Medizinische Klinik m.S. Rheumatologie & Klinische ImmunologieUniversitätsmedizin Charité

cDMARDs and bDMARDs in the

treatment of rheumatoid arthritis

Prof. Dr. Frank Buttgereit

Modified after:

Josef S Smolen, Désirée van der Heijde, Klaus P Machold, Daniel Aletaha, Robert Landewé

Ann Rheum Dis. 2014;73(1):3-5

Disease-modifying antirheumatic drugs (DMARDs)

Synthetic DMARDs (sDMARDs) Biological DMARDs (bDMARDs)

Conventional

synthetic DMARDs

(csDMARDs)

Targeted synthetic

DMARDs (tsDMARDs)

Biological originator

DMARDs (boDMARDs)

Biosimilar

DMARDs

(bsDMARDs)

MTX, Leflunomid, CsA, Tofacitinib INF, ETA, ADA,CTZ, bsINF (i.e.

SSZ, Gold GOL, ABA, TCZ, RTX Remsima)

Proposal for a New Nomenclature of Disease-

Modifying Antirheumatic Drugs

Management of rheumatoid arthritis:

“Hit Hard and Early!“

Symptomatische Behandlung sofort nach Symptombeginn

(NSAR, Coxibe)

Basistherapie (z.B. MTX) innerhalb der ersten Wochen

Glucocorticoide

Kombinationstherapie(z.B. MTX + Leflunomid) nach 3-4 Monaten

Biologikum nach 6-8 Monaten

(anti-TNF, Abatacept, Tocilizumab)

Rituximab

Recommendations

1. Therapy with DMARDs should be started as soon as the diagnosis of RA is made.

2. Treatment should be aimed at reaching a target of remission or low disease activity

in every patient.

3. Monitoring should be frequent in active disease (every 1-3 months); if there is no

improvement by at most 3 months after treatment start or the target has not been

reached by 6 months, therapy should be adjusted.

4. MTX should be part of the first treatment strategy in patients with active RA.

5. In case of MTX contraindications (or early intolerance), sulfasalazine or leflunomide

should be considered as part of the (first) treatment strategy.

6. In DMARD naïve patients, irrespective of the addition of glucocorticoids,

conventional synthetic DMARD monotherapy or combination therapy of

conventional synthetic DMARDs should be used.

7. Low dose glucocorticoids should be considered as part of the initial treatment

strategy (in combination with one or more conventional synthetic DMARDs) for up to

six months, but should be tapered as rapidly as clinically feasible.

EULAR Recommendations for the management of RA

with synthetic and biological disease modifying

antirheumatic drugs – 2013 UPDATE

18% 27%

40%

6%

15%

≤7,5mg (1996) >7,5mg (1996)

<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)

Glucocorticoide55%

50%

49%

20%

11%

38%

3%

6%

26%

14%

60%

17%

9%

61%

11%

13%

45%

0% 10% 20% 30% 40% 50% 60% 70%

Osteoporosemittel

Analgetika

Coxibe

trad. NSAR

parenterales Gold

Sulfasalazin

Biologika

Leflunomid

Methotrexat

1995 2013

Treatment of RA in Germany:

Data from the Kerndokumentation

Methotrexate - a folic acid antagonist

Dosage:

10-20 mg; usually once weekly as a single dose

Adverse effects (selection):

dizziness, nausea, abdominal pain, hepatotoxicity,

ulcerative stomatitis, low white blood cell count,

predisposition to infection, fatigue, acute pneumonitis,

rarely pulmonary fibrosis and kidney failure, teratogenic

Monitoring:

Renal & liver function tests, blood cell count, (X-ray chest)

Risks to be considered:

renal dysfunction, liver disease, active infectious disease,

excessive alcohol consumption, co-medication with

Trimethoprim/sulfamethoxazole, NSAIDs, retinoids …

MTX: „In the 70´s it was experimental. Now it´s the

standard treatment for RA.“; „MTX is now considered

the first-line DMARD agent for most patients with RA.“

Inhibition of the dihydrofolate reductase

Inhibition of synthesis of nucleic acid precursors

→ anti-inflammatory action

Inhibition der AICAR transformylase

Release of the endogenous adenosine

→ anti-inflammatory action

Mechanisms of actions

Methotrexate has only weak effects on the

humoral and cellular immune responses!

The main effect is the inhibition of inflammation !

18% 27%

40%

6%

15%

≤7,5mg (1996) >7,5mg (1996)

<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)

Glucocorticoide55%

50%

49%

20%

11%

38%

3%

6%

26%

14%

60%

17%

9%

61%

11%

13%

45%

0% 10% 20% 30% 40% 50% 60% 70%

Osteoporosemittel

Analgetika

Coxibe

trad. NSAR

parenterales Gold

Sulfasalazin

Biologika

Leflunomid

Methotrexat

1995 2013

Treatment of RA in Germany:

Data from the Kerndokumentation

Disease-modifying therapeutic effects in

rheumatoid arthritis: Glucocorticoids …

... reduce clinical

signs and symptoms

of inflammation

... retard radiographic

progression of the

disease.

EULAR Recommendations for the management of RA

with synthetic and biological disease modifying

antirheumatic drugs – 2013 UPDATE

8. If the treatment target is not achieved with the first DMARD strategy, in the absence of poor

prognostic factors change to another conventional synthetic DMARD strategy should be

considered; when poor prognostic factors are present, addition of a biological DMARD

should be considered.

9. In patients responding insufficiently to MTX and/or other conventional synthetic DMARD

strategies, with or without glucocorticoids, biological DMARDs (TNF-inhibitors*, abatacept or

tocilizumab, and under certain circumstances rituximab) should be commenced with MTX.

10. Patients who have failed a first biological DMARD should be treated with another biological

DMARD; patients who have failed a first TNF-inhibitor therapy, may receive another TNF-

inhibitor or a biologic with another mode of action*.

11. Tofacitinib may be considered after biological treatment has failed.

12. If a patient is in persistent remission, after having tapered glucocorticoids, one can consider

tapering# biological DMARDs§, especially if this treatment is combined with a conventional

synthetic DMARD.

13. In cases of sustained long-term remission, cautious reduction of conventional synthetic

DMARD dose could be considered, as a shared decision between patient and physician.

14. When adjusting therapy, factors apart from disease activity, such as progression of

structural damage, co-morbidities and safety issues, should be taken into account.

18% 27%

40%

6%

15%

≤7,5mg (1996) >7,5mg (1996)

<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)

Glucocorticoide55%

50%

49%

20%

11%

38%

3%

6%

26%

14%

60%

17%

9%

61%

11%

13%

45%

0% 10% 20% 30% 40% 50% 60% 70%

Osteoporosemittel

Analgetika

Coxibe

trad. NSAR

parenterales Gold

Sulfasalazin

Biologika

Leflunomid

Methotrexat

1995 2013

Treatment of RA in Germany:

Data from the Kerndokumentation

0.9

1.5%

2.0%

3.5%

4.9%

9.5%

7.3%

6.0%

6.4%

7.2%

7.1%

7.3%

8.2%

9.1%

1.1

2.5%

3.0%

4.8%

6.0%

7.2%

7.9%

11.2%

13.6%

15.9%

15.5%

16.6%

17.2%

17.3%

0% 5% 10% 15% 20% 25% 30%

2000

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2013

Monotherapie Kombinationstherapie

Treatment of RA in Germany: Data from the

Kerndokumentation – Use of biologics

HUMIRA®

Adalimumab

Enbrel®

Etanercept

Remicade®

Infliximab

Cimzia®

Certolizumab

Simponi®

Golimumab

Orencia®

Abatacept

Mabthera®

Rituximab

RoActemra®

Tocilizumab

Firma

Struktur

MolekülVollhumaner

Monoklonaler

Antikörper

Vollhumanes

Fusionsprotein

Chimärer

Monoklonaler

Antikörper

Humanisiertes

PEGyliertes Fab-

Fragment

Vollhumaner

Monoklonaler

Antikörper

Vollhumanes

Fusionsprotein

Chimärer

Monoklonaler

Antikörper

Humanisierter

Monoklonaler

Antikörper

Target TNF-α TNF-α TNF-α TNF-α TNF-α T Zelle B Zelle IL-6R

Dosierung40 mg

a2W

50 mg 1/W

or

25 mg 2/W

Bolus: 3mg in Woche 0,2,6

3–7.5 mg/kg

alle 6-8 Wochen

Bolus: 400mg in Woche 0,2,4

200 mg a2W

50 mg

Monatlich

Bolus: wks 0,2,4

10mg/kg

Monatlich

1000mg a2W

Insfusionen erfolgen bei

Bedarf

8mg/kg

Monatlich

DarreichungSC

(FeSpr, PEN)

SC

(FeSpr, Pen)

120 min

Infusion

SC

(FeSpr)

SC

(FeSpr, Pen)

30 min

Infusion

195–255 min

Infusion60 min Infusion

Zulassung 09/2003 02/2000 08/1999 (CD) 10/2009 10/2009 05/2007 03/2006 02/2009

* *

* Abatacept (Orencia®) and Tocilizumab (RoActemra®) are meanwhile also

available for subcutaneous administration.

Biologics used in the RA treatment

Etanercept: Mechanism of action

Mechanisms in Rheumatology ©2001

Click here to run the animation

Mechanisms in Rheumatology ©2001

Infliximab: Mechanism of action

Click here to run the animation

MINT/REMS-15006 Date of preparation: February 2015

Remsima® is licensed by the EMA for use in a number of chronic inflammatory diseases

• Rheumatoid arthritis

• Adult Crohn’s disease

• Paediatric Crohn’s disease

• Ulcerative colitis

• Paediatric ulcerative colitis

• Ankylosing spondylitis

• Psoriatic arthritis

• Psoriasis

Celltrion Healthcare. Remsima 100 mg powder. Summary of product characteristics.

Please refer to the Remsima® summary of product characteristicsfor specific information relating to each indication

EMA, European Medicines Agency.

MINT/REMS-15006 Date of preparation: February 2015

PLANETRA: Study design

Double-blind phase Open-label phase

Remsima® 3mg/kg at weeks 0,2,6, then every 8 weeksMTX 12.5 – 25 mg, weekly(n = 302)

Remsima® 3mg/kg (n = 302)

Remicade® 3mg/kg at weeks 0,2,6, then every 8 weeksMTX 12.5 – 25 mg, weekly(n = 304)

0 14 30 54 78 102Week:

Assessments:

Randomisation(N = 606)

Completed double-blind phase (N = 455)

MTX, methotrexate.Yoo DH, et al. Ann Rheum Dis 2013;72:1613-20.Yoo DH, Arthritis Rheum 2013;72(Suppl 3):73. Abstract #OP0068.Yoo DH, et al. Arthritis Rheum 2013;65:3319-3329 [abstract L1].

MINT/REMS-15006 Date of preparation: February 2015

PLANETRA: Efficacy

60.9

76.8

58.6

77.5

0

20

40

60

80

100

Week 30 Week 54

ACR20 response

Res

po

nse

rat

e, %

Redrawn from Yoo DH, et al. Ann Rheum Dis 2013;72:1613-20.Yoo DH, et al. Arthritis Rheum 2013;65:3319-3329 [abstract L1].

Remsima® Remicade®

• ACR20 response at Weeks 30 and 54

*

*Baseline data from PLANETRA extension study.ACR, American College of Rheumatology.

Biologics used in the RA treatment

HUMIRA®

Adalimumab

Enbrel®

Etanercept

Remicade®

Infliximab

Cimzia®

Certolizumab

Simponi®

Golimumab

Orencia®

Abatacept

Mabthera®

Rituximab

RoActemra®

Tocilizumab

Firma

Struktur

MolekülVollhumaner

Monoklonaler

Antikörper

Vollhumanes

Fusionsprotein

Chimärer

Monoklonaler

Antikörper

Humanisiertes

PEGyliertes Fab-

Fragment

Vollhumaner

Monoklonaler

Antikörper

Vollhumanes

Fusionsprotein

Chimärer

Monoklonaler

Antikörper

Humanisierter

Monoklonaler

Antikörper

Target TNF-α TNF-α TNF-α TNF-α TNF-α T Zelle B Zelle IL-6R

Dosierung40 mg

a2W

50 mg 1/W

or

25 mg 2/W

Bolus: 3mg in Woche 0,2,6

3–7.5 mg/kg

alle 6-8 Wochen

Bolus: 400mg in Woche 0,2,4

200 mg a2W

50 mg

Monatlich

Bolus: wks 0,2,4

10mg/kg

Monatlich

1000mg a2W

Insfusionen erfolgen bei

Bedarf

8mg/kg

Monatlich

DarreichungSC

(FeSpr, PEN)

SC

(FeSpr, Pen)

120 min

Infusion

SC

(FeSpr)

SC

(FeSpr, Pen)

30 min

Infusion

195–255 min

Infusion60 min Infusion

Zulassung 09/2003 02/2000 08/1999 (CD) 10/2009 10/2009 05/2007 03/2006 02/2009

* *

* Abatacept (Orencia®) and Tocilizumab (RoActemra®) are meanwhile also

available for subcutaneous administration.

gp130 gp130

Classical membrane signalling Trans-signalling

IL-6 IL-6

Mihara M, et al. Int Immunopharmacol 2005; 5:1731–1740.

mIL-6R sIL-6R

Tocilizumab is a humanised anti-IL-6Rmonoclonal antibody that inhibits IL-6R signalling

Dayer J-M & Choy E. Rheumatology 2010; 49:1524.1Smolen J, et al. Nat Rev Drug Disc 2003; 2:473488.

Synoviocytes

Osteoclast activation

Bone resorption

Endothelial cells

VEGF

Pannus formation

Joint destruction

Mediation of chronic

inflammation

IL-6Macrophage

T-cell

B-cell

Neutrophil

Antibody

production

MMPs1

RANKL

Articular effects of IL-6 in RA

Dayer J-M & Choy E. Rheumatology 2010; 49:1524.

IL-6

The acute-phase

response

Anaemia

Hypothalamic-

pituitary-adrenal

(HPA) axis

Acute-phase

proteins (e.g. CRP)

Hepcidin productionAlterations in iron

homeostasis

Systemic osteoporosis

Increased

cardiovascular

risk

Thrombocytosis

Fatigue

Systemic effects of IL-6 in RA

Inflammation

Efficacy and safety of subcutaneous tocilizumabversus intravenous tocilizumab in combination with traditional DMARDs in patients with RA at

week 97 (SUMMACTA)

Burmester GR, Rubbert-Roth A, Cantagrel A, et al.

Ann Rheum Dis. 10 May 2015.

[Epub ahead of print]

Study design

All patients received ≥1 dose of study drug and were eligible for inclusion in the intent-to-treat and safety populations

Randomization(n = 1262)

TCZ-SC 162 mg qw + Placebo-IV

q4w(n = 631)

TCZ-IV 8 mg/kg q4w + Placebo-

SC qw(n = 631)

Completed and Re-Randomized

at week 24 (n=572)

Completed and Re-Randomized

at week 24 (n=564)

TCZ-SC 162 mg qw

TCZ-IV 8 mg/kg q4w

TCZ-SC 162 mg qw

TCZ-IV 8 mg/kg q4w

Baseline Week 24 Week 25 Week 49 Week 97

24-week DB period 1-week Dose Interruption

72-week Open Label extension

(n = 524)

(n = 48)

(n = 186)

(n = 377)

(n = 445)

(n = 40)

(n = 160)

(n = 311)

Burmester GR, Rubbert-Roth A, Cantagrel A, et al. Ann Rheum Dis. 10 May 2015. [Epub ahead of print]

n= 517 517 516 499 445n= 365 368 371 354 317n= 182 185 186 177 162n= 46 45 47 44 39

ResultsDAS28 remission and HAQ-DI response

The proportion of patients retaining DAS28 remission was similar in all groups at week 24 and was maintained to week 97. The proportions of patients who achieved HAQ-DI

response at week 97 were comparable between TCZ-SC and TCZ-IV arms

Burmester GR, Rubbert-Roth A, Cantagrel A, et al. Ann Rheum Dis. 10 May 2015. [Epub ahead of print]

TCZ-SC qw (n=521)TCZ-IV q4w (n=372)

9749241202

100

90

80

70

60

50

40

30

20

10

0

Pat

ien

ts w

ho

ach

ieve

d

DA

S28

<2

.6 (

%)

Weekn= 505 516 517 498 446n= 354 364 370 352 306n= 174 183 185 176 162n= 45 46 47 45 40

TCZ-IV-SC (n=186)TCZ-SC-IV (n=48) 100

90

80

70

60

50

40

30

20

10

0

Pat

ien

ts w

ho

ach

ieve

d a

dec

reas

eo

f ≥0

.3 in

HA

Q-D

I sco

re (

%)

974902 2412Week

TCZ-SC qw (n=521)TCZ-IV q4w (n=372)

TCZ-IV-SC (n=186)TCZ-SC-IV (n=48)

HAQ-DI

http://www.phusewiki.org

Patients reporting clinically relevant

improvement in PROs from BL to WK 52

Burmester et al. EULAR 2014, Poster SAT0226

Numerically higher proportions of patients in TCZ groups vs. MTX group reported improvement ≥MCID from BL to WK 52 re. HAQ-DI, SF-36 PCS and MCS, FACIT-Fatigue, and Patient Pain and Patient Global Assessment of Disease Activity VAS

SF 36

Question (numbers) Scale

3a-j Physical Functioning (PF)

4a-d Role Physical (RP)

7,8 Bodily Pain (BP)

1, 11a-d General Health (GH)

9a, 9e, 9g, 9i Vitality Energy Fatigue (VT)

6,10 Social Functioning (SF)

5a-c Role Emotional (RE)

9b, 9c, 9d, 9f, 9h Mental Health (MH)

PHYSICAL HEALTH

MENTAL HEALTH

The SF-36 (Short form with 36 questions)

quantifies health-related quality of life

is not disease specific

has 8 dimensions

Physical Functioning (PF)

Role Physical (RP)

Bodily Pain (BP)

General Health (GH)

Vitality Energy Fatigue (VT)

Social functioning (SF)

Role Emotional (RE)

Mental Health (MH)

Age/gender matched

population = reference

Week 16Baseline

0

20

40

60

80

100

RAPID 1

Mean changes in health-related quality of life

(SF-36): Therapeutic effects after 16 weeks

EULAR Recommendations for the management of RA

with synthetic and biological disease modifying

antirheumatic drugs – 2013 UPDATE

8. If the treatment target is not achieved with the first DMARD strategy, in the absence of poor

prognostic factors change to another conventional synthetic DMARD strategy should be

considered; when poor prognostic factors are present, addition of a biological DMARD

should be considered.

9. In patients responding insufficiently to MTX and/or other conventional synthetic DMARD

strategies, with or without glucocorticoids, biological DMARDs (TNF-inhibitors*, abatacept or

tocilizumab, and under certain circumstances rituximab) should be commenced with MTX.

10. Patients who have failed a first biological DMARD should be treated with another biological

DMARD; patients who have failed a first TNF-inhibitor therapy, may receive another TNF-

inhibitor or a biologic with another mode of action*.

11. Tofacitinib may be considered after biological treatment has failed.

12. If a patient is in persistent remission, after having tapered glucocorticoids, one can consider

tapering# biological DMARDs§, especially if this treatment is combined with a conventional

synthetic DMARD.

13. In cases of sustained long-term remission, cautious reduction of conventional synthetic

DMARD dose could be considered, as a shared decision between patient and physician.

14. When adjusting therapy, factors apart from disease activity, such as progression of

structural damage, co-morbidities and safety issues, should be taken into account.

… …

…

…

…

Baricitinib

- Oral, reversible inhibitor of JAK-1 and JAK-2- Inhibition of proinflammatory cytokines

IL6 - JAK1/JAK2 or JAK1/TYK2IL-23 - JAK2/TYK2IL12 - JAK2/TYK2INFg - JAK1/JAK2INF/ß - JAK1/TYK2

- In vitro selectivity for JAK1/JAK2 (IC50)JAK1/JAK2 ca. 2-5nMTYK2 ca. 53nM JAK3 ca. 560nM

- Development for RA and other autoimmune diseases

According to Wikipedia

Baricitinib Phase 3 RA Program1

1. http://origin-qps.onstreammedia.com/origin/multivu_archive/ENR/Lilly_v12_infographic.pdf

2. http://clinicaltrials.gov/ct2/show/NCT01721044

cDMARD = Conventional DMARD; DMARD = Disease-Modifying Antirheumatic Drugs; IR = Inadequate Response; MTX = Methotrexate; RA = Rheumatoid Arthritis; TNFi = Tumor Necrosis Factor Inhibitor

3. http://clinicaltrials.gov/ct2/show/NCT017210574. http://clinicaltrials.gov/ct2/show/NCT017103585. http://clinicaltrials.gov/ct2/show/NCT02265705

6. http://clinicaltrials.gov/ct2/show/NCT017113597. http://clinicaltrials.gov/ct2/show/NCT01885078

RA-BEAM Studydesign

Key inclusion criteria− Inadequate response to

MTX− ≥3 erosions1

− Stable background MTX− ≥6/68 tender joints− ≥6/66 swollen joints− hsCRP ≥6 mg/L

Key exclusion criteria− Prior bDMARD use

Randomization Primary

(ACR20)

Follow-up

W0 W12 W52 W56W24

• At Week 16 or subsequent visits, inadequate responders rescued to baricitinib 4 mg QD

• At Week 24, non-rescued patients in the placebo group were switched to baricitinib 4 mg QD

• At Week 52, patients could enter long-term extension study or 28-day post-treatment follow-up

1. Patients with 1-2 erosions could enroll if RF or ACPA positive

NCT01721057 @ clinicaltrials.gov

Baricitinib in MTX-IR RA pts

Adalimumab 40 mg Q2W (N=330)(background MTX)

Baricitinib 4 mg QD (N=487)(background MTX)

Placebo QD (N=488)(background MTX)

Baricitinib 4 mg QD(background MTX)

Taylor PC., Oral Presentation at ACR-Congress 2015, San Francisco, 6-11 November, Late breaking Abstract Number 2L

3:3:2

0

20

40

60

80

40

70

61

17

45

35

5

19

13

37

74

66

19

51

45

8

30

22

***

***

***

***

***

***

***

***

***

***

***

***

+

+

++

+

+

71

62

56

47

37

31

++

++

ACR Response rates

Placebo Baricitinib 4 mg Adalimumab

Week 12 Week 24

% P

atien

ts (

NR

I)

ACR20 ACR50 ACR70

Baricitinib in MTX-IR RA pts

vs. placebo

***p≤.001

**p≤.01

*p≤.05

Primary endpoint = ACR20 for baricitinib 4 mg vs. placebo at Week 12

Patients who were rescued or permanently discontinued were imputed thereafter as non-responders

vs. adalimumab++p≤.01

+p≤.05

Week 52

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

Taylor PC., Oral Presentation at ACR-Congress 2015, San Francisco, 6-11 November, Late breaking Abstract Number 2L

Electronic Daily Diary PROs Baricitinib in MTX-IR RA pts

Week

0 2 4 6 8 10 12

Med

ian

, m

inu

tes

0

10

20

30

40

50

60

70

80

90 Placebo

Baricitinib 4 mg Adalimumab

Duration of Morning Joint StiffnessA

***

***

***

***

***

***

***

***

+

***

+

Week

0 2 4 6 8 10 12

LS

Me

an

, N

RS

0-1

0

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Severity of Morning Joint Stiffness

***

***

***

B

**

***

***

***

++

+++

***

++

***

***

Week

0 2 4 6 8 10 12

LS

Me

an

, N

RS

0-1

0

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Worst TirednessC

******

***

*****

+

**

+

***

***

***

***

Week

0 2 4 6 8 10 12

LS

Me

an

, N

RS

0-1

0

2.0

2.5

3.0

3.5

4.0

4.5

5.0

5.5

6.0

Worst PainD

***

***

***

***

******

***

**

+++

+++

***++

+++

***

Duration of Morning Joint StiffnessM

ed

ian

, m

inu

tes

Week Week

Severity of Morning Joint Stiffness

LS

Me

an

, N

RS

0-1

0

Week

LS

Mean, N

RS

0-1

0

Worst Joint Pain

Week

LS

Me

an

, N

RS

0-1

0

Worst Tiredness

vs. placebo ***p≤.001

**p≤.01

*p≤.05

vs. adalimumab+++p≤.001

++p≤.01+p≤.05

Pts recorded these measures in a daily diary; MJS severity, worst joint pain, and worst tiredness were recorded using a numeric rating scale (0-10), higher score indicates worse state

Taylor PC., Oral Presentation at ACR-Congress 2015, San Francisco, 6-11 November, Late breaking Abstract Number 2L

Patient-Level Changes in van der HeijdemTSS at Week 52

Baricitinib in MTX-IR RA pts

vs. placebo

***p≤.001

**p≤.01

*p≤.05

0 20 40 60 80 100

-10

0

10

20

30

40

50

Cumulative Percentile (%)

Δfr

om

baselin

e

Placebo

Baricitinib 4 mg

Adalimumab

ΔmTSSPlacebo

(N=452)

Bari 4 mg

(N=473)

ADA

(N=312)

≤0 70.4 79.1** 81.1**

≤0.5 70.4 85.2*** 86.5***

≤SDC (1.98) 78.8 91.5*** 92.0***

% Patients with no progression

SDC=smallest detectable change

Linear extrapolation used to impute after rescue, switch, or discontinuation. N = number of patients in the analysis.

Taylor PC., Oral Presentation at ACR-Congress 2015, San Francisco, 6-11 November, Late breaking Abstract Number 2L

Inhibition of radiographic progression

comparable with adalimumab

Safety Baricitinib vs. AdalimumabWeeks 0-24 Weeks 0-52

Placebo(N=488)

Bari 4 mg(N=487)

ADA(N=330)

Bari 4 mg(N=487)

ADA(N=330)

SAEsa 22 (5) 23 (5) 6 (2) 38 (8) 13 (4)

Serious infections 7 (1) 5 (1) 2 (<1) 10 (2) 5 (2)

AEs study discontinuation 17 (3) 24 (5) 7 (2) 36 (7) 13 (4)

AEs temporary interruption 45 (9) 48 (10) 29 (9) 72 (15) 38 (12)

TEAEs 295 (60) 347 (71) 224 (68) 384 (79) 253 (77)

Infections 134 (27) 176 (36) 110 (33) 233 (48) 145 (44)

Herpes zoster 2 (<1) 7 (1) 4 (1) 11 (2) 5 (2)

TB 0 0 1 (<1) 0 1 (<1)

Malignancies 3 (<1) 2 (<1) 0 3 (<1) 0

NMSC 1 (<1) 0 0 0 0

Breast cancer 1 (<1) 1 (<1) 0 1 (<1) 0

Lung squamous cell 0 1 (<1) 0 1 (<1) 0

Ovarian cancer 1 (<1) 0 0 0 0

Clear cell renal cell carcinoma 0 0 0 1 (<1) 0

Lymphoproliferative disorder 0 0 1 (<1) 0 1 (<1)

MACE 0 1 (<1) 0 2 (<1) 1 (<1)

Baricitinib in MTX-IR RA pts

Data displayed are n (%) patients, up to the time of rescue. aSAEs reported using conventional ICH definitions. No lymphoma or GI perforation was

observed. MACE was defined as CV death, MI or stroke positively adjudicated by the independent CV evaluation committee. 2 esophageal candidiasis

(bari 4 mg) were reported. Taylor PC., Oral Presentation at ACR-Congress 2015, San Francisco, 6-11 November, Late breaking Abstract Number 2L

Conclusions• Baricitinib Phase 3 Study-Program with more than 3000 patients

• Significant improvement (ACR –Response, remission, LDA) in various cohorts ofRA patients with a fast onset of action

• Inhibition of radiographic progression comparable with adalimumab, 3 studieswith data for inhibition radiographic progression (RA-BEGIN, RA-BUILD, RA-BEAM)

• Clinical effectiveness in monotherapy comparable with MTX Combo (RA-BEGIN)

• Significant improvement in Patient-Reported Outcomes (PRO)

• Safety-Profile: small increase of Herpes Zoster, no opportunistic infections, nocase of Tuberculosis, no increased incidence of malignoms, no increasedincidence of MACE

Vielen Dank!

Efficacy and safety of tofacitinib followinginadequate response to conventional

synthetic or biological disease-modifying antirheumatic drugs *

Charles-Schoeman C, Burmester G, Nash P et al.

Annals of the Rheumatic Diseases. 2015 Aug 14. 2015;0:1–9. doi:10.1136/annrheumdis-2014-207178

[Epub ahead of print]

* This study included four Phase II studies and five Phase III studies

ACR20 response at month 3

In both bDMARD-naive and bDMARD-IR patients, a significantly (p<0.05) greater proportion of patients in the tofacitinib 5 mg BID group versus placebo achieved

ACR20 response rates at month 3

***p<0.0001 versus placebo

Charles-Schoeman C, Burmester G, Nash P et al. Annals of the Rheumatic Diseases. 2015 Aug 14. 2015;0:1–9.

bDMARD-naïve bDMARD-IR

70

60

50

40

30

20

10

0

AC

R2

0 r

esp

on

se r

ate

(95

% C

I) %

n/N= 169/638 629/1043 705/1066

26.5

60.3***

66.1***

47/191 112/258 130/251

24.6

43.4***

51.8***

placebo 5 mg tofacitinib BID 10 mg tofacitinib BID

Month 3 LS mean change from baseline (95% CI)

LS mean changes from baseline at month 3 in HAQ-DI and DAS28-4(ESR) were significantly (p<0.05) higher for tofacitinib 5 mg twice daily versus placebo

Charles-Schoeman C, Burmester G, Nash P et al. Annals of the Rheumatic Diseases. 2015 Aug 14. 2015;0:1–9.

0.0

-0.1

-0.2

-0.3

-0.4

-0.5

-0.6

-0.7

LS m

ean

(9

5%

CI)

ch

ange

fro

m

bas

elin

e in

HA

Q-D

I

N

-0.14

581 996 1008

-0.46***

-0.54***

169 236 230

-0.09

-0.31***

-0.42***

bDMARD-naïve bDMARD-IR

-0.78

511 877 873

-1.90***-2.13***

156 213 207

-0.67

-1.62***

-1.98***

bDMARD-naïve bDMARD-IR

LS m

ean

(9

5%

CI)

ch

ange

fro

m

bas

elin

e in

DA

S28

-4(E

SR)

0.0

-0.5

-1.0

-1.5

-2.0

-2.5

placebo 5 mg tofacitinib BID 10 mg tofacitinib BID

HAQ-DI DAS28-4(ESR)

Vielen Dank!

Medizinische Klinik m.S. Rheumatologie & Klinische ImmunologieUniversitätsmedizin Charité

JAK/STAT-Inhibitoren:Wo liegt der künftige Stellenwert?

Prof. Dr. Frank Buttgereit

Window of

opportunity

Kra

nkh

eit

s-

beg

inn

Früh Etabliert Endstadium

50% der Patienten

haben radiologische

Veränderungen

innerhalb der

ersten 2 Jahre!

Frühe intensive Therapie der RA

extraartikuläre

Manifestationen

systemische

Entzündung

Lymphomrisiko

kardiovask. Risiko

frühe Invalidisierung

Lebenserwartung (~7 J.)

ModerneTherapie der Rheumatoiden Arthritis

“Hit Hard and Early!“

Symptomatische Behandlung sofort nach Symptombeginn

(NSAR, Coxibe)

Basistherapie (z.B. MTX) innerhalb der ersten Wochen

Glucocorticoide

Kombinationstherapie(z.B. MTX + Leflunomid) nach 3 - 4 Monaten

Biologikum nach 6 - 8 Monaten

(anti-TNF, Abatacept, Tocilizumab)

Rituximab

„Therapeutische Lücke“ bei RA

90

80

70

60

50

40

30

20

10

0

0 2 324 8 12 16 20 24 40 48 52

time (weeks)

Unmet medical need

Anti-TNF + MTX

Anti-TNF alone

MTX alone

AC

R70 R

esp

on

ders

(%

)

Modified from Klareskog et al. Lancet 2004

Neue Behandlungsansätze

Bisherige therapeutische Ansätze in der RA

van Vollenhoven RF. Nat Rev Rheumatol 2009;5:531–41

58

Infliximab: Wirkungsmechanismus

Mechanisms in Rheumatology ©

Neue Behandlungsansätze greifen an intrazellulären Signalwegen an

60

Rheumatoide

Arthritis1

Biologics

beinflussen Zytokine und

extrazelluläre Signale2

Small molecules

greifen an intrazellulären

Signalwegen an 3

IL=interleukin; JAK=Janus kinase; STAT=signal transducer and activator of transcription; TNF=tumor necrosis factor. 1. Smolen JS, Steiner G. Nat Rev Drug Discov. 2003;2:473-488. 2. Costenbader KH, et al. J Fam Pract. 2007;56:S1-S7; 3. Ghoreschi K, et al. Immun Rev. 2009;228:273-287. Figure adapted from Smolen JS, Steiner G. Nat Rev Drug Discov. 2003;2:473-488; Costenbader KH, et al. JFP. 2007;56:S1-S7; and Shuai K, et al. Nat Rev Immunol. 2003;3:900-911.

Dendriticsche

Zelle

T Zelle

B Zelle

Macrophage

Zytokine

IL-1,IL-6

TNF

Rheumafaktor

und andere

Antiörper

Co-Stimulation

Zytoplasma

Kinasen

ZellkernGen Transcription

Zytokine

Immun-und Entzündungsreaktionen: Die treibenden Kräfte in der Pathogenese der RA

Normal RA

Plasmazellen

Pannus

Bildung

Dendritische ZellenMakrophagen

Neutrophile

Mastzellen

Synoviozyten

Zellen des angeborenen und

adativen Immunsystems

Extensive

Angiogenese

B Zellen

T Zellen

Otero M, et al. Arthritis Res Ther. 2007:9;220; 2. Schett G, et al. Arthritis Rheum. 2008;58:2936-2948.Figure adapted from Strand V, et al. Nat Rev Drug Disc. 2007;6:75-92.

Aktivierte

Immunzellen

Zytokine

Immunzellen

RA

1. Otero M, et al. Arthritis Res Ther. 2007; 2. Schett G, et al. Arthritis Rheum. 2008; Figure adapted from Strand V, et al. Nat Rev Drug Disc. 2007.

Aktivierte Immunzellen

Zytokine

Immunzellen

Aktivierte Zellen

produzieren Zytokine

1Die Zytokine aktivieren

diese Zellen durch

verschiedene Signalwege

2

Dadurch wird die

Produktion weiterer pro-

inflammatorischer Zytokine

induziert

3

Dies führt zu

einer weiteren Rekrutierung

und Aktivierung von Zellen

4

Immun-und Entzündungsreaktionen: Die treibenden Kräfte in der Pathogenese der RA

Zytokin-

Rezeptoren

Zytokine regulieren viele biologische Prozesse

SCF, IL-3, TPO, EPO,

GM-CSF, G-CSF, M-CSF

Hematopoetisch

PDGF, EGF, FGF, IGF,

TGFβ, VEGF

Wachstum/Differenzierung

TGFβ, IFNγ, IL-2, IL-4,

IL-5, IL-7, IL-9, IL-10, IL-11,

IL-12, IL-13, IL-15, IL-16,

IL-17, IL-18, IL-232

Immunoregulatorisch

IL-1α, IL-1β, TNF, LT,

IL-6, LIF, IL-17, IL-182,

IL-333

Pro-inflammatorisch

IL-1RA, IL-4, IL-10, IL-13

Anti-inflammatorisch†

IL-8, MIP-1α, MIP-1β,

MCP-1, RANTES

Chemotaktisch

*The definition of cytokine function is ever-changing, with many cytokines playing multiple roles.†Some cytokines, such as IL-4, IL-10 and IL-13, can be either pro -or anti-inflammatory, depending on the environment and circumstances.1. Arend WP. Arthritis Rheum. 2001;45:101-106; 2. Murphy K, et al. Janeway’s Immunobiology. 7th ed. NY: Garland; 2008; 3. Hsu C-L, et al. PLOS One. 2010;5:E11944.

63

Zytokin-RezeptorklassenZytokine vermitteln Informationen an Zelle über spezifische Rezeptoren

ChemokineToll/IL-1 TGFβTNFTyp I/II

Zytokine

Rezeptor

Tyrosin

Kinase

Trimeres

Protein,

normalerweise

mit der

Zelloberfläche

assoziiert

Rezeptor Serin/

Threonin

Kinase

G-protein-

gekoppelte

Rezeptorfamilie

Enzyme-

gekoppelte

Rezeptoren

spezifisch für

Thyrosinreste

Heterodimerer

oder

homodimerer

Rezeptor

Tyrosinkinase

Single-pass

Membran -

Rezeptoren mit

Toll-IL-1

Rezeptor-

domänen

Adapted from Baker SJ, et al. Oncogene. 2007;26:6724-6737 and; Murphy K, et al. Janeway’s Immunobiology. 7th ed. NY: Garland Science Publishing; 2008.

64

Zytokine benutzen unterschiedliche intrazelluläre Signalwege

ZytoplasmaZellkern

Kinases

Kinases

p38

JNKERK

Syk

IKK

NFκB

JAKJAK

STAT

STAT

STAT

STAT

ERK=extracellular signal related kinases; IKK=inhibitor of kappaB kinase; JAK=Janus kinase; JNK=c-Jun N-terminal kinase; MAPK=mitogen-activated

protein kinase; NFκB=nuclear factor kappa B; PI3K=Phosphoinositide 3-kinase; STAT=signal transducer and activator of transcription;

Syk=spleen tyrosine kinase.

Adapted from Mavers M, et al. Curr Rheum Rep. 2009;11:378-385 and Rommel C, et al. Nat Rev Immunol. 2007;7:191-201.

Gen Transkription

PI3K

PI3KPI3K

Lipid

messengers

Second

messengers

MAPK

Signalweg

SYK

Signalweg

NFKB

SignalwegJAK

Signalweg

PI3K

Signalweg

PI3K

Zell-

menbran

Syk (spleen tyrosine kinase) pathway

• wichtige Rolle in der Immunrezeptor

vermittelten Aktivierung von MAPK in

Immunzellen.

JAK (Janus kinase) pathway

• Wichtig für Entwicklung, Überleben

Proliferation und Differenzierung von

Immunzellen, sowie für die Vermittlung der

entzündlichen Immunantwort

PP

P

Der JAK/STAT Signalweg

JAK JAK

Zytokin

gb

PPP

STA

T

STA

T

STA

T

STA

T

P

P

mRNA

Die Bindung von Cytokinen an

die Zelloberflächen-Rezeptoren führt

zur Rezeptor-Polymerisation und

Autophosphorylierung der damit

verbundenen JAKs

1

Aktivierte JAKs phosphorylieren

den Rezeptor2

Aktivierte JAKs phosphorylieren STATs, die dimerisieren in den Kern wandern

und die Gen-Transkription aktivieren3

Zentrale Bedeutung des JAK/STAT SignalwegSignaling verschiedener Zytokine über den JAK/STAT Signalweg1

STAT4, 3

STAT1, 3, 5, 6

JAK

1

JAK

3

JAK

1

JAK

2

JAK

2

JAK

2

gc Zytokine(IL-2, IL-4, IL-7,

IL-9, IL-15, IL-21)

IL-6

IFNγ

EPO,TPO

GM-CSFIL-23

IL-12

JAK

2

TY

K2

STAT1, 3

STAT3, 5

6 STAT

Proteine

Regulierte Immunzellen2

T Zellen B Zellen Makrophagen

JAK

1

TY

K2

Type I IFNs

IL-10

STAT1, 2, 3, 4

EPO=erithropoetin; GM-CSF=granulocyte/macrophage colony stimulating factor; IFN=interferon; IL=interleukin; JAK=Janus kinase; STAT=signal transducer and activator of transcription; TPO=thrombopoietin; TYK2=tyrosine kinase 2.

1. O’Sullivan LA, et al. Mol Immunol. 2007;44:2497-506; 2. Murray PJ. J Immunol. 2007;178:2623-2629. Figure adapted from Riese RJ, et al. Best Pract Clin Res Rheumatol. 2010;24:5113-526.

4 JAKsJAK JAK

STAT

PSTAT

PSTAT

P

• Wachstum/

Reifung von

Lymphozyten

• Differenzierung/

Homeostase von

T-Zellen, NK-

Zellen

• Entzündung

• Antiviral

• Entzündung

FU

NK

TIO

N3 • Erythropoese

• Myelopoese

• Bildung von

Megakaryozyten/

Plättchen

• Wachstum

• Angeborene

Immunantwort

• Differenzierung

/ Proliferation

von Th17-

Zellen

• Entzündung

• Antiviral

• Entzündung

Zentrale Bedeutung des JAK/STAT SignalwegSignaling verschiedener Zytokine über den JAK/STAT Signalweg1

STAT1, 3, 5, 6

JAK

1

JAK

3

gc Zytokine(IL-2, IL-4, IL-7,

IL-9, IL-15, IL-21)

• Wachstum/

Reifung von

Lymphozyten

• Differenzierung/

Homeostase von

T-Zellen, NK-

Zellen

• Entzündung

GH=growth hormone.1. Murray P. J Immunol. 2007;178:2623-2629; 2. Ghoreschi K, et al. Immunol Rev. 2009;228:273-287.

JAK1 und JAK3 sind notwendig für diejenigen

Zytokinrezeptoren, die eine gemeinsame γ-

Kette haben:

Cytokine signalling pathways relevant to RA

CYTOPLASM

NUCLEUS

Kinases

Kinases

p38

JNKERK

Syk

IKK

NFκB

JAKJAK

STAT

STAT

STAT

STAT

Gene transcription

PI3K

PI3KPI3K

Lipid

messengers

Second

messengers

MAPK

signalling

cascade

Syk (& BTK)

signalling

cascade

NFKB

signalling

cascadeJAK

signalling

cascade

PI3K

signalling

cascade

PI3K

BTK

Adapted from Mavers M, et al. Curr Rheum Rep 2009;11:378–385; Rommel C, et al. Nat Rev Immunol 2007;7:191–201.

Oral Compounds in Development for

Rheumatoid Arthritis

Fostamatinib(R788)

LY3009104(INCB28050)

VX-509 GLPG0634Tofacitinib(CP-690,550)

Class Syk inhibitor JAK inhibitor JAK inhibitor JAK inhibitor JAK inhibitor

Company AstraZeneca/

Rigel

Incyte/Eli Lilly Vertex Galapagos Pfizer

Stage Phase 3 Phase 2 Phase 2 Phase 2 Regulatory

review

Administr. Oral Oral Oral Oral Oral

Dosing* BID/QD QD BID/QD BID/QD BID

*Preliminary dosing only; dosing studies are ongoing

BID, twice daily; QD, once daily.

*

* EMA: under review

FDA approval November 2012:

Tofacitinib (CP-690,550)

• Struktur von Tofacitinib und ATP

• Tofacitinib ist ein reversibler competitor der

ATP Bindungsstelle der Janus Kinasen

N

N

N

HN

NN

O

CN

CP-690550

C16H20N6O•C6H8O7

Molekulargewicht (Salz): 504.5 Da

Hemmung des JAK/STAT Signalwegs

JAK JAK

Zytokin

gb

STA

T

STA

T

mRNA

Tofacitinib (CP-690,550):

RA Phase 3 Studienprogramm

IR = inadequate responders

At Month 3, all placebo patients blindly advanced to tofacitinib 5 or 10 mg BID

Primary endpoints

• ACR20 response (Month 3; vs placebo)

• Change from baseline in HAQ-DI (Month 3; vs placebo)

• Rate of patients achieving DAS28-4(ESR) <2.6 (Month 3; vs placebo)

• Safety and tolerability (Months 0-6)

Key secondary endpoints at all visits

• ACR20/50/70 and DAS28-4(ESR) assessments

5 mg BID + MTX (n=133)

5 mg BID + MTX (n=66)

10 mg BID + MTX (n=134)

5 mg BID + MTX (n=133)

10 mg BID + MTX (n=134)

10 mg BID + MTX (n=66)

Placebo + MTX (n=66)

Placebo + MTX (n=66)

Month 6

Study endMonth 3Day 1 Randomization

Burmester et al, Lancet, 2013

Einsatz von Tofacitinib bei TNF-IR

Patienten mit RA: ORAL-Step

Oral STEP: Medikation vor Studienbeginn

0

5

10

15

20

25

30

35

40

45

ORAL Step: ACR Ansprechen zu den

Monaten 3 und 6

Patients

, %

0

10

20

30

40

50

60

***

*

24.43

n= 32/131 n= 55/132 n= 64/133

41.67

48.12

Tofacitinib 10 mg BID

Placebo

Tofacitinib 5 mg BID

Months

0.5

***

***

******

**

*0 1 3 6

Tofacitinib 5 mg BID Tofacitinib 10 mg BIDPlacebo5 mg Placebo10 mg

Pa

tie

nts

, %

***

*****

Months

0.5 1 3 60

Pa

tie

nts

, %

0

5

10

15

20

25

ACR20: *p≤0.05; ***p<0.0001 vs PBO at Month 3 (unadjusted)ACR50//70: No preservation of type I error was applied for secondary endpoints; no multiple-comparisons correction was applied to p-values; and statistical significance was defined as *p≤0.05; **p0.001; ***p<0.0001 vs baseline, FAS, full analysis set; NRI, non-responder imputation

ACR20 (Month 3) ACR50

ACR70

Burmester et al, Lancet, 2013

ORAL Step: DAS 28

ORAL Step: AEs bis Monat 3

ORAL Step: Laborergebnisse

ORAL Step: Neutropenien

ORAL Step: Hämoglobinverminderung

ORAL Step: Abnormalitäten in den Transaminasen

ACPA-positive

ACPA-negative

NSAIDs, CoxibsGlucocorticoids

Conventional DMARDs

Cytokine inhibition

B-cell depletion

Inhibition of co-modulation

Small molecules e.g. Jak-Inhibitors

Remission

TJC , SJC CRP ≤ 1

SDAI ≤ 3.3

Treatment population Treatment goal

Mögliche zukünftige Behandlungsoption

bei Rheumatoider Arthritis

Modified from: Burmester GR, Nature Rev Rheumatol 2012

Vielen Dank !

Tofacitinib

• Selective inhibitor of Janus Kinases (JAKs)

• Specificity at cellular level shows inhibition of JAK 1 and 3, with functional specificity over JAK2

• Potent inhibitor of gC cytokine receptor signaling which requires both JAK3 and JAK1

• At efficacious exposures in RA disease models, CP-690,550 shows:– Reduction in systemic inflammation (cytokines, chemokines, STAT1

responsive genes)

– Reduction in inflammatory cell infiltration (Mf, T cells, NK & NKT cells)

• Due to potential for JAK/STAT pathway to affect multiple cytokines, efficacy in RA may be achieved without complete inhibition of any given cytokine for the entire dosing interval

ORAL Step: HAQ-DI

ORAL Step: TEAEs und Abbrüche wegen AEs

Oral STEP: Ein- und Ausschlusskriterien

Burmester et al, Lancet, 2013

Vielen Dank !