ASH IR Event December 6, 2015€¦ · This presentation contains forward-looking statements, ......

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


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


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


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


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


94

POMALYST®/IMNOVID® Multiple Myeloma Late Stage Programs

Patient Population RRMM

T i l NMM-007

Trial NameOPTIMISMM®

Phase III


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


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


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


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


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


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


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


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


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


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


104


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


Patient Population Relapsing Multiple Sclerosis Relapsing Multiple Sclerosis

Molecule Ozanimod OzanimodMolecule Ozanimod Ozanimod

Trial Name SUNBEAM RADIANCE

Phase III II/III


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


Patient Population Moderate-to-Severe Ulcerative Colitis

Molecule Ozanimod

Trial Name TRUE NORTH

Phase IIIPhase III


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

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