charting the path from pioneering biology to impactful
TRANSCRIPT
Charting the path from pioneering biology to impactful therapeutics
Q1 2019
NASDAQ: SRRA
S A F E H A R B O R S TAT E M E N TExcept for statements of historical fact, any information contained in this presentation may be a forward-lookingstatement 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 todiffer significantly from those expressed in any forward-looking statement. In some cases, you can identifyforward-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 growth opportunities, preclinical and clinical development activities, the timing and results of preclinicalresearch, clinical trials and potential regulatory approval and commercialization of product candidates. Althoughthe Company believes that the expectations reflected in such forward-looking statements are reasonable, theCompany cannot guarantee future events, results, actions, levels of activity, performance or achievements. Theseforward-looking statements are subject to a number of risks, uncertainties and assumptions, including thosedescribed 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 torevise 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 arereliable. However, the Company cannot guarantee the accuracy of, and has not independently verified, suchinformation.
T R A D E M A R K S :
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.
Addressing Unmet Medical Needs with a Broad Pipeline
momelotinibTARGETING JAK1/2 AND ACVR1
THERAPEUTIC FOCUS
Myelofibrosis
SRA737TARGETING Chk1
THERAPEUTIC FOCUS
High Grade Serous Ovarian Cancer
Squamous Cell Carcinoma & Other Solid Tumors
SRA141TARGETING Cdc7
THERAPEUTIC FOCUS
Colorectal Cancer
DDR Network Programs
3
Our Pipeline of Targeted TherapeuticsPreclinical Phase 1 Phase 2 Phase 3 Focus
SIMPLIFY-1
SIMPLIFY-2
Additional Registration Study
Myelofibrosis
M O M E L O T I N I B
Preclinical Phase 1 Phase 2 Phase 3 Focus
SRA737-01 Monotherapy
SRA737-02 LDG Combination
PARP Inhibitor Combination
I/O Combination
S R A 7 3 7
Preclinical Phase 1 Phase 2 Phase 3 Focus
Monotherapy
S R A 1 4 1
High Grade Serous Ovarian
Prostate
Colorectal
4
Myelofibrosis
Myelofibrosis
Solid Tumors
High Grade Serous Ovarian
MOMELOTINIBTarget ing JAK1, JAK2 and ACVR1
6
MOMELOTINIBUniquely positioned to provide robust benefits in myelofibrosis: spleen, symptoms and anemia
>20 studiesPhase 1, 2 and 3
>1,200 peopledosed with momelotinib
>550 patientswith myelofibrosis treated
>7 yearson treatment for several patients
Momelotinib Potentially Addresses Key Needs in Myelofibrosis Treatment
7
Opportunity2nd-line myelofibrosis = anemic and
transfusion dependent; large unmet need with no approved therapies
BenefitOnly agent to impact all three myelofibrosis
hallmarks: anemia, enlarged spleen and constitutional symptoms
Robust DataTwo Phase 3 SIMPLIFY studies
support efficacy profile
RegistrationTotality of data supports potential path to
registration; strong KOL support for momelotinib
MyelofibrosisA Chronic Myeloproliferative Neoplasm (MPN)
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• Chronic, progressive myeloid cancer • Bone marrow disorder disrupting the body’s normal
production of blood cells• Leads to fibrosis of bone marrow limiting blood cell
production
CONSTITUTIONAL SYMPTOMS
SPLENOMEGALY
ANEMIA
Myelofibrosis
Inflammation
Inefficient hematopoiesis
Extramedullary hematopoiesis
The Three Hallmarks of a Progressive Disease
Tefferi A, et al. Mayo Clin Proc. 2012 9
Three Hallmarks of a Progressive Disease
> 1 Y E A R A F T E R D I A G N O S I S
CONSTITUTIONAL SYMPTOMSAnemia, chronic inflammation, and splenomegaly lead to constitutional symptoms
ANEMIAProgressive bone marrow fibrosis due to inflammation; decreased erythropoiesis
45% Transfusion Dependent
64%46%34%
MyelofibrosisThe 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; company conference call October 2018
SPLENOMEGALYExtramedullary hematopoiesis in the spleen and other organs
Myelofibrosis: More Treatment Options Needed
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• Only one agent approved: ruxolitinib(Jakafi®) for 1st-line myelofibrosis
• Ruxolitinib:• Addresses ~70% 1st-line patients• Projected global market: >$2B• Only treats spleen and symptoms
Anemia is not addressed by ruxolitinib
I N I T I A L T R E AT M E N T:
• Optimal myelofibrosis therapeutic would address all three hallmarks:
• Anemia and transfusion dependency • Splenomegaly• Constitutional symptoms
Physicians need more choices after ruxolitinib
U N M E T M E D I C A L N E E D S :
T R E AT I N G A N E M I A A N D T R A N S F U S I O N D E P E N D E N C Y R E M A I N S I G N I F I C A N T U N M E T M E D I C A L N E E D S
MOMELOTINIBAddresses all Three Hallmarks of Myelofibrosis
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INHIBITSACVR1
INHIBITSJAK2
INHIBITSJAK1
ANEMIA• Hepcidin impaired erythropoiesis
SPLENOMEGALY• JAK-STAT-driven clonal
myeloproliferation
CONSTITUTIONAL SYMPTOMS• Aberrant cytokine production
and immune dysregulation
AnemiaCritical Prognostic Factor in Myelofibrosis
Nicolosi et al; Leukemia 2018 12
Baseline Anemia:Mild = Hgb ≥ 10 g/dl but below lower limit of normalModerate = Hgb between 8 g/dl and <10 g/dlSevere = Hgb <8 g/dl or transfusion dependent
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
P<0.0001
Multiple Pathways to Anemia in Myelofibrosis
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BONE MARROW FIBROSIS INFLAMMATION JAK THERAPYHEPCIDIN
Displacement of marrow erythropoietic tissue by fibrosis
Extramedullary hematopoiesis and splenomegaly
Pro-inflammatory cytokine profile
ANEMIA
Inadequate extramedullary erythropoiesis and red blood cell
sequestration
Impaired erythroiddifferentiation
JAK inhibitor therapy induced
myelosuppression
Impairment of iron metabolism
Elevated hepcidin
Activated ACVR1Alterations in
bone marrow cytokine expression
Momelotinib Mechanism of Action: Reducing Hepcidin Restores Red Blood Cell Production
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P L A S M A I R O N D E F I C I E N C Y
Fe2+
Hepcidin
Erythroblast Precursors
Hgb Accumulation Reticulocytes RBCs
Momelotinib-mediated plasma iron elevation leads to stimulation of erythropoiesis and red blood cell production
P L A S M A I R O N N O R M A L I Z AT I O N
Hepcidin
Fe2+
The KOL View on Myelofibrosis
15
Thoughts from:
Srdan Verstovsek, MD, PhDProfessor in the Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston
Unmet Medical Needs In Myelofibrosis KOL Presentation, October 17, 2018; ASH Analyst Call, December 3, 2018
“Ruxolitinib may control the signs and symptoms of the disease for some time… but it doesn’t prevent progression.”
“The leading cause of loss of response that has been published is anemia.”
“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.”
“Momelotinib… unlike any other JAK inhibitor, can benefit patients to a great extent on all three aspects.”
Completed Phase 3 Studies with Momelotinib
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1st-Line Population: Previously untreated with JAKi
SIMPLIFY-1
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
Goal: Non-Inferiority
MMB: N=215
RUX: N=217
Primary Endpoint Splenic Response Rate
Secondary Endpoints • Total Symptom Score• Effects on red blood cell
transfusion requirements
Goal: Superiority
MMB: N=104
RUX: N=52
Primary Endpoint Splenic Response Rate
Secondary Endpoints • Total Symptom Score• Effects on red blood cell
transfusion requirements
2nd-Line Population: Anemic or thrombocytopenic subjects previously treated with ruxolitinib
SIMPLIFY-2
JAK ExposedOpen label,
N=156Momelotinib 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
RBC transfusions on RUX = 64%RUX dose adjustment for: • thrombocytopenia = 21%• anemia/hematoma = 35%
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SIMPLIFY-1
66%
Statistically significant transfusion
independence rate (p < 0.001)
vs 49% ruxolitinib
PREVENTS TRANSFUSIONS
43%PREVENTS
TRANSFUSIONS
SIMPLIFY-2
of patients were transfusion independent at week 24 on
momelotinib
Maintenance of Transfusion Independence
vs 21% best available therapy
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SIMPLIFY-1
49.1%≥ 12 WEEK TRANSFUSION
INDEPENDENCE RATE
46.6%≥ 12 WEEK TRANSFUSION
INDEPENDENCE RATE
SIMPLIFY-2
Conversion from Transfusion Dependent to Transfusion Independent
Data from Sierra’s post-hoc analyses of SIMPLIFY-1 & SIMPLIFY-2 studies
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Hemoglobin Improvement after Momelotinib Crossover
SIMPLIFY-1
9
10
11
12
13Open-Label PhaseDouble-Blind Phase
Baseline
BL 12 24 36 48 60 72 84
HG
B (g
/dL)
All patients on momelotinib
Weeks
MomelotinibRuxolitinib
Crossover
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Non-Inferior Head-to-Head Activity on Splenomegaly
SIMPLIFY-1
SRR: Splenic Response Rate
Momelotinib statistically non-inferior to ruxolitinib on spleen (p=0.011)
Only JAKi to show equivalent splenic response to ruxolitinib in 1st-line
26.5% SRRvs 29% ruxolitinib
Pronounced Activity on Symptoms in Phase 3 Studies
TSS: Total Symptom Score*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. 21
SIMPLIFY-1
Both momelotinib and ruxolitinib substantially improved all symptoms relative to baseline*
Med
ian
Base
line
and
Med
ian
Wee
k 24
4-W
eek
Aver
age
Sym
ptom
Sco
re
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
absent
worst20
19
18
17
16
15
Base
line
TSS
MeanMedian
MMB arm: More symptomatic at baseline
Clinically Comparable H2H Symptom BenefitSIMPLIFY-2
26.2% TSSvs 5.9% best available therapy
Statistically Significant Symptom Response
Momelotinib compared to best available therapy (~90% ruxolitinib)
in 2nd-line patients
(p < 0.001)
Baseline
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Noteworthy Survival Post-Ruxolitinib vs Historical Controls
Mehra et al. Blood 2016; Newberry et al, Blood 2017
Momelotinib compared to historical controls in post-ruxolitinib
treated patients
28 months vs 7-14 months*
SIMPLIFY-2
Median Overall Survival
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Momelotinib (MMB) Ruxolitinib (RUX) Fedratinib (FED) Pacritinib (PAC)
Status in MyelofibrosisPhase 3
(Two completed P3s; P2 translational biology)
Approved(intermediate / high-risk; platelets ≥50 × 103/dL)
Post-Phase 3(P3 safety and efficacy study;
NDA Filed Q4 2018)
Phase 2(P3 trial requested by FDA;
EA MAA withdrawn)
Targets JAK1, JAK2, ACVR1 JAK1, JAK2 JAK2, FLT3 JAK2, FLT3
Splenic Response
Symptom Benefit
Anemia Benefit
Toxicity: Anemia and Thrombocytopenia LOW HIGH HIGH HIGH
Momelotinib Poised to be the Only Treatment Addressing All Three Hallmarks of Myelofibrosis
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Momelotinib 2nd-Line Market Opportunity*
*Company estimates in US and EU
• ~50K patients living with myelofibrosis
• ~75% are intermediate/high risk
Diagnosis
~70% receive 1st-line treatment1st-Line
• >70% of INT-2/Highmyelofibrosis patients have anemia
• >50% of patients aretransfusion dependent
“The majority of patients in second line would potentially be candidates for momelotinib.”
Dr. Srdan VerstovsekAnalyst Call, December 3, 2018
>75% will need 2nd-line treatment2nd-Line
Momelotinib Registration Strategy:Addressing 2nd-Line Medical Needs
• Reviewing and mining the robust body of existing clinical data generated by Gilead
• Focus on 2nd-line anemic and transfusion dependent patients, major unmet need in myelofibrosis
• Advancing regulatory interactions to determine registration path and requirements for additional Phase 3 study in 2nd-line setting
• Registration plan clarity projected for H1 2019
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Maintain maximal/stable spleen response
ANEMIACONSTITUTIONAL SYMPTOMS
SPLENOMEGALYConvert TD patients to TI
Reduce transfusionsIncrease hemoglobin
Improve constitutional symptoms
2ND-LINE DEVELOPMENT STRATEGY
SRA737 + SRA141Target ing the DNA Damage Response
SRA737: Chk1i Program Focused on Ovarian Cancer
• SRA737 has significant anti-tumor activity and profound survival benefit in CCNE1-driven background HGSOC preclinical models
• PARP inhibitors inactive in this population• Supports focus on development for ovarian cancer
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Orthotopic PDX (CCNE1 amplified + TP53 mutated)
• 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
Hong et al. Lancet Oncology 2018
Prexasertib Efficacy
33% ORR (8/24) Evaluable42% ORR (8/19) CCNE1 (All)33% ORR (4/12) CCNE1 amplification
SRA737-01 Monotherapy:Program Expansion and Prioritized Design
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• Focus on genetically-defined replication stress driven patient populations
• Continuous, daily oral administration
Dose escalation(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
Dose Optimization(non-selected)
Ovarian (CCNE1)
Ovarian (non-CCNE1)
SRA737-02 LDG Combination:Program Expansion and Amended Design
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• Low dose gemcitabine (day 1) followed by intermittent oral dosing of SRA737 (days 2 & 3); Administer weekly for 3 weeks every 28 days
Target enrollmentN=80 (20x4)
PRIORITIZING FOR OVARIAN CANCER
Dose escalation(non-selected)
Phase 2 cohorts
Continued dose escalation to MTD (non-selected)
Tumor SuppressorTP53, RAD50...
Oncogenic DriversCCNE1, MYC…
Replicative StressATR, CHEK1…
DNA Repair MachineryBRCA1, FANCA…
Prospective patient selection using NGS
technology
Ovarian
Small Cell Lung
Sarcoma
Cervical + Anogenital
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
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• SRA141 IND cleared by FDA; Phase 1/2 clinical trial focused on colorectal cancer planned
• 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.
t TBD Initiate Phase 1/2
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2019 Milestones
1H 2019 Registration Plan Clarity
M O M E L O T I N I B
SRA737-01 Monotherapy 1H 2019 Preliminary Clinical Data
SRA737-02 LDG Combination 1H 2019 Preliminary Clinical Data
SRA737-03PARP Inhibitor Combination TBD Initiate Phase 1b/2
S R A 7 3 7
S R A 1 4 1
We are a clinical stage drug development company advancing targeted therapeutics for the treatment of patients with unmet medical needs in hematology and oncology
Targeted Hematology and Oncology Therapeutics
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• Bold drug development company oriented to registration and commercialization
• Lead asset, momelotinib, for the treatment of myelofibrosis with large 2nd-line market opportunity
• Two assets focused on DNA Damage Response (DDR) targeting: SRA737 and SRA141
• Highly experienced management team with proven track record in drug development
• Strong financial standing:• Shares (as of September 30):
74.4M outstanding 85.2M fully diluted
• $116.1M in cash and cash equivalents (as of September 30)
• $5M borrowed in structured debt