1 benefit-risk of crohn’s disease therapeutics william sandborn, md mayo clinic and mayo college...
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Benefit-Risk of Crohn’s Disease Therapeutics
William Sandborn, MDMayo Clinic and
Mayo College of MedicineRochester, MN, USA
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Back up slides shown
3CD303: Response and Remission at Month 6
37
30 30
18
67
56 55
47
0
10
20
30
40
50
60
70
80
Overall TNF-F Overall TNF-F
Placebo
Natalizumab
Pe
rce
nt
Response Remission
P ≤ 0.001
N=40 N=32 N=40 N=32
P ≤ 0.001
P = 0.006
P = 0.016
N=171 N=168 N=171 N=168
CD303
4CD303: Response and Remissionat Month 12
2420 22
18
59
5055
47
0
10
20
30
40
50
60
70
80
Overall TNF-F Overall TNF-F
Placebo
Natalizumab
Pe
rce
nt
Response Remission
P ≤ 0.001 P = 0.006 P ≤ 0.001
P = 0.006
N=171 N=168 N=171 N=168N=40 N=32 N=40 N=32
CD303
5CD307: Response by Varying CRP Cut-Point
CRP Cutoff (mg/dl)
Placebo Response (%)
Natalizumab Response (%)
P-value
2.87 (n=477) 32 49 <0.001
5 (n=415) 32 51 <0.001
10 (n=283) 29 53 <0.001
15 (n=235) 30 52 <0.001
20 (n=187) 28 53 <0.001
25 (n=147) 23 56 <0.001
50 (n=51) 13 56 0.003
CD307
6CD301: CRP - Response in patients with disease
confined to the ileum
2730
33
37
50 50
39
44
5351 52
56
20
25
30
35
40
45
50
55
60
2 4 6 8 10 12
Placebo (n=30)
Natalizumab (n=135)
Pa
tie
nts
(%
)
Time (weeks)
7CD301: Week 10 Response by Baseline CRP
ITT population - LOCF
35
40
45
50
55
60
65
0 5 10 15 20 25 30
NatalizumabPlacebo
p<0.05 for all thresholds but CRP=9, 11
Pa
tient
s in
Res
pon
se (
%)
C-Reactive Protein Baseline Threshold Level (mg/L)
8
Pulmonary Aspergillosis 75-year-old male with Crohn’s disease had received
10 infusions of natalizumab
– Concomitant NSAID use and high-dose steroids in tapering regimen
Perforated duodenal ulcer, severe GI hemorrhage, and peritonitis 1 month following last dose of natalizumab
Spent several weeks in hospital, including ICU
– CT of lungs showed bilateral infiltrates
– Sputum culture revealed Aspergillus sp
Patient developed multi-organ failure and died 3 months after last dose of natalizumab
CD301 / 303 / 351
9
Pneumocystis carinii Pneumonia 69-year-old male with Crohn’s disease had received 34
infusions of natalizumab
History of cirrhosis due to nonalcoholic steatohepatitis with varices, portal hypertension, splenomegaly, and ascites
– Developed hepatic encephalopathy 1 month after last dose of natalizumab
– Natalizumab stopped; patient treated and recovered
Hospitalized 1 month later with hepatic encephalopathy, acute renal failure, and anemia
– Treated in ICU, intubated, and transfused
– Sputum culture revealed PCP
– Developed multi-organ failure and died
CD301 / 303 / 351
10
Burkholderia cepacia Pneumonia 62-year-old woman with CD, type II DM, HT, and
tobacco use– Received 3 infusions of natalizumab
– Developed non-productive cough with dyspnea
– Cardiomegaly, hydrothorax, pulmonary vessel congestion with atelectasis
• Diagnosed and treated as CHF
– Bronchoscopic lavage revealed Burkholderia cepacia
• Treated with antibiotics
11Table 13 Efficacy of Natalizumab: Effect of
Concomitant Immunosuppressants
No Immunosuppressants at Baseline1
Immunosuppressants at Baseline1
n/N (%) Natalizumab Placebo p-value Natalizumab Placebo p-value
Induction (CD307) (ITT Population)2
Response 81/162 (50) 49/153 (32) 0.001 43/97 (44) 32/97 (33) 0.106
Remission 41/162 (25) 25/153 (16) 0.052 27/97 (28) 15/97 (15) 0.039
Maintenance (CD303) (Efficacy Population)3
Response 58/106 (55) 20/110 (18) <0.001 32/62 (52) 14/60 (23) 0.002
Remission 32/79 (41) 12/77 (16) <0.001 19/51 (37) 6/43 (14) 0.0141.Patients on immunosuppressants at baseline had to be given a stable dose of immunosuppressants (azathioprine, 6-MP or methotrexate) during induction and maintenance2. Proportion of patients in response (or remission) at both Weeks 8 and 12 3. Proportion of patients in response (or remission) at Month 3 who maintained response (or remission) through 12 additional months of therapy to Month 15.p-values are from logistic regression Source: CD307, Tables 37 and 38; CD303, Section 15.2, Tables 2.16c and 2.17c
12CD303: Response and Remission at Months 6 and 12Tertiary Endpoints
37
24
30
22
67
5955 55
0
10
20
30
40
50
60
70
80
Month 6 Month 12 Month 6 Month 12
Placebo (n=170) Natalizumab (n=168)
Pa
tie
nts
(%
)Response Remission
P ≤ 0.001P ≤ 0.001P ≤ 0.001P ≤ 0.001
13CD307: Response in Anti-TNF Failure Subgroups
(Weeks 8 +12)
Placebon/n (%)
Natalizumabn/n (%)
OR
ITT 81/250 (32) 124/259 (48) 1.9
All TNF - F 12/83 (14) 34/89 (38) 3.7
Intolerant 4/38 (11) 16/36 (44) 6.7
Unresponsive 8/45 (18) 18/53 (34) 2.4
w/o immuno-suppressants
7/51 (14) 22/54 (41) 4.5
with immuno-
suppressants
5/32 (16) 12/35 (34) 2.8
FavorsPlacebo
Favors Natalizumab
0.1 1 10 100
On immuno-suppressants
No immuno-suppressants
Unresponsive
Intolerant
TNF-F
ITT
Log Odds Ratio
14CD301: CRP - Response for Patients with
No response to initial TNF therapy
8
15 15
23 23
15
26
3840
48
38
49
0
5
10
15
20
25
30
35
40
45
50
2 4 6 8 10 12
Placebo (n=13)
Natalizumab (n=55)
Pa
tie
nts
(%
)
Time (weeks)