Disclosures

I have the following relevant financial relationships:
− Research grants: Novartis Pharma AG
Efficacy and Safety of Canakinumab in Patients
with TNF Receptor Associated Periodic
Syndrome
− Consulting fees: Novartis Pharma AG
− Speaker’s bureau: Novartis Pharma AG, Swedish Orphan Biovitrum AB
Marco Gattorno1, Laura Obici2, Antonella Meini3, Vincent
Tormey4, Ken Abrams5, Nicole Davis5, Christopher Andrews6
and Helen J. Lachmann7
1G
Gaslini Institute, Genova, Italy, 2IRCCS Policlinico San Matteo, Pavia,
Italy, 3Pediatric Immunology and Rheumatology, Brescia, Italy, 4Galway
University Hospitals, Galway, Ireland, 5Novartis Pharmaceutical
Corporation, East Hanover, NJ, USA, 6Novartis Pharmaceuticals UK
Limited, Surrey, United Kingdom, 7University College London Medical
School, London, United Kingdom
1
TNF receptor-associated periodic syndrome
(TRAPS)
2
Study design: 33-month, open-label study
 Rare autoinflammatory disease due to
mutations of TNFRSF1A gene (type I receptor
for tumor necrosis factor [TNF])
 Autosomal dominance, no ethnic distribution
 Recurrent, non-periodic (2-4 yearly),
long-lasting (6-20 days) fever episodes
associated with rash, musculoskeletal and
abdominal pain, conjunctivitis and periorbital
edema




Treatment period:
4 months
Screening
Day
30
1
15
85
Long-term treatment:
24 months
Follow-up period:
5 months (maximum)
113
253
281
953/EOS
Primary
endpoint
Current
dose
Amyloidosis is a long-term complication
Selected
dose
Incomplete response to etanercept1
Good response to anakinra2,3
Interim results from open label 4-months
cankinumab therapy and 5-months follow-up in
active TRAPS patients is presented
1. Bulua AC, et al. Arthritis Rheum 2012;64(3).
2. Gattorno M. et al. Arthritis Rheum 2008;58(5).
3. Ter Haar N, et al. Ann Rheum Dis 2012; [Epub ahead of print].
Baseline
Dosing visits q4wk
Canakinumab 150
mg (or 2 mg/kg for
patients ≤40 kg)
Uptitration to 300 mg (4 mg/kg
for pts ≤ 40 kg) at Day 8 for
non-responders
Re-dose at relapse and then
advanced to end of follow-up period
Q4wk dosing until PK modeling
data available for possible dose
change
 Patient visits: Days 1, 3, 8, 15, 28 and then every 4 weeks
3
Objectives
EOS, end of study; PK, pharmacokinetic; Q4wk, every 4 week.
4
Key definitions
Primary objective
Complete response
 Clinical remission (physician’s global assessment [PGA] 0 or 1 [absent or
minimal]) and serological remission (CRP <10 mg/L and/or SAA <10 mg/L)
 To assess if canakinumab induces complete or almost complete
response in patients with active TRAPS at Day 15
Almost complete response
 Clinical remission and partial serological remission (≥70% reduction of
baseline CRP and/or ≥70% reduction of baseline SAA)
Key secondary objectives






Complete/almost complete response at Day 8
Percentage of patients with clinical remission at Day 8 and Day 15
Percentage of patients with CRP and SAA ≤10 mg/L at Day 8 and Day 15
Complete/almost complete response in non-responders at Day 15
Profile over time in CRP, SAA, physician’s and patient’s global assessments
To assess PK/PD relationships to derive a canakinumab dose and dosing
frequency required to treat active TRAPS and to prevent recurrence/relapse
of TRAPS
Exploratory objective
Non-response
1) No change or worsening from baseline PGA
AND/OR
2) Increased or <50% reduction from baseline CRP and/or SAA value(s)
Physician’s Global Assessment of TRAPS clinical signs and symptoms
0 = None (no), 1 = Minimal, 2 = Mild, 3 = Moderate, and 4 = Severe
 To explore health-related quality of life (HRQoL) of canakinumab treatment
using SF-36® for patients ≥18 years old
CRP, C-reactive protein; PK/PD, pharmacokinetic/pharmacodynamic; SAA, serum amyloid A.
5
CRP, C-reactive protein; SAA, serum amyloid A.
6
1
Baseline demographics
Major inclusion and exclusion criteria
Inclusion
 Males/females aged ≥4 years old
 Positive for mutation of TNFRSF1A gene
 Recurrent TRAPS
Canakinumab
N=20
Sex, n (%)
− History of >6 episodes/year before receiving an effective biologic therapy
Male
− Episode duration ≥8 days
13 (65)
Female
 Active TRAPS
7 (35)
− Physician’s global assessment ≥2
Median age, years (range)
− Elevated CRP >10 mg/L and/or SAA >10 mg/L
Predominant race, n (%)
39 (7-77)
Caucasian
Exclusion
 Use of anakinra, TNFα-inhibitors, DMARDs or any other investigational
19 (95)
Asian
1 (5)
biologics within a specified period prior to baseline
 Positive tuberculosis screen
 Active or persistent/recurrent infection
DMARDs, disease-modifying anti-rheumatic drugs; TNF, tumor necrosis factor.
7
Baseline disease characteristics
8
Efficacy results
Day 8:
 18 (90%) achieved clinical remission
 16 (80%) achieved complete or almost complete response
Canakinumab
N=20
20
TNFRSF1A gene mutation indentified
TRAPS diagnosis to study entry, median
3.7 yr (0.01-11.7)
(range)
C-reactive protein, median (range)
125 mg/L (6-564)
Serum Amyloid A, median (range)
198 mg/L (16-2270)
Number of attacks per year, median (n; range)
10 (n=9; 7-12)
Attack duration, median (n; range)
10 days (n=9; 8-20)
Physician’s global assessment of TRAPS
activity n (%)
Mild
13 (65)
Moderate
6 (30)
Severe
1 (5)
Chronic TRAPS
11 (55)
− 2 with clinical remission but with <70% reduction of CRP/SAA
− 2 without clinical improvement and <70% reduction of CRP/SAA; both received
dose up-titration
 7 (35%) had normalized both CRP and SAA levels
Day 15:
 19* (95%) complete/almost complete response
− Includes all 4 who did not achieve it at Day 8
 20 (100%) achieved clinical remission
 12 (60%) had normalized both CRP and SAA levels
 Time to clinical remission: median 4 days (95% CI:3,8)
9
Clinical remission
*1 patient who achieved complete remission at Day 8, developed acute rise in CRP and SAA due to viral infection at Day
15 which did not return below 70% of baseline until Day 87. This patient did not meet protocol-defined primary endpoint.
CRP, C-reactive protein; SAA, serum amyloid A.
10
CRP and SAA decreased rapidly
Physician’s global assessment of TRAPS activity by visit
Median CRP and SAA (mg/L) by visit, n=20
225
100%
100
1
90%
90
6
2
5
70%
70
2
2
4
*1
200
2
7
150
60%
60
5
50%
50
40%
40
30%
30
20%
20
18
16
13
19
18
13
11
198
175
7
mg/L
Patients (%)
80%
80
125
100
156
125
CRP
SAA
89
75
8
50
10%
10
25
0
0%
Baseline Day 3
Absent
Day 8
Minimal
Day 15 Day 29 Day 57 Day 85 Day 113
Mild
Moderate
0
BL 3 8
Severe
*Patient experienced a relapse at Day 85 and received rescue treatment. PGA of TRAPS activity changed from minimal
(at Day 57) to mild (at Day 85).
11
10
11
4
4
4
4
5
3
3
4
2
2
15
29
57
Days
85
113
Normal CRP = 0-10 mg/L
Normal SAA = 0-10 mg/L
BL, baseline; CRP, C-reactive protein; SAA, serum amyloid A; ULN, upper limit of normal.
ULN
12
2
Canakinumab withdrawal and re-dose at relapse
Time to relapse after canakinumab withdrawal
PGA of TRAPS activity after
canakinumab re-dose
TRAPS severity at relapse
 Median 91.5 (71.5, 121.5) days to relapse after last canakinumab dose
Kaplan-Meier estimates of remaining relapse-free after last
canakinumab dose
Median CRP=140 mg/L
Median SAA=477 mg/L
(n=20)
12
11
11
10
Number of patients
Median CRP=8 mg/L
Median SAA=4 mg/L
(n=18)*
8
7
6
7
4
2
2
0
14 Days post relapse
At relapse
Mild
Moderate
Severe
0
absent
minimal
*2 patients had relapse within 2-weeks of end of follow-up period hence their 2-week post
relapse visit occurred in the long-term treatment period.
13
Health-related quality of life changes
SF-36 physical and mental component summary scores
US general population norms
Baseline
Day 15
General Health
50
40
60
Physical Function
Mental Health
20
20
0
Role Emotional
Bodily Pain
0
Social Function
15
Health-related quality of life changes
N = 15 for baseline, 14 for Day 15, 15 for Day 113, and 13 for end of follow-up.
The scoring for SF-36v2 scales has been constructed using US Population norms, so that the average score for the
US population is 50 and the standard deviation is 10 (also referred to as a T-score).
Baseline
Day 15
Day 113
Physical Function
Mental Health
50
40
30
30
20
20
0
Social Function
US general population norms
60
10
Role Emotional
End of follow-up
General Health
60
40
16
SF-36 physical and mental component summary scores
US general population norms
General Health
50
Bodily Pain
Health-related quality of life changes
SF-36 physical and mental component summary scores
Mental Health
Role Physical
Vitality
N = 15 for baseline, 14 for Day 15, 15 for Day 113, and 13 for end of follow-up.
The scoring for SF-36v2 scales has been constructed using US Population norms, so that the average score for the
US population is 50 and the standard deviation is 10 (also referred to as a T-score).
Day 113
Physical Function
10
Role Physical
Vitality
Day 15
40
30
Social Function
Baseline
50
30
10
Role Emotional
US general population norms
General Health
60
Mental Health
14
Health-related quality of life changes
SF-36 physical and mental component summary scores
Baseline
CRP, C-reactive protein; PGA, physician’s global assessment; SAA, serum amyloid A.
Physical Function
10
Role Physical
Role Emotional
Bodily Pain
Social Function
Vitality
N = 15 for baseline, 14 for Day 15, 15 for Day 113, and 13 for end of follow-up.
The scoring for SF-36v2 scales has been constructed using US Population norms, so that the average score for the
US population is 50 and the standard deviation is 10 (also referred to as a T-score).
0
Role Physical
Bodily Pain
Vitality
17
N = 15 for baseline, 14 for Day 15, 15 for Day 113, and 13 for end of follow-up.
The scoring for SF-36v2 scales has been constructed using US Population norms, so that the average score for the
US population is 50 and the standard deviation is 10 (also referred to as a T-score).
18
3
Most common (≥3 patients) AEs by system
organ class up to end of follow-up period
AEs by primary system organ class
Number of patients with AE(s)
Infection and infestations
Nervous system disorders
General disorders and administration site conditions
Musculoskeletal and connective tissue disorder
Gastrointestinal disorders
Respiratory, thoracic, and mediastinal disorders
Eye disorders
Skin and subcutaneous tissue disorders
Vascular disorders
Infection adverse events
Canakinumab,
N=20
n (%)
Infections and infestations
20 (100)
15 (75)
12 (60)
11 (55)
11 (55)
10 (50)
8 (40)
4 (20)
5 (25)
3 (15)
Total
Nasopharyngitis
Upper respiratory tract infection
Pharyngitis
Cystitis
Fungal skin infection
Lower respiratory infection
Streptococcal pharyngitis
Pharyngotonsillitis
Respiratory tract infection
Rhinitis
Tonsillitis
Tooth infection
Urinary tract infection
Viral infection
Viral upper respiratory tract infection
 Headache was most common AE (n=9; 45%).
 2 SAEs: URTI (strep and H. Flu +) diagnosed day of first dose which resolved
within 2 days; and a severe TRAPS flare with chest pain.
 Of the AEs reported, 87% were mild, 11% were moderate and 2% were severe.
AE, adverse event; SAE, serious adverse event.
19
Canakinumab,
N=20
n (%)
15 (75)
4 (20)
3 (15)
2 (10)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
1 (5)
20
Interim results conclusions
 Canakinumab 150 or 300 mg was a rapid and effective treatment in
patients with active TRAPS
− By Day 15: 95% had complete/almost complete response; 100% achieved
clinical remission, median CRP and SAA levels had normalized, and HRQoL
(SF-36) improved; many aspects to general population age/gender matched
norms
− Clinical and serologic remission and improved HRQoL (SF-36) was
maintained with monthly canakinumab dosing
− Upon canakinumab withdrawal, relapses were mostly mild/moderate in
severity and took a median 3 months to occur
− Clinical and serologic response was regained upon re-dosing
 Adverse events were manageable
− A majority of AEs were mild and infections, mostly of upper respiratory tract,
were the most common type of adverse event
 PK/PD data may better define canakinumab optimal dosing to be tested
in long-term treatment period
CRP, C-reactive protein; HRQoL, health-related quality of life; SAA, serum amyloid A.
21
4