Targeted Therapeutics for Hematology & Oncology Q4 2018
Targeted Therapeutics for Hematology & Oncology Q4 2018
SIERRA ONCOLOGY
Safe Harbor Statement
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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.
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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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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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• 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
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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
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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
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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
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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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SIERRA ONCOLOGY
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