Transcript Biologic Therapy in Crohn's

BIOLOGIC THERAPY
IN CROHN’S DISEASE
ATILLA ERTAN, M.D.
THERAPEUTIC GOALS IN IBD








Clinical improvement
Clinical remission
Corticosteroid weaning
Maintenance of remission
Maintained tissue healing
Decrease in hospitalization & surgical
interventions
Prevention of complications
Change natural course of the disease
HISTORY OF CROHN’S DISEASE
TREATMENT
1979
1980
1993
1994
1995
1998
2004
Sulfasalazine, steroids
Antibiotics, Azathioprine, 6-MP
5-ASA
Budesonide
Mtx
Infliximab
Second generation biologics
TNF Biophysiology

Most TNF is produced by monocytes,
macrophages and lymphocytes. TNF also
produced by intestinal epithelial cell in
response to bacterial invasion.

TNF increases secretion of chemokines,
cytokines and activates adoptosis from the
epithelial cells.

TNF activates adhesion molecules, such as
ICAM-I.
Key Actions Attributed to TNF
Synthesis and Actions of TNF
Mechanism for Antibody
Neutralization of TNF
van Deventer S. Gut. 1997; 40:443-48.
Scallon BJ. Cytokine. 1995; 7:251-59.
Feldman M, et al. Adv Immunol. 1997; 64:283-350.
Monoclonal Antibodies, Fusion Proteins
and Fab' fragments against TNF
Chimeric
monoclonal
antibody
Human
monoclonal
antibody
Human recombinant
receptor/Fc fusion
protein
Humanized
Fab' fragment
VL
Receptor
C
VH
CH1
Constant 2
Fc
IgG1
Fc
Constant 3
PEG
Infliximab
mAb
Adalimumab
mAb
Etanercept
PEG
Certolizumab pegol
Fab'
Chimeric A2 (cA2) Monoclonal
Antibody
Infliximab
Mouse
(Binding Sites for TNF)
Human (IgG1)
 Chimeric


(mouse/human)
IgG1 monoclonal antibody
 Binds to TNF with high specificity, high
affinity, and high avidity
Infliximab in Patients with Crohn’s
Disease
Clinical Response defined as at least a 70-point reduction in CDAI.
Clinical Remission defined as a decline of the CDAI below 150.
Targan S, et al. New Engl J Med.
1997;337:1029-35.
Infliximab in Patients
with Fistulizing Crohn’s Disease
Present D, et al. New Engl J Med. 1999; 340:1398405.
Clinical Response at Week 8, 30
and 54
Proportion of Patients (%)
ACT 1
100
80
*p<0.001
**p=0.002
69 *
62 *
60
40
52* 51**
45.5 *44.3 *
37
30
19.8
20
0
Week 8
Placebo
Week 30
Week 54
5 mg/kg Infliximab
10 mg/kg Infliximab
Rutgeerts P et al. NEJM. 2005;353(23):30-44.
Clinical Remission at Week 8, 30
and 54
Proportion of Patients (%)
ACT 1
100
80
*p<0.001
**p=0.002
†p=0.001
60
38.8 *
40
20
33.9 †36.9
32**
14.9
15.7
*
†
†
34.7 34.4
16.5
0
Week 8
Placebo
Week 30
5 mg/kg Infliximab
Week 54
10 mg/kg Infliximab
Rutgeerts P et al. NEJM. 2005;353(23):30-44.
Patients in Clinical Remission at
Week 54
Week 2 Responders
Clinical Remission with Steroid
Withdrawal at Week 54
Week 2 Responders Receiving Steroids at Baseline
082201.1 Lindenbaum (on screen) 15
Maintenance Therapy was
Associated with Greater
Mucosal Healing
Rutgeerts, et al. Gastroenterology 2004;126:402-413.
Number of Crohn’s-related
Hospitalizations per 100 Patients
All Randomized Patients
Rutgeerts, et al. Gastroenterology 2004;126:402-413.
Maintenance Therapy Is
Associated with Fewer CD
Surgeries
Rutgeerts, et al. Gastroenterology 2004;126:402-413.
Conclusions
 The ACCENT
I trial proves that when
REMICADE® (infliximab) is dosed every
8 weeks, patients are more likely to




Maintain clinical remission
Discontinue steroids
Maintain clinical response
Achieve mucosal healing
 REMICADE

maintenance is safe
Results consistent with earlier experience
Rutgeerts, et al. Gastroenterology 2004;126:402-413.
Conclusions cont.
 Regular
maintenance treatment with 5 or
10 mg/kg REMICADE® (infliximab)
substantially reduces the rate and
duration of hospitalization in Crohn’s
disease patients, compared with single
infusion plus episodic retreatment with 5
mg/kg
Rutgeerts, et al. Gastroenterology 2004;126:402-413.
Conclusions cont.
 Regular
maintenance treatment with 5 or
10 mg/kg REMICADE may reduce the
number of all surgeries/procedures in
Crohn’s disease patients, compared with
single infusion plus episodic retreatment
with 5 mg/kg
Infusion Reactions
Important Safety Information:
Hypersensitivity
Infliximab should not be administered to patients
with hypersensitivity to murine proteins or other
components of the product. Infliximab has been
associated with hypersensitivity reactions that
differ in their time of onset. Acute urticaria,
dyspnea, and hypotension have occurred in
association with Infliximab infusions. Serious
infusion reactions including anaphylaxis were
infrequent. Medications for the treatment of
hypersensitivity reactions should be available.
TREAT Registry
Infusion Reactions
Infliximab
infusions:
20,309
Infusions with reactions:
4.6%
Infusions with serious reactions: 0.12%
Lichtenstein GR, et al. Gastroenterology. 2005;128(4):A-580.
Infections
INFECTIONS DURING INFLIXIMAB THERAPY
(n=170.000)
INFECTION
Myobacterium tbc
Pneumocystis carinii
Listeria monocytogenes
Histoplasmosis
Candidiasis
Aspergillosis
Cryptococcosis
Coccidioidomycosis
n
84
12
11
9
7
6
2
2
Tuberculosis: Context

Patient Screening


Every patient being considered for an anti-TNF
agent requires screening
Thorough screening may reveal potential risks:
• Past exposure
• TB treatment
• Place of birth and travel history

Why is TB reactivation still occurring?
• Many cases occur in patients who were not adequately
screened and prophylaxed
• Some cases occur in patients with false-negative screening
tests


TB should always be considered in all immunosuppressed
patients, even if their screening PPD was negative
Monitoring for potential infections is always
required when treating patients with
immunosuppressive drugs
JAMA. 2004;292(14):1676-1678.
Serious Infections: Context
Other IBD Immunosuppressive
Agents
 Annual
rate of serious infections in
infliximab-treated patients 6.4%
 There is also an increased risk of serious
infections with other IBD
immunosuppressive agents
 Many conventional therapies for Crohn’s
disease have not been well studied in
clinical trials
Malignancy &
Lymphoma
Lymphoma in CD Patients
CD Publication
Relative incidence of
lymphoma
Greenstein, 1985
4.7- fold increase
Mellemkjaer, 2000
1.5- fold increase
Lewis, 2001
1.4- fold increase
Bernstein, 2001
2.4- fold increase
Malignancies and Lymphomas:
Other Treatments
Treatment
AZA1
6-MP2
6-MP3
Cancer
(% of patients)
4.1%
6.3%*
3.1%
*Including 0.7% with lymphoma
1Connell
2Warman JI.
WR et al., Lancet. 1994;343:1249–52.
3Present D et al.,
J Clin Gastroenterology. 2003;37(3):220–225.
Annals of Internal Medicine. 1989;111:641–9.
Clinical Trials
Malignancies in Controlled Portions
of Clinical Trials Compared with
General Population
Patientyears of F/U
Expected #
From SEER
Database**
General U.S.
Population
Observed
Number in
Infliximab Trials
Placebo
892
5.65
1
Infliximab
4990
29.04
29
32
**Excludes non-melanoma skin cancers because also excluded in SEER database
Data on file, Centocor, Inc.
Malignancy: Context




At the present time, it is not possible to be certain
whether the use of anti-TNF agents increases a
patient’s chance of developing a malignancy
There is also concern conventional
immunomodulators may increase the risk of
malignancy
Risks must always be weighed against the risks of
inadequate treatment of the underlying disease
Caution should be exercised when treating any
patient with a current or past history of malignancy
Certolizumab pegol

Humanized PEGylated Fab' fragment of
an anti-TNF-αmonoclonal antibody

Single Fab' fragment



Molecular structure of certolizumab pegol
The chains of the Fab' fragment are shown in
green and blue and the PEG is shown in yellow
© UCB 2006. All rights reserved.

engineered for production in E.coli

no need for glycosylation of Fc portion
2 x 20 kD PEG

to extend half life (ca. 2 weeks) to a
value compared with a whole antibody
product

compatible with sc administration
Site specific PEGylation

to hinge thiol

using proprietary linkage technology
In vitro no monocytes and lymphocytes
apoptosis, no complement activation,
no ADCC
Chapman A et al., Nature Biotech 1999; 17: 780-3
Fossati G and Nesbitt AM. Am J Gastroenterol 2005;100 (Suppl 9):S299
Monoclonal Antibodies, Fusion Proteins
and Fab' fragments against TNF
Chimeric
monoclonal
antibody
Human
monoclonal
antibody
Human recombinant
receptor/Fc fusion
protein
Humanized
Fab' fragment
VL
Receptor
C
VH
CH1
Constant 2
Fc
IgG1
Fc
Constant 3
PEG
Infliximab
mAb
Adalimumab
mAb
© UCB 2006. All rights reserved.
Etanercept
PEG
Certolizumab pegol
Fab'
Adapted with permission from: Hanauer. Rev
Gastroenterol Disord 2004; 4 (supp 3): S18-24
Phase II: Clinical Response
in Patients (ITT)
Placebo (N=73)
Certolizumab pegol 400 mg (N=72)
% of Patients
100
80
60
p=0.005
p=0.010
p=0.006
40
p=0.010
20
0
0
2
4
6
8
10
12
Weeks
© UCB 2006. All rights reserved.
Adapted from: Schreiber et al. Gastroenterology. 2005;29(3):807
Phase II: Clinical Response in Patients
(Baseline CRP 10 mg/L)
Placebo (N=28)
Certolizumab pegol 400 mg (N=32)
% of Patients
100
p=0.004
80
p<0.001
p<0.001
p<0.001
p=0.005
p=0.002
60
40
20
0
0
2
4
6
8
10
12
Weeks
© UCB 2006. All rights reserved.
Adapted from: Schreiber et al. Gastroenterology. 2005;29(3):807-18
PRECiSE 2: Clinical Response
at Week 26 (ITT)
3 inj. Certolizumab pegol + Placebo
% of Patients
100
80
Certolizumab pegol 400 mg sc
p<0.001
62.8
p<0.001
61.6
60
40
36.2
33.7
20
0
CRP 10 mg/L
All
(n=210)
(n=215)
(n=101)
(n=112)
Schreiber, et al. Gut 2005; 54 (Suppl VII) A82
PRECiSE 2: Clinical Response at
Week 26 by Prior Anti-TNF Use
Certolizumab pegol 400 mg
100
p<0.001
68.7
% of Patients
80
3 inj. Certolizumab pegol
+ Placebo
P=0.018
60
44.2
39.6
40
25.5
20
0
No prior Anti-TNF
(n=159)
© UCB 2006. All rights reserved
(n=163)
Prior Anti-TNF (IFX)
(n=51)
(n=52)
UCB, Inc. Data on File
PRECiSE 2: Conclusions
 PRECiSE
2 demonstrated that in the
clinical trial certolizumab pegol
induced clinical response and
maintained clinical response and
remission in patients with active
Crohn’s disease, regardless of
baseline CRP level.
PRECISE 2: Conclusions cont.
 Certolizumab
demonstrated efficacy
across a broad patient population
and well tolerated safety profile.
 Certolizumab
400 mg q 4wk with an
additional induction dose at wk 2, will be
a valuable addition to the Crohn’s
disease treatment armamentarium,
when approved.
(Pegylated antibody fRagment
Evaluation
in Crohn’s disease Safety and
Efficacy)
 PRECiSE
1 and 2 are large
international, Phase III, placebocontrolled studies designed to
demonstrate the safety and efficacy
of certolizumab pegol in inducing and
maintaining response and remission
in patients with moderate to severe
BIOLOGICS (TNF-Abs) In CROHN'S DISEASE
Name
Humanized
Route antibody % Efficacy
Immunogenicity
INFLIXIMAB/REMICADE
IV
75
Yes
High
CERTOLIZUMAB/CIMZIA
SC
100
Yes
Low
ADALIMUMAB/HUMIRA
SC
100
Yes
Low
ETANERCEPT
No
ONERCEPT
No
CD571
No
Infliximab Benefit:Risk in IBD:
Summary
 The
natural history of inflammatory bowel
disease results in a poor quality of life for
many patients
 Infliximab has been a major advance in
treating IBD
 Infliximab therapy is associated with
risks, but these risks must be placed in
context:


Benefits patients derive from infliximab
Risks of under-treating IBD
Clinical Trials
Infections in All Completed Clinical Trials
Placebo
Infliximab
1600
29.0
115.6
54.8
5706
45.5
132.3
61.2
# serious infections per 100 pt-yrs 5.6
Pneumonia
0.11
Abscess
0.45
Cellulitis
0.45
Sepsis
0.22
Tuberculosis
0.11
6.4
1.08
0.84
0.32
0.32
0.38
Patients treated
Average wks follow-up
# infections per 100 pt-yrs
# infections requiring
treatment per 100 pt-yrs
Data on file, Centocor, Inc.
Important Safety Information:
Risk of Infection
Tuberculosis (tb) (frequently disseminated or
extrapulmonary at clinical presentation), invasive fungal
infections, and other opportunistic infections, have been
observed in patients receiving infliximab. Some of these
infections have been fatal. Patients should be evaluated
for latent tb infection with a skin test.1 treatment of latent
tb infection should be initiated prior to therapy with
infliximab. Active tb has developed in patients receiving
infliximab who were tuberculin skin test–negative prior to
receiving infliximab. Monitor patients receiving infliximab
for signs and symptoms of active tb, including those who
are tuberculin skin test–negative.
1American
Thoracic Society, Centers for Disease Control and Prevention. Targeted tuberculin testing and treatment of latent
tuberculosis infection.Am J Respir Crit Care Med. 2000;161:S221–S247.
47
Lymphomas Observed
During Infliximab Clinical Trials
Pt Yrs
followup
Observed
Lymphomas
Expected
Lymphomas in
Non-RA
Population*
All
Studies
4996
5
1.10
RA
Studies
2428
2
0.62
Data on file, Centocor, Inc.
Important Safety Information:
Contraindications
Infliximab is contraindicated in patients with moderate
to severe (NYHA Class III/IV) congestive heart failure
(CHF) at doses greater than 5 mg/kg. Higher
mortality rates at the 10 mg/kg dose and higher rates
of cardiovascular events at the 5 mg/kg dose have
been observed in these patients. Infliximab should be
used with caution and only after consideration of
other treatment options. Patients should be
monitored closely. Discontinue infliximab if new or
worsening CHF symptoms appear. Infliximab should
not be administered to patients with hypersensitivity
to murine proteins or other components of the
product.
Important Safety Information:
Hepatotoxicity
Severe hepatic reactions, including acute liver failure,
jaundice, hepatitis, and cholestasis have been reported
rarely in patients receiving infliximab postmarketing. Some
cases were fatal or required liver transplant.
Aminotransferase elevations were not noted prior to
discovery of liver injury in many cases. Patients with
symptoms or signs of liver dysfunction should be evaluated
for evidence of liver injury. If jaundice and/or marked liver
enzyme elevations (e.g., 5 times the upper limit of normal)
develop, infliximab should be discontinued, and a thorough
investigation of the abnormality should be undertaken.
Infliximab has been associated with reactivation of hepatitis
B. Chronic carriers of hepatitis B should be evaluated and
monitored prior to and during treatment.
Important Safety Information:
Neurologic Events
TNF inhibitors, including infliximab, have
been associated with rare cases of new or
exacerbated symptoms of demyelinating
disorders including multiple sclerosis, and
optic neuritis, seizure, and CNS
manifestations of systemic vasculitis.
Exercise caution when considering
infliximab in all patients with these
disorders. Consider discontinuation for
significant CNS adverse reactions.
Rationale for Protocol C87042
 Infliximab
(IFX), a chimeric monoclonal
antibody against TNF-alpha, is the only
approved biological therapy for treatment of
Crohn’s disease.
 IFX
contains substantial murine protein
sequences in the variable region. Thus, it is
immunogenic and intermittent administration
results in antibodies to IFX (ATIs).
 Humanized
monoclonal antibodies are
relatively less immunogenic than chimeric
Baert F, et al. NEJM 2003; 348: 601-8; Farrell RJ, et al. Gastroenterology 2003; 124:917-24;
Hanauer S, et al. Gastroenterology 1999; 116: A731; Breedveld FC, Lancet 2000; 355:735-740.