This talk was given by Dr. Daniel Lovell of Cincinnati Children's Hospital to a group of patient families, at Systemic Juvenile Idiopathic Arthritis (or SJIA) Family Day on July 22nd, 2017.

1. Current Clinical Trials in SJIA &
MAS
Daniel J. Lovell, MD, MPH
Joseph E. Levinson Professor and Chair in Pediatric
Rheumatology
Chairman, Pediatric Rheumatology Collaborative Study
Group
1

2. Recent Clinical Trials in SJIA
• Recent breakthroughs have been the
testing of inflammatory mediators known
to have a central role in the SJIA disease
process
–Interleukin 1- Anakinra (Kineret) and
Canakinumab (Ilaris)
–Interleukin 6- Tocilizumab (Actemra)
• Ilaris and Actemra have been approved by
the FDA for the treatment of SJIA
2

3. Effects of Interleukin 1
3

4. Fever Joint Inflammation
Growth Impairment
Interleukin-6
in sJIA
Anemia
Thrombocytosis
J Exp Med 1998
J Clin Invest 1997
Endocrinol 2001
A&R 1991
A&R 1991
Lancet 1995
Blood 1996
J Clin Invest 1994
IL6/soluble IL6R and CRP
MAS
Osteoporosis
A&R 2006

5. JIA CLINICAL TRIAL METHODS
AND DEFINITIONS
5

6. JIA core set and response criteria
JIA core set
1. Physician global assessment of overall disease activity
2. Parent or patient global assessment of overall well-being
3. Functional ability (CHAQ)
4. Number of joints with active arthritis
5. Number of joints with limited range of motion
6. Index of inflammation: ESR or CRP
7. (FEVER for systemic JIA)
ACR Criteria: 3/6 core set variables improved ≥ 30% (50%, 70%, 90%,
100%) with no more than 1/6 worsened by >30% (AND NO FEVER)
FDA and EMA accepted
Giannini, Ruperto et Al. Arthritis Rheum 1997

7. JIA clinical inactive disease/remission
Inactive disease
– No joints with active arthritis
– No fever, rash, serositis, splenomegaly, or generalized
lymphadenopathy attributable to JIA
– No active uveitis (to be defined)
– Normal ESR or CRP
– No disease activity according to MD evaluation
– Morning stiffness ≤ 15 minutes
Clinical remission
– On medication for 6 months and
– off medication for 12 months Wallace, Ruperto et al J Rheumatol 2004
Wallace…for CARRA/PRINTO/PRCSG. Arthritis Care Res 2011

8. BLINDED WITHDRAWAL STUDIES
Screen
Blinded Follow-Up
Placebo Arm
Experimental Arm
EndOfStudy
All subjects receive
experimental therapy
for several months
Responders Randomized
Flares go to Open
3-6 mo
open
Open label extension

9. S1
S2
S3
S4
S5
S6
S7
S8
S9
0
3
6
9
12
Baseline 1 week 1 month follow-up
S1
S2
S3
S4
S5
S6
S7
S8
S9
baseline 1 week 1 month follow-up
n.ofactivejoints
CRP(mg/dL)
A
NS
P = 0.005
P = 0.005
P = 0.005
P = 0.005
P = 0.005 P = 0.005
B
S10
S10
0
2
4
6
8
10
12
14
16
18
20
30
Gattorno et al, Arthritis Rheum 2008
Anti IL-1 (anakinra) and systemic JIA
Pascual et al: J Exp Med 2005

10. Anakinra in systemic JIA: study design
Quartier et al. Annals Rheum Dis 2012

11. Anakinra in systemic JIA (1 month results)
Response Anakinra
(N=12)
Placebo
(N=12)
P value
Mod ACR 30 10 (83%) 3 (25%) 0.004
Mod ACR 50 7 (58%) 0 0.005
Mod ACR 70 5 (42%) 0 0.038
Mod ACR 100 0 0 1
Quartier et al. Annals Rheum Dis 2012

12. Long-term Efficacy and Safety of
Canakinumab in Patients With Active
Systemic Juvenile Idiopathic Arthritis
(SJIA): Results From a Phase III
Extension Study
H. I. Brunner1
, N. Ruperto2
, P. Quartier3
, T. Constantin2
, E. Alexeeva2
, I.
Kone-Paut4
, K. Marzan2
, N. Wulffraat2
, R. Schneider1
, S. Padeh2
, V.
Chasnyk2
, C. Wouters2
, J. B. Kuemmerle-Deschner2
, T. Kallinich2
, B.
Lauwerys5
, E. Haddad2
, E. Nasonov2
, M. Trachana2
, O. Vougiouka2
, K.
Leon6
, E. Vritzali7
, K. Lheritier7
, A. Martini2
, D. Lovell1
1
PRCSG, Cincinnati, United States; 2
PRINTO-Istituto Gaslini, Genoa, Italy; 3
Necker-Enfants
Malades Hospital, Paris; 4
Bicêtre hospital, Paris Sud, France; 5
Cliniques Universitaires Saint-Luc
and Université Catholique de Louvain, Brussels, Belgium; 6
Novartis Pharmaceuticals Corporation,
East Hanover, United States; 7
Novartis Pharma AG, Basel, Switzerland

13. 13
Patients aged ≥2 to <20 yrs, with active SJIA
features (≥2 of the following):
1. Spiking intermittent fever of >38°C for 1 day within
1 week of baseline
2. ≥2 joints with active arthritis
3. CRP levels of >30 mg/L [normal <10 mg/L]
4. Rash, serositis, lymphadenopathy and
hepatosplenomegaly were included
Methods
Eligibility Criteria

14. 14
Results
Demographics and Baseline Disease Characteristics
Variable
Overall
N=123
Age (years), mean (SD) 9.0 (4.5)
Female, n (%) 75 (61.0)
Predominant race: Caucasian, n (%) 111 (90.2)
Fever at entry, n (%) 70 (57.0)
Presence of systemic signs after first 6 months of disease, n (%) 95 (77.2)
Time from SJIA diagnosis to study entry (years), mean (SD) 2.66 (3.27)
Prior use of other biologics, n (%) 32 (26.0)
CRP at baseline (mg/L), median (Q1, Q3) 79 (22.0, 170.0)
PGA (VAS, mm), median (Q1, Q3) 54.7 (39.0, 70.0)
Number of active joints median (Q1, Q3) 5.0 (3.0, 14.0)
Number of joints with limitation of motion, median (Q1, Q3) 5.0 (2.0, 12.0)
CHAQ score, median (Q1, Q3) 1.37 (0.62, 2.0)
JADAS10-CRP, median (Q1, Q3) 22.3 (17.2, 28.0)
JADAS27-CRP, median (Q1, Q3) 21.5 (16.8, 28.4)
Mean prednisone-equivalent dose (mg/kg/day) (SD) 0.95 (2.3)

15. 15
 Canakinumab treatment
provided a rapid response
at Day 15. Over 50% of
patients had aACR70
responses; 23.5% had
aACR100 responses at
Day 15
 At last assessment, 67%
of patients had aACR ≥70
responses and 51% were
aACR100
Results
Efficacy: aACR Responses in Naïve Patients

16. 16
Results
Efficacy: Clinical remission on medication
*At least 6 consecutive months of inactive disease; #at least 12 consecutive months of inactive disease
#
%of123patients

17. 17
 SAEs were reported in 40 (32.5%) patients
 No deaths occurred
Results: Rates of Most Common Serious
Adverse Events (SAEs)
SAEs by preferred term (>2 events) Canakinumab
(N= 123; rate /100 pt days)
Total SAEs, n (incidence rate/100 Pt days)* 103 (0.15)
Juvenile idiopathic arthritis flare 16 (0.02)
Macrophage activation syndrome 8 (0.01)
Fever 5 (0.01)
Pneumonia 3 (<0.01)
Lymph node inflammation 3 (<0.01)
Lymph node enlargement 3 (<0.01)
Hepatitis toxic 2 (<0.01)

18. 18
 Rapid response and sustained therapeutic efficacy
were demonstrated in canakinumab-naïve patients with
active SJIA
• More than 50% of the patients achieved aACR 70 response by
Day 15, and the response was sustained until last assessment
• At least 50% with inactive disease at the last assessment
• Almost 1/3 of the patients were in clinical remission for 1 year
 No new safety findings were observed upon long-term
use of canakinumab, and the safety profile was
consistent with that observed in the pivotal program
Conclusions

19. Efficacy and Safety of Tocilizumab
(TCZ) in Patients with Systemic
Juvenile Idiopathic Arthritis (sJIA):
TENDER 52-Week Data
F. De Benedetti, H. Brunner, N. Ruperto, I. Calvo,
R. Cuttica, C. Malattia, R. Schneider, P. Woo,
C. Wouters, R. Xavier, L. Zemel, S. Wright,
A. Kenwright, D. Lovell, A. Martini

20. TENDER: 12-Week Randomized, Double-blind, Placebo-
Controlled, Parallel Group, 2-Arm Study (Part I) with Single Arm
Open-label Extension (Parts II and III)—5 Years in Total
Open-Label Period (Parts II - III)
Tocilizumab 8 or
12 mg/kga
every 2 weeks for
92 weeks (subsequent 3-
year extension added)
Double-Blind Period (Part I)
Tocilizumab
8 or 12 mg/kga
x 6
Placebo x 6
75 pts
37 pts
Screening&Randomization
0
Escape with rescue therapy
2 4 6 8 10 12 Week
Day 3
Study Design

21. TENDER: Key Inclusion Criteria
• Diagnosis of sJIA according to ILAR criteria
• Age 2–17 years
• Persistent disease activity for ≥6 months, with an
inadequate response to corticosteroids and NSAIDs due
to toxicity or lack of efficacy
• ≥5 active joints OR ≥2 active joints with fever >38°C
• Maximum dose of oral corticosteroids: 0.5 mg/kg/day of
prednisone equivalent
• Stable dose of oral corticosteroids, MTX, and/or NSAIDs
• No other DMARDs or biologic allowed

22. TENDER: Efficacy in Double-Blind Phase
24.3
85.3
0
20
40
60
80
100
Placebo
(n=37)
TCZ (n=75)
61.5% (95% CI: 44.9–78.1)*,†
n=9 n=64
JIA ACR30 +
Absence of Fever at Week 12
JIA ACR 50/70/90
responses at Week 12
10.8
90.7
8.1
85.3
5.4
70.7
0
20
40
60
80
100
JIA
ACR50
JIA
ACR70
JIA
ACR90
Placebo (n=37) TCZ (n=75)
†
†
†
Responders(%)
Responders(%)

23. TENDER: Demographic and
Baseline Characteristics
N = 112
Age (y), mean (SD) 9.7 (4.6)
Disease duration (y), mean (SD) 5.2 (4.1)
Number of previous DMARDs, mean (SD) 1.3 (1.2)
Number of previous biologics, mean (SD) 1.8 (1.4)
Physician VAS, mean (SD) 64.9 (22.3)
Parent/patient VAS, mean (SD) 58.7 (24.4)
Number of active joints, mean (SD) 19.8 (15.7)
Number of joints with LOM, mean (SD) 19.8 (15.6)
ESR (mm/hr) mean (SD) 57.6 (34.2)
CHAQ, mean (SD) 1.7 (0.9)
CRP (mg/l), mean (SD) 166.43 (349.25)
Fever (last 7 days), n (%) 48 (43)
Background oral corticosteroid dose, (mg/kg/day PDN eq), mean (SD) 0.30 (0.20)

24. TENDER: JIA ACR Responses + Absence of
Fever Over 52 Weeks
N = 112*
20
40
60
80
100
0 6 12 18 24 30 36 42 48 54
Time (weeks)
Response(%)
JIA ACR30 + absence of fever JIA ACR50 + absence of fever
JIA ACR70 + absence of fever JIA ACR90 + absence of fever
2 52
0

25. TENDER: Mean Active Joints and Joints with
Limited Motion Over 52 Weeks
112 111 111 110 105 107 105 99n =
0
2
4
6
8
10
12
14
16
18
20
Mean±SEJointCount
Active Joints (71 Joints)
Joints with Limited Motion (67 Joints)
0 6 12 18 24 30 36 42 48 54
Time (weeks)
2 52

26. TENDER: Mean Oral Corticosteroid Dose
Over 52 Weeks
0.3
0.06
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0 6 12 18 24 30 36 42 48 54
Time (weeks)
112112 112 109 109 109 108 99n =
522
Mean±SEdose(mg/kg/day)

27. Tocilizumab Cumulative Safety
Week 104
Exposure to TCZ, y 202.03
Rate of SAEs/100PY (n) 23.3 (47)
Rate of infections and infestations/100PY (n) 282.1 (570)
Rate of serious infection AEs/100PY (n) 10.9 (22)
SAEs related (remotely, possibly, probably) to TCZ/100 PY (n) 7.4 (15)
Macrophage activation syndrome/100PY (n) 1.5 (3)
AEs leading to withdrawal/100PY (n) 3.0 (6)c
Deaths/100PY (n)d
1.5 (3)+3
Pneumothorax 1
Sepsis (possibly related) 1
Road Traffic Accident 1

28. TENDER: Clinical Laboratory Evaluations
No. (%)
Neutrophils Low (500-1,000 cells/mm3
) 17 (15.2)
Very low (< 500 cells/mm3
) 2 (1.8)
Platelets Low (25,000-50,000 cells/mm3
) 1 (0.9)
Very low (< 25,000 cells/mm3
) 0 (0)a
ALT High (> 5-20 times ULN) 7 (6.3)
Very high (> 20 times ULN) 1 (0.9)a

29. Tocilizumab Conclusions
• Year 1 results from this first global phase 3 study
demonstrated that tocilizumab was highly effective for
the treatment of sJIA
– The response to tocilizumab increased over time
– Over 50% of the patients were able to discontinue oral
corticosteroids by week 52
– 55% in inactive disease status by week 52
• In this population of sJIA patients, tocilizumab exhibited
an acceptable safety profile

30. MAS and IL-1 and IL-6 treatment
• Cases of MAS have occurred in both clinical trials even in patients
with very well controlled disease
• Treatment with either IL-1 or IL-6 does not seem to increase the risk
for MAS- the rate is the same or less than in overall SJIA
• Causes of MAS are the same as the general population
– Infection
– Flare of SJIA
– No obvious explanation
• Manifestations of MAS and response to treatment generally the
same as MAS in those not on biologic therapy
– With MAS and canakinumab lower ferritin compared to those not on
canakinumab
– With MAS and tocilizumab less often fever and more severe lab
abnormalities compared to those not on tocilizumab
30

31. Earlier treatment with anti IL-1?
…It is possible, but far from
proven, that anakinra or other
biologic agents may take
advantage of a «window of
opportunity» in which
disease pathophysiology can
be altered to avoid chronic
arthritis. Testing this
hypothesis represents and
important scientic priority in
pediatric rheumatology
PA Nigrovic

32. What’s next
Test effect of earlier treatment with biologics
Determine if biologics have effect on joint
erosions/narrowing
Determine clinical or lab tests that can predict
response/steroid discontinuation/clinical remission
Determine long term safety and efficacy data
Entirely new mechanism of action- JAK kinase
inhibition- tofacitinib in SJIA trial starting now in
many PR centers

33. Roles for JAK in Arthritis

34. Overall Conclusions
• Both IL-1 and IL-6 blocking biologics represent huge
breakthroughs in the treatment of SJIA especially in
those with systemic features
• Other companies are developing other IL-1 and IL-6
blocking biologics that will likely have similar results
• Frequency and causes of MAS are similar with or
without these treatments but manifestations are slightly
different
• Effect of early onset treatment with either IL-1 or IL-6 is
being evaluated
• Other types of treatments such as tofacitinib (a pill) will
be tested in SJIA very soon
34