Building Momentum for Patients with Myelofibrosis ASH Annual - - PowerPoint PPT Presentation

Building Momentum for Patients with Myelofibrosis

ASH Annual Meeting December 8, 2019

NASDAQ: SRRA

S A F E H A R B O R S TAT E M E N T

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”,

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• pportunities, preclinical and 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. 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.

Mark Kowalski, MD, PhD Chief Medical Officer Nick Glover, PhD President and CEO Barbara Klencke, MD Chief Development Officer Sukhi Jagpal, CA, CBV, MBA Chief Financial Officer Gregg Smith, PhD, MBA Senior Vice President, Drug Development

Sierra’s Proven Leadership in Drug Development

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• Dr. Ruben Mesa:

Director of the Mays Cancer Center

• Dr. Mesa is Director of the Mays Cancer Center, home of UT Health

San Antonio MD Anderson Cancer Center.

• He has been involved in MPN research for more than 20 years.
• Dr. Mesa led the development of the National Comprehensive Cancer

Network’s panel guidelines, the first US guidelines on the diagnosis and treatment of myelofibrosis (MF), polycythemia vera and essential thrombocythemia.

• Dr. Mesa has been the Principal Investigator of more than 70 clinical
• trials. He co-led the research team leading to the FDA’s approval of

ruxolitinib for polycythemia vera and myelofibrosis. He is currently leading the investigation of several other drugs for the treatment of myeloproliferative disorders.

• Dr. Mesa has been involved in the development of momelotinib from

initial Phase 1 clinical trials through Phase 3. He is an investigator on the MOMENTUM confirmatory Phase 3 trial.

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Ruben Mesa, MD

Director of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center

MOMELOTINIB

Positioned to potentially provide benefits

• n all three myelofibrosis hallmarks:

symptoms, anemia and spleen

>20 studies

Phase 1, 2 and 3

>1,200 people

dosed with momelotinib

>820 patients

with myelofibrosis treated

• incl. SIMPLIFY 1 & 2 P3 trials

>8 years

• n treatment for several patients

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Myelofibrosis Biology: JAK1, JAK2 & ACVR1 Drive MF Disease Hallmarks

BMP2, BMP6

ACVR1

SMAD1,5 P

• Aberrant activation of hepcidin

transcription via hyperactivated ACVR1 signaling resulting in profound functional iron deficiency anemia.

Interleukins Interferons Cytokine Receptors STAT STAT EPOR / MPL Ligand P

• Clonal proliferation leading to

extramedullary hematopoiesis and burdensome splenomegaly.

• Inflammation and aberrant

cytokine signaling producing debilitating constitutional symptoms.

P

JAK2 JAK1 JAK2 JAK2

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Momelotinib: SIMPLIFY Data Support Benefits in 3 Hallmarks of MF

INHIBITS

ACVR1

INHIBITS

JAK2

INHIBITS

JAK1

ANEMIA SPLENOMEGALY

Only JAKi to show equivalent splenic response to ruxolitinib in 1L

CONSTITUTIONAL SYMPTOMS

Pronounced TSS benefit: clinically consistent symptom improvement across all domains in 1L & 2L Increased hemoglobin: lower rates of RBC transfusion, fewer transfusion dependent patients, etc. in 1L & 2L

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The Three Hallmarks of a Progressive Disease Three Hallmarks of a Progressive Disease

>1 Y E A R A FTE R DI A G NO S I S

CONSTITUTIONAL SYMPTOMS

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

ANEMIA

Progressive bone marrow fibrosis due to inflammation; decreased erythropoiesis.

45%

Transfusion Dependent

64% 46% 34%

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, PhD Professor 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

SPLENOMEGALY

Extramedullary hematopoiesis in the spleen and other organs.

Tefferi A, et al. Mayo Clin Proc. 2012

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Myelofibrosis Anemia: Severe Anemia &Transfusion Dependency Predict Poor Survival

Transfusion dependency results in substantially shortened survival Anemia predicts poor survival in myelofibrosis

Nicolosi M et al; Leukemia. 2018.

5 10 Years 20 25 30 35 15 2 4 6 Survival 8 10

P<0.0001 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

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http://www.haematologica.org/content/96/1/167

Time since diagnosis 18 16 14 12 10 8 6 4 2 0.4 0.6 0.8 1.0 Time since diagnosis Cumulative proportion surviving Transfusion-dependent Transfusion-independent

Anemia in Myelofibrosis: The Burden of Transfusions

• Time Consuming and Costly
• Impacts patients, caregivers and health care systems.
• Costs include clinic visits, blood banking & associated

processing.

• Management of transfusion-related complications.
• Acute Health Risks
• Transfusion reactions.
• Fluid overload.
• Chronic Health Risks
• Iron overload with subsequent end organ damage.
• Risk of transmission of blood borne pathogens.
• Transfusions Only Offer Transient Benefits
• Must be continually repeated.
• Regular blood count monitoring required.

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Myelofibrosis Anemia:

Momelotinib Positively Impacts Multiple Pathways to Anemia

OTHER JAKi THERAPIES HEPCIDIN (ACVR1)

ANEMIA

Other JAK inhibitors induce myelosuppression Impairment of iron metabolism Elevated hepcidin Activated ACVR1

FIBROSIS & EXTRAMEDULLARY HEMATOPOIESIS (JAK2)

Displacement of marrow erythropoietic tissue by fibrosis Extramedullary hematopoiesis and splenomegaly Inadequate extramedullary hematopoiesis and red blood cell sequestration

INFLAMMATION (JAK1)

Pro-inflammatory cytokine profile Impaired erythroid differentiation Alterations in bone marrow cytokine expression

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Myelofibrosis Anemia: High Hepcidin Correlates With Severe Anemia

Pardanani et al; American Journal of Hematology 2013.

Hepcidin predicts poor survival in myelofibrosis Anemia predicts poor survival in myelofibrosis

Nicolosi M et al; Leukemia. 2018.

5 10 Years 20 25 30 35 15 2 4 6 Survival 8 10

P<0.0001 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 Years Cumulative Survival 4 2 6 8 10 5 10 15

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Clinical Validation of Anemia Mechanism: Acute & Chronic Hepcidin Suppression by Momelotinib

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• Phase 2 Translational biology study (GS-US-352-1672), N=41 transfusion dependent subjects.
• Primary endpoint: Transfusion independence.
• 34% 12 Week TI response rate; 39% TI for ≥ 8 Weeks.
• PD analyses demonstrates consistent effects on hepcidin, hematocrit, Hgb and serum iron consistent with increased

momelotinib-driven erythropoiesis.

Hepcidin Levels At every study visit, median blood hepcidin decreased 6 hours after dosing with momelotinib. Overall trend to reduced hepcidin

• ver time.

Reinforces ACVR1i mechanism of action.

Visit: Timepoint

Baseline Enrollment Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24

Median actual value (Q1, Q3)

Pre-dose 6 hours post-dose

Oh et. al. ASH 2018. Abstract# 4282.

Anemia in Myelofibrosis: 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

P L A S M A I R O N N O R M A L I Z AT I O N

Hepcidin

Fe2+ M o m e l o t i n i b - m e d i a t e d p l a s m a i r o n e l e v a t i o n l e a d s t o s t i m u l a t i o n o f e r y t h r o p o i e s i s a n d r e d b l o o d c e l l p r o d u c t i o n

Myelofibrosis Biology: Momelotinib Uniquely Inhibits All Three Disease Drivers

BMP2, BMP6

ACVR1

Interleukins Interferons Cytokine Receptors EPOR / MPL Ligand

JAK2 JAK1 JAK2 JAK2

• Decreased hepcidin transcription

restores iron homeostasis and increases hemoglobin leading to array of anemia benefits.

• Reduced extramedullary

hematopoiesis improves splenomegaly.

• Decreased inflammation and

aberrant cytokine signaling improves constitutional symptoms. JAK1 Inhibition JAK2 Inhibition ACVR1 Inhibition

SMAD1,5 P STAT STAT P P

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Momelotinib’s Clinical Development: Completed SIMPLIFY Phase 3 Studies

1st-Line Population: Previously untreated with JAKi

SIMPLIFY-1

JAK Naïve Double-blind, N=432 Momelotinib 200 mg QD Ruxolitinib 20 mg BID Momelotinib 200 mg QD

1:1 randomization Double-blind treatment Open label LTFU Year 7 Day 1 Week 24 Primary Endpoint

Goal: Non-Inferiority MMB: N=215 RUX: N=217 Primary Endpoint Splenic Response Rate Secondary Endpoints

• Total Symptom Score
• Transfusion Independence Rate
• Transfusion Dependence Rate
• RBC Transfusion Requirements

Goal: Superiority MMB: N=104 BAT: N=52 Primary Endpoint Splenic Response Rate Secondary Endpoints

• Total Symptom Score
• Transfusion Independence Rate
• Transfusion Dependence Rate
• RBC Transfusion Requirements

2nd-Line Population: Anemic or thrombocytopenic subjects previously treated with ruxolitinib

SIMPLIFY-2

JAK Exposed Open label, N=156 Momelotinib 200 mg QD Momelotinib 200 mg QD

2:1 randomization Randomized treatment Extension LTFU Year 7 Day 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%

BAT: Best Available Therapy

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Mesa et al. J Clin Oncol. 2017 Harrison et al. Lancet Haematol. 2018

SIMPLIFY-1: Standard Analyses Demonstrate Momelotinib’s Anemia Benefits vs. Ruxolitinib

• Relevant baseline characteristics well balanced between arms:
• A variety of standard landmark analyses of anemia benefit were conducted as secondary endpoints

in SIMPLIFY-1, demonstrating consistently positive benefits in favor of momelotinib :

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Momelotinib Ruxolitinib p-value % TI at Week 24 67% 49% < 0.001 % TD at Week 24 30% 40% 0.019 % TD → TI (rolling 12-week) 49% 29% 0.0455 Momelotinib Ruxolitinib Median hemoglobin 10.5 10.3 % TD at baseline 25% 24% % TI at baseline 68% 70%

Dynamic Analyses of MMB’s Anemia Benefits vs RUX: ASH 2019 Poster / Abstract #1663

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• Dr. Ruben Mesa

Director of the Mays Cancer Center Home to UT Health San Antonio MD Anderson Cancer Center

SIMPLIFY-1: Novel Dynamic Analyses of Transfusion Burden

• Landmark or other “static” analyses alone do not completely describe the patient burden of transfusions
• r fully elucidate the differences in therapeutic options for clinicians.
• Retrospective analyses of S1 data were performed using a variety of novel dynamic anemia benefit

endpoints to explore the relative burden of transfusions in patients treated with momelotinib vs. ruxolitinib. 1) A Kaplan-Meier (KM) time to event estimates of time-to-first, time-to-third, and time-to-fifth RBC unit(s) transfused were employed to determine and compare relative ‘transfusion events’ between groups. 2) A zero-inflated negative binomial (ZINB) model was fit to the transfusion data to compare the proportions of patients with zero transfusion burden (i.e. transfusion free) and the mean transfusion rates between treatment groups. 3) A proportional hazards recurrent events (mean cumulative function) model was employed to determine the relative cumulative transfusion burden between groups across the duration of treatment.

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Time to First Transfusion: More Patients Require No Transfusions on Momelotinib

• The first RBC unit transfused provides an

alternate relative assessment of the proportion of patients who are transfusion free over the course of treatment.

• KM time-to-first RBC unit transfused

analysis indicated an immediate and sustained momelotinib treatment effect compared to ruxolitinib (log-rank p < 0.0001).

• Patients randomized to momelotinib were

more likely to receive no transfusions (73%) compared to patients randomized to ruxolitinib (46%).

• The odds of receiving no transfusions

during treatment was 3.2 times higher on momelotinib than on ruxolitinib.

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Time to Third Unit Transfused: Immediate & Sustained Reduction in Transfusion Burden on MMB

• Assuming two units of RBCs per typical

transfusion, the third and fifth RBC units transfused represent the second and third ‘transfusion event’ respectively.

• Odds of receiving fewer than three

transfusions was 3.7 times higher on momelotinib (81%) compared to ruxolitinib (54%, p < 0.0001).

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Time to Fifth Unit Transfused: Immediate & Sustained Reduction in Transfusion Burden on MMB

• Odds of receiving fewer than five transfusions

was 3.0 times higher on momelotinib (83%) compared to ruxolitinib (62%, p < 0.0001).

• KM data demonstrate that more patients

remain transfusion free on momelotinib vs. ruxolitinib.

• For those patients who do receive

transfusions, the relative burden of transfusions is demonstrably reduced for momelotinib.

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ZINB Covariate Analysis: MMB Patients Have an Increased Odds of Zero Transfusions

• The outcomes of the covariate ZINB

model demonstrate that a typical patient in S1 had an 82% chance of receiving no transfusions when receiving momelotinib vs. only a 33% chance when receiving ruxolitinib.

• The odds of zero RBC units transfused

were 9.3 times higher on momelotinib than on ruxolitinib (p < 0.0001).

*covariates were disease diagnosis (PMF, post-PVMF, post-ETMF), bone marrow fibrosis grade and number of RBC units transfused in the 8 weeks prior to randomization (0, 1-3, > 4).

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Transfusion Burden Analysis:

Twice as Many RBC Units Transfused on RUX vs. MMB at Any Timepoint

• The model focused on the hazard, or

risk, of an RBC unit being transfused as a “mean cumulative function” (MCF) of the average cumulative RBC unit transfusions for patients in each group.

• The hazard ratio for an RBC unit

transfused for patients receiving momelotinib was approximately

• ne-half that for ruxolitinib patients

(HR 0.522; p < 0.0001) for models both with and without patients’ baseline characteristics as covariates.

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Maintenance of Transfusion Independence: Extended Durability of Transfusion Independence on MMB

• The duration of transfusion

independence (TI) response in S1 was determined by a KM analysis

• f time to loss of TI.*
• The analysis demonstrated that

the median time to loss of TI was not reached for momelotinib- treated patients, with a follow up period exceeding 3 years.

*Loss of TI was defined by the requirement for RBC transfusion or hemoglobin < 8.5 g/dL at any time

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• Key finding – momelotinib’s immediate and sustained anemia benefit manifests in an overall

reduced transfusion burden on momelotinib directly compared to ruxolitinib.

• Patients had more than nine times higher odds of receiving zero transfusions on momelotinib.
• Momelotinib patients also had a significantly reduced chance of receiving either one

transfusion or multiple transfusions as compared to ruxolitinib.

• At any given time, twice as many RBC units are transfused on ruxolinib as compared to

momelotinib.

• Sustained and durable TI was maintained over long-term treatment on momelotinib.
• Data are robust, statistically persuasive and clinically compelling across all measurements
• f anemia benefit - both standard and novel - in this randomized, blinded, Phase 3 dataset.
• Clinical relevance – Assuming momelotinib is approved, its ability to achieve clinically

comparable benefits on symptoms and splenomegaly while demonstrably improving the transfusion burden for patients would provide an attractive addition to the myelofibrosis armamentarium.

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SIMPLIFY-1: Novel Dynamic Analyses of Transfusion Burden - Summary

Building Momentum for Patients with Myelofibrosis LAUNCHED Q4 2019!

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A Randomized, Double-Blind, Phase 3 Study to Evaluate the Activity of Momelotinib (MMB) versus Danazol (DAN) in Symptomatic, Anemic Subjects with Primary Myelofibrosis (PMF), Post-Polycythemia Vera (PV) Myelofibrosis, or Post Essential Thrombocythemia (ET) Myelofibrosis who were Previously Treated with JAK Inhibitor Therapy

Previously Treated with JAK inhibitor Symptomatic (TSS ≥ 10) and Anemic (Hgb < 10 g/dL) 2:1 randomization Double-Blind Treatment Open Label/Crossover Long Term Follow-up

Day 1 Week 24

Primary Endpoint

Momelotinib 200 mg daily + Placebo

Subjects N=180

MOMENTUM P3 Trial: Phase 3 Registration Trial Schema

Danazol has been selected as an appropriate treatment comparator given its use to ameliorate anemia in myelofibrosis patients, as recommended by NCCN and ESMO guidelines.

Spleen progression (Momelotinib 200mg)

Danazol 600 mg daily + Placebo Momelotinib 200 mg daily

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MOMENTUM P3 Trial: Study Objectives

Primary Endpoint:

• Total symptom score (TSS) response rate of momelotinib vs. danazol at Week 24 in symptomatic and

anemic patients with PMF, post-PV myelofibrosis, or post-ET myelofibrosis who were previously treated with an approved JAK inhibitor therapy.

Secondary & Exploratory Endpoints:

• Transfusion independence (TI) rate at Week 24 for subjects treated with momelotinib vs. danazol.
• Splenic response rate (SRR) at Week 24 for subjects treated with momelotinib vs. danazol.
• Duration of TSS response for subjects treated with momelotinib.
• Other measures of anemia benefit, including TD-TI rate and measures of cumulative transfusion burden.
• Additional Patient Reported Outcomes, including assessments of fatigue and physical function.

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MOMENTUM P3 Trial: Key Design Elements

Endpoint Order & Powering Supporting Data/Rationale Symptom (TSS) response rate Primary (W24) 99% powered; p < 0.05 FDA preferred measure of clinical benefit in Myelofibrosis Consistent and meaningful TSS responses in S-1 & S-2 Transfusion Independence rate Secondary (W24) >90% powered; p < 0.05 Favorable & statistically significant TI rates in S-1 & S-2 Spleen (SRR) response rate Secondary (W24) >90% powered; p < 0.05 Defined washout allows for splenic rebound & SRR benefit Non-inferior SRR benefit H2H vs RUX in S-1 Durability of TSS response Secondary (W48) Durability of symptomatic benefit to W48 established in S-1 & S-2 Other anemia measures Secondary & Exploratory Consistent suite of benefits: TD-TI rates, improved HGB, reduced transfusion frequency, etc.

Chief Investigator:

• Dr. Srdan Verstovsek, MD Anderson Cancer Center, Houston, Texas, USA

*Stratified for baseline TSS, RBC transfusions & spleen

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MOMENTUM P3 Trial: Key Trial Assumptions

Study Launched Q4 2019

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Estimated Time to Enroll ~18 months* Potential Regulatory Approval ~Q4 2022**

**Assuming priority regulatory review *Company estimates

Topline Data ~Q4 2021* (~6 months to primary endpoint after enrollment)* Filing Date ~Q2 2022* Patients: 180 (2:1 randomization) Territory: Global study (North America, EU, APAC, etc.) 2020 2021 2022 Fast Track Designation Granted (May 2019): Patients with intermediate/high-risk myelofibrosis who have previously received a JAK inhibitor

EXTENDED ACCESS PROGRAM

Momelotinib: Totality of Data to Support Potential Registration

PHASE 3 CLINICAL TRIAL Patient data from completed studies

>550 subjects

• Statistically non-inferior spleen response vs. RUX

(S-1; p = 0.011).

• Statistically significant TSS response vs. BAT/RUX

(S-2; p < 0.001).

• Statistically significant transfusion independent

rates (S-1; p < 0.001) (S-2; p = 0.001).

• Crossover data: momelotinib efficacy and safety

data in patients who switch from RUX (S-1) or BAT/RUX (S-2) after Week 24.

SIMPLIFY-1 SIMPLIFY-2

XAP

Pivotal study data

~180 subjects

• Primary endpoint: TSS response rate

(99% powered; p < 0.05).

• Secondary endpoints:
• Transfusion Independence rate.
• Spleen (SRR) response rate.
• Durability of TSS response.
• Other anemia measures.

Long term treatment data

>120 subjects; >15 countries

• Durable response data (some patients treated

>8 years).

• Long term safety and tolerability data.

32 32

Momelotinib 2nd-Line Market Opportunity*

• ~50K patients living

with myelofibrosis

• ~75% are

intermediate/high risk

Diagnosis

~70% receive 1st-line treatment

1st-Line

• >70% of INT-2/High

myelofibrosis patients have anemia

• >50% of patients are

transfusion dependent

“The majority of patients in second line would potentially be candidates for momelotinib.”

• Dr. Srdan Verstovsek

Chief Investigator MOMENTUM

>75% will need 2nd-line treatment

2nd-Line

Favorable patent exclusivity

• potential extensions to 2040** provide a

compelling commercial opportunity

*Company estimates **assumes anticipated 5 years PTE and SPC extensions

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Momelotinib Opportunity: Well Positioned for ‘Switch’ from Approved JAKi Therapy

Switch

Approved JAKi therapy may provide symptom and splenomegaly benefits… …while exacerbating or inducing reductions of platelets and RBC’s with diminishing dose intensity. Momelotinib delivers mechanism-driven anemia benefits in addition to symptom and splenomegaly benefits Switching to momelotinib leads to an immediate and sustained increase in hemoglobin, platelets and an array of anemia benefits with sustained dose intensity.

OTHER JAKi THERAPIES

RBCs & PLTs Time Dose intensity Time

3 - D I M E N S I O N A L A C T I V I T Y

RBCs & PLTs Time Dose intensity Time

2 - D I M E N S I O N A L A C T I V I T Y

Targeted Hematology and Oncology Therapeutics

• Drug development company oriented to commercialization.
• Momelotinib – differentiated JAKi potentially addressing all

three hallmarks of myelofibrosis.

• MOMENTUM Phase 3 in 2L MF launched in Q4 2019.
• Highly experienced management team with proven track

record in drug development.

• Strong financial standing:
• $67.7M in cash and cash equivalents

(as of September 30, 2019)

• $5M borrowed in structured debt

(as of September 30, 2019)

• $103M gross proceeds from recent equity raise; included

Vivo Capital, Longitude Capital, OrbiMed and Abingworth

(closed November 13, 2019)

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