Transcript Novel Therapeutic Agents State Of The Art Targeting

Positioning our recent and future advances in
therapies for Crohn’s disease
William J. Sandborn, MD
Professor & Chief, Division of Gastroenterology
Director, UCSD IBD Center
Recent and future advances
• Azathioprine – new data
• Deep remission and treat to target
• New agents
Mild to moderate disease
Rifaximin EIR
Moderate to severe disease
Vedolizumab (anti-alpha 4 beta 7)
Ustekinumab (anti-interleukin 12/23
Tocilizumab (anti-interleukin 6)
Tofacitinib (Janus Kinase [JAK] inhibitor)
Eldelumab (Anti-IP 10)
Top Down Therapy With Azathioprine + Prednisone Versus
Step Up Therapy With Prednisone And Then Azathioprine In
Adults With Newly Diagnosed Crohn’s Disease
Cosnes J. Gastroenterology 2013
Top Down Therapy With Azathioprine + Prednisone
Versus Prednisone In Adults With Newly Diagnosed
Crohn’s Disease
Sustained steroid free remission
Survival free of relapse
Panes J. Gastroenterology 2013
Treat-to-Target Algorithm
)
CRP, C-reactive protein.
Bouguen G, et al. Clin Gastroenterol Hepatol. 2013 Sep 10. [Epub Ahead of Print]
Rifaximin Extended Intestinal Release for
Crohn’s Disease: Results at Week 12
Prantera C, et al. Gastroenterology 2012
Therapeutic Targets for Lymphocyte Trafficking
Leucocyte Adhesion
NATALIZUMAB
CD 11a/CD18
VEDOLIZUMAB
LEUCOCYTE
41
(VLA-4)
47
ISIS-2302
CCX282-B
CCR9
MAdCAM mAb (PF547659)
ICAM-1
CCL-25
MAdCAM-1
ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS
Adapted from Danese S Gut 2011;60:998-1008
ETROLIZUMAB
VCAM-1
Vedolizumab: A Humanized, Monoclonal Antibody
(mAb) Against 47 Integrins
N
• Targets only a4b7 integrin
• Created by insertion of ACT1 CDRs into human IgG1
framework
• Two amino acid substitutions
abrogate Fc-receptor binding
and complement fixation
(ADCC)
• IV infusion over 30 – 60
minutes
N
N
CDR1
CDR2
CDR3
N
VH
VL
CH1
CL
C
C
CH2
CH3
C
C
Vedolizumab For Active Crohn’s Disease
Response and Remission at Week 8
P=NS
P=0.04
Response or
Remission (%)
• 185 patients with active Crohn’s
disease receiving a stable dose of 5ASA or antibiotics or no medical
therapy
• Randomized to receive IV doses of
placebo, 0.5 mg/kg, or 2.0 mg/kg MLN02 on days 1 and 29
• The primary endpoint was % clinical
response (decrease in CDAI of 70
points) at day 57
• Secondary endpoint was % remission
(CDAI < 150) at day 57
• Saturation of 47 on peripheral blood
lymphocytes was not consistently
achieved
Feagan Clinical Gastroenterology & Hepatology 2008
Vedolizumab For Active Crohn’s Disease
Remission at Week 8
*
* p-value < 0.05
ITT population
*
*
Feagan Clinical Gastroenterology & Hepatology 2008
MLN0002 induced a
significantly
greater clinical
remission rate in
patients with
Crohn’s disease
compared to
placebo (2 mg/kg
group) at days 15,
29, and 57.
Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely
Active Crohn’s Disease: Results at Week 6 in 368 Patients
Induction ITT Population
Patients, %
P=0.23
P=0.02
95% CI:
Δ 7.8
1.2, 14.3
Δ 5.7
–3.6, 15.0
Sandborn W.
N Engl J Med 2013
Vedolizumab (Anti- 47 Integrin) For Maintenance of Response in Moderately-toSeverely Active Crohn’s Disease: Results at Week 52 in 461 Patients
Maintenance ITT Population
*
**
**
**
*
Patients, %
*
Δ17.4 Δ14.7
Δ13.4 Δ15.3
Δ15.9 Δ12.9
Δ7.2 Δ2.0
*P<0.05 **P<0.01
†CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.
Sandborn W.
N Engl J Med 2013
Other Drugs in this Class
• Anti-MAdCAM1 (PF-00547,659)
• Etrolizumab (anti-7, rhumab beta 7)
• Anti-7 (AMG181)
Biology of Interleukins 12 and 23
IL-12
Stimulus
TLR?
AntiIL-12/23
p35 p40
IL-12R1
2
Ag
Antigen
Presenting Cell
MHCII
CD4+
TCR
IL-23R
IL-12R1
p19
p40
IL-23
AntiIL-12/23
X
IFNg
(Th1)
IL-17
(Th17)
Anti-IL-12/23
• Ustekinumab and
briakinumab are fully
human IgG1 monoclonal
antibodies
• Bind the p40 subunit of
human IL-12/23
• Prevent IL-12 and IL-23
from binding IL-12Rb1
• Normalize IL-12 and IL23 mediated signaling,
cellular activation, and
cytokine production
• In development in
Crohn’s disease and
psoriasis
Ustekinumab (anti-IL 12/23p40) for Induction of Clinical
Response in Moderate to Severe Crohn’s Disease
All Patients
60
P=.02
P=.019
P=.335
P=.337
20
0
2
4
6
Weeks
1.2
100
Infliximab-Experienced
Patients (%)
80
40
Previously Treated with Infliximab
Placebo
Ustekinumab
Median CRP (mg/dL)
Patients (%)
100
80
60 P=.046
P=.001
P=.004
P=.022
4
6
8
40
20
0
2
8
CRP in All Patients
Weeks
Week 0
Week 8
1.0
0.8
0.6
0.4
0.2
0
Subcutaneous
Intravenous
Placebo
Subcutaneous
Intravenous
Ustekinumab
Sandborn WJ. Gastroenterology 2008;135:1130-1141.
Ustekinumab (Anti-IL-12/23p40) for Induction of Moderate to Severe
Crohn’s Disease
Clinical Response
Clinical Remission
+
+
+
+
+
+ +
+
+
+
+p<0.05 vs. PBO by CMH test
Sandborn WJ. N Engl J Med 2012; 367:1519-1528
Ustekinumab (Anti-IL-12/23p40) for Maintenance of
Moderate to Severe Crohn’s Disease
p<0.001
p=0.029
Sandborn WJ. N Engl J Med 2012; 367:1519-1528
Tofacitinib an Oral Janus Kinase (JK) Inhibitor
Cytokine
α
γ
β
JAK
P
STAT
STAT
STAT
JAK
P
STAT
P
Tofacitinib blocks
phosphorylation of
STAT and
downstream
activation
P
mRNA
P
Cytokine
Effects on the immune system
IL-2
Stimulate the proliferation and differentiation of Th, Tc, B,
and natural killer (NK) cells
IL-4
Induce the differentiation of Th0 to Th2
Induce immunoglobulin switching
IL-7
Promote the development, proliferation and survival of T,
B, and NK cells
IL-9
Stimulate intrathymic T cell development
IL-15
Promote the proliferation, cytotoxicity and cytokine
production of NK cells
IL-21
Enhance T and B cell function
 Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor
 Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3
over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of
pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21
Sandborn W. New England Journal of Medicine 2012
Tofacitinib for Induction in Moderate to Severe Crohn’s
Disease: Clinical Response and Remission at Week 4
Clinical
Response-70
Estimated
clinical
response
rate (80%
CIs)
Clinical
Response-100
49.9%
60
42.9%
48.0%
44.8%
50
60
40.8%
50
33.7%
40
40
30
30
20
20
10
10
N=34
N=36
N=34
N=35
0
38.8%
28.1%
N=34
N=36
N=34
N=35
0
Placebo
1 mg
BID
5 mg
BID
Tofacitinib
Sandborn W. Gastroenterology 2011 Abstract
15 mg
BID
Placebo
1 mg
BID
5 mg
BID
Tofacitinib
15 mg
BID
Mean percentage change from baseline in log transformed
CRP (mg/L) in those patients with baseline CRP ≥5 mg/L (B)
Sandborn W. Gastroenterology 2011 Abstract
Tocilizumab (Humanized Monoclonal Antibody Interleukin-6 Receptor –
Previously Atlizumab or MRA) For Active Crohn’s Disease
• 36 patients with active Crohn’s
disease (CDAI > 150, ↑ CRP)
• Randomized to receive IV placebo,
tocilizumab (previously atlizumab,
MRA) 8 mg/kg every 2 weeks, or
atlizumab 8 mg/kg every 4 weeks
for 12 weeks
• The endpoints were % response
(decrease in CDAI  70) and
remission (CDAI  150) at week 12
• Frequency of adverse events
similar in all groups
P=0.019
P=NS
Ito Gastroenterology 2004
Other Drugs in this Class
• BMS-945429 (fully human antibody to interleukin-6)
• PF-04236921 (fully human IgG2 antibody to interleukin-6)
Interferon Gamma Inducible Protein 10
(IP-10 or CXCL-10)

Belongs to CXC family of chemokine ligands
 Induced by IFN- and produced by various cell types including hematopoietic & stromal
cells
 Mechanism of action


CXCR3-mediated recruitment of T cells to inflamed tissues
CXCR3-independent (or dependent) modulation of functions of other cells including
epithelial, endothelial and islet  cells
CXCR3
IP-10
Unidentified
receptor
Heparan
sulfate
TLR4 (?)
T cell
↑ Trafficking
Epithelial
↓ Proliferation
& Migration1,2
Endothelial
↓ Proliferation3
Islet  cell
↑ Apoptosis4
1 Suzuki et al. Pathology International 2007; 57(7):413-420; 2. Soejima et al, J Immun 2001; 167:6576-6582;
3. Luster et al. J Exp Med 1995; 182:219-231; 4. Schulthess et al. Cell Metabolism 2009;9(2):125-139
Drug in this Class
• Eldelumab (fully human antibody to IP-10)
Conclusions
• Top down therapy with steroids and
azathioprine is not effective in adults with
newly diagnosed Crohn’s disease
• Treatment goals in Crohn’s disease are
evolving towards deep remission achieved
via a treat to target strategy
• Agents targeted against multiple targets
including beta 7 integrin, MAdCAM-1, and
the p40 subunit of interleukin 12/23, and
possibly JAK, IP-10, and interleukin-6, hold
great promise for the future