Tofacitinib has been shown to significantly reduce signs and symptoms of RA as monotherapy and in combination with DMARDs. While treatments have improved, unmet needs remain like pain, fatigue, and psychological issues. ORAL Strategy showed tofacitinib + MTX was non-inferior to adalimumab + MTX. Tofacitinib provides an oral option for patients after inadequate response to csDMARDs and has an extensive safety profile from clinical trials and real-world use.

1. Evolving Unmet Needs:
Meeting The Expectations of
Today's Patient with RA
DR. MAZEN AL ZOU’UBI, MD
FELLOW OF RHEUMATOLOGY
INTERNAL MEDICINE SPECIALIST
DRMS, JORDAN

2. Potential Conflicts of Interest
RJM has acted as scientific consultant to, received grant funding from, published
scientific manuscripts with and/or participated as Faculty in meetings sponsored by
manufacturers of:
• Innovator Biologics: Amgen, BMS, Cellgene, Chugai, Genzyme, Hospira, Janssen,
MSD, Novartis, Pfizer, Roche, Sanofi, UCB Pharma
• Biosimilars: Pfizer, Hospira, Napp, Sandoz
• JAK inhibitors: Eli Lilly, Pfizer

3. The Evolution of Pharmacotherapy for RA
• Therapies for RA have come a long way in the last 100 years
• However, new agents and treatment strategies are still needed

4. Still Not Enough Patients Are Achieving
Treatment Goals
 Treatment should be aimed at reaching remission, or low disease activity as an alternative.
 On a daily basis, clinicians see patients who are not achieving treatment goals despite
advancement in current interventions.

5. Still Not Enough Patients Are Achieving
Treatment Goals
Percentage of patients with RA according to disease activity measured by
DAS28 criteria

6. Nature of Unmet Needs is Changing
Fatigue
Treatment
targets
Depression, mood
disturbance
Pain
Data from the BSRBR
registry reported
38.8% of patients with
severe fatigue
Restrictions in social
participation is
associated with pain,
fatigue, and
psychological status
61% of patients with
RA experience poor
sleeps
Fatigue impacts on
work ability
Clinical outcomes in RA have improved but unmet needs remain, for example, pain, fatigue, and
psychological issues

7. Fatigue Remains a Significant Problem for
Patients With RA
RABBIT registry: Severity of fatigue in patients
with RA
Severity of fatigue in 8 years of RA

8. How Patients Define Criteria for Treatment
Success in RA
 Successful treatment was most commonly defined as the reduction of pain and/or
joint swelling/inflammation

9. Importance of Patient Preferences
 Patient preference considers more than just benefits of different treatments
- Patients may not want or are unable to take an infusion/injectable medication
 A study of patient preference in patients with RA found 79% preferred an oral
medication over intravenous administration or injection
 However, patient preference must be balanced with other factors
- Patients with more severe disease seem to assign less value to mode and frequency of
administration, and prioritize improvement in pain and function
 Patient motivation to adhere to treatment is a result of the balance between perceived
need for the medication and concerns about its use
 According to EULAR guidelines, patient perspective should be considered in the
choice of their treatments

10. Route of Administration is One of the Most
Important Attributes in Treatment Selection,
With a Preference for Oral Therapy
A stud) al 1400 patients In 8 European countries found that most
patients with RA would prefer an oral therapy if It met safety and
efficacy expectations
39% of patients with RA demonstrate primary non-adherence to injectable bDMARD therapy
A German patient preference study found that route of administration was the most
important factor, and 49% would prefer oral administration

11. Introducing XELJANZ
Hot Topics

12. XELJANZ Has Been
Evaluated in One of
the Most Extensive
RA Clinical
Development
Programs to Date
Phase 3 Study

13. Significant Reduction
of RA Signs and
Symptoms with
XELJANZ as
Monotherapy and
Combination Therapy

14. In 2 Separate Studies, XELJANZ Demonstrated Significant
Improvement in RA Signs and Symptoms as Early as 2 Weeks in
DMARD-IR Patients
ORAL Solo Study: XELJANZ Monotherapy
ORAL Sync Study: XELJANZ Combination
Therapy

15. In ORAL Start, XELJANZ Demonstrated Superior ACR
Response Rates as Monotherapy vs MTX at Month 6
and Sustained at Year 2
XELJANZ is not indicated in MIX-naive patients

16. ORAL Strategy: a Phase4 head-to-head non
Inferiority Study
Inadequate
responders
to MTX
N=1152
Day
-28
HZ vaccine
Day
1
Month
1.5
Month 3 Month 6 Month 9 Month 12
Tofacitinib 5 mg bid n=384
Adalimumab 40 mg q2w + MTX n=386
Tofacitinib 5 mg bid + MTX n=376
Three Independent noninferiority comparisons
(adjusted for multiplicity)
• Tofacitinib + MTX vs adalimumab + MTX
• Tofacitinib vs adalimumab + MIX
• Tofacitinib vs Tofacitinib + MTX

17. ORAL Strategy: Tofacitinib MTX was non-
Inferior to Adalimumab MTX as Measured by
ACR50 at Month 6
 Similar ACR50 response rate at month 6 in MTX-IR patients for tofacitinib + MTX vs adalimumab + MTX
 Tofacitinib as a single agent not meet noninferiority criteria compared with Tofacitinib + MTX
 Tofacitinib as a single agent not meet noninferiority criteria compared with adalimumab +MTX
 Clinically relevant efficacy responses across all 3 treatment arms

18.  Similar ACR50 response rate at month 6 in MTX-IR patients for tofacitinib + MTX
vs adalimumab + MTX
 Tofacitinib as a single agent not meet noninferiority criteria compared with
Tofacitinib + MTX
 Tofacitinib as a single agent not meet noninferiority criteria compared with
adalimumab +MTX
 Clinically relevant efficacy responses across all 3 treatment arms
ORAL Strategy: Tofacitinib + MTX was non-Inferior to
Adalimumab + MTX as Measured by ACR50 at Month
6

19. Proportion of Patients With No Radiographic
Progression With XELJANZ as Monotherapy and
Combination Therapy
ORAL Start Study: MTX naive patients ORAL Scan Study. MTX-IR Patients
% of Patients With No Radiographic Progression (mTSS <0.0) — Secondary Endpoint In 2
Separate Studies_ ORAL Start and ORAL Scan

20. In 2 Separate
Studies,
Improvements in
Physical Function
With XELJANZ as a
Single Agent

21. In 2 Separate Studies, Sustained Improvement in
Arthritis Pain Scores With XELJANZ Monotherapy
ORAL Solo: Monotherapy in DMARD-IR
Patients
ORAL Start: Monotherapy In MTX-naive
Patients
Patient Assessment of Arthritis Pain (VAS, 0-100 Scale) — Secondary Endpoint

22. Patient-Reported
Outcomes at Week
12 With Approved
Dose of Tofacitinib
5 mg Twice Daily
Monotherapy

23. XELJANZ Is
Included In the
2015 ACR RA
Treatment
Guidelines Post
MTX in Established
RA

24. 2016 EULAR
Recommendations:
Phase II

25. 2016 EULAR Update: Targeted Synthetic
DMARDs
 tsDMARDs (JAK inhibitors Tofacitinib and Baricitinib) are recommended in
patients with RA who have not achieved targeted disease control with a
csDMARD, such as MTX, and who have poor prognostic factors.
 JAK inhibitors were moved up in the treatment algorithm as a result of additional
safety data.

26. 2016 EULAR
Update:
Targeted
Synthetic
DMARDs

27. Overview of XELJANZ RA Safety Profile

28. XELJANZ Has a Well-Characterized Safety and Efficacy
Profiles, in the Largest RA Clinical Programs to Date

29. The Incidence Rate of Serious Infections in Pooled RA
LTE Analyses Through 8 Years is Consistent With the
XELJANZ Phase 3 Program
 In the 7 controlled clinical trials, during the 0 to 3 months of exposure, serious
infections were reported In 1 patient (0.5 event per 100 pt-yrs) who received placebo
and II patents (1.7 event per 100 pt-yrs) who received XELJANZ 5 or 10 mg twice daily
 In the 7 controlled clinical trials, during the 0 to 12 months of exposure, serious
infections were reported In 34 patents (27 events per 100 pt-yrs) who received
XELJANZ 5 mg twice daily.
 A serious Infection was defined as an Infection that required hospitalization or
parenteral antimicrobial therapy, or met other criteria that required it to be classified as
a serious AE.
 A patient who experienced a serious infection was to be discontinued from the study
by protocol.

30. Incidence Rates of HZ (Nonserious and Serious) for
XELJANZ Across Treatment Groups
 HZ events (nonserious and serious) in the XELJANZ RA phase 2, phase 3 and LTE
studies, occurred more frequently in the XELJANZ groups compared with the
placebo groups.
 The effect of XELJANZ on chronic viral hepatitis reactivation is unknown.
 Patients who screened positive for hepatitis B or C were excluded from clinical
trials. Screening for viral hepatitis should be performed in accordance with clinical
guidelines before starting therapy with XEUANZ

31. The Incidence Rate of Malignancies (Excluding NMSC)
In Pooled RA LTE Analysis Through 8 Years Is
Consistent With the XEUANZ Phase 3 Program
 In the 7 controlled clinical trial, 11 solid cancers and 1 lymphoma were diagnosed
in 3328 patents receiving XELJANZ with or without DMARDs, compared with 0
solid cancers and 0 lymphomas in 809 patients In the placebo with or without
DMARD group during the first 12 months of exposure.
 As of January 2016 in the pooled LTE studies, 58 malignancies were reported In
1525 patients for XEUANZ 5 mg twice daily (incidence rate of 1.03 per 100 pt-yrs)

32. Conclusion
 Despite the availability of numerous therapies within RA, many unmet needs still exist.
 Tofacitinib with or without conventional synthetic DMARDs demonstrated significant differences
versus control across the 3 domains of RA with improvements in signs and symptoms, physical
function, and reduction in the progression of structural damage.
 Findings from the Oral Strategy trail suggest that, in MTX-IR patient, the addition of Tofacitinib or
ADA to MTX is equally efficacious.
 Tofacitinib belongs to a new class of RA therapies described as oral synthetic small molecule JAK
inhibitors, or targeted synthetic DMARDs and it provides an alternative option to injections as a
therapeutic choice after inadequate response to csDMARDs or to bDMARDs.
 Tofacitinib is the first JAK inhibitor with an extensive safety data and a Real-world experience of
more than 90,000 patients.