New Small Molecule Therapies in Rheumatoid Arthritis · Different Kinase Pathways can be Exploited...

New Small Molecule Therapies in

Rheumatoid Arthritis

Mark C. Genovese, MD

James W. Raitt Professor of Medicine

Division of Immunology and Rheumatology

Stanford University, USA

Disclosures

• Pfizer

• Astellas

• Lilly

• Pharmacyclics

• Abbott

• Sanofi

• Regeneron

• Gilead

• Vertex

• Johnson & Johnson

• Celgene

• Principia

• Galapagos

• GSK

Cytokine Signaling Pathways Involved in Inflammatory Arthritis NEJM

Different Kinase Pathways can be Exploited

for Therapeutic Purposes in RA1-10

1. Adapted from Šenolt L, et al. Autoimmun Rev. 2009;9:102-107. 2. Braselmann S, et al. J Pharmacol Exp Ther. 2006;19:998-1008. 3. Cha HS,

et al. J Pharmacol Exp Ther. 2006;317:571-578. 4. Drexler SK, et al. Arthritis Res Ther. 2008;10:216-227. 5. McInnes IB, et al. Nat Rev Immunol.

2007;7:429-442. 6. Brennan FM, et al. J Clin Invest. 2008;118:3537-3545. 7. Alexander WS. Nat Rev Immunol. 2002;2:1-7. 8. Paunović V, et al.

Rheumatology. 2008;47:771-776. 9. Gaestel M, et al. Curr Med Chem. 2007;14:2214-2234. 10. Cohen P. Curr Opin Cell Biol. 2009;21:317-324.

Cell membrane

JAK JAK P

JAK inhibitors

STAT P

STAT P

STAT P

MAPKKK

MAPKK

MAPK-p38, ERK, JNK

p38

P

P

p38 inhibitors

SYK

P

ERK P

P

JNK

P

P

SYK inhibitors

STAT P

STAT P

TNF, IL-1, IL-6, MMPs, etc.

Inflammation and tissue damage

Cytoplasm

Small Molecule enzyme Inhibitors

• JAK- Inhibition

• SYK-Inhibition

• PDE4-Inhibition

• BTK-Inhibition

• PI3K-Inhibition

• Tyrosine Kinase Inhibition

– C-FMS

– C-KIT

Binding of cytokine receptors activates

JAK signalling pathways

7

7 JAKs activate STATs, which then act as transcription factors

1. Shuai K et al. Nat Rev Immunol 2003;3:900–911.

JAK, Janus kinase; P, phosphate;

STAT, signal transducer and activator of transcription.

Gene transcription

• Rapid membrane to nucleus signalling:

– Cytokines bind trans-membrane

receptors that are associated with JAKs

– Binding activates JAKs

– JAKs phosphorylate receptors

– STATs bind to receptors

– JAKs phosphorylate STATs

– STAT translocate to the nucleus

– STATs bind DNA and activate

transcription to produce proteins

that mediate immune

responses/inflammation

Activation of JAK/STAT Signaling by

Cytokines in RA1-3

SOCS1/3

STAT3

gp130

STAT4 P

IL-6

p40 p35

STAT3

IL-12

STAT4

Cellular response

1. Adapted from Paunović V, et al. Rheumatology. 2008;47:771-776. 2. Kishimoto T. Arthritis Res Ther. 2006;8(suppl 2):S2. 3. Alexander WS.

Nat Rev Immunol. 2002;2:1-7.

Cytoplasm

Cell membrane

• There are four JAK family members: JAK1, JAK2, JAK3, and TYK2

The JAK/STAT signalling pathways

γ-chain

cytokines2

STAT

1, 3, 5, 6

IL-10

IL-22

STAT

1, 3, 5

IL-6†

IL-11

STAT

1, 3, 5

IFN-γ

STAT

1, 3, 5

IL-12

IL-23

STAT

3, 4

EPO

TPO

GM-CSF

STAT

5

Example of cytokines that signal through JAK/STAT combinations1

JAKs mainly work in pairs within the cell and signal via

JAK/STAT combinations

1. O’Sullivan LA et al. Mol Immunol 2007;44:2497–2506.

2. Ghoreschi K et al. Immunol Rev 2009;228:273-287.

EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor;

IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and

activator of transcription; TPO, thrombopoietin; TYK, tyrosine kinase.


• JAK- Inhibition

– Tofacitinib

– Baracitinib

– VX-509 (Decernotimib)

– Ast015k

– Galapagos

Tofacitinib Phase 3 studies:

Overview

1. Fleischmann R et al. NEJM 2012;367:495–507.

2. Kremer J et al. Ann Intern Med 2013;159:253–261.

3. van der Heijde D et al. Arthritis Rheum 2013;65:559–570.

4. van Vollenhoven R et al. NEJM 2012;367:508–519.

5. Burmester GR et al. Lancet 2013;381:451–60.

6. Lee EB et al. Arthritis Rheum 2012:64(10Suppl):S1049;Abstract #2486.

DMARD, disease-modifying anti-rheumatic drug;

IR, inadequate responder; mTSS, modified total Sharp score;

MTX, methotrexate; TNFi, tumour necrosis factor inhibitor.

Study

(N)

ORAL Solo1

(N=610)

ORAL Sync2

(N=792)

ORAL Scan3

(N=797)

ORAL

Standard4

(N=717)

ORAL Step5

(N=399)

ORAL Start6

(N=952)

Duration 6 months 12 months 24 months 12 months 6 months 24 months

Background

treatment None

Non-biologic

DMARDs MTX MTX MTX None

Feature Monotherapy Background

DMARDs X-ray

Active control

(adalimumab) TNFi failure

mTSS scores

with

monotherapy

MTX-IR TNFi-IR DMARD-IR MTX-naive

EFFICACY

Background DMARD studies

ACR20 Response Rates at Primary Time Point –

Phase III Background DMARD Studies

MTX, methotrexate

Pfizer Inc. Advisory Committee Briefing Materials: Available to General Public. 9th May 2012:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdfuller

1044/Scan-24-month, MTX background, X-ray evaluation of joint damage

1046/Sync-12-month, various background non-biologic DMARDs

1064/Standard-12-month, MTX background, adalimumab active control

1032/Step-6-month, MTX background, TNF-inadequate responders

EFFICACY

Monotherapy study

ACR20, ACR50, ACR70 Response Rate (%)

(NRI, Comparisons to Placebo), 1045/Solo Study

*p≤0.05; ** p<0.01; *** p<0.001, compared to placebo

NRI, non-responder imputation

Pfizer Inc. Advisory Committee Briefing Materials: Available to General Public. 9th May 2012:

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdfuller

1045/Solo, 6-month, monotherapy (n = 610)

RADIOGRAPHIC OUTCOMES

0.0

0.2

0.4

0.6

0.8

1.0

Month 6

0.84

0.04

**

*** 0.18

ORAL Start: ∆ mTSS at Month 6 – co-

primary endpoint

BID, twice daily; LS, least squares; MTX, methotrexate. 17

LS

mean

ch

an

ge (±

SE

) fr

om

baselin

e

Tofacitinib 10 mg BID

monotherapy

MTX

Tofacitinib 5 mg BID

monotherapy

**p<0.001; ***p<0.0001 vs MTX; Full analysis Set

Fleischmann R et al. Presented at ACR 2012; Washington, DC,

November 10–14; Presentation 2486

ORAL Step: Study design

Burmester et al. Lancet 2013;381(9865):451–460.

ACR, American College of Rheumatology; BID, twice daily; DAS, Disease Activity Score; ESR,

erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index;

MTX, methotrexate; TNFi, tumour necrosis factor inhibitor.

BIOLOGIC-IR COMBO-TX

2:2

:1:1

ra

nd

om

isa

tio

n

Month 6

study end

Baseline Month 3

Placebo + MTX Tofacitinib 5 mg BID + MTX

Tofacitinib 10 mg BID + MTX Placebo + MTX

Tofacitinib 10 mg BID + MTX


Co-primary efficacy endpoints

ACR20 response (month 3) Mean change in HAQ-DI from baseline (month 3) Rate of achieving DAS28-4(ESR)<2.6 (month 3)

Inadequate responders to

≥1 TNFi (N=399)

24.4

41.7

48.1

0

10

20

30

40

50

60Placebo + MTX



ORAL Step: ACR20 primary endpoint

Burmester et al. Lancet 2013;381(9865):451–460.

ACR, American College of Rheumatology;

BID, twice daily; MTX, methotrexate.

ACR20 (Month 3)

Pa

tie

nts

(%

)

n= 32/131 55/132 64/133

*

***

BIOLOGIC-IR COMBO-TX

*p≤0.05; ***p<0.0001 vs placebo at month 3 (unadjusted)

SAFETY

• Most common (≥2%) adverse events reported during the first 3 months

(placebo-controlled) in Phase III studies were:1

– Upper respiratory tract infections, headache, nasopharyngitis, diarrhoea,

nausea, urinary tract infection, hypertension, dyspepsia, oedema, peripheral,

blood creatine phosphokinase increased, arthralgia, and RA

• Treatment with tofacitinib was associated with an increased incidence of

neutropenia (<2,000 cells/mm3)

– A dose-dependent mean decrease in ANC, which reached a plateau within

3 months of treatment, was observed in RA patients treated with tofacitinib1

– Confirmed decreases in ANC below 1,000 cells/mm3 occurred in 0.07% of

patients

treated with tofacitinib2

• Confirmed decreases in lymphocyte counts below 500 cells/mm3

occurred in 0.04% of patients treated with tofacitinib during the first 3

months of exposure2

Side-effects of JAK inhibition with

tofacitinib

1. FDA Advisory Committee Meeting, 9 May 2012 (NDA 203214). Briefing book. [Accessed November 2012]

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM302960.pdf

2. Tofacitinib US Prescribing Information. 2012.

ANC, absolute neutrophil count.

Incidence Rates for Serious Adverse Events:

All Doses of Tofacitinib

5671

1199

5671

273

4678

227

4075

217

3239

156

2845

129

2382

88

1844

47

852

62

N

n

Duration of tofacitinib exposure (months)

IR/1

00

pt-

yrs

(9

5%

CI)

*within 30 days of receiving last dose of study medication

Bars indicate 95% confidence limits. IRs are per 100 pt-yrs. Phase 2, Phase 3 and LTE data

as of 10 April 2013. N, number of patients exposed to tofacitinib, n, number of patients with events

The most common serious AEs were infections and infestations, musculoskeletal and connective tissue disorders, and injury, poisoning and procedural complications

The IR for mortality* was 0.276 (0.198, 0.385)

Incidence Rates for Serious and Non-serious

Herpes Zoster: All Doses of Tofacitinib

Duration of tofacitinib exposure (months)

39 patients permanently discontinued study treatment due to HZ

Serious HZ* was reported in 35 patients (IR: 0.276 [0.199, 0.385])

● 34/35 events resolved, 1/35 events resolving

Multidermatomal HZ (n=6) , ophthalmic HZ (n=6) and HZ oticus (n=1) were reported rarely

There were no cases of visceral dissemination of HZ

5671

504

5671

107

4731

103

4129

77

3314

67

2924

53

2479

55

1918

26

890

16

N

n

*Require hospitalisation or meeting other SAE criteria

Bars indicate 95% confidence limits. IRs are per 100 pt-yrs. Phase 2, Phase 3 and LTE data

as of 10 April 2013

IR/1

00

pt-

yrs

(9

5%

CI)

Safety Conclusions

• The pattern and rate of serious AEs and AEs of

special interest observed in patients with RA

following >12 000 pt-yrs of overall exposure to

tofacitinib was stable across time intervals

• No new risks were identified compared with

previous reports

• Longer-term follow-up, observational research

and pharmacovigilance activities will further

characterize the safety profile of tofacitinib in

RA


• JAK- Inhibition

– Tofacitinib

– Baracitinib

– VX-509 (Decernotimib)

– Ast015k

– Galapagos

Baricitinib (LY3009104; INCB28050)

• Baricitinib is an oral, reversible inhibitor of

JAK1 and JAK2

– In-vitro potency (IC50)

• JAK1 and JAK2 ~ 2 - 5 nM

• TYK2 ~ 53 nM

• JAK3 ~ 560 nM (JAK3 sparing)

• Baricitinib is currently being developed for the

treatment of RA and other autoimmune

disorders

Randomized, Double-Blind, Placebo-

Controlled Trial on Background MTX

Oral Placebo QD (N=98)

Baricitinib 1 mg QD (N=49)




12 Weeks

Primary Endpoint

0 Week

Part A (12 weeks) Part B (12 weeks) Extension

Study

Patients and Investigators remained blinded during Parts A and B

R

Baricitinib 2 mg BID (N=61)





24 Weeks 128

Weeks

Baricitinib 8 mg QD

Baricitinib 4 mg QD

Safety and Efficacy Baricitib 24 weeks Genovese MC. et. al. ACR 2012

% P

atients

* p<0.05 ** p<0.01 *** p<0.001 vs placebo

Week 12 Week 24

Placebo 1 mg 2 mg 4 mg 8 mg

63

20

10

78

48

28

73

55

24

ACR20 ACR50 ACR70

*** ***

*** ***

*** ***

**

*

*

57

31

12

54

17

8

75

35

23

78

40

20

0

20

40

60

80

100

ACR20 ACR50 ACR70

Placebo

Extrapolated Placebo 1 mg 2 mg 4 mg 8 mg

-1.5

-0.5

0.5

1.5

2.5

3.5

24 Weeks

-1.5

-0.5

0.5

1.5

2.5

3.5

12 Weeks

MRI study of Baricitib 24 weeks

Change in Total Damage Score Peterfy. et. al.

p=0.01

p=0.03

NS

p=0.02 p=0.07

NS

p=0.10

NS

P value Top: Wilcoxon rank-sum test

P value Bottom : ANCOVA as prospectively defined in SAP


• JAK- Inhibition

– Tofacitinib

– Baracitinib

– VX-509 (Decernotinib)

– ASP015k

– Galapagos

VX-509 is an oral, selective Janus Kinase

3 (JAK3) inhibitor

3

2

JAK3 associates only with the common

gamma chain receptor subunit

• Exclusively involved in immune function and

shared by receptors for IL-2, IL-4, IL-7, IL-9,

IL-15, and IL-211

• Both JAK1 and JAK3 inhibitors will prevent

signaling by these cytokines.

JAK3 selectivity may have advantages over

other JAK inhibitory approaches

• Selective inhibition of JAK3 will not affect

JAK1 signals mediated by other JAK1 pairs

controlling a diverse set of physiologies2,3

• Selectivity against JAK2 avoids impact on

hematopoietic and growth factor signaling

pathways (e.g. erythropoietin)

1Kawamura M, et al. Proc Natl Acad Sci USA. 1994;91(14):6374-78. 2Leonard WJ, et al. Annu Rev Immunol. 1998;16:293-322. 3Ihle JN, et al. Rev Immunol. 1995;13:369-98.

Phase II MTX-IR Study Design

33

Primary assessments

OLE

(104 weeks)

n=72

n=71

n=72

n=72

n=72

N=359

0

Lead-in

Patients with <20% improvement in

TJC, SJC and Pain can enter

escape arm (VX-509 150 mg QD or

200 mg QD)

Week

VX-509 200 mg QD + MTX


8 12

Treatment

(24 weeks)

−4 18 24

Escape

200 QD + MTX

150 QD+ MTX

Randomized to

150 mg or

200 mg QD

VX-509 100 mg BID + MTX

Placebo + MTX


Patients • Age 18–80 years

with active RA

• CRP > ULN

• SJC/TJC ≥6

of 66/68 joints

• Stable dose

of MTX

• ≤20% for whom 1

TNF inhibitor failed

SJC, swollen joint count; TJC, tender joint count; MTX, methotrexate

ACR Responses at Week 12

34 Nonresponder imputation

18

7 3

47***

23**

10

67***

39***

11*

58***

36***

11*

68***

39***

22***

0

10

20

30

40

50

60

70

80

ACR20 ACR50 ACR70

Placebo (n=71)

VX-509 100 mg QD (n=71)

VX-509 150 mg QD (n=72)

VX-509 200 mg QD (n=72)

VX-509 100 mg BID (n=72)

AC

R R

esp

on

se (

%)

*P<0.05; **P<0.01; ***P<0.001; P values vs placebo.

∆ 50%

Most Common Infections†

36

†Occurring in ≥1% of VX-509 subjects

VX-509 QD VX-509 BID

Event, n (%)

Placebo

(n=71)

100 mg

(n=71)

150 mg

(n=72)

200 mg

(n=72)

100 mg

(n=72)

All VX-509

(n=287)

Nasopharyngitis 2 (2.8) 2 (2.8) 1 (1.4) 4 (5.6) 3 (4.2) 10 (3.5)

Upper resp tract

infection 2 (2.8) 1 (1.4) 1 (1.4) 3 (4.2) 3 (4.2) 8 (2.8)

Bronchitis 3 (4.2) 1 (1.4) 3 (4.2) 2 (2.8) 1 (1.4) 7 (2.4)

Urinary tract infection 0 4 (5.6) 1 (1.4) 1 (1.4) 0 6 (2.1)

Herpes Zoster 0 2 (2.8) 1 (1.4) 2 (2.8) 1 (1.4) 6 (2.1)

Gastroenteritis 1 (1.4) 1 (1.4) 3 (4.2) 1 (1.4) 0 5 (1.7)

Pharyngitis 1 (1.4) 0 4 (5.6) 1 (1.4) 0 5 (1.7)

Rhinitis 0 2 (2.8) 1 (1.4) 0 1 (1.4) 4 (1.4)

Sinusitis 0 0 1 (1.4) 1 (1.4) 2 (2.8) 4 (1.4)


• JAK- Inhibition

– Tofacitinib

– Baracitinib


– ASP015k

– Galapagos

• ASP015K is an oral immunosuppressant that

acts by inhibiting Janus Kinase (JAK), a critical

element in gamma-chain dependent cytokine

signaling.

• In vitro kinase activity suggests that ASP015K

has greater selectivity for JAK3 as compared to

JAK1, JAK2, and TYK2.

• The pharmacokinetic profile of ASP015K

supports its use as once daily dosing

– Tmax 1.5～4 hrs

– Terminal t1/2 between 7 to 13 hrs

Introduction

JAK=Janus kinase; Tmax=time to maximal concentration; t1/2=half life; TYK=tyrosine kinase.

29.4%

22.0%

36.8%

48.3%*

56.3%**

0%

10%

20%

30%

40%

50%

60%

70%

80%

Placebo(n=51)

ASP015K25 mg(n=59)

ASP015K50 mg(n=57)

ASP015K100 mg(n=58)

ASP015K150 mg(n=64)

Primary Endpoint: ACR20 Response at Week 12

DMARD-IR patients not on MTX

*p<0.05; **p<0.01, based on normal approximation to binomial distribution for difference in proportions.

44.4% 43.9%

61.5%*

46.4%

57.7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Placebo(n=72)

ASP015K25 mg(n=66)

ASP015K50 mg(n=78)

ASP015K100 mg(n=84)

ASP015K150 mg(n=78)

ACR20 Response at Week 12

MTX-IR patients on MTX

Dose-response p-value = 0.201

*p<0.05

50.0%

28.1%

75.0%

54.2%

27.6%

61.5% 61.8%

51.6%

84.6%

35.7%

53.8%

47.1%

60.6%

56.3% 53.8%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

United States Europe Latin America

Placebo ASP015K 25 mg ASP015K 50 mg ASP015K 100 mg ASP015K 150 mg

ACR20 Response at Week 12 by Region

(Pre-specified Analysis)

N=28 N=24 N=34 N=28 N=33 N=32 N=29 N=31 N=39 N=32 N=12 N=13 N=13 N=17 N=13

* *

*p<0.05


• JAK- Inhibition

– Tofacitinib

– Baracitinib


– ASP015k

– Galapagos

Efficacy and Safety of GLPG0634, a Selective JAK1 Inhibitor,

After Short-Term Treatment of Rheumatoid Arthritis: Results

of a Phase 2a Trial

• Double-blind, placebo-controlled phase 2a proof-of-concept

trial of 91 patients with active RA

• Single center in Moldova; study duration 4 wks

• 3 treatment arms

– GLPG0634 200 mg QD (n =12)

– GLPG0634 100 mg BID (n =12)

– PBO (n = 12)

• Patients continued stable background therapy of MTX, low-dose steroids and/or NSAIDs

Vanhoutte FP, et al. Presented at: EULAR Annual Meeting; June 6-9, 2012; Berlin, Germany. Abstract OP0263.

SAFETY AND EFFICACY OF GLPG0634, A SELECTIVE JAK1

INHIBITOR, IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS

OF A 4-WEEK PHASE IIA DOSE RANGING, MULTI-CENTER TRIAL

• Double-blind, placebo-controlled phase 2a proof-of-concept

trial of 91 patients with active RA

• Multinational study duration 4 wks

• 5 treatment arms

– GLPG0634 300 mg QD (n =22)

– GLPG0634 150 mg QD (n =15)

– GLPG0634 75 mg QD (n =22)

– GLPG0634 30 mg QD (n =15)

– PBO (n = 17)

Vanhoutte FP, et al. Presented at: EULAR Annual Meeting; June 6-9, 2012; Berlin, Germany. Abstract OP0263.

Generalizability to all JAK Inhibitors?

• Efficacy?

• Safety?

Enzyme Inhibitors

• JAK- Inhibition

• SYK-Inhibition

• PDE-4-Inhibition

• BTK-Inhibition

• PI3K-Inhibition


– (FMS/c-kit)

– (c-kit inhibitor)

P

SYK

SLP P

Ras

ERK JNK

Rac

Transcription factors

Tissue damage

PKC

PLC

Ca2+

IP3 DAG

Btk P

BCR FcγR/FcεR/DAP-12

Cytokines Lipid mediators Degranulation

P SYK P

P

ITAMs

P

Lyn

Spleen Tyrosine Kinase (SYK)1-6

1. Adapted from Bajpai M, et al. Expert Opin Investig Drugs. 2008;17:641-659. 2. Braselmann S, et al. J Pharmacol Exp Ther. 20063;19:998-1008. 3.

Cha HS, et al. J Pharmacol Exp Ther. 2006;317:571-578. 4. Drexler SK, et al. Arthritis Res Ther. 2008;10:216-227. 5. McInnes IB, et al. Nat Rev

Immunol. 2007;7:429-442. 6. Brennan FM, et al. J Clin Invest. 2008;118:3537-3545.

Small-Molecule Enzyme Inhibitors

• JAK-Inhibition

• SYK-Inhibition

• PDE4-Inhibition

• BTK-Inhibition

• PI3K-Inhibition

• Tyrosine kinase inhibition

– C-FMS

Kinase Inhibitors

• JAK- Inhibition

• SYK-Inhibition


• BTK-Inhibition

• PI3K-Inhibition


– cFMS

– c-kit inhibitor

Bruton’s Tyrosine Kinase (BTK)

Nature Chemical Biology 2011

Kinase Inhibitors

• JAK- Inhibition

• SYK-Inhibition


• BTK-Inhibition

• PI3K-Inhibition


– cFMS

– c-kit inhibitor

Phosphoinositide 3-kinase

Summary

• Intra-cellular kinase pathways can be exploited for therapeutic

purposes in the treatment of RA and other autoimmune diseases

• The current targets with the greatest excitement include:

– JAK

– SYK

– BTK

– PI3K

• Human trials are necessary to fully understand the potential risks

and benefits of these approaches

• Impossible at this point to generalize either response or side effect

profiles based on the selectivity of compounds in a class

New Small Molecule Therapies in Rheumatoid Arthritis · Different Kinase Pathways can be Exploited...

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