PowerPoint Presentationfilecache.investorroom.com/mr5ircnw_sierra/262... · “Anemia is major area...
Transcript of PowerPoint Presentationfilecache.investorroom.com/mr5ircnw_sierra/262... · “Anemia is major area...
Q3 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
3
momelotinibTARGETING JAK1/2 AND ACVR1
THERAPEUTIC FOCUS
Myelofibrosis
SRA737TARGETING Chk1
THERAPEUTIC FOCUS
Anogenital Cancer& Other Solid Tumors
SRA141TARGETING Cdc7
THERAPEUTIC FOCUS
Colorectal Cancer
DDR Network ProgramsLead Program
Our Pipeline of Targeted TherapeuticsPreclinical Phase 1 Phase 2 Phase 3 Focus
SIMPLIFY-1
SIMPLIFY-2
Myelofibrosis
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
Solid Tumors
Prostate
Myelofibrosis
Myelofibrosis
Squamous Ca.
Anogenital
Colorectal
4
M O M E L O T I N I B
Prim
ary
finan
cial
focu
sEv
alua
ting
and
expl
orin
g op
tions
MOMELOTINIBTarget ing JAK1, JAK2 and ACVR1
5
6
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
>7 yearson treatment for several patients
Momelotinib Potentially Addresses Key Needs in Myelofibrosis Treatment
7
OpportunityIntermediate/High-Risk MF who have
previously received a JAKi*; large unmet need with no approved therapies
BenefitOnly agent to robustly impact all three myelofibrosis hallmarks: constitutional
symptoms, anemia, and enlarged spleen
Robust DataTwo P3 SIMPLIFY studies
support further development; provide confidence for MOMENTUM design
RegistrationRegulatory clarity & Fast Track designation
obtained; MOMENTUM P3 study launch planned for Q4 2019; topline data anticipated Q4 2021
*Momelotinib Fast Track Designation, May 2019
• Only one agent approved: ruxolitinib(Jakafi®) for 1st-line myelofibrosis
• Ruxolitinib:• Addresses ~70% 1st-line patients• Projected global market: >$2.5B• Only treats spleen and symptoms
Anemia is not addressed by ruxolitinib
8
Myelofibrosis: More Treatment Options Needed
I N I T I A L T R E AT M E N T:
• Optimal myelofibrosis therapeutic would address all three hallmarks:
• Constitutional symptoms• Anemia and transfusion dependency • Splenomegaly
Physicians need more choices than ruxolitinib
U N M E T M E D I C A L N E E D S :
P R E V I O U S LY J A K i - T R E AT E D M F R E M A I N S A 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
The Three Hallmarks of a Progressive Disease
Three Hallmarks of a Progressive Disease
9
> 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
Tefferi A, et al. Mayo Clin Proc. 2012
10
Momelotinib: Attractive Acquisition Terms & Patent Life
• Sierra Management has unique insight into MMB.
• Full asset acquisition.
• $3M upfront; $5M at start of Phase 3.
• $195M in additional Milestones; heavily weighted to commercial success.
• Royalties from mid-teens to high-twenties; tiered by commercial success.
• Long patent life remaining: U.S. exclusivity projected to 2040* EU exclusivity projected to 2032-2040*/**
*assumes anticipated 5 years PTE and SPC extensions**pending issue
Myelofibrosis Biology: JAK1, JAK2 & ACVR1 Drive MF Disease Hallmarks
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 & aberrant cytokine signaling producing debilitating constitutional symptoms
P
JAK2/3JAK1JAK2JAK2
11
Myelofibrosis Biology: Momelotinib Uniquely Inhibits All Three Disease Drivers
BMP2, BMP6
ACVR1
InterleukinsInterferons
Cytokine Receptors EPOR / MPL
Ligand
JAK2/3JAK1JAK2JAK2
• 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
JAK1Inhibition
JAK2Inhibition
ACVR1Inhibition
SMAD1,5 PSTAT STAT PP
12
Myelofibrosis Anemia:Momelotinib Could Positively Impact Multiple Pathways to Anemia
13
OTHER JAKi THERAPIES
HEPCIDIN (ACVR1)
ANEMIA
Other JAK inhibitorsinduce myelosuppression
Impairment of iron metabolism
Elevated hepcidin
Activated ACVR1
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
Myelofibrosis Anemia: High Hepcidin & Severe Anemia Predict Poor Survival
14
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.
0 5 10Years
20 25 30 35150
2
4
6
Surv
ival
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
Cum
ulat
ive
Surv
ival
0
4
2
6
8
10
5 10 150
Myelofibrosis Anemia: Reducing Hepcidin Restores Red Blood Cell Production
15
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+
Momelotinib:SIMPLIFY Data Strongly Support Benefits in Three Hallmarks of MF
16
INHIBITSACVR1
INHIBITSJAK2
INHIBITSJAK1
ANEMIA
SPLENOMEGALYOnly JAKi to show equivalent splenic response to ruxolitinib in 1L
CONSTITUTIONAL SYMPTOMSPronounced 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
Momelotinib:Regulatory Clarity Announced
• MOMENTUM Phase 3 pivotal trial designed to support registration of momelotinib
• Productive interactions with US and EU regulators
• FDA supportive of delineating a regulatory path for momelotinib in context of SIMPLIFY study data
• FDA provided constructive input to help delineate P3 study intended to yield data to support momelotinib’s potential registration
• Focus of MOMENTUM on unmet need population of 2L MF patients previously treated with a JAKi
• Momelotinib is positioned to potentially provide all three clinical benefits for this substantial population of patients: symptoms, anemia & spleen
17
18
Momelotinib:Fast Track Designation Granted (May 2019)
Patients with intermediate/high-risk myelofibrosis who have previously received a JAK inhibitor
FDA FAST TRACK DESIGNATION
Planned Launch Q4 2019
19
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
rand
omiz
atio
n
Double-Blind Treatment Open Label/CrossoverLong Term Follow-up
Day 1 Week 24
Primary Endpoint
Momelotinib 200 mg daily + Placebo
SubjectsN=180
20
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
Momentum P3 Trial:Study Objectives
Primary Endpoint:• Total symptom score (TSS) response rate of MMB vs DAN 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 MMB vs DAN.• Splenic response rate (SRR) at Week 24 for subjects treated with MMB vs DAN.• Duration of TSS response for subjects treated with MMB.• 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.
21
Momentum P3 Trial:Key Design Elements
22
Endpoint Order & Powering Supporting Data/Rationale
Symptom (TSS) response rate Primary (W24)99% powered; p<0.05
FDA preferred measure of clinical benefit in MyelofibrosisConsistent 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 benefitNon-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
**Dependent on regulatory review process (priority or standard)
Momentum P3 Trial:Key Trial Assumptions
23
Key Assumption Comment*
# Patients 180 (2:1 randomization)
Territory Global study: North America, EU, APAC, etc.
Study Start Planned launch in Q4 2019
Estimated Time to Enroll ~18 months
Estimated Time to Primary Endpoint ~6 months to primary endpoint after enrollment
Estimated Topline Data ~Q4 2021
Estimated Filing Date ~Q2 2022
Potential Regulatory Approval ~Q4 2022-Q2 2023**
*Company estimates
24
Momentum P3 Trial:Chief Investigator
• Dr. Srdan (Serge) Verstovsek, Chief, Section for Myeloproliferative Neoplasms, MD Anderson Cancer Center, Houston, has been named Chief Investigator of MOMENTUM.
• World-renowned physician-scientist, and a leading global authority on the treatment of myelofibrosis.
• Dr. Verstovsek’s clinical and translational research is focused on understanding the biology of and developing new therapies for myeloproliferative neoplasms (MPNs).
• Principal investigator for more than 50 clinical trials testing novel therapies for patients with MPNs.
• Published more than 400 peer-reviewed manuscripts. • Recipient of numerous awards and accolades. Srdan Verstovsek, MD, PhD
Chief, Section for Myeloproliferative Neoplasms, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
25
Momentum P3 Trial:KOL Views on Danazol Use in MF
References citing danazol in MF: • Cervantes F, Isola IM, Alvarez-Larrán A, et al. Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long term results. Annals
of Hematology. 2015; 94(11):1791-6.• Cervantes F, Alvarez-Larrán A, Domingo A, et al. Efficacy and tolerability of danazol as a treatment for the anaemia of myelofibrosis with myeloid metaplasia: Long term results in 30
patients. British Journal of Haematology. 2005; 129: 771–5.• Cervantes F, Hernández-Boluda JC, Alvarez A, et al. Danazol treatment of idiopathic myelofibrosis with severe anemia. Haematologica 2000; 85:595-9.• Luo X, Xu Z, Li B, et al. Thalidomide plus prednisone with or without danazol therapy in myelofibrosis: a retrospective analysis of incidence and durability of anemia response. Blood
Cancer Journal. 2018; 8:9. • Gowin K, Kosiorek H, Dueck A, et al. Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis. Leukemia Research 2017;60:31-5.• Levy V, Bourgarit A, Delmer A, et al. Treatment of agnogenic myeloid metaplasia with danazol: A Report of Four Cases. American Journal of Hematology. 1996;53:239-41. • Chabannon C, Pegourie B, Sotto JJ, et al. Clinical and hematological improvement in a patient receiving danazol therapy for myelofibrosis with myeloid metaplasia. Nouv Rev Fr
Hematol. 1990;32(2):165-6.• Xu ZF, Qin TJ, Zhang HL, et al. Ruxolitinib combined with prednisone, thalidomide and danazol for treatment of myelofibrosis: a pilot study.
“In my experience as a practicing hematologist who has treated many patients with danazol, I do not believe danazol will have any marked activity on symptoms and spleen, and small benefit on anemia in these late stage patients; as such, the use of danazol as a control arm in MOMENTUM is appropriate as we expect it to have minimal activity and enable us to see a very strong treatment effect.”
Dr. Serge Verstovsek June 10, 2019Srdan Verstovsek, MD, PhDChief, Section for Myeloproliferative Neoplasms, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
26
EXTENDED ACCESS PROGRAM
Momelotinib:Totality of Data to Support Potential Registration
PHASE 3 CLINICAL TRIAL
Patient data from completed studies>600 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-1SIMPLIFY-2
‘1672
XAPTRANSLATIONAL BIOLOGY STUDY IN TD PATIENTS
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>130 subjects; >15 countries
• Durable response data (some patients treated>8 years)
• Long term safety and tolerability data
27
Momelotinib 2nd-Line Market Opportunity*
• ~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 VerstovsekJune 2019
>75% will need 2nd-line treatment2nd-Line
Favorable patent exclusivity • potential extensions to 2040** provide a
compelling commercial opportunity
*Company estimates**assumes anticipated 5 years PTE and SPC extensions
Planned Launch Q4 2019
28
FDA FAST TRACK DESIGNATION
SRA737
Target ing Chk1
30
SRA737 Program Overview:Broad Signal Seeking Across Indications & Genetics
SRA737 Monotherapy (-01)
SRA737 + LDG (-02)
Intrinsic RS
Intrinsic +Extrinsic RS
Tumor SuppressorTP53, RAD50...Oncogenic DriversCCNE1, MYC…
Replicative StressATR, CHEK1…
DNA Repair MachineryBRCA1, FANCA…
mCRPC
NSCLC
SCC (H&N, anogenital)
HGSOC
mCRC Indication/genomic signature with
enriched response to SRA737 +/-LDG
SCLC
Cervical/Anogenital
HGSOC
STS
Clinical Trial Clinical Hypothesis Indications Tumor Genetics Ph2 Directional Efficacy Signal
SRA737 is an active and well tolerated drug candidate that warrants further development. Sierra is evaluating potential next steps for SRA737, exploring options that could enable its continued advancement, while focusing the company’s resources on momelotinib.
SRA737+LDG:Demonstrates Anti-Cancer Activity Across Multiple Indications
31
• PRs observed in six subjects (3x anogenital cancer; 1x rectal, cervical, and ovarian cancer). Generally, responses were first recorded at the end of Cycle 2 (first on-study scan).
• 41 subjects had best response of Stable Disease (SD); durable SD lasting ≥ 4 months was recorded in 32 subjects and was observed in all expansion cohorts.
SRA737+LDG:Promising 30% Response Rate in Anogenital Cancer
32
Noteworthy anti-tumor activity observed in subjects with advanced anogenital cancer (ORR = 30%; DCR=60%)
Best
% C
hang
e fro
m B
asel
ine
in S
um o
f Tar
get T
umor
Dia
met
ers
SRA737+LDG in Anogenital Cancer:Illustrative Clinical Activity
33
70 yo male with anal cancer; extensive liver metastasisPrior therapy: radiation and 1 line of systemic therapy Genetic Profile: FA/BRCA, PI3K and TMB-IBest tumor response: -41% Duration on treatment: 11 cycles (response ongoing at discontinuation; patient decision)
59 yo female with anal cancer, mediastinal mass compression and malignant pleural effusionPrior therapy: 3 lines of systemic therapy FMI Genetics: FA/BRCA and TMB-IBest tumor response: -26% + resolution of pleural effusionDuration on treatment: 7 cycles; ongoing (as of data cut: 03 May 2019)
Targeted Hematology and Oncology Therapeutics
34
• Bold drug development company oriented to potential registration and commercialization
• Momelotinib – differentiated JAKi potentially addressing all three hallmarks of myelofibrosis• MOMENTUM P3 in 2L MF planned launch in Q4 2019
• SRA737 oriented to potential registration-intent studies in anogenital cancer; exploring non-dilutive options to advance
• Highly experienced management team with proven track record in drug development
• Strong financial standing:• Shares (as of June 30):
74.7M outstanding 88.0M fully diluted
• $78.8M in cash and cash equivalents (as of June 30)
• $5M borrowed in structured debt