unmet needs in myelofibrosis: addressing anemia
TRANSCRIPT
NASDAQ: SRRA
Unmet Needs in Myelofibrosis: Addressing Anemia & Transfusion Dependency
NASDAQ: SRRA
May 13, 2020
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S A F E H A R B O R S TAT E M E N T
Mark Kowalski, MD, PhDChief Medical Officer
Nick Glover, PhDPresident and CEO
Barbara Klencke, MDChief Development Officer
Sukhi Jagpal, CA, CBV, MBAChief Financial Officer
Gregg Smith, PhD, MBASenior Vice President, Drug Development
Sierra’s Proven Leadership in Drug Development
33
Dr. Ruben Mesa:Director of the Mays Cancer Center
• Director of the Mays Cancer Center, UT Health San Antonio MD Anderson Cancer Center
• Myeloproliferative neoplasm (MPN) researcher for >20 years
• Led development of NCCN Guideline for myelofibrosis (MF)
• Architect of MPN Symptom Assessment Form, key tool to assess symptomatic burden in MF; basis of primary endpoint measurement in MOMENTUM confirmatory Phase 3 trial
• Principal Investigator >70 clinical trials. Co-led team leading to FDA’s approval of ruxolitinib in MF. Currently leading investigation of several agents for MPN treatment
• Actively engaged in development of momelotinib from initial clinical trials through Phase 3, including the MOMENTUM Phase 3 trial
4
Ruben Mesa, MDDirector of the Mays Cancer Center, home to UT Health San Antonio MD Anderson Cancer Center
• Myelofibrosis (MF) primarily driven by dysregulated JAK-STAT signaling leading to clonal proliferation in the bone marrow
• Progressive fibrosis reduces hematopoietic capacity of the marrow (anemia), triggering extramedullary hematopoiesis in the spleen (splenomegaly)
• Constitutive activation of JAK-STAT signaling & progressive fibrosis creates both local and systemic pro-inflammatory cytokine profile (constitutional symptoms); drives production of hepcidin, the master iron regulator
• Elevated hepcidin restricts iron availability for erythropoiesis, further reducing red blood cell (RBC) production (anemia)
• These factors coalesce leading to the classic disease hallmarks of anemia, constitutional symptoms and splenomegaly
Etiology of Myelofibrosis:A Disease of Dysregulated JAK-STAT Signaling
5
Dysregulated JAK Signaling
Inflammation Fibrosis & Extramedullary Hematopoiesis
Elevated Hepcidin
The Three Hallmarks of a Progressive Disease
Three Hallmarks of a Progressive Disease
6
> 1 Y E A R A F T E R D I A G N O S I S
64%46%34%
MyelofibrosisThe Challenge of Anemia
“Anemia is major area of unmet need… 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”
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
Tefferi, A et al. Mayo Clin Proc. 2012
CONSTITUTIONAL SYMPTOMSPatients also experience debilitating symptoms that dramatically impact their lives
ANEMIA
45% Transfusion Dependent
Spleen tries to compensate by making blood cells, leading to pain and discomfort
Many patients need regular blood transfusions to sustain life
Bone marrow cancer that significantly impairs red blood cell production
SPLENOMEGALY
Unmet Needs in Myelofibrosis: Inadequate Current Treatment Options for Anemia
• Approved MF agents (ruxolitinib and fedratinib) offer certain benefits for splenomegaly and symptoms, but fail to address – actually, worsen - anemia and thrombocytopenia
• Anemia in myelofibrosis is multifactorial (hypersplenism, ineffective erythropoiesis, hemolysis, functional iron deficiency, chronic inflammation, etc)
• Multiple options have been deployed to attempt to manage MF anemia; none are approved or have been shown demonstrably effective:
• Danazol• ESAs• Steroids• IMiDs
• In the absence of an effective therapeutic option, frequent, chronic red blood cell (RBC) transfusions are employed as the default form of anemia management in MF
• Optimal MF therapeutic would provide robust and sustained benefits for anemia,constitutional symptoms and splenomegaly
7
Anemia in Myelofibrosis: The Burden of Transfusions
Time Consuming and Costly • Impacts patients, caregivers and health care systems• Costs include clinic visits, blood banking and
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
8Jochen Sands/Digital Vision/Thinkstock
Myelofibrosis Anemia: Prognostic Criticality of Anemia in MF
• Anemia negatively recognized in prognostic models for MF
• Moderate to severe anemia scored twice as heavily as all other risk factors
• Dynamic International Prognostic Scoring System plus (DIPSS-plus) model includes transfusion dependency as an additional independent prognostic variable
• Transfusion dependency or anemia - in context of constitutional symptoms - automatically places a patient into the intermediate-2 or high-risk DIPSS-plus category
9
Variable DIPSS1 DIPSS-plus2
Age > 65 years + +
Constitutional Symptoms + +
Hgb < 10 g/dL ++ ++Leukocyte count > 25x109/L + +
Circulating blasts ≥ 1% + +
Platelet count < 100X109/L +
RBC Transfusions ++Unfavorable karyotype +
1 Passamonti, F et al. Blood. 20102 Gangat, N et al. J Clin Oncol. 2011
Prognostic Risk DIPSS1 DIPSS-plus2
Low 0 0
Intermediate-1 1-2 1
Intermediate-2 3-4 2-3
High ≥5 ≥4
Myelofibrosis Anemia: Anemia &Transfusion Dependency Predict Poor Survival
10
Transfusion dependency results in substantially shortened survival
Anemia predicts poor survival in myelofibrosis
Nicolosi M et al. Leukemia. 2018.
0 5 10Years
20 25 30 35150
0.2
0.4
0.6
Surv
ival
0.8
1.0
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 (incl. transfusion dependency)Median survival 2.1 years
Elena C et al. Haematologica. 2011
Time since diagnosis18161412108642
0.2
00
0.4
0.6
0.8
1.0
Time since diagnosis
Cum
ulat
ive
prop
ortio
n su
rviv
ing
Transfusion-dependent
Transfusion-independent
0 4 8 12 16 20 249
10
11
12
Weeks
Mea
n He
mog
lobi
n (g
/dL)
Myelofibrosis Anemia: Approved JAKi Therapies Exacerbate Anemia
• Approved JAK inhibitors demonstrably reduce Hgb and exacerbate underlying anemia• Partial Hgb recovery driven by dose reductions and frequent RBC transfusions
• Ruxolitinib dose reductions = 31% COMFORT-1; 56% SIMPLIFY-1 & 54% needed RBC transfusions• Fedratinib dose reductions = 24% JAKARTA-1; 51% needed RBC transfusions1
11
Ruxolitinib (JAK1, JAK2)
Verstovsek, S. et al. N Engl J Med. 2012 SIMPLIFY-1, unpublished
Fedratinib (JAK2)
SIMPLIFY-1COMFORT-1 JAKARTA-1
Adopted from Pardanani, A. et al. JAMA Oncol. 2015
Partial Hgb recovery driven by RUX dose reductions & Tsfs
1 INREBIC package insert
12
11
10
90 4 8 12 16 20 24 28 32 36
9
10
11
12
Weeks
Mean
Hem
oglo
bin
(g/d
L)
Fedratinib 400 mg
Myelofibrosis Anemia: Approved JAKi Therapies Exacerbate Anemia (Cont’d)
• Anemia & need for RBC transfusions are frequently present prior to initiation of ruxolitinib; anemia is clearly and profoundly exacerbated throughout ruxolitinib treatment
• Anemia continues to worsen following ruxolitinib discontinuation due to underlying progressive disease• Data reinforce the significant unmet need of anemia in myelofibrosis for patients receiving ruxolitinib and after ruxolitinib
treatment discontinuation
12
Patients with Anemia andRBC Transfusion
Following Ruxolitinib Initiation (n = 290)
Following Ruxolitinib Discontinuation (n = 163)
Adapted from Mascarenhas, J et al. J Med Econ. 2020
Exacerbation of Underlying Anemia on Ruxolitinib Anemia Progression after Ruxolitinib
0 30 60 90 120 150 1800
25
50
75
100
Days
% o
f Pat
ient
s
0 30 60 90 120 150 1800
25
50
75
100
Days
% o
f Pat
ient
s
MOMELOTINIBPositioned to potentially provide benefits on all three myelofibrosis hallmarks: symptoms, anemia and spleen
>20 studiesPhase 1, 2 and 3
>1,200 peopledosed with momelotinib
>820 patientswith myelofibrosis treated
incl. SIMPLIFY 1 & 2 P3 trials
>8 yearson treatment for several patients
13
Myelofibrosis Biology: JAK1, JAK2 & ACVR1 Drive Myelofibrosis Disease Hallmarks
14
BMP2, BMP6
ACVR1
SMAD1,5P
• Aberrant activation of hepcidin transcription via hyperactivated ACVR1 signaling resulting in profound functional iron deficiency anemia
InterleukinsInterferons
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
JAK2JAK1JAK2JAK2
Myelofibrosis Biology: JAK1, JAK2 & ACVR1 Drive Myelofibrosis Disease Hallmarks
15
BMP2, BMP6
ACVR1
SMAD1,5P
• Aberrant activation of hepcidin transcription via hyperactivated ACVR1 signaling resulting in profound functional iron deficiency anemia
InterleukinsInterferons
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
JAK2JAK1JAK2JAK2
Myelofibrosis Anemia: Elevated Hepcidin Impairs Red Blood Cell Production
16
P L A S M A I R O N D E F I C I E N C Y
Chronically activated ACVR1 in MF leads to marked elevation in hepcidin.Elevated hepcidin reduces iron availability for erythropoiesis.
Fe2+
Increasedhepcidin
BMP2, BMP6
ACVR1
SMAD1,5 P
Myelofibrosis Anemia: High Hepcidin Correlates With Severe Anemia and Poor Survival
17
Pardanani, A et al. Am J Hematol. 2013
Hepcidin predicts poor survival in myelofibrosis Anemia predicts poor survival in myelofibrosis
Nicolosi, M et al. Leukemia. 2018
0 5 10Years
20 25 30 35150
0.2
0.4
0.6
Surv
ival
0.8
1.0
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
Cum
ulat
ive
Surv
ival
0
0.4
0.2
0.6
0.8
1.0
5 10 150
Myelofibrosis Biology: Momelotinib Uniquely Inhibits All Three Disease Drivers
18
BMP2, BMP6
ACVR1
InterleukinsInterferons
Cytokine Receptors EPOR / MPL
Ligand
JAK2JAK1JAK2JAK2
• Decreased hepcidin transcription via ACVR1 inhibition 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
JAK1Inhibition
JAK2Inhibition
ACVR1Inhibition
SMAD1,5 PSTAT STAT PP
X X X
Myelofibrosis Biology: Momelotinib Uniquely Inhibits All Three Disease Drivers
19
BMP2, BMP6
ACVR1
InterleukinsInterferons
Cytokine Receptors EPOR / MPL
Ligand
JAK2JAK1JAK2JAK2
• Decreased hepcidin transcription via ACVR1 inhibition 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
JAK1Inhibition
JAK2Inhibition
ACVR1Inhibition
SMAD1,5 PSTAT STAT PP
X X X
Myelofibrosis Anemia: Reducing Hepcidin Restores Red Blood Cell Production
20
P L A S M A I R O N D E F I C I E N C Y P L A S M A I R O N N O R M A L I Z AT I O N
Momelotinib-mediated inhibition of ACVR1 markedly decreases hepcidin. Results in plasma iron elevation leading to stimulation of erythropoiesis and red blood cell production.
Fe2+
Fe2+
Increasedhepcidin
Decreased hepcidin
BMP2, BMP6
ACVR1
SMAD1,5 P
X
BMP2, BMP6
ACVR1
SMAD1,5 P
Clinical Validation of Anemia Mechanism:Acute & Chronic Hepcidin Suppression by Momelotinib
21
• Phase 2 Translational biology study (GS-US-352-1672), N=41 transfusion dependent MF subjects• Primary endpoint: Transfusion independence rate
• 41% ≥ 12 Week TI response rate (at any time); 39% became TI for at least 8 weeks (by Week 24)• 78% of subjects who did not become TI achieved ≥ 50% decrease in transfusion requirements for ≥ 8 weeks
• Pharmacodynamic analyses demonstrate 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 momelotinibOverall trend to reduced hepcidin over timeReinforces ACVR1i mechanism of action
Visit: Timepoint
Baseline Enrollment Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24
Med
ian
actu
al v
alue
(Q1,
Q3)
Pre-dose6 hours post-dose
Oh, S et. al. ASH Abstract# 4282. 2018Sierra manuscript in preparation
Clinical Validation of Anemia Mechanism:Momelotinib Acutely and Sustainably Improves Hgb Levels
• Mean Hgb levels in SIMPLIFY-1 rapidly increase following initiation of momelotinib treatment
• Increased Hgb levels are durably maintained
• Hgb increase reflected in momelotinib’s robust anemia benefits, including decreased transfusion burden and durable transfusion independence
• Clinical data are consistent with momelotinib’sdifferentiated mechanism of action via ACVR1 inhibition
• Notably distinct Hgb benefits for momelotinib vs. exacerbation of anemia with ruxolitinib
• Additionally, momelotinib is a potent inhibitor of NF-κB signaling - might further contribute to overall benefit; ruxolitinib has no effect on NF-κB*
22
SIMPLIFY-1
n = 215 200 191 188 174 181 171 154 152 147
* Unpublished data
Momelotinib
Ruxolitinib
Myelofibrosis Anemia:Momelotinib Positively Targets Multiple Pathways to Anemia
23
OTHER JAKiTHERAPIES
HEPCIDIN (ACVR1)
ANEMIA
Other JAK inhibitorsinduce 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 erythroiddifferentiation
Alterations in bone marrow cytokine
expression
Momelotinib’s Clinical Development:SIMPLIFY-1 Phase 3 Study
24
1st-Line Population: JAK inhibitor naïve subjects
SIMPLIFY-1
JAK-i NaïveDouble-blind,
N=432
Momelotinib 200 mg QD
Ruxolitinib 20 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
Momelotinib: N=215
Ruxolitinib: N=217
Primary Endpoint Splenic Response Rate
Secondary Endpoints • Total Symptom Score*• Transfusion Independence Rate• Transfusion Dependence Rate• RBC Transfusion Requirements
Mesa, R et al. J Clin Oncol. 2017 *not stratified for symptoms
• SIMPLIFY-1 (S1) remains the only randomized, double blind head-to-head study conducted in 1st-line MF vs ruxolitinib
• Large (N=432) international Phase 3 study
• S1 met the primary endpoint of non-inferior splenic response rate for momelotinib vs. ruxolitinib, and showed clinically comparable symptomatic benefit
• Key biological and clinical differences between momelotinib and ruxolitinib revealed through analyses of various anemia endpoints
66%Statistically significant
transfusion independence rate (p < 0.001)
vs 49% ruxolitinib
30%Maintenance of Transfusion Independence
vs 40% ruxolitinib)
Statistically significant transfusion dependence rate
(p = 0.019)
25
Transfusion Independence response defined as the proportion of subjects who were transfusion independent at Week 24, where transfusion independence was defined as the absence of RBC transfusion and no hemoglobin level below 8 g/dL in the prior 12 weeks
Momelotinib Ruxolitinib
Median hemoglobin 10.5 10.3
% TD at baseline 25% 24%
% TI at baseline 68% 70%
Relevant baseline characteristics well balanced between arms:
Conversion from Transfusion Dependent to Transfusion Independent 49.1%
≥ 12 Week Transfusion Independence Response Rate*
*Data from Sierra’s post-hoc analyses of SIMPLIFY-1
vs 28.8% ruxolitinib
Transfusion Dependent Subset AnalysisEliminating Need for Frequent Transfusions
(p = 0.0299)
26
Transfusion Independence Response defined as the proportion of transfusion dependent subjects who became transfusion independent for any 12 week or greater period on study, where transfusion independence was defined as the absence of RBC transfusion and no hemoglobin level below 8 g/dL
ASH 2019 Poster Presentation:Dynamic Analyses of Momelotinib’s Anemia Benefits vs Ruxolitinib
27
Dr. Ruben MesaDirector of the Mays Cancer CenterHome 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 patient burden of transfusions
• Retrospective analyses of S1 data were performed using variety of novel dynamic anemia benefit endpoints to explore relative burden of transfusions for momelotinib vs. ruxolitinib
28
1) Time-to-first, third & fifth RBC unit(s) transfusedcompare relative ‘transfusion events’ by treatment arm
2) Zero-inflated negative binomial (ZINB) modelfit to transfusion data to compare proportions of patients with zero transfusion burden (i.e. transfusion free) and mean transfusion rates
3) Duration of transfusion independenceassess durability of transfusion free period
Time to First Transfusion:More Patients Require No Transfusions on Momelotinib
• First RBC unit transfused = relative assessment of proportion of transfusion free patients
• KM time-to-first RBC unit transfused analysis showed immediate and sustained momelotinibtreatment effect(log-rank p < 0.0001)
• Patients randomized to momelotinib more likely to receive no transfusions (73%) compared to patients randomized to ruxolitinib(46%)
• Odds of receiving no transfusions during treatment was 3.2 times higher on momelotinib vs. ruxolitinib
29
Time to Third Unit Transfused:Immediate & Sustained Reduction in Transfusion Burden on MMB
• Assuming two units of RBCs per typical transfusion, third and fifth RBC units transfused represent a 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)
30
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
31
ZINB Covariate Analysis:MMB Patients Have an Increased Odds of Zero Transfusions
• Covariate ZINB model demonstrates 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)
32
Maintenance of Transfusion Independence:Extended Durability of Transfusion Independence on MMB
• Duration of transfusion independence (TI) response in S1 was determined by a KM analysis of time to loss of TI*
• 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
33*Loss of TI was defined by the requirement for RBC transfusion or hemoglobin < 8.5 g/dL at any time
Momelotinib’s Anemia Benefit:Momelotinib Rapidly Ameliorates JAKi Suppressed Hgb
• Even with frequent ruxolitinib dose reductions and RBC transfusions, 1st-line MF patients treated with ruxolitinib experience rapid and prolonged suppression of Hgb
• Importantly, upon crossover from ruxolitinib to momelotinib, patients experienced rapid and robust increase in Hgb levels
• Mean Hgb post-crossover eclipsed that reported at baseline for ruxolitinib!
• Data consistent with momelotinib’s differentiated ACVR1 activity
• Reinforces momelotinib’s potential to alleviate anemia i) in naïve patients and ii) those previously treated with ruxolitinib
34
SIMPLIFY-1: Crossover
SIMPLIFY-1, unpublished
Baseline Hgb
Cro
ssov
er
Momelotinib’s Enhanced Cytopenia Profile:Momelotinib Treatment Results in Sustained Platelets
• Despite frequent ruxolitinib dose reductions for thrombocytopenia, 1st-line MF patients treated with momelotinib had substantially better maintenance of platelets compared to ruxolitinib
• Observation supported by sustained mean baseline platelet values for momelotinibtreatment compared to ruxolitinib
• Upon crossover from ruxolitinib to momelotinib, patients experienced a demonstrable increase in platelets, sustained over time
35
SIMPLIFY-1
SIMPLIFY-1, unpublished
Unmet Medical Needs in MF:Addressing Anemia & Transfusion Dependency
Context:
• Cytopenias are very common in MF; anemia is the most prevalent cytopenia
• Anemia and transfusion dependency are associated with poor prognosis and impaired survival in MF
• Treatment options are desperately lacking
Key Finding:
• Momelotinib’s immediate and sustained anemia benefits manifest in an overall reduced transfusion burden compared to ruxolitinib
• Long-term, maintained hemoglobin increase
• Extended transfusion free duration
36
Unmet Medical Needs in MF:Addressing Anemia & Transfusion Dependency (Cont’d)
Clinical Relevance:
Ability to achieve clinically comparable benefits on symptoms and splenomegaly while increasing hemoglobin and demonstrably improving the transfusion burden for patients – while sparing platelets –would provide a potentially important addition to the myelofibrosis armamentarium
Potential Clinical Usage:
Momelotinib is likely to be broadly used:
i) in first line patients with severe anemia and transfusion dependency at presentation, and
ii) across the largely cytopenic second line MF population
37
38
LAUNCHED Q4 2019Now Recruiting Globally!
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
2:1 randomization
Double-Blind Treatment Open Label/CrossoverLong Term Follow-up
Day 1 Week 24
Primary Endpoint
Momelotinib 200 mg daily + Placebo
SubjectsN=180
Momentum Phase 3 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
39
JAKi taper/washout≥ 21 day
Previously Treated with JAK inhibitor
Symptomatic (TSS ≥ 10) and Anemic
(Hgb < 10 g/dL)
*Early crossover to open label in the event of confirmed symptomatic splenic progression
MOMENTUM Phase 3 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
4040
* 99% powered; p<0.05** >90% powered; p<0.05
Late Stage Drug Development Company Oriented to Potential Registration and Commercialization
41
• Momelotinib – differentiated JAKi potentially addressing all three hallmarks of myelofibrosis
• MOMENTUM Phase 3 in 2nd-line myelofibrosis launched in Q4 2019
• Highly experienced management team with proven track record in drug development
• Strong financial standing:
• $133.5M in cash and cash equivalents (as of March 31, 2020)
• Key investors include Vivo Capital, Longitude Capital, OrbiMedand Abingworth
• Topline data warrant: Expires 75 days post-announcement; Potential ~$34M in additional funding
