Rheumatoid Arthritis: New and

Emerging Agents and Trends

Arthur Kavanaugh, MD

Director, Center for Innovative Therapy

Professor of Medicine

Division of Rheumatology, Allergy, and

Immunology

University of California San Diego

La Jolla, CA

Rheumatoid Arthritis: New and

Emerging Agents and Trends

Arthur Kavanaugh, MD

Director, Center for Innovative Therapy

Professor of Medicine

Division of Rheumatology, Allergy, and Immunology

University of California San Diego

San Diego, CA

Arthur Kavanaugh: Disclosures

Abbott

Amgen

Astra-Zeneca

Biogen-Idec

BMS

Celgene

Centocor

Genentech

TREG Consultants LLC

ITN

LCTC

MedImmune

NIH

Roche

Sanofi-Aventis

Teva

UCB

RA: Therapeutic Interventions Adjunctive (NSAIDs / COX-2 / Corticosteroids ), analgesics, PT/OT, etc

DMARDs

– MTX, LEF, SSZ, HCQ >> CsA, Min, IM gold, etc

– Tofacitinib (Jak3/1 inhibitor)

Biologics

– TNF-Inhibitors: etanercept, infliximab, adalimumab, certolizumab pegol, golimumab

– IL-1 Inhibitors: anakinra (IL-1ra); rilonacept (IL-1-TRAP), canakinumab

– Abatacept (CTLA-4-Ig)

– Rituximab (-CD20 mAb)

– Tocilizumab (-IL-6R mAb)

Experimental / Emerging

– other B cell (-CD22 [epratuzumab]: -BAFF/BLyS,TACI, APRIL)

– other IL-6 inhibitors (sirukimab, sarilumab etc)

– kinase inhibitors (Syk [fostamatinib], Jak, MEK, etc)

– -IL-12/23 mAb (ustekinumab, briakinumabetc)

– -IL-17 (secukinumab, ixekizumab, brodalumab)

– biosimilars

PEG PEG

Human receptor / Fc fusion protein

Humanised Fab’

fragment

Human monoclonal

antibody

Humanized monoclonal

antibody

Chimeric monoclonal

antibody

CDR

VL VH

CH1

Fc

Receptor

Constant 2

Constant 3

Mouse

Human

CDR = Complementarity-determining region

PEG = Polyethylene glycol

infliximab

IgG1

adalimumab

golimumab

IgG1

etanercept

IgG1

certolizumab

pegol

CDP571

IgG4

Naming mAb: 1) first 2 - 4 letters – WHO/sponsor picks 2) middle part:

disease/target e.g. immune –li-; cardiac –ci-; tumor –tu- 3) type of antibody

-omab =murine, -ximab = chimeric, -zumab = humanized, -umab = human.

TNF Inhibitors

Current Status: TNF-inhibitors

Most patients respond, (some do not) - some achieve “remission”

Clinical efficacy usually requires continued therapy (i.e. no tolerance or “cure”); ?, especially in early disease, can TNFi be tapered or stopped after ‘induction’ into remission or low disease activity

TNFi highly effective in AS, PsA, psoriasis. In uveitis, psoriasis, mAb appear more effective. ? mAb more effective in IBD (Crohn’s disease, ulcerative colitis). mAb ? less safe (e.g. TB). ? Dose

TNFi not effective in sepsis, CHF, Wegener’s, PMR/TA, sarcoid, Sjogrens

Biosimilar TNF-i: Likely to be introduced worldwide (?which/when?)

Personalized Medicine: Promise and Pitfalls

For individual patients, this could

Predict responses to individual drugs

Predict toxicities to individual drugs

Optimize benefits / risks of treatment

Achieve better outcomes

Reduce costs

Personalized Medicine: Promise and Pitfalls

For individual patients, this could

Predict responses to individual drugs

Predict toxicities to individual drugs

Optimize benefits / risks of treatment

Achieve better outcomes

Reduce costs

Response to TNF-I Therapy: PTPRC gene

1,115 UK RA patients on TNF-I therapy

29 SNPs established as RA susceptibility variants

PTPRC rs10919563 SNP associated with improved

treatment response; no association with other loci seen

“meta-analysis combining these data with results from

previous study strengthened the evidence (p=5.13 X 10-5)”

* P 0.04; Plant D, et al. Arthritis Rheum 2012;64:665-70

Genotype Baseline DAS28 Change in DAS28

1/1 6.66 ± 0.95 -2.53 ± 1.51

1/2 6.73 ± 0.99 - 2.32 ± 1.46*

2/2 6.75 ± 1.00 - 2.35 ± 1.43*

Personalized medicine: KRAS and other

mutations in colorectal and NSCLC

*Van Cutsem E et al. N Engl J Med 2009;360:1408-17

FDA approves Therascreen KRAS PCR Kit (Qiagen). www.cancer.gov July 6,

2012. New test for 280 (Foundation Medicine) different genetic mutations

($5,800); ‘~ 70% cases mutation targeted by an approved or in-trial drug’

Oncogene

(prevalence)

Rx Response,

NSCLC pts

EGFR (40%

Asian,10% Cau

erlotinib: ~ 82%

geftinib: ~ 72%

KRAS a-EGFR ~0-5%

ALK crizotinib ~55%

*

Personalized Medicine

Chen R, et al. Cell

2012;148:1293-1307.

“integrated personal omics

profile”; included genomics,

transcriptomics, proteomics,

metabolomics, and

autoantibody profiles.

Correlated with “health and

disease” including development

of type II DM

>3 X 109 measurements, 20

time points over 14 months,

single pt (Michael Snyder, PI)

Clinical Responses to TNF Inhibitors

28 Swollen Joint Count

Co

un

t

50

40

30

20

10

0 -20 -15 -10 -5 0 5 10 15 20 25

Co

un

t

50

40

30

20

10 5

0 -20 -15 -10 -5 0 5 10 15 20 25

28 Tender Joint Count

30

100

ESR

Co

un

t

50

40

30

20

10

0 -40 -20 0 20 40 60 80

60 70

60

50

40

30

20

10

0 -2.5 2.0 -1.5 -.5 0 .5 1 1.5 2.0 2.5 -1.0

HAQ Score

Co

un

t

Van Vollenhoven RF, Klareskog L. Clinical responses to TNF antagonists do not

show a bimodal distribution. Arthritis Rheum 2003;48:1500–1503.

Med

ian

AD

A C

on

cen

trati

on

0

2

4

6

8

10

12

14

0 16 40 78 130

No AAA AAA 13-100 AU/ml AAA > 100 AU/ml

P < 0.001* *

Serum Levels of ADA Correlate With

Antidrug Antibody Levels

Bartelds GM, et al. JAMA 2011;305(14):1460–1468.

Week

Rapid reversal of pain induced BOLD

signals after TNFi on fMRI in RA

Hess A. PNAS (Epub Feb 2011)

BOLD blood-oxygen level-dependent signals

Biosimilar (CT-P13) vs IFX in MTX-IR RA

and in AS: Two studies

• 606 RA patients – 1:1 IFX (n=304) vs CT-P13 (n=302)

– 3 mg/kg + MTX at Weeks 0, 2, 6,

14, 22, 30

– 1º outcome ACR20 at Week 30

CT-P13 has efficacy, safety and PK similar to IFX in MTX-IR

RA patients and in AS patients

CT-P13 IFX

AE (%) 35.2% 35.9%

Infection AE (%) 15.3% 16.9%

Infusion Rx (%) 5% 6%

TB (n) 3 1

ACR responder rates at Week 30

Yoo DH, et al. EULAR 2012, Berlin, #FRI0143;

Park W, et al bid OP0167

• 250 AS patients:

– 5 mg/kg at wks 0, 2, 6, 14, 22, 30

– 1º outcome: PK (AUC/Cmax) similar

– ASAS20: 70.5% vs 72.4% IFX

– ASAS40: 51.8% vs 47.4% IFX

adalimumab

biosimilar

launch US

RA – emerging and future therapies

2010 2020 2011 2012 2013 2014 2019 2018 2017 2016 2015

rituximab

biosimilar

launch EU

etanercept

/Infliximab

biosimilar

launch EU

abatacept

biosimilar

launch EU adalimumab

biosimilar

launch EU

rituximab

biosimilar

launch US

Etanercept/IFX

biosimilar

launch US

2009

B-Cell Inhibitors

New small molecules

T-Cell Inhibitors

Anti-TNF

Anti-IL6

Simponi iv

Actemra sc

Olokizumab

Sirukumab (CNTO136)

ALD-518

Ofatumumab sc

Simponi sc

Cimzia

Actemra iv

tofacitinib Fostamatinib INCB 28050

Orencia sc

Sarilumab (REGN-88)

abatacept

biosimilar

launch US

tocilizumab

biosimilar

launch EU

Anti-IL17

Secukinumab

Fibroblast Lymphoid Myeloid

Early Synovial Histopathology

Macrophage

Dendritic cell

T-cell

B-cell

Synoviocyte

BONE & CARTILAGE

Cytokine

Interplay IL-2, IL-4, IL-7 IL-

9, IL-10, IL-12 IL-

13 IL-15, IL-21, IL-

23, IL-27, IFNg,

TGFb

IL-1, TNF

IL-6

IL-11, IL-10, IL-

12 IL-27, IL-32,

OSM GM-CSF,

M-CSF, IFNg,

PDGF, RANKL,

TGFb

IL-1, TNF

IL-6

OSM, IL-11, IL-

17, IL-18, IFNg,

IL-19, IL-20, IL-

22 TGFb

IL-1, TNF

IL-6 (sIL-6R)

Choy E, Kavanaugh A, Jones S. Nat Rev Rheumatol 2013;9:154-63

Novel Immunomodulatory Targets

– Anti-cytokine biologics

– p38 pathway

– NFkB pathway

– ERK pathway

– Proteases

– Ion channels

– Angiogenesis

– Synoviocyte apoptosis

Mechanisms Examples of targets Class

Anti-cytokines/

Growth factors

Anti-B-cells

– TNF,IL-1b, IL-7,IL-12,IL-15,IL-1,7 IL-18, IL-23, IL-6,IL32,etc

– p38

– NFkB pathway ( IKKb, IRAK-4, MEKK-3)

– ERK, COT

– ICE, TACE, TRRE

– P2X7

– B-cell biologics

– B-cell signaling

– B-cell recruitment

– CD-20, CD-19, CD40, IL-6, BAFF/BLYS,

APRIL

– BTK, NIK, SYK

– CXCR-5

Anti-

Cell trafficking

– Leukocyte recruitment

– Anti-chemoattractants

– Adhesion molecules

– CCR-1, CCR-2, C5a receptor, LT/b

– CCR-2,MIF

– Integrins, selectins, ICAMs

Anti-T cell /

co-stimulation

– Co-stimulation

– Antigen presentation

– T-cell activation

– TH-1 / TH-2 / TH-17 /

T-Reg balance

– B7 (CTLA-4 Ig), CD40L, CD-28

– Cat S, GILT

– PKC, LCK, TIRC-7, FK506BP, IFN, JAK-3

– DHODH, DHFR

– T-cell epitope

– VEGF, Tubulin, Angio/Endostatin,Tie-2, vb3, PAR-2,

BCL-2, p53

Th Cell Development

O’Garra A, et al. Nature Immunology 2008;9:588.

IL-12

p35 p40

IL-23

p19 p40

IL-12Rb1 IL-12Rb2 IL-12Rb1 IL-23R

IL-23

receptor

IL-12

receptor

IL17 Family

Patel D, et al Ann Rheum Dis 2013 (Epub 5 March)

Brodalumab (anti-IL-17R IgG2 mAb):

Phase 2 study in MTX-IR patients

• DBPCRCT in 252 MTX-IR

patients

• PBO, 70, 140 or 210 mg

SC Day 1 and Wks 1, 2

and q2w thereafter

• 1° EP: ACR50 at Week

12

• ACR50: Subset analyses

unrevealing

• Despite impressive efficacy

in psoriasis, no evidence of

benefit or change in CRP

in RA

Lin S-L, et al. ACR 2012, Washington DC, #831;

To date, 3 anti IL-17 mAbs have not shown impressive

efficacy in RA

All NS

ACR20, 50, and 70 responders

Pati

en

ts (

%)

Interleukin TLR agonist

NF-kB MAP Kinase

Interleukin Interferon Growth factor TNF family

STAT

JAK JAK

outside

inside

outside

inside

Survival Proliferation Death

Classic cytokine regulated responses

Differentiation Gene expression

Tofacitinib

Ruxolitinib

VX-509

R-348

INCB-28050

AC-430

CEP-33779

Tocilizumab

Sarilumab

ALX-0061

Olokizumab

Sirukumab

Situximab

Ustekinumab

Bevacizumab Anakinra

Ixekizumab

Secukinumab

Etanercept

Brodalumab

Infliximab,

Adalimumab,

Golimumab,

Certolizumab

Choy E, Kavanaugh A, Jones S. Nat Rev Rheumatol 2013;9:154-63

Nucleus

DNA RNA

TNF

Inhibitors of

transcription

or translation;

modulation of

mRNA

TNF

Cell Surface TNF converting

enzyme

4

5 Inhibition

2 Soluble TNFr1 or

TNFr2 constructs

3 Inhibitory

peptides

or

peptido-

mimetics

1 Anti-TNF

antibody

6 Inhibitors of

downstream

signal

transduction

Signal

transduction TNFr1

TNFr2

7 Factors

increasing

secretion of

soluble forms of

TNFr1 and

TNFr2

Intracellular Signaling Pathways / Molecules

MAPK Syk

P13K cAMP/PKA

JAK

Kinases

ERK

PI3K

Lipid

messengers

cAMP

STAT

STAT

STAT

STAT

Syk PI3K

AC Gas

JAK JAK

Gene transcription

Nucleus

Kinases

p38

JNK

PKA

Second

messengers

PKC

Second

messengers

PKA

NF-κB

IKK

PDE4

NF-κB

Tas SW, et al. Curr Pharm Design. 2005;11:581-611; Schafer P. Biochem Pharmacol. 2012;83: 1583–1590.

Janus Kinases (JAK) family

JAK Family Cytokine Small Molecule inhibitor

JAK-1 IL-2, IL-4 IL-7, IL-9, IL-13 IL-15, IL-21

IL-6, IL-11, IL-27, LIF, OSM, CNTF, CT1, Leptin

IL-10, IL-19, IL-20, IL-22, (IL-24, IL-26)

IFN, IFNb, IFNg, IL-28, IL-29, IL-30 (type-III IFN)

Tofacitinib

Ruxolitinib

INCB-28050

GLPG-0634

JAK-2 IL-3, IL-5, GM-CSF

IL-6, IL-11, IL-27, LIF, OSM, CNTF, CT1, CLC

IL-12, IL-23

EPO, GH, PRL, Leptin

Tofacitinib

Ruxolitinib

INCB-28050

AC-430

JAK-3 IL-2, IL-4 IL-7, IL-9, IL-13 IL-15, IL-21 Tofacitinib

VX-509

R-348

TYK-2 IL-6, IL-11, IL-27, LIF, OSM, CNTF, CT1, CLC

IL-12, IL-23

IFN, IFNb, IFNg, IL-28, IL-29, IL-30 (type-III IFN)

Leptin

--

Cytokine regulation of JAK family members and small

molecule targeted interventions

Baricitinib, Oral JAK 1/2 inhibitor: 12-week Phase 2b

dose-ranging study in MTX-IR (Lilly/Incyte)

Keystone E, et al. EULAR 2012, Berlin, #LB0005;

Genovese M, et al. ACR 2012 Wash DC, #2487

Statistical significance w/ 1, 4, 8 mg by 1° EP at Wk 12;

Clinical benefit at 12 weeks sustained with further improvement

at 24 weeks

41

10 2

57*

31*

12*

54

17

8

75*

35*

23*

78*

40*

20*

0

20

40

60

80

100

ACR20 ACR50 ACR70

Placebo 1 mg QD 2 mg QD

4 mg QD 8 mg QD

ACR Responses at Week 12

*1, 4 and 8 mg all p<0.001

vs PBO

Pati

en

ts (

%)

ACR Responses at Week 24

Treat to target algorithm

Smolen JS et al. Ann Rheum Dis. 2010;69:631-637

Active RA Sustained Remission

Sustained Low Disease

Activity

Assess disease activity about every 3 to 6

months

Use a composite measure of

disease activity every 1 to 3

months

Adapt therapy according to

disease activity

Adapt therapy according to

disease activity

Adapt therapy if state is lost

Adapt therapy if state is lost

Low Disease Activity

Alternative target

Remission

Main target

PRESERVE: Established RA, can TNFi be

lowered or discontinued?

• 604 RA pts w/ moderate RA (DAS28 3.2–5.1) on ETN/MTX x 9 mos LDAS

• DBRCT: 1) Continue E50/MTX; 2) Reduce E25/MTX; 3) Placebo/MTX

•

• No differences in SAE: 2 deaths in E50/M

• SIE = 6; Malignancies = 7; TB = 0

After 9 mo induction of LDAS with MTX/ETN, pts can safely continue or ↓

ETN dosing; maintenance on MTX alone insufficient to maintain LDAS

Time to loss of LDAS & DAS >0.6

Smolen J, et al. Lancet 2013

Week 88 outcomes

Period 2 Arm LDAS Rem mTSS

E50/M (continue) 82.6 66.7 –0.06*

E25/M (Reduce) 79.1 60.2 +0.5

P/M (MTX w/d) 42.6 29.4 +0.6*

**P<0.001 vs P/M; *P<0.05 vs P/M

Kap

lan

-Meie

r su

rviv

al

esti

mate

s (

%)

20

40

60

80

100

100 0 200 300 400

Days relative to first double-blind dose

0

ETN 50 mg + MTX

ETN 25 mg + MTX

PBO + MTX

In P2; mITT, observed cases. P<0.0001, ETN 50 mg/

25 mg + MTX vs PBO +MTX, from log rank test

T2T strategies in early RA:

OPTIMA Study design

MTX titrated to 20 mg/wk by Wk 8

*Period 1 DAS28 <3.2 (LDA) at BOTH weeks 22 AND 26

MTX

Yes ADA 40 mg

EOW+MTX

OL ADA 40 mg

EOW+MTX No

No OL ADA 40 mg

EOW+MTX

Yes

MTX

ADA 40 mg

EOW+MTX *

DAS28

<3.2

MTX*

ARM 1

ADA+MTX / MTX

ARM 2

Sustained ADA+MTX

ARM 3

ADA+MTX IR/ADA+MTX

ARM 4

Sustained MTX

ARM 5

MTX IR/ADA+MTX

PERIOD 1 PERIOD 2 0 w 26 w 78 w

Primary

efficacy

outcome†

† DAS28 <3.2

and mTSS <0.5

at Week 78

n=466**

n=460**

*n=112(24.3%)

n=348

n=259

*n=207(44.4%) n=102

n=105

DAS28

<3.2

• MTX-naive pts ≥18 ys with RA <1 y & active disease (DAS28>3.2, ESR ≥28 mm/h or CRP ≥1.5 mg/dL), and either >1 erosions, RF+ or anti-CCP+

www.TREGdocs.com

Kavanaugh, A, et al. Ann Rheum Dis 2012 (in press) E pub

OPTIMA: ADA+MTX / MTX vs

sustained ADA+MTX

89.0 85.0 81.0

89.0 88.0 89.0

0

20

40

60

80

100

26 52 78

% p

ts ∆

mT

SS

≤0.5

(%

)

Weeks

Radiographic prog: % pts

ADA+MTX / MTX (n=88) Sustained ADA+MTX (n=94)

For many early RA patients in LDA on TNFi/MTX, TNFi can be

withdrawn for a year; some patients may need continued treatment

Smolen J, et al. EULAR 2011, London, #THU0243

40

60

80

100

26 30 34 38 42 46 50 54 58 62 66 70 74 78

Pati

en

ts (

%)

Weeks

ACR ACR20

ACR50

ACR70

The Benefit / Risk Balance

Benefit Risk

Infection

Malignancy

Other adverse events

Cost

Signs / symptoms

Quality of life / function

Prevent X-ray damage

Work / home productivity

Cost-efficacy

Patient demographics

Comorbidity

Disease characteristics

Other medications

Rheumatoid Arthritis: New and

Emerging Agents and Trends

Arthur Kavanaugh, MD

Director, Center for Innovative Therapy

Professor of Medicine

Division of Rheumatology, Allergy, and Immunology

University of California San Diego

San Diego, CA