L treatment

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*Company estimates

~50%are transfusion

dependent

>75%will need 2L treatment

75-80%Intermediate /

High risk

“The majority of patients in second line would potentially be candidates for momelotinib.”Srdan Verstovsek, MD, PhDAnalyst Call, ASH, December 3, 2018

SIERRA ONCOLOGY

Momelotinib’s Opportunity:Redefining The Narrative In Myelofibrosis

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Targeting the DNA Damage Response30

SIERRA ONCOLOGY

• Phase 2 study of Lilly’s Chk1i prexasertib in BRCA wild type (PARPi insensitive) high-grade serous ovarian cancer demonstrates clinical efficacy in CCNE1-driven genetic background

SRA737:Chk1i Program Focused on Ovarian Cancer

• SRA737 has significant anti-tumor activity and a profound survival benefit in CCNE1-driven background HGSOC preclinical models.

• PARPi inactive in this population.• Supports our ovarian cancer development focus.

Orthotopic PDX (CCNE1 amplified + TP53 mutated)

Hong et al. Lancet Oncology 2018

Prexasertib Efficacy

33% ORR (8/24) Evaluable42% ORR (8/19) CCNE1 (All)33% ORR (4/12) CCNE1 amplification

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SIERRA ONCOLOGY

SRA737-01 Monotherapy: Program Expansion & Prioritized Design

• Focus on genetically-defined replication stress driven patient populations.

• Continuous daily oral administration.

Dose escalation(non-selected)

Dose optimization (non-selected)

Tumor SuppressorTP53, RAD50...

Oncogenic DriversCCNE1, MYC…

Replicative StressATR, CHEK1…

DNA Repair MachineryBRCA1, FANCA…

Target enrollmentN=80 (20x4)

Target enrollmentN=65

Prioritizing for Ovarian Cancer

Prospective patient selection using NGS

technologyPhase 2 cohorts

Prostate

Non-Small Cell Lung

Head & Neck + Anus

Colorectal

Ovarian (CCNE1)

Ovarian (non-CCNE1)

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SRA737-02 LDG Combination: Program Expansion & Amended Design

• Low dose gemcitabine (day 1) followed by intermittent oral dosing of SRA737 (days 2 & 3); Administer weekly for 3 weeks every 28 days.

Tumor SuppressorTP53, RAD50...

Oncogenic DriversCCNE1, MYC…

Replicative StressATR, CHEK1…

DNA Repair MachineryBRCA1, FANCA…*One or more mutations required for eligibility.

Dose escalation (non-selected)

Continued dose escalation to MTD (non-selected)

Prioritizing for Ovarian Cancer

Prospective patient selection using NGS

technology*Phase 2 cohort Target enrollment

N=80 (20x4)

Ovarian

Small Cell Lung

Sarcoma

Cervical + Anogenital

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SIERRA ONCOLOGY

SRA141: Cdc7i Program Focused on Colorectal Cancer

• SRA141: potent, orally bioavailable, selective cell division cycle 7 (Cdc7) inhibitor.

• Cdc7 (serine/threonine kinase): emerging ‘next generation’ DDR target.

• Key regulator of both DNA replication and DNA damage response, as well as mitosis.

• Phase 1/2 clinical trial focused on colorectal cancer.

• Takeda Cdc7i clinical data demonstrate preliminary monotherapy responses; P2 ongoing in colorectal.

COLO205 model: TP53 & MSS - relevant genetics for Cdc7i. Tumor growth inhibition (TGI) = 99%; CRs in 4/7 (57%) animals.

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SIERRA ONCOLOGY

Sierra Oncology:Targeted Hematology & Oncology Therapeutics

Nasdaq: SRRAHeadquarters: Vancouver, BCShares (09/30/18):

74.4M outstanding85.2M fully diluted

Cash and cash equivalents: $116.1M (09/30/18)

Structured debt facility: $5M borrowed

We are an ambitious drug development company oriented to registration and commercialization.

We have a highly experienced management team with a proven track record in drug development.

A clinical-stage drug development company advancing targeted therapeutics for patients with significant unmet needs in hematology and oncology.

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SIERRA ONCOLOGY

Sierra’s Management Team:Proven Leadership In Drug Development

Mark Kowalski, MD, PhDChief Medical Officer

Nick Glover, PhDPresident and CEO

Barbara Klencke, MDChief Development Officer

Sukhi Jagpal, CA, CBV, MBAChief Financial Officer

Christian Hassig, PhDChief Scientific Officer

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Gregg Smith, PhD, MBASenior Vice President, Drug Development

SIERRA ONCOLOGY

momelotinibJAK1/2 AND ACVR1

SRA141TARGETING Cdc7

SRA737TARGETING Chk1

SRA737-01

SRA737-02

SRA737-03

SRA737-04

Sierra Oncology:Our Pipeline of Targeted Therapeutics

Program UpdateFeb 2018

Program UpdateFeb 2018

CCNE1 HGSOC Cohort Initiated

Trial prioritized for HGSOC

Preliminary clinical data

Asset acquisition

Registration plan clarity

Trial prioritized for HGSOC

Preliminary clinical data

Initiate Phase 1b/2

AACR PreclinicalApr 2018

Submit IND

Preclinical data

Product Q1 18 Q2 18 Q3 18 Q4 18 H1 19

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ASH clinical data