Gazing into the Crystal Ball: How will Evolving Future Therapies
Change how we Position Biologics for Use in IBD?
William J. Sandborn, MD
Professor & Chief, Division of Gastroenterology
Director, UCSD IBD Center
Therapies for IBD: the Pipeline
• Anti-Selective Adhesion
Molecule
Anti-integrin antibodies
Etrolizumab (anti-β7)
AMG 181 (anti- β7)
Anti-MAdCAM-1
• S1P1 Receptor modulator
(RPC1063)
• Antagonist to Janus kinase 3
(JAK3)
Tofacitinib
• Anti-Interleukin 12/23
Ustekinumab (CNTO 1275,
Stelara)
• Anti-Interleukin-23
• Anti-interleukin 6
• Anti-IP 10 antibody
•
Eldelumab
Clinical trials of JAK STAT inhibitors (jakinibs) in autoimmunity and cancer
O’Shea, J. J. et al. (2013) Back to the future: oral targeted therapy for RA and other autoimmune diseases Nat. Rev. Rheumatol.
doi:10.1038/nrrheum.2013.7
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 Moderately to Severely Active
Ulcerative Colitis: Clinical Response at Week 8
P<0.001
P=0.10
P=0.39
Sandborn W. New Engl J Med 2012.
Tofacitinib for Moderately to Severely Active
Ulcerative Colitis: Clinical Remission at Week 8
P<0.001
P<0.001
P=0.76
Sandborn W. New Engl J Med 2012.
Tofacitinib for Moderately to Severely Active
Ulcerative Colitis: Endoscopic Response
P=.07
P=.001
P=0.64
Sandborn W. New Engl J Med 2012.
Tofacitinib for Moderately to Severely Active Crohn’s
Disease: Clinical Remission at Week 4
P=.42
P=.54
Sandborn W. Clin Gastroenterol Hepatol 2014
Mean percentage change from baseline in log transformed
CRP (mg/L) in those patients with baseline CRP ≥5 mg/L (B)
Sandborn W. Clin Gastroenterol Hepatol 2014
Mean percentage change from baseline in log transformed
fecal calprotectin (mg/kg) in in those patients with baseline
fecal calprotectin ≥250 mg/kg (B)
Sandborn W. Clin Gastroenterol Hepatol 2014
Tofacitinib: Adverse Events in
Rheumatoid Arthritis
• Severe, sometimes fatal, infections have occurred. Tuberculosis
(TB) and other opportunistic infections have been reported.
• 11 solid cancers and 1 lymphoma were diagnosed among 3328
patients taking tofacitinib with or without a DMARD for ≤12
months, compared to no solid cancers or lymphoma in 809
patients taking a placebo with or without a DMARD for 3-6
months
• Gastrointestinal perforation has been reported during clinical
trials with tofacitinib; patients with a history of diverticulitis may
be at higher risk.
• LDL and HDL cholesterol have increased in patients taking
tofacitinib; cholesterol levels should be checked 4-8 weeks after
starting treatment.
Tofacitinib: Adverse Events in
Rheumatoid Arthritis (Continued)
• Elevations in liver aminotransferase levels have occurred; liver
enzymes should be monitored regularly.
• Lymphocytopenia, neutropenia and low hemoglobin levels can
develop in patients taking tofacitinib. Lymphocytes should be
monitored at baseline and then every 3 months. Neutrophils and
hemoglobin levels should be monitored at baseline, after 4-8
weeks of treatment, and then every 3 months.
• Tofacitinib is classified as category C (risk cannot be ruled out)
for use during pregnancy. It is fetocidal and teratogenic in rats
and rabbits.
Biology of Interleukins 12 and 23
IL-12
Stimulus
TLR?
AntiIL-12/23
p35 p40
IL-12Rb1
b2
Ag
Antigen
Presenting Cell
MHCII
CD4+
TCR
IL-23R
IL-12Rb1
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 (Stelara)
• Approved for psoriasis and psoriatic arthritis
at a dose of 45 mg (90 mg for weight > 100
kg) at weeks 0 and 4 and then every 12
weeks
• Indication is for the treatment of adults with
moderate to severe plaque psoriasis who
are candidates for phototherapy or systemic
therapy
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
Corticosteroid-free Remission at 22 Weeks Following
Treatment with Ustekinumab
Sandborn WJ, et al. N Engl J Med 2012;367:1519-28.
Ustekinumab: Adverse Events in Psoriasis
and Psoriatic Arthritis
• Serious infections requiring hospitalization occurred
including diverticulitis, cellulitis, pneumonia, appendicitis,
cholecystitis, sepsis, osteomyelitis, viral infections,
gastroenteritis and urinary tract infections
• 1.7% of ustekinumab-treated patients reported
malignancies excluding non-melanoma skin cancers (0.60
per hundred patient-years of follow-up). Non-melanoma
skin cancer was reported in 1.5% of ustekinumab-treated
patients (0.52 per hundred patient-years of follow-up).
Malignancies other than non-melanoma skin cancer in
ustekinumab-treated patients were similar in type and
number to what would be expected
Ustekinumab: Adverse Events in Psoriasis
and Psoriatic Arthritis (Continued)
• Reversible Posterior Leukoencephalopathy Syndrome
(RPLS). RPLS is a neurological disorder, which is not
caused by demyelination or a known infectious agent.
RPLS can present with headache, seizures, confusion and
visual disturbances. Conditions with which it has been
associated include preeclampsia, eclampsia, acute
hypertension, cytotoxic agents and immunosuppressive
therapy. One case of RPLS was observed in the clinical
trial safety databases for psoriasis and psoriatic arthritis.
Sphingosine 1‐Phosphate Receptor 1 Modulation
Mechanism of Action
• S1P1R agonism induces receptor
internalization lymphocytes lose response
to S1P gradient
• Become trapped in lymph nodes causing
peripheral lymphopenia
• Upon drug withdrawal receptor expression
is restored and lymphocytes leave nodes
reversing lymphopenia
Courtesy Dr. Alan Olsen
RPC1063 (an S1P receptor modulator)
• RCT of oral RPC1063 at doses of 0.5 mg and 1 mg versus
placebo in 199 patients with moderate to severe UC
• Remission at week 8 in 16.4% on 1 mg dose (p<0.05),
13.8% on 0.5 mg dose (p=NS), and 6.2% on placebo
• Clinical response at week 8 in 58.2% on 1 mg dose
(p<0.05), and 36.9% on placebo
• All other secondary endpoints at week 8, including change
in the Mayo score and mucosal improvement on
endoscopy were also positive and statistically significant for
the 1 mg dose, trends were observed for the 0.5 mg dose
group that demonstrated dose response
Receptos press release October 27, 2014
Conclusions
• Agents targeted against multiple targets
including the p40 subunit of interleukin
12/23, JAK, and S1P receptor hold great
promise for the future