.

1. Medizinische Klinik m.S. Rheumatologie & Klinische Immunologie
Universitätsmedizin Charité
cDMARDs and bDMARDs in the
treatment of rheumatoid arthritis
Prof. Dr. Frank Buttgereit

2. 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

3. 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

4. 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

6. 18% 27%
40%
6%
15%
≤7,5mg (1996) >7,5mg (1996)
<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)
Glucocorticoide
55%
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

7. Methotrexate - a folic acid antagonist

8. 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.“

9.  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 !

11. 18% 27%
40%
6%
15%
≤7,5mg (1996) >7,5mg (1996)
<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)
Glucocorticoide
55%
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

12. Disease-modifying therapeutic effects in
rheumatoid arthritis: Glucocorticoids …
... reduce clinical
signs and symptoms
of inflammation
... retard radiographic
progression of the
disease.

13. 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.

17. 18% 27%
40%
6%
15%
≤7,5mg (1996) >7,5mg (1996)
<5mg (2013) 5-7,5mg (2013) >7,5mg (2013)
Glucocorticoide
55%
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

18. 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

19. HUMIRA®
Adalimumab
Enbrel®
Etanercept
Remicade®
Infliximab
Cimzia®
Certolizumab
Simponi®
Golimumab
Orencia®
Abatacept
Mabthera®
Rituximab
RoActemra®
Tocilizumab
Firma
Struktur
Molekül
Vollhumaner
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
Dosierung
40 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
Darreichung
SC
(FeSpr, PEN)
SC
(FeSpr, Pen)
120 min
Infusion
SC
(FeSpr)
SC
(FeSpr, Pen)
30 min
Infusion
195–255 min
Infusion
60 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

20. Etanercept: Mechanism of action
Mechanisms in Rheumatology ©2001
Click here to run the animation

21. Mechanisms in Rheumatology ©2001
Infliximab: Mechanism of action
Click here to run the animation

22. 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 characteristics
for specific information relating to each indication
EMA, European Medicines Agency.

23. 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
weeks
MTX 12.5 – 25 mg, weekly
(n = 302)
Remsima® 3mg/kg (n = 302)
Remicade® 3mg/kg at weeks 0,2,6, then every 8
weeks
MTX 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].

24. 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
Responserate,%
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.

25. Biologics used in the RA treatment
HUMIRA®
Adalimumab
Enbrel®
Etanercept
Remicade®
Infliximab
Cimzia®
Certolizumab
Simponi®
Golimumab
Orencia®
Abatacept
Mabthera®
Rituximab
RoActemra®
Tocilizumab
Firma
Struktur
Molekül
Vollhumaner
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
Dosierung
40 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
Darreichung
SC
(FeSpr, PEN)
SC
(FeSpr, Pen)
120 min
Infusion
SC
(FeSpr)
SC
(FeSpr, Pen)
30 min
Infusion
195–255 min
Infusion
60 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.

26. 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-6R
monoclonal antibody that inhibits IL-6R signalling

27. Dayer J-M & Choy E. Rheumatology 2010; 49:1524.
1Smolen J, et al. Nat Rev Drug Disc 2003; 2:473488.
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

28. Dayer J-M & Choy E. Rheumatology 2010; 49:1524.
IL-6
The acute-phase
response
Anaemia
Hypothalamic-
pituitary-adrenal
(HPA) axis
Acute-phase
proteins (e.g. CRP)
Hepcidin production
Alterations in iron
homeostasis
Systemic osteoporosis
Increased
cardiovascular
risk
Thrombocytosis
Fatigue
Systemic effects of IL-6 in RA
Inflammation

29. Efficacy and safety of subcutaneous tocilizumab
versus 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]

30. 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]

31. n= 517 517 516 499 445
n= 365 368 371 354 317
n= 182 185 186 177 162
n= 46 45 47 44 39
Results
DAS28 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
Patientswhoachieved
DAS28<2.6(%)
Week
n= 505 516 517 498 446
n= 354 364 370 352 306
n= 174 183 185 176 162
n= 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
Patientswhoachievedadecrease
of≥0.3inHAQ-DIscore(%)
974902 2412
Week
TCZ-SC qw (n=521)
TCZ-IV q4w (n=372)
TCZ-IV-SC (n=186)
TCZ-SC-IV (n=48)

32. HAQ-DI
http://www.phusewiki.org

33. Patients reporting clinically relevant
improvement in PROs from BL to WK 52
Burmester et al. EULAR 2014, Poster SAT0226
NumericallyhigherproportionsofpatientsinTCZgroupsvs.MTX groupreported improvement≥MCIDfromBLtoWK 52re.HAQ-DI,SF-36
PCSandMCS,FACIT-Fatigue,and PatientPainand PatientGlobal AssessmentofDiseaseActivityVAS

34. 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

35. 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

36. 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.

37. … …
…
…
…

39. Baricitinib
- Oral, reversible inhibitor of JAK-1 and JAK-2
- Inhibition of proinflammatory cytokines
IL6 - JAK1/JAK2 or JAK1/TYK2
IL-23 - JAK2/TYK2
IL12 - JAK2/TYK2
INFg - JAK1/JAK2
INF/ß - JAK1/TYK2
- In vitro selectivity for JAK1/JAK2 (IC50)
JAK1/JAK2 ca. 2-5nM
TYK2 ca. 53nM JAK3 ca. 560nM
- Development for RA and other autoimmune diseases
According to Wikipedia

40. 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/NCT01721057
4. http://clinicaltrials.gov/ct2/show/NCT01710358
5. http://clinicaltrials.gov/ct2/show/NCT02265705
6. http://clinicaltrials.gov/ct2/show/NCT01711359
7. http://clinicaltrials.gov/ct2/show/NCT01885078

41. 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

42. 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
%Patients(NRI)
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

44. Electronic Daily Diary PROs Baricitinib in MTX-IR RA pts
Week
0 2 4 6 8 10 12
Median,minutes
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
LSMean,NRS0-10
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
LSMean,NRS0-10
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
LSMean,NRS0-10
2.0
2.5
3.0
3.5
4.0
4.5
5.0
5.5
6.0
Worst PainD
***
***
***
***
***
***
***
**
+++
+++
***
++
+++
***
Duration of Morning Joint Stiffness
Median,minutes
Week Week
Severity of Morning Joint Stiffness
LSMean,NRS0-10
Week
LSMean,NRS0-10
Worst Joint Pain
Week
LSMean,NRS0-10
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

45. Patient-Level Changes in van der Heijde
mTSS 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 (%)
Δfrombaseline
Placebo
Baricitinib 4 mg
Adalimumab
ΔmTSS
Placebo
(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

46. Safety Baricitinib vs. Adalimumab
Weeks 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

47. Conclusions
• Baricitinib Phase 3 Study-Program with more than 3000 patients
• Significant improvement (ACR –Response, remission, LDA) in various cohorts of
RA patients with a fast onset of action
• Inhibition of radiographic progression comparable with adalimumab, 3 studies
with 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, no
case of Tuberculosis, no increased incidence of malignoms, no increased
incidence of MACE

48. Vielen Dank!

50. Efficacy and safety of tofacitinib following
inadequate 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

51. 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
ACR20responserate(95%CI)%
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

52. 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
LSmean(95%CI)changefrom
baselineinHAQ-DI
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
LSmean(95%CI)changefrom
baselineinDAS28-4(ESR)
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)

53. Vielen Dank!

54. Medizinische Klinik m.S. Rheumatologie & Klinische Immunologie
Universitätsmedizin Charité
JAK/STAT-Inhibitoren:
Wo liegt der künftige Stellenwert?
Prof. Dr. Frank Buttgereit

55. Window of
opportunity
Krankheits-
beginn
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.)

56. 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

57. „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
ACR70Responders(%)
Modified from Klareskog et al. Lancet 2004
Neue Behandlungsansätze

58. Bisherige therapeutische Ansätze in der RA
van Vollenhoven RF. Nat Rev Rheumatol 2009;5:531–41
58

59. Infliximab: Wirkungsmechanismus

Mechanisms in Rheumatology ©

60. 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
Zellkern
Gen Transcription
Zytokine

61. Immun-und Entzündungsreaktionen: Die
treibenden Kräfte in der Pathogenese der RA
Normal RA
Plasmazellen
Pannus
Bildung
Dendritische Zellen
Makrophagen
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

62. 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
1
Die 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

63. 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

64. Zytokin-Rezeptorklassen
Zytokine vermitteln Informationen an Zelle über spezifische Rezeptoren
ChemokineToll/IL-1TGFβTNFTyp 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

65. Zytokine benutzen unterschiedliche
intrazelluläre Signalwege
Zytoplasma
Zellkern
Kinases
Kinases
p38
JNK
ERK
Syk
IKK
NFκB
JAK
JAK
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
PI3K
PI3K
Lipid
messengers
Second
messengers
MAPK
Signalweg
SYK
Signalweg
NFKB
Signalweg
JAK
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

66. PP
P
Der JAK/STAT Signalweg
JAK JAK
Zytokin
g
b

PP
P
STAT
STAT
STAT
STAT
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 Rezeptor
2
Aktivierte JAKs phosphorylieren STATs, die dimerisieren in den Kern wandern
und die Gen-Transkription aktivieren
3

67. Zentrale Bedeutung des JAK/STAT Signalweg
Signaling verschiedener Zytokine über den JAK/STAT Signalweg1
STAT
4, 3
STAT
1, 3, 5, 6
JAK1
JAK3
JAK1
JAK2
JAK2
JAK2
gc Zytokine
(IL-2, IL-4, IL-7,
IL-9, IL-15, IL-21)
IL-6
IFNγ
EPO,TPO
GM-CSF
IL-23
IL-12
JAK2
TYK2
STAT
1, 3
STAT
3, 5
6 STAT
Proteine
Regulierte Immunzellen2
T Zellen B Zellen Makrophagen
JAK1
TYK2
Type I IFNs
IL-10
STAT
1, 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
P
STAT
P
STAT
P
• Wachstum/
Reifung von
Lymphozyten
• Differenzierung/
Homeostase von
T-Zellen, NK-
Zellen
• Entzündung
• Antiviral
• Entzündung
FUNKTION3
• Erythropoese
• Myelopoese
• Bildung von
Megakaryozyten/
Plättchen
• Wachstum
• Angeborene
Immunantwort
• Differenzierung
/ Proliferation
von Th17-
Zellen
• Entzündung
• Antiviral
• Entzündung

68. Zentrale Bedeutung des JAK/STAT Signalweg
Signaling verschiedener Zytokine über den JAK/STAT Signalweg1
STAT
1, 3, 5, 6
JAK1
JAK3
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:

69. Cytokine signalling pathways relevant to RA
CYTOPLASM
NUCLEUS
Kinases
Kinases
p38
JNK
ERK
Syk
IKK
NFκB
JAK
JAK
STAT
STAT
STAT
STAT
Gene transcription
PI3K
PI3K
PI3K
Lipid
messengers
Second
messengers
MAPK
signalling
cascade
Syk (& BTK)
signalling
cascade
NFKB
signalling
cascade
JAK
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.

70. Oral Compounds in Development for
Rheumatoid Arthritis
Fostamatinib
(R788)
LY3009104
(INCB28050)
VX-509 GLPG0634
Tofacitinib
(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:

71. Tofacitinib (CP-690,550)
• Struktur von Tofacitinib und ATP
• Tofacitinib ist ein reversibler competitor der
ATP Bindungsstelle der Janus Kinasen
N
N
N
H
N
N
N
O
CN
CP-690550
C16H20N6O•C6H8O7
 Molekulargewicht (Salz): 504.5 Da

72. Hemmung des JAK/STAT Signalwegs
JAK JAK
Zytokin
g
b

STAT
STAT
mRNA

73. Tofacitinib (CP-690,550):
RA Phase 3 Studienprogramm
IR = inadequate responders

74.  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 end
Month 3Day 1 Randomization
Burmester et al, Lancet, 2013
Einsatz von Tofacitinib bei TNF-IR
Patienten mit RA: ORAL-Step

75. Oral STEP: Medikation vor Studienbeginn

76. 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 BID
Placebo5 mg Placebo10 mg
Patients,%
***
****
*
Months
0.5 1 3 60
Patients,%
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

77. ORAL Step: DAS 28

78. ORAL Step: AEs bis Monat 3

79. ORAL Step: Laborergebnisse

80. ORAL Step: Neutropenien

81. ORAL Step: Hämoglobinverminderung

82. ORAL Step: Abnormalitäten in den Transaminasen

83. ACPA-positive
ACPA-negative
NSAIDs, Coxibs
Glucocorticoids
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

84. Vielen Dank !

85. 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

86. ORAL Step: HAQ-DI

88. ORAL Step: TEAEs und Abbrüche wegen AEs

89. Oral STEP: Ein- und Ausschlusskriterien
Burmester et al, Lancet, 2013

90. Vielen Dank !