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ASH IR EventDecember 6, 2015
Forward Looking Statements and Adjusted Financial Information
This presentation contains forward-looking statements, which are generally statements that are nothistorical facts. Forward-looking statements can be identified by the words “expects,” “anticipates,”“believes,” “intends,” “estimates,” “plans,” “will,” “outlook” and similar expressions. Forward-looking, , , p , , p gstatements are based on management’s current plans, estimates, assumptions and projections, andspeak only as of the date they are made. We undertake no obligation to update any forward-lookingstatement in light of new information or future events, except as otherwise required by law. Forward-looking statements involve inherent risks and uncertainties, most of which are difficult to predict andare generally beyond our control Actual results or outcomes may differ materially from those impliedare generally beyond our control. Actual results or outcomes may differ materially from those impliedby the forward-looking statements as a result of the impact of a number of factors, many of whichare discussed in more detail in our Annual Report on Form 10-K and our other reports filed with theSecurities and Exchange Commission.
In addition to financial information prepared in accordance with U.S. GAAP, this presentation alsocontains adjusted financial measures that we believe provide investors and management withsupplemental information relating to operating performance and trends that facilitate comparisonsbetween periods and with respect to projected information. These adjusted financial measures arenon-GAAP and should be considered in addition to but not as a substitute for the informationnon GAAP and should be considered in addition to, but not as a substitute for, the informationprepared in accordance with U.S. GAAP. We typically exclude certain GAAP items thatmanagement does not believe affect our basic operations and that do not meet the GAAP definitionof unusual or non-recurring items. Other companies may define these measures in different ways.Further information relevant to the interpretation of adjusted financial measures, and reconciliations
f th dj t d fi i l t th t bl GAAP b f d
2
of these adjusted financial measures to the most comparable GAAP measures, may be found onour website at www.Celgene.com in the “Investor Relations” section.
Jackie Fouse, PhDPresident, Global Hematology & Oncology
ASH 2015 Accepted Abstracts
PRODUCT/TOPIC MM Myeloid Disease NHL/CLL Other TOTAL
REVLIMID® 69 16 24 109REVLIMID® 69 16 24 109
POMALYST®/IMNOVID® 22 2 1 25
VIDAZA® 53 53
CC-122 4 4
CC-486 1 1
Luspatercept 3 3
Sotatercept 1 1 2
AG-221 2 2
AG-120 2 22 2
Other 5 2 11 2 20
Disease 2 4 1 7
TOTAL 99 86 40 3 228TOTAL 99 86 40 3 228
4
Celgene at ASH 2014
Maximizing Our Opportunity in Multiple Myeloma
Strengthening Our Business in Myeloid DiseaseStrengthening Our Business in Myeloid Disease
REVLIMID®’s Growing Potential in Lymphoma
Emerging Presence in Immuno-Oncology
5
2015 Hematology Advances
Maximizing Our Opportunity in Multiple Myeloma
Strengthening Our Business in Myeloid Diseases Approval for REVLIMID® in NDMM in U.S. and EU
Strengthening Our Business in Myeloid Diseases Initiating luspatercept and AG-221 pivotal trials
Ad d 5 h III t i l ith REVLIMID® i NHLREVLIMID®’s Growing Potential in Lymphoma Advanced 5 phase III trials with REVLIMID® in NHL
Established strategic collaborations with AZ/MEDI for
Emerging Presence in Immuno-Oncologydurvalumab and with Juno Therapeutics for CART
6
Celgene at ASH 2015
IMiD® Products as Backbone in MM
Expansion in Myeloid DiseaseExpansion in Myeloid Disease
Lymphoma Program Momentum Accelerating
Immuno-Oncology Advancing Rapidly
7
Agenda
Clinical Update in HematologyJay Backstrom, MDSVP, Global Hematology & Oncology Clinical R&D
The Evolving MM Treatment Landscape
Paul Richardson, MDClinical Program Leader and Director of Clinical Research at Dana-Farber Cancer Institute
T Cells and Heme Malignancies Robert Hershberg, MD PhDSVP, Immuno-Oncology
Immuno-Oncology Clinical Plan U d t
Jay Backstrom, MDSVP, Global Hematology & Oncology ClinicalUpdate SVP, Global Hematology & Oncology Clinical R&D
Business Update Jackie Fouse, PhD President, Global Hematology & Oncology
Q&A
Closing Remarks Peter KelloggEVP and Chief Financial Officer
8
Jay Backstrom, MDSVP, Global Hematology &
Oncology Clinical R&DOncology Clinical R&D
Celgene at ASH 2015
Expansion in Myeloid Disease
Lymphoma Program Momentum AcceleratingLymphoma Program Momentum Accelerating
IMiD® Products as Backbone in MM
Immuno-Oncology Advancing Rapidly
10
Myeloid Disease
Advancement of the pipeline in MDS/AMLAdvancement of the pipeline in MDS/AML1
Emerging pipeline in myeloid disease2
Evolving myeloid disease landscapeEvolving myeloid disease landscape3
11
Key Myeloid Disease Abstracts
Author Abstract Title
Advancement of the pipeline in MDS/AMLAdvancement of the pipeline in MDS/AML1
Author Abstract TitleStein #323 Safety and Efficacy of AG-221, a Potent Inhibitor of Mutant IDH2
That Promotes Differentiation of Myeloid Cells in Patients withAdvanced Hematologic Malignancies: Results of a Phase 1/2 TrialOral, Sunday 5:30PM
Giagounidis #92 Luspatercept Treatment Leads to Long Term Increases in Hemoglobin and Reductions in Transfusion Burden in Patientswith Low or Intermediate-1 Risk Myelodysplastic Syndromes: Preliminary Results from the Phase 2 PACE-MDS ExtensionPreliminary Results from the Phase 2 PACE-MDS Extension StudyOral, Saturday 12:15PM
Platzbecker #2862 Biomarkers of Ineffective Erythropoiesis Predict Response to Luspatercept in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes: Final Results from the Phase 2 PACE MDS StudyResults from the Phase 2 PACE-MDS StudyPoster, Sunday
DiNardo #1306 Molecular Profiling and Relationship with Clinical Response in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Potent Inhibitor of Mutant IDH1, in Addition to Data from the Completed D E l ti P ti f th Ph 1 St d
12
Dose Escalation Portion of the Phase 1 StudyPoster, Saturday
Stein: Robust CR and ORR Rates
Ph I/II l b l dAll R/R AML
• Phase I/II, open-label, dose escalation trial
• Primary endpoints: Safety, MTD li i l ti it
N=181 N=128
n (%)
ORR 74 (41) 52 (41)MTD, clinical activity
• AG-221 daily for a 28-day cycle; treatment to progression
t bl t
CR 30 (17) 23 (18)CRp 3 (2) 1 (1)CRi 1 (1) 1 (1) or unacceptable tox
• CR and ORR rates consistent with earlier presentations
CRi 1 (1) 1 (1)mCR 15 (8) 8 (6)PR 25 (14) 19 (15)SD 81 (45) 57 (45)
• Consistent regardless of number of prior regimens or mIDH2 type
SD 81 (45) 57 (45)PD 9 (5) 7 (6)Not evaluable
17 (9) 12 (9)
13
evaluable
Stein, EM, et.al. ASH 2015. Abstract 323
Stein: AG-221 Shows Durable Responses
14
Stein, EM, et.al. ASH 2015. Abstract 323
Phase III Trial of AG-221 in IDH2-Mutated Relapsed/Refractory AML Initiating
Key Inclusion Criteria AG-221 (CC-90007)
N=280Methods
Key Inclusion Criteria• ≥ 60 years• IDH-2 mutated R/R AML
after 2nd or 3rd line
miz
atio
n
ress
ion
or
e to
xici
ty
AG 221 (CC 90007)Starting dose, 100mg QDAG-221 + BSC
vs.Stratification By• Prior intensive therapy• Prior refractory• Prior HSCT 1:
1 R
ando
m
eat t
o Pr
ogna
ccep
tabl
vs.
BSC, VIDAZA® + BSC, Low-dose Ara-C + BSC, Intermediate-dose Ara-C• Prior HSCT 1
Tre un
Intermediate dose Ara C + BSC
• Primary endpoint: Overall survivaly p
• Key secondary endpoints: Event free survival, overall response rate, duration of response, 1-year survival, CR rate, safety
15
Footnote: Trial ID NCT02577406
Giagounidis: Luspatercept in MDS Phase II Extension Study
• Phase II extension study (24 mos, N=32); 13 patients with l t f i b d (LTB) d 19 ith hi h t f ilow transfusion burden (LTB) and 19 with high transfusion burden (HTB)
• 68% patients with HTB patients achieved IWG HI E• 68% patients with HTB patients achieved IWG HI-E (≥ 4 units reduction in transfusion burden ≥ 8 weeks)
• 42% patients with HTB achieved RBC transfusion42% patients with HTB achieved RBC transfusion independence
• 69% of LTB patients achieved IWG HI-E (Hb increase ≥ 1.5 g/dL for ≥ 8 weeks)
• No grade 3 or higher treatment-related AEs
16
Giagounidis A, et al. ASH 2015. Abstract 92
Giagounidis: Luspatercept Shows Increase in Mean Hemoglobin in LTB Patients
17
Platzbecker: Biomarkers Predict Response to Luspatercept in Low or INT-1 MDS
In patients (n=49) receiving 0.75-1.75 mg/kg, 49% of patients responded per IWG HI-E (Hb increase ≥1.5 g/dL for LTB patients
d ti f ≥ 4 RBC it /8 k f HTB ti t )or reduction of ≥ 4 RBC units/8 weeks for HTB patients)
Patient Subgroup IWG HI-E Response R t (0 75 1 75 /k )Patient Subgroup Rate (0.75-1.75 mg/kg)
RS positive 22/40 (55%)RS negative 2/7 (29%)g ( )
SF3B1 mutation present 18/30 (60%)SF3B1 mutation absent 6/17 (35%)
Ring sideroblasts, splicing factor gene mutations and other biomarkers of ineffective erythropoiesis may help define an MDS population most likely to respond to luspatercept treatment
18
population most likely to respond to luspatercept treatment
Platzbecker U, et al. ASH 2015. Abstract 2862
Phase III Trial of Luspatercept in Low- and INT-1 Risk MDS Initiating
Patient PopulationVery low, low or intermediate
N=210Methods
yrisk MDS patients with ring sideroblasts who require RBC transfusions
Key Inclusion Criteria miz
atio
n
essi
on o
r e
toxi
city
Luspatercept SC,Starting dose at 1 mg/kg, once every 21 daysKey Inclusion Criteria
• Refractory/ intolerant to prior ESA or ESA ineligible
• Ring sideroblast positive• Require regular blood
t f i :1 R
ando
m
at to
Pro
grac
cept
ableLuspatercept + BSC
vs.
BSCtransfusions• No prior REVLIMID®,
hypomethylating agents or immunosuppressive therapy
2
Trea un
aBSC
• Primary endpoint: Proportion of patients that become RBC-transfusion independent (≥ 8 weeks) during the first 24 weeks
• Key secondary endpoint: Proportion of patients that become RBC-
19
transfusion independent (≥ 12 weeks) during the first 24 weeks
Key Myeloid Disease Abstracts
Emerging pipeline in myeloid disease2
Author Abstract Title
Piga #752 Luspatercept (ACE-536) Reduces Disease Burden, Including Anemia, Iron Overload, and Leg Ulcers, in Adults with Beta-Thalassemia: Results from a Phase 2 StudyyOral, Monday 4:45PM
Savona #452 CC-486 (Oral Azacitidine) Monotherapy in Patients with Acute Myeloid LeukemiaOral, Monday 7:15AMOral, Monday 7:15AM
20
Piga: Luspatercept Phase II in beta-Thalassemia
• Phase II open-label ascending dose study; N=64 ti tpatients
• Luspatercept administered subcutaneous (SC) every three weeks up to 5 cyclesthree weeks up to 5 cycles
• Non-transfusion dependent patients (N=25)– 8 received 0.8-1.25 mg/kg. 50% had Hb ≥ 1.5 g/dL for ≥ 12 weeks
• Transfusion dependent patients (N=14, 10 evaluable)– 10 patients achieved >40% reduction in transfusion burden over 12-
week period and reduction in liver iron concentration (LIC)week period and reduction in liver iron concentration (LIC)– 3 patients with chronic leg ulcers has substantial, rapid healing with 6
weeks of first treatment
21
Piga A, et al. ASH 2015. Abstract 752
Phase III Trial of Luspatercept in beta-Thalassemia Initiating
Patient Population re-
or
y
N=300Methods
Patient PopulationAdult beta-thalassemia patients who are regularly transfused
Key Inclusion Criteria omiz
atio
nsp
ectiv
e p
nt p
erio
d
ogre
ssio
n o
ble
toxi
city
Luspatercept SC + BSCStarting dose at 1 mg/kg, once every 21 days
Patients who receive 6-20 units of RBC over past 24 weeks and no transfusion-free period ≥ 35 days (regularly transfused patients)
2:1
Ran
do2-
wee
k pr
ostr
eatm
en
reat
to P
roun
acce
ptab
vs.
BSCpatients)
12 Tr u
• Primary endpoint: Proportion of patients with ≥ 33% reduction in transfusion burden from k 37 48 d t th 12 k di t t tweeks 37-48 compared to the 12 weeks preceding treatment
• Key secondary endpoint: Proportion of patients with ≥ 33% reduction in transfusion burden from weeks 37-38 compared to the 12 weeks preceding treatment; Proportion of patients with ≥ 50% reduction in transfusion burden from weeks 13-24 compared to the 12 weeks preceding treatment
22
preceding treatment
Footnote: Trial ID NCT02604433
Savona: CC-486 Monotherapy in AML Active Across All Dosing Regimens
23
Savona M, et al. ASH 2015. Abstract 452
QUAZAR® Program Continues to Enroll
CC-486-AML-001CC-486 vs Placebo
AZA-MDS-003CC-486 vs BSC
CC-486-AML-002CC-486CC-486 vs Placebo
Phase III Maintenance in AML
CC-486 vs BSC
Phase IIILow risk/INT 1
CC-486
Phase I/IIMaintenance postMaintenance in AML Low risk/INT-1
transfusion-dependent MDS
Maintenance post-transplant in AML or
MDS
24
Celgene Products Cover the Myeloid Disease Landscape
Transfusion-dependent
Non-Del 5q (~45K Pts)
w R
isk
5K P
ts)
Del 5q (~10K Pts)Transfusion-independent
Low
(~55
s)
Del 5q (~5K Patients)
Non-Del 5q (~25K Patients)
Luspatercept (RS+)
Int-1
Ris
k(~
30K
Pat
ient
s ( 5K Patients)
CC-486
Transfusion-dependentTransfusion-independent
Int-2
/ H
igh
Ris
k ~4
0K P
ts)
(
Durvalumab + CC-486 (HMA failures)
Luspatercept (RS+)
H (~
CC-486
AM
L0K
Pts
)
25
IDH Platform: AG-221 (IDH2-mutations, 9-13% of AML) and AG-120 (IDH1-mutations, 6-10% of AML)Patient numbers are 10-year prevalence in US and EU G5
A(~
70 Durvalumab +
B-Cell Malignancies
Advancement of the Pipeline1
REVLIMID® in DLBCLREVLIMID® in DLBCL2
26
CC-122: A Differentiated IMiD® Compound
1 2 3
Advancement of the pipelineAdvancement of the pipeline1
CC-122 T Cell Impact in DLBCL and MM
1CC-122/Obinutuzumab Preclinical DLBLC/FL
2Intermittent CC-122 in
R/R DLBCL
3
Gandhi (#2704)• Pre-clinical trial indicates
CC-122 is a potent modulator of T Cell
Chiu (#4007)• Preclinical proof of concept to combine CC-122 and obinutuzumab (GA101) in
/ CCarpio (#1494)• In a parallel dose escalating
study (N=22) intermittent CC 122 dosing at 4 mgmodulator of T Cell
numbers and activation, increasing cytotoxic and helper T-cell subsets in DLBCL
obinutuzumab (GA101) in DLBCL/iNHL
• In vitro: Showed synergistic apoptotic effects in FL and dditi i DLBCL
CC-122 dosing at 4 mg, 5/7d selected as MTD
• Mitigates neutropenia-related dose reductions with i d li i l ti itDLBCL
• Provides rationale for immunotherapy combinations
additive in DLBCL • In vivo: significant tumor volume reduction in xenograft models
improved clinical activity and maintains immunomodulatory effects
27
Poster, Sunday Poster, Monday Poster, Saturday
REVLIMID® in DLBCL Maintenance
1 2
REVLIMID® in DLBCLREVLIMID® in DLBCL2
REVLIMID® and R2
Maintenance in DLBCL
1REVLIMID® Maintenance in
DLBCL
2
Reddy (#2739)Phase II REVLIMID® and R2
post-1st line R-CHOP2 DFS 86%
Ferreri (#1547) Phase II REVLIMID®
maintenance in chemo-sensitive, relapsed DLBCL post–ASCT• 2-year DFS: 86%
• 2-year OS: 91%• No difference between
REVLIMID® and R2
relapsed DLBCL post ASCT• 6/16 pts with PR converted to
CR during maintenance• 1-year PFS: 75%
• Most common AEs: 57% neutropenia, 9% fatigue, 8% diarrhea, 1% rash
• 1-year OS: 84%• Most common AEs: diarrhea
and rash
28
Poster, Sunday Poster, Saturday
Broad Lymphoma Program Targets Unmet Needs
Relapsed/Refractory
Maintenance/ ConsolidationInduction/1L
HR patientsNew agents - CHOP• ROBUST®
• R2-CHOP in ABC DLBCL • REMARC• CC-122• Novel-Novel combo• Durvalumab in comboD
LBC
L
• Durvalumab in combo
• AUGMENTTM
D
• RELEVANCE® • RELEVANCE®
AUGMENT• MAGNIFYTM
• CC-122• Durvalumab in combo
FL
• R2 IITs • MCL Network R2 • MCL-001• MCL-002M
CL
29
M
Broad Lymphoma Program Targets Unmet Needs
Relapsed/Refractory
Maintenance/ ConsolidationInduction/1L
REMARC – Data expected mid-2016
HR patientsNew agents - CHOP• ROBUSTTM
• R2-CHOP in ABC DLBCL • REMARC • Novel-Novel combo
DLB
CL
REMARC Data expected mid 2016
RELEVANCE® – Data expected H1:2017
D
AUGMENTTM – Trial over 60% enrolled
ROBUST® – Recruitment accelerating• RELEVANCE® • RELEVANCE®
• AUGMENTTM
• MAGNIFYTMFL
g
MAGNIFYTM – Trial ongoing
• R2 IITs • MCL Network R2• MCL-001• MCL-002M
CL
CC-122 – Program advancing
Durvalumab – Ph I/II combo trial in R/R NHL/CLL starting in 2016
30
MCL 002M
Multiple Myeloma
REVLIMID®: Backbone Across All Lines of TherapyREVLIMID®: Backbone Across All Lines of Therapy1
POMALYST®/IMNOVID®: Backbone in 3rd Line+2
Future of Multiple Myeloma Treatments – I/OFuture of Multiple Myeloma Treatments – I/O3
31
Key Multiple Myeloma Abstracts
Author Abstract Title
REVLIMID® : Backbone Across All Lines of TherapyREVLIMID® : Backbone Across All Lines of Therapy1Author Abstract Title
Durie #25 Bortezomib, Lenalidomide and Dexamethasone Vs. Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma without an Intent for Immediate Autologous Stem Cell Transplant: Results of the Randomized Phase III Trial SWOG S0777Oral, Saturday 7:30AM
Richardson #28 Eloquent-2 Update: A Phase 3, Randomized, Open-Label Study of Elotuzumab in Combination with Lenalidomide/Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma - 3-Year Safety and Efficacy Follow upFollow-upOral, Saturday 8:15AM
Moreau #727 Ixazomib, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone, Significantly Extends Progression-FreeSurvival for Patients with Relapsed and/or Refractory Multiple Myeloma: The p y p yPhase 3 Tourmaline-MM1 StudyOral, Monday 2:45PM
Plesner #507 Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503)
32
Updated Results of a Phase 1/2 Study (GEN503)Oral, Monday 7:30AM
SWOG 0777: RVd, a Potential New Standard of Care in NDMM
Progression-Free SurvivalBy Assigned Treatment Arm
33
Durie B, et al. ASH 2015. Abstract 25
SWOG 0777: RVd, a Potential New Standard of Care in NDMM
Overall SurvivalBy Assigned Treatment Arm
34
Durie B, et al. ASH 2015. Abstract 25
REVLIMID® Combinations in RRMM
Trial/RegimenPrior lines ORR PFS medianTrial/Regimen lines
(median)ORR PFS median
REVLIMID®/ixazomib/dex vs REVLIMID®/dex (Phase III)
1-3 (1) 78% vs. 72%(p=0.035)
20.6 mos vs 14.7 mos (HR=0.742, p=0.012)
REVLIMID®/elotuzumab/dex vs REVLIMID®/dex (Phase III)
1-3 (2) 79% vs 66%(p=0.0002)
19.4 mos vs. 14.9 mos(HR=0.73, p=0.0014)
REVLIMID®/daratumumab/dex 1-3 (2) 88%(Phase I/II)
35
Dimopoulos, MA, et al. ASH 2015. Abstract 28Moreau, P, et al. ASH 2015. Abstract 727Plesner, T, et al. ASH 2015. Abstract 507
Key Multiple Myeloma Abstracts
Author Abstract Title
POMALYST®/IMNOVID®: Backbone in 3rd Line+2
Voorhees #375 Alliance A061202. a Phase I/II Study of Pomalidomide, Dexamethasone and Ixazomib Versus Pomalidomide and Dexamethasone for Patients with Multiple Myeloma Refractory to Lenalidomide and Proteasome Inhibitor Based Therapy: Phase I ResultspyOral, Sunday 5:00PM
Shah #378 Oprozomib, Pomalidomide, and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma: Initial Results of a Phase 1b Study Oral, Sunday 5:45PM
Spencer #4220 Phase 1, Multicenter, Open-Label, Combination Study (NPI-0052-107; NCT02103335) of Pomalidomide, Marizomib , and Low-Dose Dexamethasone in Patients with Relapsed and Refractory Multiple MyelomaPoster, Monday
Chari #508 Open-Label, Multicenter, Phase 1b Study of Daratumumab in Combination With Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple M lMyelomaOral, Monday 7:45AM
36
POMALYST®/IMNOVID® Combinations in RRMM
Trial/Regimen Prior lines (median) ORR(median)
POMALYST®/IMNOVID®/ixazomib/dex vs POMALYST®/IMNOVID®/dex (Phase I/II)
82% refractoryto Rev and bort
62% (PID arm)
POMALYST®/IMNOVID®/oprozomib/dex 4 5 86%POMALYST /IMNOVID /oprozomib/dex (Phase Ib)
4.5 86%
POMALYST®/IMNOVID®/marizomib/dex (Phase I)
5 64%
POMALYST®/IMNOVID®/daratumumab/dex(Phase Ib)
3.565% double refractory
58.5%
37
Voorhees, PM, et al. ASH 2015. Abstract 375Shah, JJ, et al. ASH 2015. Abstract 378Spencer, A, et al. ASH 2015. Abstract 4220Chari, A, et al. ASH 2015. Abstract 508
Key Multiple Myeloma I/O Abstracts
Author Abstract Title
Future of Multiple Myeloma Treatments – I/OFuture of Multiple Myeloma Treatments – I/O3
San Miguel #505 Pembrolizumab in Combination with Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma: Keynote-023Oral, Monday 7:00AM, y
Badros #506 A Phase II Study of Anti PD-1 Antibody Pembrolizumab, Pomalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple MyelomaOral, Monday 7:15AM
Efebera #1838 First Interim Results of a Phase I/II Study of Lenalidomide in Combination With Anti-PD-1 Monoclonal Antibody MDV9300 (CT-011) in Patients with Relapsed/Refractory Multiple MyelomaPoster, Saturday
Kochenderfer #LBA-1 Remissions of Multiple Myeloma during a First-in-Humans Clinical Trial of T Cells Expressing an Anti-B-Cell Maturation Antigen Chimeric Antigen ReceptorOral, Tuesday 7:30AM
38
IMiD® Product Combinations with Monoclonal Antibodies and PD-1/PD-L1s
Trial/Regimen Prior lines (median) ORR(median)
REVLIMID®/pembrolizumab/dex (Phase I) ≥2 76%
POMALYST®/IMNOVID®/pembrolizumab/dex(Phase II)
375% double
50%(Phase II) 75% double
refractoryREVLIMID®/MDV9300(Phase I/II)
267% w/ high-risk
t ti
30%
cytogenetics
39
San Miguel, J, et al. ASH 2015. Abstract 505Badros, AZ, et al. ASH 2015. Abstract 506Efebera, YA, et al. ASH 2015. Abstract 1838
Kochenderfer: Late-Breaker on Remissions in Multiple Myeloma with BCMA
40
Multiple Myeloma Coping with a Disrupted ImmuneMultiple Myeloma-Coping with a Disrupted Immune Environment
Paul Richardson, M.D.
Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute
Harvard Medical SchoolHarvard Medical School
Future of Multiple Myeloma TherapiesIMiDs MoAbs Checkpoint InhibitorsCART cellsVaccinesVaccines EpigeneticsNext generation PIs and IMiD compoundsNext generation PIs and IMiD compoundsOther small molecule therapeutics
A key future direction is combination immune therapies to restore long-term autologoustherapies to restore long-term autologous
immunity against myeloma. 42
Immune Suppressive Microenvironment in MM
IL-6, IL-10, TGFβ, PGE, ARG1, NO, ROS, COX2TAMMDSC
pDC
pDC, MDSC induced immune suppression
G , O, OS, CO
Depletion of cysteineTAM
PD-L1MDSCPD-L1
NK BNKT
CD8MM
PD1PD-L1
T PD1
PD1PD1
NKCD4
MM
MMMM MM induced
immune suppression
PD1TregPD1
PD-L1
Tumor promotion and induction of PD-L1
expression
Stroma
Görgün GT, et al. Blood 2013;121:2975-8743
IMIDsThalidomide,
Reduction of immunosuppression
TumorTumorLenalidomide, Pomalidomide
CheckpointTregs cells pDCMDSCs
Tumor promoting
cells
Tumor promoting
cells
Checkpoint blockersPD-L1/PD-1 inhibitors
Induction of anti-MM tumoral activity
Immune adjuvantsTLR-7/9 agonists
MoAbsNK cells Cytotoxic T cellsDCAnti-tumor cellular
Anti-tumor cellular MoAbs
SLAMF7,CD38
VaccinesN ti idi t
cellularimmunitycellular
immunity
Native idiotype protein,PVX-410, CD138, MM-DCCAR T cells CD19
Th cellsB cells Cytotoxic T cells
anti-Kappa, CD138,BCMA, NKG2D
CAR T cellsCottini et al 2015 44
Lenalidomide in Myeloma
MM cellsIL 6
C
B M
IL-6TNFIL-1A
B
Bone Marrow Stromal Cells
A
ICAM-1
IL-2
IFN
Bone Marrow Vessels
NK Cells
PKCNFAT
IL-2
Dendritic CD8+ T Cells E
VEGFbFGF
D
NK CellsNK-T Cells
PI3K CD28
Cells EDHideshima et al. Blood 96: 2943, 2000Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001
Mitsiades et al. Blood 99: 4525, 2002Lentzsch et al Cancer Res 62: 2300, 2002 LeBlanc R et al. Blood 103: 1787, 2004Hayashi T et al. Brit J Hematol 128: 192, 2005
45
IMiD-Compound Binding to Cereblon Induces Degradation of Ikaros and Aiolos
IMiDCompound Transcription
FactorProteasome
Roc1
CUL-4
DDB
CRBN E3ubiquitin
ligase
CRB
IkarosAiolos
X XDDB1
CRBN
Ub IRF4Myc
X
IL-2
X
IkarosAiolos
Myc
Transcription Factor
Degradation
Tumoricidal
Myeloma Cell
Immuno-modulatory
NK/T CellMyeloma Cell NK/T Cell
1. Kronke J, et al. Science. 2014;343(6168):301-305. 2. Lu G, et al. Science. 2014;343(6168):305-309. 2. Stewark AK, et al. Science 2014;343(6168):256-257. 3. Bjorklund C, et al. Blood Cancer Journal. 2015;5:e354. 4. Gandhi AK, et al. Br J Haematol. 2014;164(6):811-821.
46
A tib d d d t A t i / th tC l t d d t
MoAb Based Therapeutic Targeting of MM Antibody-dependentCellular Cytotoxicity
(ADCC)
Apoptosis/growth arrestvia intracellular
signaling pathways
Complement-dependentCytotoxicity (CDC)
C1qEffector cells:
NK cellmacrophage
neutrophil MMCDC
C1q
C1q
ADCC neutrophil
FcR huN901-DM1* (CD56) nBT062 maytansinoid
MM
Daratumumab (CD38)
MM
nBT062-maytansinoid /DM4* (CD138)
BHQ880 (DKK)RAP-011 (activin A)
Daratumumab (CD38)SAR650984 (CD38)
Lucatumumab or Dacetuzumab (CD40)
Elotuzumab (SLAMF7)
( )BMS936564 (CXCR4)Daratumumab (CD38)SAR650984 (CD38)GSK2857916* (BCMA)
Tai & Anderson. Immunotherapy. 2015 Sep 15.
( )Daratumumab (CD38)XmAb5592 (HM1.24)SAR650984 (CD38)
GSK2857916 (BCMA)* Ab drug conjugate
47
Lenalidomide Pretreatment Augments Elotuzumab-Mediated ADCC
A: effector MM1S80 MM1R80 MM patient cells50MM1S
40
60
MM1R
40
60
80 MM patient cells
20304050
% lysis
0
20
0
20
0 1 100
1020lysis
iso IgG1, Lenalidomide HuLuc63, Lenalidomideiso IgG1 HuLuc63
100p<0.01
mAb, g/mlB: target
% lysis
20406080
100p
iso IgG1
HuLuc63
p<0.05 Tai et al Blood 2008:112: 1329-37.
020
con Lenalidomide
0.05 0.2Target: MM1R
48
Extended Progression-Free Survival
1.01-year PFS 2-year PFS
Extended follow-up
E Ld Ld
0.7
0.8
0.9
ssio
n fr
ee
68%
E-Ld Ld
HR 0.73 (95% CI 0.60, 0.89);p=0.0014
Median 19.4 mo 14.9 mo
0 3
0.4
0.5
0.6
bilit
y pr
ogre
s
E-Ld41%
26%
57%
PFS (95% CI)
(16.6,22.2)
(12.1,17.2)
0.0
0.2
0.3
Prob
ab
Ld0.1
27%18%
480 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45
No. of patients at risk:E-LdLd
321325
293266
259215
227181
171130
144106
12580
10767
9460
8551
5936
3415
197
83
PFS (months)30
195157
00
E-Ld-treated patients had a 27% reduction in the risk of disease progression or death and a 44% relative improvement in PFS vs Ld-treated patients at 36 months
49
Daratumumab: Mechanisms of Action• CD38 is highly and ubiquitously expressed on myeloma cells1,2
• DARA is a human IgG1 monoclonal antibody that binds CD38-expressing cells
• DARA binding to CD38 induces tumor cell death through direct and indirect mechanisms3-5
DARA
ImmunomodulationImmune-mediated activity
ADPC ADCCCDC reas
ed
supp
ress
ion
enzy
mat
ic
hibi
tion
Directanti-tumor effect
is v
ia
king
NK cellMacrophageComplement
C CCC C
CD38+
T reg DARA
CD38
Dec
rim
mun
os
ADPRNAD
MM cell
CD
38
inh
Apop
tosi
cros
s-lin
MM cellCD38
DARA
AdenosineCD8+
T cell
CD38 cADPRADPRNAADP
Ca2+ Adenosine
AMPCa2+
Ca2+
Ca2+
Tumor celldeath
1. Lin P, et al. Am J Clin Pathol. 2004;121(4):482-488.2. Santonocito AM, et al. Leuk Res. 2004;28(5):469-477.3. de Weers M, et al. J Immunol. 2011;186(3):1840-1848.4. Overdijk MB, et al. MAbs. 2015;7(2):311-321.5. Krejcik J, et al. Presented at: 57th American Society of
Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 3037.
CD38
CD38
MDSCB reg
50
Effects of Lenalidomide Pretreatment of PBMCs on Daratumumab-Induced ADCC Against MM1S Cells
Donor #1 Donor #2
150
200
150
200
Donor #1 Donor #2
50
100
150
% lysis
50
100
150
0
50
iso len 2 M
daratumumab 20 / l
0
50
iso len 2 M
daratumumab20 / l2 M 20g/ml 2 M 20 g/ml
PBMC/MM1S=1000.010 1 10Daratumumab isoFcR
ADCC
0.1
10
10(g/ml) (g/ml)MMNK 1
DeWeers, Tai et al J Immunol 2011;186: 1840-8.51
Daratumumab in Combination with Lenalidomide and Pomalidomide in RRMM: ASH 2015
• Phase 1/2 study dose escalation study, results of dara+Rd (n = 32)• Median number of prior lines of therapy was 2
ORR 88% i h 11 (34%) PR 17 (53%) VGPR
Main conclusions
Rd+Daratumumab • ORR: 88%, with 11 (34%) PR, 17 (53%) ≥VGPR• 7 (22%) sCR, 1 (3%) CR, and 9 (28%) VGPR
• Median time to first response: 1 month • Median time to best response: 4.5 months
M di d ti f NR
Rd+Daratumumab
Plesner et al. Abs 507
• Median duration of response: NR • 26 (93%) of 28 responders had not progressed and remained
on treatment at data cutoff
• Phase 1b evaluating dara in combination with backbone therapies • Results of dara+Pd (n=77)
Main conclusions
Pd+Daratumumab
Chari et al. Abs 508
• Median number of prior therapies was 3.5, 65% refractory to both a PI and IMiD
• ORR: 58.5%, 3 sCR, 1 CR, 12 VGPR, 15 PR, 2 MR, 18 SD, and 2 PD• Among the evaluable double refractory patients (n = 40):
1 sCR, 1 CR, 10 VGPR, and 11 PR with an ORR of 57.5%• Median time to first response was 1 month• After a median follow‐up of 148 days, 4/ 31 responders progressed
52
Targeting the Multiple Myeloma Immunosuppressive Microenvironment
Blockade of PD1/PD L1 alone or in combination:
pp
Blockade of PD1/PD-L1, alone or in combination:
Inhibits accessory (BMSC, MDSC, pDCs) cell and augments immune cell (CD4T CD8T NK NKT Monocyte/Macrophage)immune cell (CD4T, CD8T, NK,NKT,Monocyte/Macrophage) function
Inhibits multiple myeloma (MM) cell growth in the BM milieu.p y ( ) g
Trials of ongoing combination therapies : MoAbs, Vaccines, IMiDs, Cellular Therapies, and PD-L1/PD-1 blockade
53
Checkpoint Blockade Targets Immune Suppressive Microenvironment in MM
TAMPD-L1MDSC
PD-L1
pDCLen
LenLen
CPB
pDC, MDSC induced immune suppression
PD L1
PD1
CPB
CPB CPB
CPB
BNKT
CD4MM
PD-L1
PD1TregPD1
CD8PD1
PD1PD1
CPB C
PB
NK
MMMM
MM MM induced immune
suppressionPD-L1
Immune effector cell activation
Reversal of tumor andCPB
PD-L1
Tumor promotioninduction of PD-L1 exp
Reversal of tumor and immune suppressor accessory cell mediated-immune suppression
Induction of anti tumor
CPB
Stroma Induction of anti-tumor
immune responses
Görgün GT, et al. Blood 2013;121:2975-8754
PD 1 i l i h k i tTargeting the PD-1/PD-L1 Pathway
PD-1 immunologic checkpoint
Postow, MA, et al. J Clin Oncol. 2015 55
Lenalidomide Enhances Checkpoint Blockade Induced Cytotoxicity Against MM cellsy y g
Görgün G. et al. Clin Cancer Res. 2015 Oct 15;21(20):4607-1856
Summary: Checkpoint Inhibition in RRMM
Antibody Target Phase N Response
Nivolumab1 PD-1 1 27 Nivo mono: 0%
2Pembrolizumab2 PD-1 1 34 Pembro+Rd: 76%
VGPR (n=4) Pembrolizumab3 PD-1 1 24 Pembro+Pd: 50%
nCR (n=3), VGPR ( 2)(n=2)
1. Lesokhin AM, et al. ASH 2014. Abstract 291. 2. San Miguel J, et al. ASH 2015. Abstract 505. 3. Badros A, et al. ASH 2015. Abstract 506.
57
Myeloma CAR therapy
• Multiple promising targets:– CD19, CD138, CD38, CD56, kappa, Lewis Y, CD44v6, CS1, BCMA
• Functional CAR T cells can be generated from MM patients• CAR T and NK cells have in vitro and in vivo activity against MM• Clinical trials underway
– Anecdotal prolonged responses but no robust efficacy data available yet
M ti i b t CAR d i• Many questions remain about CAR design:– optimal co-stimulatory domains– optimal vector– optimal dose and schedule– need for chemotherapy– Perhaps ‘cocktails’ of multiple CARs or CARs + chemotherapy will be
required for best outcomes
Stadtmauer et al, 201558
Vaccines Targeting MM Ag Specific Peptides to Delay Progression of Smoldering to Active MM
Using cocktails of immunogenic HLA-A2-specific XBP1, CD138, CS1 peptides to induce MM-specific and HLA-restricted CTL
y g g
responses against several MM antigens
Polyfunctional responses: IFN-γ, cytotoxicity, proliferation, y p γ, y y, p ,CD107a degranulation to patient MM cells and MM cell lines
Peptide-specific responses: Individual differences in specificity,Peptide specific responses: Individual differences in specificity, more broad response to cocktail.
Clinical trial: immune responses to vaccine; lenalidomide andClinical trial: immune responses to vaccine; lenalidomide and vaccine cohort enrolled 2014; PDL-1 and vaccine cohort 2015
Bae et al, Leukemia 2011; 25:1610-9.Bae et al, Brit J Hematol 2011; 155: 349-61.Bae et al, Brit J Hematol 2012; 157: 687-701.Bae et al, Clin Can Res 2012; 17:4850-60. Bae et al, Leukemia. 2015 Jan;29(1):218-29
59
Phase I Trial of Vaccination with DC/MM Fusions in Relapsed Refractory MM
Well tolerated, no autoimmunity y
Induced tumor reactive lymphocytes in a majoritylymphocytes in a majority of patients
Induced humoral Induced humoral responses to novel antigens (SEREX analysis)DC/MM fusions induce antiDC/MM fusions induce anti-- y )
Disease stabilization in 70% of patients
MM immunity in vitro and MM immunity in vitro and inhibit MM cell growth in inhibit MM cell growth in vivo in xenograft modelsvivo in xenograft models 70% of patients
Rosenblatt et al Blood 2011; 117:393-402.Vasir et al. Brit J Hematol 2005; 129: Vasir et al. Brit J Hematol 2005; 129: 687687--70070060
Future of Myeloma: Immune Therapies
IMiDs M AbMoAbs Checkpoint InhibitorsCART cellsVaccinesVaccines
A key future direction is combination immune ytherapies to restore long-term autologous
immunity against myeloma.
61
Rob Hershberg, MD PhDSVP, Immuno-OncologySVP, Immuno Oncology
Celgene’s Immuno-Oncology Portfolio Addresses Multiple Aspects of the Anti-Tumor Immune Response
DurvalumabIMiD® compoundsVTX-2337
IMiD®
compounds
VTX-2337BCMA (bluebird bio)Bispecific MoAbs (Sutro)
Anti-CD47VTX-2337
ABRAXANE®
CC-486 IMiD® compoundsVTX-2337NK cells (CCT)NK cells (CCT)
IMiD®
compounds
63
compounds
Celgene Immuno-Oncology Strategy
Maximize opportunity for existing assets that areMaximize opportunity for existing assets that areMaximize opportunity for existing assets that are Maximize opportunity for existing assets that are mechanistically unique and complementary to checkpoint mechanistically unique and complementary to checkpoint
inhibitorsinhibitors®® ®® ®®ABRAXANEABRAXANE®®, REVLIMID, REVLIMID®®, POMALYST, POMALYST®®, CC, CC--486, CC486, CC--122122
Develop durvalumab in multiple hematologicalDevelop durvalumab in multiple hematologicalDevelop durvalumab in multiple hematological Develop durvalumab in multiple hematological malignancies in collaboration with malignancies in collaboration with AstraZeneca/MEDIAstraZeneca/MEDI
Develop novel emerging assets (including Develop novel emerging assets (including CARTCART) with ) with combination potential beyond checkpointscombination potential beyond checkpoints
64
Key Investments in Next-Generation Growth Drivers: T Cells
• CART cell therapy is a promising approach to treating cancers
• Data from NIH/NCI supports BCMA as a valid CART target
• Leverages Celgene core clinical expertise in
pp g• Bluebird BCMA CART collaboration in clinic in 2016
Leverages Celgene core clinical expertise in hematology/oncology
• Access to best-in-class transformative T cell therapies
• Strategic collaboration to develop and commercialize I/O therapeutics for heme malignancies
• Initial focus on PD-L1 inhibitor, durvalumab, for MM, NHL, MDS and AMLMDS and AML
• Access to proprietary pipeline for oncology and I&IPi li i l d l ti d t t l i t th t
65
• Pipeline includes selective and potent oral agonists that target RORgamma
Engineering a T Cell to Attack Cancer
Autologous Tcell harvest
CART expansionand transduction
Lentiviral vector to d li t t
Binding domains d
Patient-specific CART ll d tideliver construct and
CD3-and 4-1BB signaling domains
cell production (~ 10 day process)
66
CAR = chimeric antigen receptorTCR – T cell receptor
66
NCI BCMA CART Myeloma Trial Update
CARTmanufacturing
Dose Levels (x106/kg)1) 0 3
Apheresis CART infusion
a u actu g 1) 0.32) 1.03) 3.04) 9.0
FluCy BM BX (Wk 4)BM BX
Characteristic N = 11Age: med (range) TBC at ASH
ECOG: 0 (%); 1 (%) TBC at ASH
Prior Rx (median No. regimens) 7Cytogenetics: High risk (%); Low risk (%) TBC at ASHCytogenetics: High risk (%); Low risk (%) TBC at ASH
Kochenderfer, Late Breaker, ASH 2015
67
NCI BCMA CART Myeloma Trial Update
CARTmanufacturing
Dose Levels (x106/kg)1) 0 3
Apheresis CART infusion
a u actu g 1) 0.32) 1.03) 3.04) 9.0Dose Level N Best Response
FluCy BM BX (Wk 4)BM BX
(x 106/kg) N Best Response
0.3 3 SDx3
Characteristic N = 11Age: med (range) TBC at ASH
1.0 3 SDx2, PRx13.0 3 SDx2, VGPRx1
ECOG: 0 (%); 1 (%) TBC at ASH
Prior Rx (median No. regimens) 7Cytogenetics: High risk (%); Low risk (%) TBC at ASH
9.0 2 sCRx1, PRx1
sCR = stringent CRCytogenetics: High risk (%); Low risk (%) TBC at ASH
Kochenderfer, Late Breaker, ASH 2015
68
gVGPR = very good PR
bluebird bio BCMA Product Advancing
• Lead anti-BCMA product candidate in collaboration with bluebird bio is bb2121
• bb2121 – lentiviral anti-BCMA-41BB-zeta CAR (vs. NCI gamma-retroviral anti-BCMA-CD28-zeta CAR)
• Phase I trial expected to begin enrollment in early 2016
69
Celgene Has Access to the Depth and Breadth of Juno Therapeutics’ Capabilities
70
Juno CD19 Experience
GoalP d t C did t
Potential First-in-class
Potential Best-in-class Translational
JCAR015 and JCAR014 data to be updated on Monday, December 7
Product Candidate JCAR015 JCAR017 JCAR014
Trialr/r Adult ALL
N = 39Evaluable = 38
r/r Pediatric ALLN = 37
Evaluable = 32
r/r Adult ALLN = 30
Evaluable = 29
Complete Response / Remission 87% 91% (1) 93% (4)
Complete Molecular Remission 68% 91% (1) 90% (4)p
Severe Cytokine Release Syndrome (2) 23%(5) 27% (3), (5) 23% (5)
Severe Neurotoxicity 28%(5) 18%(5) 53% (5)
(1) One patient received steroids at line placement for apheresis. Results based on investigator reported results.(2) With respect to JCAR015 and JCAR017, sCRS is a condition defined clinically by certain side effects, which can include hypotension, or low blood pressure, and
confusion or other central nervous system side effects when such side effects are serious enough to lead to intensive care unit care with mechanical ventilation or co us o o ot e ce t a e ous syste s de e ects e suc s de e ects a e se ous e oug to ead to te s e ca e u t ca e t ec a ca e t at o osignificant vasopressor support. With respect to JCAR014, sCRS is defined as the occurrence of certain side effects, which can include hypotension, confusion, or other central nervous system side effects when such side effects are grade 3 or higher based on Lee, et al.
(3) One patient received steroids for treatment of severe CRS following CAR T cell infusion.(4) One patient who did not achieve a CR had a clear marrow but had evidence of extramedullary disease.(5) Includes all patients who received at least one T cell infusion. Data based on investigator-observed responses.
71
JCAR014: Emerging NHL DataClinical Response Correlates with Cell Expansion and Persistence
Conditioning Regimen Non-Flu/Cy Flu/Cy
NHL Results: regimens & doses
Dose Level All DosesN=12
2*105/kgN=3
2*106/kgN=11
2*107/kgN=4-6
Efficacy
1/12 1/3 7/11 1/4CR(1) 1/12(8%)
1/3(33%)
7/11(64%)
1/4(25%)
CR/PR 6/12(50%)
1/3(33%)
9/11(82%)
3/4 (75%)
Toxicity
Severe Cytokine ReleaseS d
0/12(0%)
0/3 (0%)
1/11(9%)
3/6 (50%)
CAR-T cell dose levels 1 and 2
Syndrome (0%) (0%) (9%) (50%)
Severe Neurotoxicity
2/12(17%)
1/3 (33%)
2/11(18%)
4/6(67%)
(1)At d t t ff d t ll ti t i th Fl /C h t th t hi d CR i i CR 2 9 th ft th(1)At data cutoff date, all patients in the Flu/Cy cohorts that achieved a CR remain in CR 2-9 months after therapy.
Since data cutoff date, there has been one unconfirmed PET scan anomaly.Median of 5 prior treatment regimens; 16 patients failed prior autologous and/or allogeneic transplant.29 out of 32 patients had chemorefractory disease.Flu/Cy = fludarabine & cyclophosphamide; CR = complete response; PR = partial response
72
JCAR014: Early Data Suggest Potential in CLLClinical Response Correlates with Cell Expansion and Persistence
Conditioning Regimen Non- Flu/Cy(1)
CLL Results: regimens & doses
Conditioning Regimen Flu/Cy(1) Flu/Cy(1)
Dose Level All DosesN=2
All DosesN=7
Efficacy
CR(2) 0/2(0%)
4/7(57%)
CR/PR 1/2 7/7CR/PR 1/2(50%)
7/7(100%)
Toxicity
Severe Cytokine 0/2 1/7(3)
ReleaseSyndrome
0/2(0%)
1/7(3)
(14%)
Severe Neurotoxicity
0/2(0%)
3/7 (43%)y ( ) ( )
(1)All CLL patients have been previously treated with ibrutinib.(2)All patients in CR remain in CR 2-14 months after therapy.(3)The patient died 3 months after therapy of pulmonary aspergillosis.
73
Durvalumab: Mechanism of Action
• Durvalumab is a human IgG1 monoclonal
tib d di t d i tantibody directed against PD-L11,2
• Blocks the interaction of PD-L1 with both PD-1PD L1 with both PD 1 and CD801,2
• Specifically designed to disable effector functions, such as ADCC and CDC, that would cause depletion of target cells2,3
1. Brahmer JR, et al. J. Clin. Oncol. 2014;32 [abstract 8021]. 2.Ibrahim R, et al. Semin Oncol. 2015;42:474-483. 3. Segal NH, et al. J. Clin. Oncol. 2014;32 [abstract 3002].
74
Jay Backstrom, MDSVP, Global Hematology &
Oncology Clinical R&DOncology Clinical R&D
FUSION Program with Durvalumab Enrolling
76
FUSION Program with Durvalumab Enrolling
77
Anticipated Clinical Development Strategy for Durvalumab: Combinations in Hematology
Combinations with
First Wave
Multiple Myeloma REVLIMID® and POMALYST® /
IMNOVID®
Non-Hodgkin Lymphoma
CLL
Combinations with IMiD® compounds, mAbs and targeted
th iCLL
MDS/AML
therapies
Combinations withMDS/AML Combinations with CC-486 and VIDAZA®
7878
Anticipated Clinical Development Strategy for Durvalumab: Combinations in Hematology
Combinations with
First Wave
Combinations with
Second Wave
Multiple Myeloma REVLIMID® and POMALYST® /
IMNOVID®
Combinations with pipeline assets and
novel therapies
Non-Hodgkin Lymphoma
CLL
Combinations with IMiD® compounds, mAbs and targeted
th i
Combinations with pipeline assets and
novel therapiesCLL
MDS/AML
therapies
Combinations with
novel therapies
Combinations with i li t dMDS/AML Combinations with
CC-486 and VIDAZA® pipeline assets and novel therapies
7979
Jackie Fouse, PhDPresident, Global Hematology & Oncology
New Hematology and Oncology Opportunities Expected to Accelerate Growth Through 2020
Expected Growth Opportunities in Hematology and Oncology
Expected Growth Opportunities in Hematology and Oncology
Growth from Existing Portfolio:>$17B
Growth from Existing Portfolio:• REVLIMID® (NDMM) and
POMALYST®/IMNOVID® (RRMM)• ABRAXANE® geographic expansion
$13 0
15%CAGR
New Indications & Opportunities:• REVLIMID® in novel combos MM and NHL• CC-486 in MDS and AML
$13.0
$7.45B
• Luspatercept in beta-thalassemia• AG-221 in IDH2 mutant AML• ABRAXANE® late-stage trials in:
• Adjuvant pancreatic cancerAdjuvant pancreatic cancer• Additional segments in NSCLC• Triple negative breast cancer• Neoadjuvant breast cancer
2014 2017E 2020EHematology Oncology
81
Additional Hematology and Oncology Opportunities Accelerate Momentum Through 2020
Upside Potential Through 2020Upside Potential Through 2020
• Full impact of REVLIMID® and POMALYST®/IMNOVID® treatment duration• Full impact of REVLIMID® and POMALYST®/IMNOVID® treatment duration
• REVLIMID® for non-del 5q in Europe, maintenance in CLL and earlier adoption in lymphomas
A l f l t t i MDS• Approval for luspatercept in MDS
• Earlier than expected approval for AG-221 in R/R AML (IDH2 mutations); approval for AG-120 in R/R AML (IDH1 mutations)
• Approval for CC-122 in NHL, CLL and/or MM
• Approval for durvalumab in heme malignancies
• ABRAXANE® in anti-PD-1/anti-PD-L1 combinations
• Demcizumab approval in NSCLC and PanC
• VTX-2337 in ovarian and SCCHN
CC 486 l i lid t
82
• CC-486 approval in solid tumors
IMiD® Products as Backbone Across All Lines of Therapy in Multiple Myeloma
Potential positioning of Celgene IMiD® Products by 2020
SCT I d ti
SCT M i t NSCT
2L 3L+1L
RVd+/- MoAb
RVd+/- MoAb
RVdRd + MoAb
RVdRd + MoAb
R + Ixa, R + DaraR + Ixa,
R + DaraPom
Triplets Pom
Triplets
Induction Maintenance NSCT
High Risk / Aggressive
DiseasePd
Pd + PIPd + MoAb
PdPd + PI
Pd + MoAbRVdRVdRR Rev
T i l tRev
T i l t
pp
Rd RVd Rd M AbRd RVd Rd M Ab
Disease
Standard Disease
Rd + MoAbRd + MoAbRR TripletsTripletsRd + MoAb Rd + MoAb Disease
Aggression
POMALYST®/IMNOVID® RegimensREVLIMID® Regimens
83
IMiD® Products as Backbone Across All Lines of Therapy in Multiple Myeloma
Potential positioning of Celgene IMiD® Products by 2020
SCT I d ti
SCT M i t NSCT
2L 3L+1L
RVd+/- MoAb
RVd+/- MoAb
RVdRd + MoAb
RVdRd + MoAb
R + Ixa, R + DaraR + Ixa,
R + DaraPom
Triplets Pom
Triplets
Induction Maintenance NSCT
High Risk / Aggressive
Disease
Filing REVLIMID® for maintenance post-SCT in EU and U.S. targeted
PdPd + PI
Pd + MoAb
PdPd + PI
Pd + MoAbRVdRVdRR Rev
T i l tRev
T i l t
pp
Rd RVd Rd M AbRd RVd Rd M Ab
Disease
Standard Disease
for H1:2016
Rd + MoAbRd + MoAbRR TripletsTripletsRd + MoAb Rd + MoAb Disease
Aggression
POMALYST®/IMNOVID® RegimensREVLIMID® Regimens
84
SWOG 0777 Opportunity
18%7%
1st Line Multiple Myeloma NSCT Regimens in U.S.
18%
30%RVDR-based (non V)V based (non R)
45%
V-based (non R)Other *
RVd demonstrated PFS and OS benefits vs Rd in SWOG 0777 Phase III trialPotential growth opportunity in:Potential growth opportunity in:
• Extending duration of treatment • Share gain from REVLIMID® regimens
85
NSCT includes NTE (non-transplant eligible) plus TE (transplant eligible patients not getting an SCT) and includes induction plus maintenance. This is ~65% of the first line market.
Source: Oct 2015 PSL MM Share Audit combined with Market Sizing NSCT segment, “Other” includes: 3% Thalomide, 2% Melphalan
Focused on Expanding Our Leadership in Hematology
Creating thefuture
Adding on
Solidifying ourfoundation
• REVLIMID® NDMM novel combinations
• POMALYST®/IMNOVID®
RRMM novel combos• REVLIMID® in DLBCL
• REVLIMID® in combos with other novel agents
• CC-122 in NHL, CLL, MM• ACY-1215/ACY-241 in MM• IDH platform
• REVLIMID® in Follicular Lymphoma
• CC-486 in AML and MDS• Luspatercept in MDS
and beta-thalassemia
p• Durvalumab in heme
malignancies• BCMA (bluebird bio)• CART (Juno)• CELMods®
• REVLIMID® in NDMM• POMALYST®/IMNOVID®
in RRMM• VIDAZA® in MDS
86
• AG-221 in R/R AML• CELMods
Short-term Mid-term Long-term
• VIDAZA® in MDS and AML
Questions & Answers
Moderator: Peter KelloggEVP and Chief Financial Officer
Panelists: Jackie Fouse, PhD President, Global Hematology & Oncology gy gy
Jay Backstrom, MDSVP, Global Hematology & Oncology Clinical R&D
Robert Hershberg, MD PhDSVP, Immuno-Oncology
Paul Richardson, MDClinical Program Leader and Director of Clinical Research at Dana-Farber Cancer Institute
87
Appendix
Celgene Pipeline
89
Celgene Pipeline
90
Celgene Pipeline
91
Celgene Pipeline
92
REVLIMID® Multiple Myeloma Late Stage Programs
Patient Population Maintenance Post-VMP induction
T i l NMM-026
Trial NameARUMM
Phase III
Target Enrollment 350
Design
2:1 randomizationInduction with
Melphalan/prednisone/bortezomib (VMP) for 6-9 cycles
Arm A: REVLIMID® (10mg) d 1 21Arm A: REVLIMID® (10mg) d 1-21 for 28-day cycle
Arm B: Placebo d 1-21 for 28-day cycle
Primary Endpoint Progression Free Survival
Status Trial enrolling
93
REVLIMID® Multiple Myeloma Late Stage Programs
Patient Population Maintenance in ASCT EligibleTrial Name MYELOMA XI
Phase IIIPhase III
Target Enrollment 3,970
Arm A: Cyclophosphamide (500mg) d1,8,15; THALOMID® (100mg d1-21 then 200mg daily), Dexamethasone (40mg) d1-4, 12-15 for minimum of 4 21-day cycle
Arm B: REVLIMID® (25mg) d 1 21 Cyclophosphamde (500mg) d1 8 dexamethasone (40mg)Arm B: REVLIMID® (25mg) d 1-21, Cyclophosphamde (500mg) d1,8, dexamethasone (40mg) d1-4,12-15 for minimum of 4 28-day cycles
Arm C: Cyclophosphamde (500mg) d1,8, Carfilzomib (20 mg/m2) d 1,2 cycle 1 then (36 mg/m2) d 1,2,8,9,15,16, REVLIMID® (25mg) d1-21, Dexamethasone (40mg) d 1-4,8,9,15,16 for
4 21-day cyclesPatients with no change progressive disease PR or MR randomized toDesign Patients with no change, progressive disease, PR or MR randomized to
Arm A: Bortezomib (1.3mg/m2) d 1,4,8,11, Cyclophosphamide (500mg) d 1,8,15, Dexamethasone (20mg) d 1,2,4,5,8,9,11,12 for max of 8 21-day cycles
Arm B: No treatmentAll patients go to SCT
After SCT randomization to:Arm A: REVLIMID® (10mg) d 1-21 for 28-day cycle to disease progression
Arm B: No maintenance
Primary Endpoint Overall Survival and Progression Free Survivaly p g
Status Trial enrolling
94
POMALYST®/IMNOVID® Multiple Myeloma Late Stage Programs
Patient Population RRMM
T i l NMM-007
Trial NameOPTIMISMM®
Phase III
Target Enrollment 782
D i
Arm A: POMALYST®/IMNOVID® (4mg), bortezomib (1.3 mg/m2 IV) and low-dose dexamethasone to disease progressionDesign dexamethasone to disease progression
Arm B: Bortezomib (1.3 mg/m2 IV) and low-dose dexamethasone to disease progression
Primary Endpoint Progression Free SurvivalPrimary Endpoint Progression Free Survival
Status Trial enrolling
95
MDS/AML/MF Late Stage Programs
Patient Population Non-del5Q low risk/INT-1 transfusion-dependent MDS
Low risk/INT-1 transfusion-dependent MDS
CC 486Molecule REVLIMID®
CC-486(Oral Azacitidine)
Trial Name MDS-005 AZA-MDS-003
Phase III III
Target Enrollment 239 386g
DesignArm A: REVLIMID® (10mg)
Arm B: PlaceboArm A: CC-486 (150mg or 200mg)
Arm B: Placebo
Primary Endpoint RBC-transfusion independencefor at least 8 weeks
RBC-transfusion independence for more than 12 weeks
Primary endpoint met
Status
yData presented at ASH 2014
Submitted to FDA; PDUFA date April 16, 2016
Trial enrolling
96
MDS/AML/MF Late Stage Programs
Patient Population Elderly Newly Diagnosed AML Post induction AML Maintenance
MoleculeVIDAZA® CC-486
Molecule(azacitidine) (oral azacitidine)
Trial Name AZA-AML-001 CC-486-AML-001
Phase III III
Target Enrollment 488 460
Arm A: VIDAZA®
(75 mg/m2 SC) daily for D1-7 of a 28-day cycle until disease progression
Designcycle until disease progression
Arm B: Conventional Care Regimen (intensive chemotherapy, low-dose
cytarabine or best supportive care) to disease progression
Arm A: CC-486 (150mg or 200mg)Arm B: Best Supportive Care
Primary Endpoint Overall Survival Overall Survival
StatusData presented at EHA 2014 and ASH 2014Positive CHMP opinion; Final EU decision Trial enrollingStatus Positive CHMP opinion; Final EU decision
by YE2015ETrial enrolling
97
REVLIMID® Chronic Lymphocytic Leukemia Late Stage Programs
Patient Population Maintenance in 2nd Line CLL
Trial NameCLL-002
Trial NameCONTINUUM®
Phase III
Target Enrollment 400
D iArm A: REVLIMID® (starting dosage
2.5mg/day escalated to 10mg/day) until Design
g y g y)disease progression - 28-day cycle
Arm B: Placebo
Primary Endpoint Overall Survival and ProgressionFree Survivaly p Free Survival
StatusTrial enrolling
Enrollment to complete in 2015E
98
REVLIMID® Lymphoma Late Stage Programs
Patient PopulationMaintenance in Patients with
DLBCL responding to R-CHOP to induction therapy
Newly Diagnosed Follicular Lymphoma
Trial Name REMARC RELEVANCE®
Phase III III
Target Enrollment 621 1,000
Arm A: REVLIMID® (starting dose 20mg)
DesignArm A: REVLIMID® D1-21 of 28-day
cycle for 24 monthsArm B: Placebo D1-21 of 28-day
cycle for 24 months
D2-22 for up to 18 28-day cycles and Rituximab (starting dose 375 mg/m2) weekly
for up to 12 28-day cyclesArm B: Physician’s choice of rituximab-CHOP,
rituximab-CVP or rituximab-bendamustine
Primary Endpoint Progression Free Survival Complete Response Rate and Progression Free Survival
Status Enrollment complete Enrollment completeStatus Enrollment complete Enrollment complete
99
REVLIMID® Lymphoma Late Stage Programs
Patient Population Relapsed or Refractory Follicular Lymphoma
Untreated Activated B-Cell DLBCL
T i l NAUGMENTTM ROBUST®
Trial NameNHL-007 DLC-002
Phase III III
Target Enrollment 500 560Target Enrollment 500 560
Design
Arm A: REVLIMID® (10-20mg) D1-21 / Rituximab 375 mg/m2 weekly for cycle 1
then D 1 of cycles 2-5 for 5 28-day cycles Arm a: REVLIMID® (15mg) D1-14/+ R-CHOP21 for 6 21-day cyclesDesign
Arm B: Placebo D1-21, / Rituximab 375 mg/m2 weekly for cycle 1 then D 1 of
cycles 2-5 for 5 28-day cycles
CHOP21 for 6 21 day cyclesArm B: Placebo + R-CHOP21 for 6 cycles
Primary Endpoint Progression Free Survival Progression Free Survival
Status Trial enrolling Trial enrolling
100
REVLIMID® Lymphoma Late Stage Programs
Patient Population Relapsed or Refractory Indolent Lymphoma
Trial NameMAGNIFYTM
NHL-008
Phase III
T t E ll t 500Target Enrollment 500
D i
Arm A: REVLIMID® (10-20mg) D1-21 / Rituximab 375 mg/m2 weekly for cycle 1 then D 1 of cycles 3, 5, 7,9 and 11 for 12 28-day cycles followed by REVLIMID® (10mg) D1-21 / Rituximab 375 mg/m2 D 1 of cycles 13, 15, 17,19, 21, 23, 25, 27 and 29 for
18 28-day cycles followed by REVLIMID® (10mg) D 1-21 until disease progression –28 day cycleDesign 28 day cycle
Arm B: REVLIMID® (10-20mg) D1-21 / Rituximab 375 mg/m2 weekly for cycle 1 then D 1 of cycles 3, 5, 7,9 and 11 for 12 28-day cycles followed by REVLIMID® (10mg) D1-21 / Rituximab 375 mg/m2 D 1 of cycles 13, 15, 17,19, 21, 23, 25, 27 and 29 for
18 28-day cycles
Primary Endpoint Progression Free Survival
Status Trial enrolling
101
ABRAXANE® Solid Tumor Late Stage Programs
Patient PopulationMaintenance After Induction in
Squamous Non-Small Cell Lung Cancer
Adjuvant Therapy in Surgically Resected Pancreatic Cancer
PANC-003Trial Name NSCL-003
PANC 003apact®
Phase III III
Target Enrollment 540 800
Induction: ABRAXANE® (100 mg/m2) D 1, 8,and 15 / Carboplatin (6 mg min/mL) D 1 for
4 21-day cycles Arm A: ABRAXANE® (125 mg/m2) / Gemcitabine (1000 mg/m2) D 1 8 and 15 for
Design Maintenance: Arm A: ABRAXANE® (100 mg/m2) D 1 and
8 plus BSC until disease progression –21-day cycle
Arm B: BSC until disease progression
Gemcitabine (1000 mg/m2) D 1, 8 and 15 for 6 28-day cycles
Arm B: Gemcitabine (1000 mg/m2) D 1, 8 and 15 for 6 28-day cycles.
Arm B: BSC until disease progression
Primary Endpoint Progression Free Survival Disease Free Survival
Status Trial enrolling Trial enrolling
102
ABRAXANE® Solid Tumor Late Stage Programs
Patient Population First-Line Triple Negative Metastatic Breast Cancer
First Line Stage IIIB / IV Squamous NSCLC
tnAcity® NSCL 003Trial Name
tnAcity®
ABI-007-MBC-001NSCL-003
Abound.sqm®
Phase II/III III
Target Enrollment 240/550 260Target Enrollment 240/550 260
Phase IIArm A: ABRAXANE® 1(25mg/m2) / Gemcitabine
(1000 mg/m2) D 1 and 8 – 21-day cycleArm B: ABRAXANE® (125mg/m2) / Carboplatin
Arm A: Induction – ABRAXANE® (100 mg/m2) D 1, 8 and 15 / Carboplatin (6
mg/min/ml) D 1 of a 21-day cycle; Maintenance ABRAXANE® (100 mg/m) D 1
DesignAUC 2 IV, D 1 and 8 – 21-day cycle
Arm C: Gemcitabine (1000 mg/m2) / Carboplatin AUC 2 IV, D 1 and 8 – 21-day cycle
Phase IIIArm 1: Selected phase II ABRAXANE® arm
Maintenance – ABRAXANE® (100 mg/m) D 1 and 8 of a 21-day cycle or Best supportive
careArm B: Induction – ABRAXANE® (100 mg/m2) D 1, 8 and 15 / Carboplatin (6
mg/min/ml) D 1 of a 21-day cycle; pArm 2: Gemcitabine (1000 mg/m2) / Carboplatin
AUC 2 IV, D 1 and 8 – 21-day cycle
g ) y y ;Maintenance – Best supportive care
Primary Endpoint Progression Free Survival Progression Free Survival
Status Trial enrolling Trial enrolling
103
I&I Late Stage Programs
Patient Population
Untreated Moderate-to-Severe
Late Stage Psoriatic Arthritis
Active Behçet’s Disease
Molecule OTEZLA® OTEZLA®
Trial Name PSA-006BCT-002RELIEFTM
Phase III III
Target Enrollment 214 204
D iArm A: OTEZLA® single agent
(30mg)Arm A; Placebo for 12 weeks followed by 30mg OTEZLA®
twice daily for 52 weeksDesign( g)
twice dailyArm B: Placebo
twice daily for 52-weeksArm B: 30mg OTEZLA® twice
daily for 64 weeks
Primary ACR 20 at Week 16Area under the curve (AUC) for the number of oral ulcers fromy
Endpoint ACR 20 at Week 16 the number of oral ulcers from baseline through week 12
Status Trial enrolling Trial enrolling
104
I&I Late Stage Programs
Patient Population Active Crohn’s Disease
Molecule GED-0301
Trial Name CD-002
Phase III
Target Enrollment 1,064
D i
Arm A: GED-301 160mg daily 12 weeks/GED-301 40mg daily 40 weeks
Arm B: GED-301 160mg daily 12 weeks/GED-301 40mg daily 4 weeks on/4 weeks off 40 weeksDesign 40mg daily 4 weeks on/4 weeks off 40 weeks
Arm C: GED-301 160mg daily 12 weeks/GED-301 160mg daily 4 weeks on/4 weeks off 40 weeks
Primary Endpoint Clinical remission defined by Crohn's Disease Activity Index (CDAI)
Status Enrolling
105
I&I Late Stage Programs
Patient Population Relapsing Multiple Sclerosis Relapsing Multiple Sclerosis
Molecule Ozanimod OzanimodMolecule Ozanimod Ozanimod
Trial Name SUNBEAM RADIANCE
Phase III II/III
Target Enrollment 1200 1200
Arm A: Ozanimod (0 5mg) daily/placebo IM
Phase IIArm A: Ozanimod (0.5mg) dailyArm B: Ozanimod (1mg) daily
Design
Arm A: Ozanimod (0.5mg) daily/placebo IM weekly
Arm B: Ozanimod (1mg) daily/placebo IM weekly
Arm C: Oral placebo daily/Beta-interferon IM weekly
Arm B: Ozanimod (1mg) dailyArm C: Placebo daily
Phase IIIArm A: Ozanimod (0.5mg) daily/placebo IM
weeklyweekly
Arm B: Ozanimod (1mg) daily/placebo IM weeklyArm C: Oral placebo daily/Beta-interferon IM
weekly
Primary Endpoint Annualized relapse rate at month 12 Annualized relapse rate at month 24
StatusEnrollment complete
Data expected in H1:17Enrollment complete
Data expected in H1:17
106
I&I Late Stage Programs
Patient Population Moderate-to-Severe Ulcerative Colitis
Molecule Ozanimod
Trial Name TRUE NORTH
Phase IIIPhase III
Target Enrollment 900
A A O i d (1 ) d ilDesign
Arm A: Ozanimod (1mg) dailyArm B: Placebo daily
Primary Endpoint Clinical remission
Status Trial enrollingStatus Trial enrolling
107