Optimizing Management of IBD: Beyond Anti-TNFs · Managing IBD in 2016: An evolution in IBD care...
Transcript of Optimizing Management of IBD: Beyond Anti-TNFs · Managing IBD in 2016: An evolution in IBD care...
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Optimizing Management of IBD: Beyond Anti-TNFs
Remo Panaccione, MD, FRCPC Director, Inflammatory Bowel Disease Clinic
Professor of Medicine University of Calgary
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Disclosures: R. Panaccione
Consultant for: AbbVie, ActoGeniX, AGI Therapeutics, Alba Therapeutics Albireo, Alfa Wasserman, Amgen, AM-Pharma BV, Anaphore,
Aptalis, Astellas, Athersys, Atlantic Healthcare, BioBalance, Boehringer-Ingelheim, Bristol-Myers Squibb, Celgene, Celek, Cellerix, Cerimon,
ChemoCentryx, CoMentis, Cosmo Technologies, Coronado Biosciences, Cytokine Pharmasciences, Eagle, Eisai Medical Research, Elan,
EnGene, Eli Lilly, Enteromedics, Exagen Diagnostics, Ferring, Flexion Therapeutics, Funxional Therapeutics, Genentech, Genzyme, Gilead,
Given Imaging, GlaxoSmithKline, Human Genome Sciences, Ironwood, Janssen, KaloBios, Lexicon, Lycera, Meda, Merck & Co., Merck
Research Laboratories, MerckSerono, Millennium, Nisshin Kyorin, Novo Nordisk, NPS Pharmaceuticals, Optimer, Orexigen, PDL Biopharma,
Pfizer, Procter and Gamble, Prometheus Laboratories, ProtAb, Purgenesis Technologies, Receptos, Relypsa, Salient, Salix, Santarus, Shire
Pharmaceuticals, Sigmoid Pharma, Sirtris (a GSK company), S.L.A. Pharma (UK), Targacept, Teva, Therakos, Tillotts, TxCell SA, UCB Pharma,
Vascular Biogenics, Viamet and Warner Chilcott UK.
Speaker’s fees for: Abbvie, Aptalis, AstraZeneca, Ferring, Janssen, Merck, Prometheus, Shire, Takeda
Advisory Board for: Abbvie, Abbott, Amgen, Aptalis, AstraZeneca, Baxter, Biogen Idec, Eisai, Ferring, Genentech, Janssen, Merck, Shire, Elan, Glaxo-Smith Kline, Hospira, Pfizer, Bristol-Myers Squibb, Takeda, Cubist, Celgene, Salix
Research/Educational Support from: Abbvie, Ferring, Janssen, Shire Takeda
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Objectives
1. Discuss new treatment targets in IBD
– Where we were
– Where we are
– Where we are going
2. Review the latest data that will impact your clinical practice in 2016 and beyond
3. Discuss positioning of new therapies in IBD
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Managing IBD in 2016: An evolution in IBD care
5-ASA Steroids Azathioprine1 Anti-TNFs for CD
Vedolizumab for CD5
Surgery
1995 2000 2005 2010 2015/16
1. Mulder DJ, et.al. A tale of two diseases: The history of inflammatory bowel disease. J Crohn Colitis 2013; 8:341–348 2. Botoman AV, et al. Management of Inflammatory Bowel Disease. Am Fam Physician 1998;57:57–68 3. National Institute for Health and Care Excellence technology appraisal guidance [TA40]: The clinical effectiveness and cost effectiveness of infliximab for Crohn's Disease https://www.nice.org.uk/guidance/ta40. 4. National Institute for Health and Care Excellence technology appraisal guidance [TA329]: Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerative colitis
after the failure of conventional therapy (including a review of TA140 and TA262): http://www.nice.org.uk/guidance/ta329/chapter/about-this-guidance. 5. National Institute for Health and Care Excellence technology appraisal guidance [TA342] - Vedolizumab for treating moderately to severely active ulcerative colitis. June 2015. http://www.nice.org.uk/guidance/ta342. Last
accessed June 2015.
5-ASA Steroids Azathioprine, Cyclosporin1,2
Anti-TNFs for UC
Crohn’s disease (CD)
Vedolizumab for UC5 Anti-TNFs for CD Initial report Biosimilars
Ulcerative Colitis (UC)
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Introducing Biological Therapy: Where we were
The biologic revolution began over 15 years ago with the approval of infliximab for the treatment of moderate to severe CD1.
Despite the development and approval of “newer” anti TNFs, the overall induction of remission in RCTs was ~30-50%2-5 and maintenance of remission was ~20-40%.6-10
Therefore there is a need to develop new agents for the treatment of IBD.
1. Schreiber S, et al. Gastroenterology 2005;129:807–18. 2. Sandborn WJ, et al. N Engl J Med 2007;357:228–38. 3. Hanauer SB, et al. Gastroenterology 2006;130:323–33. 4. Targan SR, et al. N Engl J Med 1997;337:1029–35.
. 1. Schreiber S, et al. N Engl J Med 2007;357:239–50. 2. Hanauer SB, et al. Lancet 2002;359:1541–9. 3. Colombel JF, et al. Gastroenterology 2007;132:52–65. 4. Sandborn WJ, et al. N Engl J Med 2007;357:228–38.
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Where we are: Lessons learned during the anti-TNF era
Anti-TNFs are safe
Antibodies are bad; adequate drug levels are good
There is value in combination therapy
Treating early is better
We can treat beyond symptoms
We can decrease surgical /hospitalization rates
We do better in real life than in clinical trials
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Retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry. Probability of surgery over time after anti-TNF prescription depending on phenotype at prescription (B1=inflammatory, B2=stricturing, B2L1=ileal stricturing , B3=penetrating)
Phenotypic features of Crohn's disease associated with anti-TNF treatment failure
Moran, Panaccione et al. Clin Gastroenterol Hepatol 2014 Mar;12(3):434-42
Cu
mu
lati
ve p
rob
abili
ty o
f m
ajo
r ab
do
min
al s
urg
ery
(%
)
Follow-up in years 0
0 1 2 3 4 5
0.1
0.2
0.3
0.4
0.5
B2 B2L1
B3
B1
8
0
Khanna R, et al. Lancet 2015
Time to first hospitalisation, surgery or complication
CM ECI
0 0 3 6 9 12 15 18 21 24
10
20
30
40
Time (months)
Ho
spit
alis
atio
n,
surg
ery
or
com
pli
cati
on
s (%
)
HR (95% CI) = 0.73 (0.62, 0.86), p<0.001
Baseline
20
40
60
80
100
Month 6 Month 12 Month 18 Month 24
p=0.790 p=0.498 p=0.389 p=0.250
Pat
ien
ts (
%)
Conventional management Early combined immunosuppression
Symptomatic remission (HBI≤4 and no corticosteroids)
20 practices 20 practices
60 patients per practice
Accelerated care treatment algorithm Usual care
REACT cluster randomisation: 898 CD in conventional management vs 1094 CD in early combined immunosuppression
Randomised Evaluation of an Algorithm for Crohn’s Treatment (REACT 1)
34.7% 27.4%
8
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Temporal trend analysis of colectomy rates: stratified by emergent vs. elective colectomy
Colectomy rates in adults hospitalised for a flare of UC
UC, ulcerative colitis. Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. Kaplan GG, et al. Am J Gastro 2012; 107:1879–87.
0 1997
1
2
3
4
5
6
Inci
denc
e pe
r 100
,000
pop
ulat
ion
Total
1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Elective Emergent
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Real Life vs. Clinical Trials: The example of ADA and IFX in UC
Sandborn et al. Curr Med Res Opin. 2016 Mar 30:1-9
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Many biologic agents have failed in IBD
Anti-IL-2 receptor
– Basiliximab1
– Daclizumab2
Anti-CTLA-4
– Abatacept3
Anti-CD3 receptor – Visilizumab4
1. Sands BE, et al. Gastroenterology 2012 Aug;143:356–64. 2. Van Assche G, et al. Gut 2006;55:1568–74. 3. Sandborn WJ, et al. Gastroenterology 2012;143:62–69. 4. Sandborn WJ, et al. Gut 2010;59:1485–92.
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The IBD therapeutic pipeline
Registration
Launched
Phase III
Phase II
Phase I Chemokine receptors
Immunomodulators
JAK3 inhibitors
IL inhibitors
CAM inhibitors
TNF-α inhibitors Stem cell therapies
Tofacitinib Pfizer
NN8555 Novo Nordisk
laquinimod Teva / Active Biotech Rifaximin EIR AlphaWessermann
RDP 58 Genzyme
ZP1848 Zealand
CCX-025 GSK
CCX282-B GSK
TNFK-005 Neovacs
C326 QPharm
Vidofludimus 4SC
PF-04236921 Pfizer
AMG 827 Amgen
PF 05230900 Pfizer
AIN 457 Novartis
GSK 1070806 GSK
QAX576 Novartis
SCH-900222 Merck & Co
Ustekinumab Centocor
ELND-004 Elan/Biogen Idec
PF-547659 Pfizer
AJM-300 Ajinomoto
Natalizumab Elan/Biogen Idec
Vedolizumab Millenium / Takeda
HMPL-004 Hutchinson
Ozoralizumab Pfizer
Debiaerse Neovacs
Adalimumab AbbVie
Infliximab Centocor
Certolizumab pegol UCB
Remestemcel-L Osiris
PDA-001 Celgene Cellular
Cellerix
OvaSave TXCell
Adapted from Danese S. Gut 2012;61:918–32.
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Emerging therapies in IBD
Leukocyte Trafficking inhibitors
– Vedolizumab
– Etrolizumab
– Anti-MAdCAM
Anti IL-12/23
– Ustekinumab
– Briakinumab
– Rizankinumab
Jak inhibitors
– Tofacitinib
Anti S1 P1
– Ozanimod
Anti-SMAD 7
– Mongersen
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Lymphocytes Preferentially Migrate to Particular Tissues Throughout the Body
Salmi M, Jalkanen S. Immunol Rev. 2005;206:100-113. Agace W. Nat Rev Immunol. 2006;6:682-692.
• As part of the body’s adaptive immune response, lymphocytes are imprinted for migration to areas of inflammation in certain tissues
• Lymphocytes become imprinted in certain lymphoid tissues in which they first encounter antigen
• After this initial activating encounter, lymphocytes preferentially leave the blood in the same type of tissue in which they became activated
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α4β7 Integrin–MAdCAM-1 is One of the Interactions That Contributes to Chronic Inflammation in UC and CD
Briskin M, et al. Am J Pathol. 1997;151:97-110.
α4β7−MAdCAM-1 interaction has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC
and CD
MAdCAM-1
α4β7 integrin
Memory T lymphocyte
MAdCAM-1
β7 subunit
α4 subunit
Accumulation of excess infiltrating lymphocytes in the gastrointestinal
tissue
MAdCAM-1=mucosal addressin cell adhesion molecule-1
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Vedolizumab is a novel gut-selective anti-inflammatory biologic
Humanized mAb that binds exclusively to the α4β7 integrin heterodimer
– Does not bind to α4β1 or αEβ7 integrin1
Selective antagonist of α4β7 integrin
– Inhibits adhesion to MAdCAM-1 and fibronectin, but not VCAM-11
Contains a mutated Fc region, preventing elicitation of2
– Complement-mediated cytotoxicity
– Antibody-dependent cellular cytotoxicity
– Cytokine release
Fc, fragment crystallisable; mAb, monoclonal antibody ; VCAM-1, vascular cell adhesion molecule-1 . 1. Soler D, et al. J Pharmacol Exp Ther 2009;330:864–75;.
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GEMINI I: vedolizumab induction therapy for UC
Phase 3, multicentre, prospective, RCT (N=374) – Randomised 3:2, patients received VDZ 300mg (IV) or PBO on days 1 & 15
Mod-to-severe active UC (Mayo 8.6, mean), despite conventional therapy – UC diagnosis ~6.4 yrs, CS (~54%), IS (~31%) and anti-TNF failures (~39%)
Rates of AEs and serious AEs were similar between VDZ and PBO groups
AE, adverse event; CS, corticosteroid; IS, immunosuppressant; RCT, randomised controlled trial Feagan et al, N Engl J Med. 2013 Aug 22;369(8):699-710.
25 5
25 47
17
41
Response Remission Mucosal healing0
20406080
100
Pat
ien
ts (
%)
PBO (n=149) VDZ 300 mg (n=225)
All p<0.0001 VDZ vs. PBO
Week 6 outcomes after 2-dose induction
Primary endpoint
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GEMINI I: vedolizumab in UC maintenance
15.9 23.8 19.8
41.8
56.6 51.6
44.8 52 56
Clinical remission at 52 weeks
Durable clinicalresponse
(at 6 and 52 weeks)
Mucosal healingat 52 weeks
0
20
40
60
80
100
Pat
ien
ts (
%)
Placebo (n=126)
VDZ 300 mg every 8 weeks (n=122)
VDZ 300 mg every 4 weeks (n=125)
Feagan BG et al, N Engl J Med. 2013 Aug 22;369(8):699-710.
Primary and secondary efficacy endpoints
p<0.0001
p<0.001
p<0.001
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GEMINI I: vedolizumab in UC maintenance
*p<0.0001, **p=0.0079, ***p=0.0009 vs placebo.
Steroid-free clinical remission
Durable clinical remission
13.9
31.4 45.2
PlaceboN=72
VDZ300 mg q8w
N=70
VDZ300 mg q4w
N=73
0
20
40
60
80
100
Perc
ent o
f sub
ject
s
8.7 20.5 24.0
PlaceboN=126
VDZ300 mg q8w
N=122
VDZ300 mg q4w
N=125
* *
** ***
Feagan BG et al, N Engl J Med. 2013 Aug 22;369(8):699-710.
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GEMINI II: vedolizumab in CD induction
45 40 35 30 25 20 15 10
5 0
Patie
nts
(%)
Clinical remission CDAI-100 response Clinical remission CDAI-100 response
Placebo
VDZ
4.3
10.5
22.9 23.8
9.0
18.3
28.2
38.3
95% CI: -9.1, 21.3 6.2 1.0
-11.8, 13.7 9.3
-0.2, 18.8 10.1
-3.3, 23.4
Induction ITT population Patients with prior anti-TNF failure
(n=175) Patients without prior anti-TNF failure
(n=193)
Sandborn W et al N Engl J Med. 2013 Aug 22;369(8):711-21
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GEMINI II: vedolizumab in CD maintenance
45 40 35 30 25 20 15 10
5 0
Patie
nts
(%)
Clinical remission CDAI-100 response CS-free remission†
Placebo
VDZ Q8wk
21.6
30.1
*p<0.05, 17.4 15.3 15.9
Maintenance ITT population
50
15.9
* 31.7 *
28.8
14.4
21.4
16.2
** 45.5 *
43.5 **
36.4
** 39.0
VDZ Q4wk
†CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.
14.7 **p<0.01
13.4 12.9 Durable remission
7.2 2.0
Sandborn W et al N Engl J Med. 2013 Aug 22;369(8):711-21
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Is there a better way forward with vedolizumab?
Bridging: co-induction with steroids?
CS, corticosteroid; IMM, immunomodulator; VDZ, vedolizumab. Colombel JF, et al. J Crohns Colitis 2015;9;S344. Abstract P528.
7.7
4.4
8.0 7.7 12.1
20.9
8.1
18.4
0
5
10
15
20
25
30
VDZ CS only and VDZ IMM only and VDZ CS and IMM and VDZ
PBO (n=148)
VDZ (n=220)
GEMINI II: Clinical Remission at Week 6 By Concomitant Medication Use at Week 0
Patie
nts,
%
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Define timeline for response? – Appropriate induction therapy / maintenance therapy for responders
– Role of combination therapy is being defined
– Allow 10-14 weeks for maximal induction response
*In GEMINI II, 31.4% patients in the vedolizumab and 25.7% of patients in the placebo group had a CDAI-100 response at week 6. This is a post-hoc analysis; therefore P values are not reported. Sandborn WJ, et al. J Crohns Colitis 2014;8;S274-275. Abstract P497.
7.2 11.6 11.6
8.7 7.2
13.2 21.7 23.1 23.9 25.4
0
10
20
30
Week 10 Week 14 Week 18 Week 22 Week 52
PBO (n=69) VDZ (n=351)
GEMINI II: CDAI-100 Response Among Week 6 Non-responders*
Patie
nts,
%
Is there a better way forward with vedolizumab?
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0
20
40
60
80
100
Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years
Vedolizumab and Infections: Exposure-Adjusted Incidence Rates in CD
Data shown for patients with any infection and common infections (defined as ≥0.5 patient events/100 PY in any patient group). aGEMINI 2 and 3 studies. bStudies C13004, GEMINI 2 and 3, and GEMINI LTS. cMedDRA PTs listed under ‘infections and infestations’ system organ class. dMedDRA high-level terms Candida infections, fungal infections NEC, tinea infections. eMedDRA PTs listed under ‘sepsis, bacteremia, viremia and fungemia NEC’ high-level term. CD, Crohn’s disease; GI, gastrointestinal; CI, confidence interval; LTS, long-term safety; MedDRA, Medical Dictionary for Regulatory Activities; NEC, not elsewhere classified; PBO, placebo; PT, preferred term; PY, person-year; VDZ, vedolizumab.
Colombel J-F, et al. Gut 2016;0:1–13. doi:10.1136/gutjnl-2015-311079.
Nu
mb
er o
f p
atie
nts
w
ith
eve
nt
/10
0 P
Y (9
5%
CI)
89.7
68.6
37.2
29.5
7.7 9.7 6.9
6.5 3.8
5.2 4.6 3.9 3.8 3.6 6.1
3.6 5.3
3.0 0.8 2.1 1.5 2.1 4.6
2.2 0.8 1.5 2.3 0.8 0.8 0.8 0 0.6
1.5 0.7 0 0.9
0.8 0.4
0.8 0.3
PBO (n=355)a
VDZ (n=1723)b
25
0
1
2
3
4
5
6
7
Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years
Vedolizumab and Serious Infections: Exposure-Adjusted Incidence Rates in CD
AGEMINI 2 and 3 studies. bStudies C13004, GEMINI 2 and 3, and GEMINI LTS. cMedDRA PTs listed under ‘infections and infestations’ system organ class. dMedDRA PTs anal abscess, perirectal abscess, rectal abscess, rectovaginal septum abscess, abdominal abscess, abscess intestinal, abscess, perineal abscess, pelvic abscess. eMedDRA high-level terms Candida infections, fungal infections NEC, tinea infections. fMedDRA PTs under ‘sepsis, bacteremia, viremia and fungemia NEC’ high-level term. CD, Crohn’s disease; CI, confidence interval; LTS, long-term safety; MedDRA, Medical Dictionary of Regulatory Activities; NEC, not elsewhere classified; PBO, placebo; PT, preferred term, PY, person-year; VDZ, vedolizumab.
Colombel J-F, et al. Gut 2016;0:1–13. doi:10.1136/gutjnl-2015-311079.
Nu
mb
er o
f p
atie
nts
wit
h
even
t /1
00
PY
(95
% C
I)
3.0 5.6
0
0.5
0.8 2.4
0
0.3
0
0.1
0
0.1
0
<0.1
0
<0.1
0
<0.1
0.8
0.3
PBO (n=355)a VDZ (n=1723)b
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Etrolizumab
Etrolizumab is a humanized mAB that targets the integrin receptors that regulate trafficking and retention of leukocyte/lymphocyte subsets in the intestinal mucosa signals
Etrolizumab differs from vedolizumab by blocking αEβ7 as well as α4β7
Etrolizumab is GI specific and targets β7 not α4β1, therefore risk PML thought to be low.
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Phase II: safety and efficacy of etrolizumab (humanized anti-beta7 mAb) for moderate-to-severe UC
• Phase 2, multicentre, prospective, RCT (N=119) • Randomised 1:1:1, patients received ETZ 100 mg/mo s.c. or 420 mg loading dose between
Week 0 & 2 then 300 mg/mo s.c. or PBO for 3 doses • Moderate-to-severe active UC: Mayo ≥5, endoscopy subscore ≥ 2 and RBS ≥1 • UC diagnosis ~9 yrs, mean Mayo ~9, CS (~42%), IS (~38%), anti-TNF failures (~60%) • Rates of AEs were comparable between ETZ and PBO groups ETZ, etrolizumab; RBS, rectal bleed severity. Clinical remission: Mayo score ≤ 2 with no individual score >1. Endoscopic remission: Mayo endoscopy subscore 0.
Week 10 clinical and endoscopic outcomes (all comers)
0 0 15
27 21 10 26 33
10 8
21 31 15 9
23 21
020406080
100
Remission EndoscopicRemission
Mucosal Healing Clinical Response
PBO (n = 41) ETZ 100 (n = 39) ETZ LD + 300 (n = 39) ETZ Pooled (n = 78)
**
Frac
tion
of p
ts (%
)
** *
*p < 0.05 **p < 0.01 vs. PBO Primary endpoint
Vermiere S et al. Lancet. 2014 Jul 26;384(9940):309-18
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Phase II: PF-00547659 (Anti-MAdCAM-1 mAb) for Mod-Sev UC
• Phase IIa: N = 357 mod-sev UC pts (total Mayo ≥ 6; endo subscore ≥ 2) were randomized to PBO, 7.5 mg, 22.5 mg, 75 mg or 225 mg PF-00547659, q4w (s.c.)
• BL mean Mayo (~8.4); anti-TNF failures (~43%)
• PF-00547659 appears to be well-tolerated and not associated with increased rate of infection
Vermeire et al. ECCO 2015, Abstract OP021
.
Primary and Secondary Endpoints at Week 12
3
29
8 11
38
16 17
54
28 16
45
25
6
50
14
0
20
40
60
80
100
Clinical Remission Clinical Response Mucosal Healing
PBO (n = 83) PF 7.5 mg (n = 71) PF 22.5 mg (n = 70)PF 75 mg (n = 73) PF 225 mg (n = 70)
Frac
tio
n o
f P
ts (
%)
* *
*P < 0.05 vs. PBO
* * Primary Endpoint
TURANDOT
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Phase II: PF-00547659 (Anti-MAdCAM-1 mAb) for Active Refractory, TNF-Experienced CD
59
23 14
62
27 37
65
28 24
58
29 39
0
20
40
60
80
100
Response(CDAI-70)
Remission Remission(BL CRP > 18)
PBO (n = 63) PF 22.5 mg (n = 67) PF 75 mg (n = 64) PF 225 mg (n = 68)
• Phase IIa: N = 267 CD pts (CDAI 220-450) randomized to PBO, 22.5 mg, 75 mg or 225 mg PF-00547659, q4w (s.c.)
• BL disease duration (~11 yrs); mean CDAI (~315); All pts were anti-TNF experienced with elevated hsCRP (> 3.0 mg/L)
• Rates of AEs similar, higher numerical GI infections noted in PF vs. PBO
D’Haens et al. ECCO 2015, Abstract OP022.
Primary and Secondary Endpoints at Week 12
Frac
tio
n o
f P
ts (
%)
Primary Endpoint
All P = NS
OPERA
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S1P Receptor Modulators and the S1P Signalling Pathway
S1P receptor modulators prevent migration of lymphocytes from lymph nodes to sites of inflammation where they contribute to immune-mediate pathology
Nielsen OH et al. Exp Opin Invest Drugs. 2016: doi.
S1P S1P1 Internalised S1P S1P modulators Degraded S1P
Endothelium Lymphocyte egression
Internalisation and degradation
Lymph node (low S1P concentration)
Lymphocyte egression blocked
Signalling
Lymphocyte
Signalling
Lymph (high S1P concentration)
S1P receptor modulation
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Phase II Trial of Ozanimod (S1P1 Receptor Modulator) in Mod-Sev UC
Sandborn et al. NEJM May 2016
*P<0.05 vs placebo; **P<0.01 vs placebo
Clinical Remission: Mayo Score ≤ 2, no subscore >1; Clinical Response: reduction ≥ 3 points and ≥ 30% of the Mayo score with a dec. RBS of ≥1 or RBS ≤1
13.8
26.2
53.8
35.4
27.7
33.8
16.4 20.9
58.2
50.7
34.3 32.8
6.2 6.2
36.9
20
12.3 12.3
0
25
50
75
100
Week 8 Week 32 Week 8 Week 32 Week 8 Week 32
Pat
ien
ts (
%)
Low dose (N=65) High dose (N=67) Placebo (N=65)
* *
**
Mucosal Improvement (endoscopy score ≤1)
*
**
* ** ** **
Clinical Response Clinical Remission
TOUCHSTONE
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Biology and site of action of interleukins 12 and 23
Ustekinumab and risankizumab are fully human monoclonal IgG1 antibodies
Ustekinumab bind the p40 subunit of IL-12/23
Risankizumab is a selective blocker of the IL23 p19 subunit
Ustekinumab is approved for the treatment of PsA and plaque psoriasis
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Ustekinumab for induction Therapy in CD: Results of Phase 3 UNITI 1 and UNITI 2: Clinical Remission (CDAI<150)
Feagan et al. NEJM in press
N=741 N=648
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-0.18 1.03
-0.14
-4.76 -5.97
-3.97
-8.61 -8.41 -8.56
-10
-8
-6
-4
-2
0
2
4
0 1 2 3 4 5 6 7 8Weeks
PBOUST 130 mgUST ~6 mg/kg
Ustekinumab Reduces CRP at Weeks 3, 6 and 8
Mean CRP Concentration Change by Week 8 M
ean
Ch
ange
fro
m
Bas
elin
e C
RP
(m
g/L)
all p<0.001 vs. PBO
UNITI-2
Feagan et al. UEGW 2015, Abstract OP054
Subjects who had insufficient data at the designated analysis time point had their last value carried forward
Feagan et al. NEJM in press
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Ustekinumab for Maintenance in CD: Results of Phase III
Feagan et al. NEJM in press
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Phase IIa: Induction Study of MEDI2070 (Anti-p19 mAb) for Active, anti-TNF-refractory CD
27 15
25
10
49
27
46 42
0
20
40
60
80
100
Clinical Effect Clinical Remission Clinical Response Clinical +Biomarkers*
PBO (n = 60) MEDI2070 (n = 59)
Frac
tio
n o
f P
ts (
%)
Primary Endpoint
Efficacy Outcomes at Week 8
• Phase II: N = 121 mod-sev CD pts (CDAI 220-450), Randomized to PBO or MEDI2070 700 mg IV at weeks 0 and 4
• BL CDAI ~320; dis. duration (~12 yrs); prior surg. (~45%); 31/58/11% failed 1/2/3 anti-TNF’s
• MEDI2070, demonstrated clinical effect and favorable safety profile over 12wks
Sands et al. ECCO 2015, Abstract OP025
Clinical Effect: CDAI-100 response or CDAI <150) Clinical + Biomarkers: Clinical Effect & ≥50% reduction in BL CRP or FC
P = 0.010
P = 0.102
P = 0.017 P < 0.001
37
Efficacy and Safety of Risankizumab as Induction Therapy in CD
Feagan et al. DDW 2016, Abstract 812a
Frac
tio
n o
f P
atie
nts
(%
)
Summary of Key Clinical Outcomes at Week 12
• Phase IIb, multicentre, RCT of risankizumab (humanized anti-IL-23p19 mAb)
• N=121 randomized to receive i.v. q4w of RSK 200 mg, 600 mg or PBO
• Mod-to-sev CD (mean CDAI ~298), CD dx (~13 yrs), aTNF-experienced (94%)
• AE rates were similar between RSK and PBO & no dose-related associations
15 21 3
13 24
37 15
27 37* 42* 20*
37*
020406080
100
Remission Response EndoscopicRemission
EndoscopicResponse
PBO (n = 39)RSK 200 mg (n = 41)RSK 600 mg (n = 41)
*p < 0.05 Primary Endpoint
Clinical Remission: CDAI of <150 points from BL Clinical Response: CDAI of <150 points or a CDAI reduction from BL of ≥100 points Endoscopic Remission: CDEIS of ≤4 Endoscopic Response: defines as a >50% CDEIS reduction from BL
38
Phase 2 Psoriasis: Risankizumab vs. ustekinumab PASI Results
39
The anti-IL-23 and anti-IL-17 wars in psoriasis
Comparison of PASI90 Scores at 12 wks Comparison of PASI100 Scores at 12 wks
• Dosing has potential to be the most patient friendly at once every 3 months
• Potential for durability above IL-12/23 and IL-17s at one year
?Best-in-class Biologic?
Sources: Humira (CHAMPION and REVEAL), Stelera (PHEONIX 1 and 2), COSENTYX (ERASURE and FIXTURE), Ixekizumab (UNCOVER 1, 2, 3), Tildrakizumab (Merck AAD 2013), Guselkumab (NEJM 2015), BI655066 (EADV 2015)
40
Tofacitinib is a JAK Inhibitor
40
JAK JAK
Cytokine
g b a
STA
T S
TAT
mRNA
Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor that is being investigated as a targeted immunomodulator for several inflammatory diseases including ulcerative colitis
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
Ig, immunoglobulin; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc , cytotoxic T cell 1ADIS. Drugs 2010; 10(4): 271-274; 2Coombs J et al. Ann Rheum Dis 2007; 66: 257; 3Li X et al. Presented at the 15th IIRA Conference, Chantilly, Virginia, September 21-24, 2008; 4Rochman Y et al. Nat Rev Immunol 2009; 9(7): 480-490
Tofacitinib (CP-690,550) blocks phosphorylation of STAT and downstream activation
Cytokine Effects on the immune system
IL-2 Stimulate the proliferation and differentiation of Th, Tc, B, and NK cells
IL-4 Induce the differentiation of Th0 to Th2 Induce Ig 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
● Safety data showed no new or unexpected observations from results in tofacitinib studies in other populations
41
Efficacy and Safety of Tofacitinib in Phase 3 Moderate to Severe UC
Tofacitinib 10 mg BID (n=476) Placebo (n=122)
18.5
31.3
8.2 15.6
0102030405060
Overall Overall
Pat
ien
ts (
%)
Mucosal Healing Remission
OCTAVE Induction 1
16.6
28.4
3.6 11.6
0102030405060
Overall Overall
Pat
ien
ts (
%)
OCTAVE Induction 2 Mucosal Healing Remission
** ***
*** ***
Δ10.3
Δ15.7 Δ16.8
Δ13.0
Difference from placebo
12.6
25.2 24.0
39.6
1.5
15.8
6.2
26.3
0
10
20
30
40
50
60
TNFi-treated
TNFi-naive
TNFi-treated
TNFi-naive
Pat
ien
ts (
%)
Δ11.1
Δ9.4 Δ17.9
Δ13.3
12.0
22.1 21.8
36.4
0 8.5 6.2
19.1
0
10
20
30
40
50
60
TNFi-treated
TNFi-naive
TNFi-treated
TNFi-naive
Pat
ien
ts (
%)
Δ12.0
Δ13.5 Δ15.6
Δ17.3
Tofacitinib 10 mg BID (n=429) Placebo (n=112)
**P<0.01 vs placebo; ***P<0.001 vs placebo. BID=twice daily; TNFi=tumor necrosis factor inhibitor. Sandborn WJ et al. ECCO 2016. Abstract A-1213.
Onset of Action of Tofacitinib in Phase 3 OCTAVE Induction Studies
42
OCTAVE Induction 1 OCTAVE Induction 2
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Baseline Week 2 Week 4 Week 8
Me
an C
han
ge F
rom
Bas
elin
e
in P
arti
al M
ayo
Sco
re (
SE)
Placebo (N=122)Tofacitinib 10 mg BID (N=476)
-4.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
Baseline Week 2 Week 4 Week 8
Placebo (N=112)Tofacitinib 10 mg BID (N=429)
***
*** ***
***
*** ***
Rapid and significant improvements in partial Mayo score were observed as early as Week 2
***P<0.001 vs placebo (linear mixed-effects model). BID=twice daily. BID=twice daily; SE=standard error.
Tofacitinib for Maintenance Treatment of Ulcerative Colitis
Pfizer press release
July 28, 2016
“Pfizer Inc. announced today top-line results from Oral Clinical Trials for tofAcitinib in ulceratiVE colitis (OCTAVE) Sustain, the third Phase 3 study of tofacitinib citrate being investigated in patients with moderately to severely active ulcerative colitis (UC).
Top-line results from the OCTAVE Sustain study showed that the proportion of patients in remission at Week 52, the primary efficacy endpoint, was significantly greater in both the tofacitinib 5 and 10 mg BID groups compared to placebo. No new or unexpected safety findings for tofacitinib were observed in the study.”
BID=twice daily. Pfizer press release. http://www.pfizer.com/news/press-release/press-release-detail/pfizer_announces_positive_top_line_results_from_pivotal_ phase_3_maintenance_trial_of_oral_xeljanz_tofacitinib_citrate_in_ulcerative_colitis. July 28, 2016.
44
Inhibition of IL-6
IL-6's role as an anti-inflammatory cytokine is mediated through its inhibitory effects on TNF-alpha and IL-1, and activation of IL-1ra and IL-10.
PF-04236921 is a fully human antibody that binds to and neutralizes the IL-6 ligand.
45
Anti-IL-6 Antibody (PF-04236921) in Subjects with CD Who Are Anti-TNF Inadequate Responders: Week 12
p- = ns
p=0.04
p-= ns
p= 0.04
Danese, Panaccione et al. Submitted NEJM
n=249 2 doses sc @ week 0 and 4
46
Anti-IL-6 Antibody (PF-04236921) in Subjects with Crohn’s Disease
* 1-sided p value < 0.05.
CDAI 70 CDAI 100
CDAI Remission CDAI Change from Baseline
Danese, Panaccione et al. Submitted NEJM
47 Danese, Panaccione et al. Submitted NEJM
Anti-IL-6 Antibody (PF-04236921) in Subjects with Crohn’s Disease: Suppression of CRP
48
SMAD7 Inhibition and the TGF- β/SMAD Pathway
Inhibition of SMAD7 restores SMAD2/3 activity and TGF-β-mediated signaling, thereby suppressing the production of proinflammatory cytokines1
Mongersen Phase 2 study in UC is ongoing2
Image adapted from Nielsen et al. Exp Opin Invest Drugs. 2016: doi 10.1517/13543784.2016.1165204.
1. Nielsen et al. Exp Opin Invest Drugs. 2016: doi 10.1517/13543784.2016.1165204. 2. ClinicalTrials.gov NCT02601300.
Nucleus
Cytoplasm
SMAD3
SMAD2 SMAD4 P
e.g. SMAD7
TGF-βRII TGF-βRI
TGF-βI
SMAD7 SMAD3
SMAD2 P
SMAD4 Mongersen
P
48
49
Smad7 Antisense Oligonucleotide Proposed Mechanism of Action
• In IBD, Smad7 appears over-expressed and this may result in decreased activity of TGF-β1 which is protective against an inflammatory state
• GED-0301 (Mongersen) is an oral antisense DNA oligonucleotide targeting Smad7 mRNA
• In mouse models, knockout of Smad7 restores TGF-β1 activity, with the downstream effect of inhibiting inflammatory cytokine production
Monteleone et al. (2012) Mol Ther 20: 870-876.
50
Phase IIa: Mongersen (GED-0301) in Active Crohn’s Disease
21 14
21 15
29 29
58
70 63
67 72
67
0
20
40
60
80
100
Day 15 Day 28 Day 84
PBO MNG 10 mg/d MNG 40 mg/d MNG 160 mg/d
• Phase IIa: N = 126 CD pts dosed for 14 days, with 3 mo f/u
• CS-dependent/resistant mod-sev CD with ileal involvement (CDAI 220-400); no strictures/fistulae; CD dx ~10 yrs, median CDAI ~250, Con-IS (~32%)
• Primary endpoint: Remission* achieved in 55% (40 mg/d) and 65% (160 mg/d) vs 9.5% PBO; P ˂ 0.0001 (no significant difference for 10 mg/d; 12.2%)
• Rates of AEs and SAEs were similar across groups
Monteleone et al. NEJM 2015.
CDAI Remission Over 3 Months
*Clinical Remission (CDAI ˂ 150 at day 15 and maintained for ≥ 2 wks)
Frac
tio
n o
f P
ts (
%)
*P < 0.0001 vs. PBO #P ≤ 0.0008 vs. PBO
# # * * * *
9/42 6/41 23/40 29/43 6/42 12/41 28/40 31/43 9/42 12/41 25/40 29/43
51
-160
-140
-120
-100
-80
-60
-40
-20
0
Me
an C
han
ge F
rom
Bas
elin
e
in C
DA
I Sco
re†
Phase IIb: Mongersen Endoscopic and Clinical Outcomes Study ΔCDAI Mean Change From Baseline Through Week 12
Data From All Treatment Groups
63 56 62 44 21 n=
Study Week
8 12 2 4
-133
* *
*
*
*P<0.0001
*CDAI mean change from baseline at Week 12 was determined in the ITT population using LOCF methodology.
Feagan et al. UEGW 2016
Pooled analysis of 3 dosing groups GED 301 160mg X 4 weeks GED 301 160 mg X 8 weeks GED 301 160 mg X12 weeks
52
53 44
67
0102030405060708090
100
GED-0301 Treatment Group
4 Weeks 8 Weeks 12 Weeks (N=19) (N=23) (N=21)
Pat
ien
ts A
chie
vin
g C
linic
al
Re
spo
nse
* (%
)
Clinical response week 12
32 35
48
0102030405060708090
100
GED-0301 Treatment Group
4 Weeks 8 Weeks 12 Weeks
(N=19) (N=23) (N=21)
Pat
ien
ts A
chie
vin
g C
linic
al
Re
mis
sio
n*
(%)
Clinical remission week 12
Phase IIb: Mongersen Endoscopic and Clinical Outcomes Study
Feagan et al. UEGW 2016
53
Phase Iib: Mongersen Endoscopic Response at Week 12: SES-CD Reduction by ≥25% and ≥50%
53
*Data as observed.
SES-CD Reduction by ≥25%
All Evaluable Patients
Baseline SES-CD >12
37
63
0
20
40
60
80
100
Pat
ien
ts A
chie
vin
g En
do
sco
pic
R
esp
on
se*
(%)
19/52 10/16
15
31
0
20
40
60
80
100
8/52 5/16 n/N=
SES-CD Reduction by ≥50%
All Evaluable Patients
Baseline SES-CD >12
Pat
ien
ts A
chie
vin
g En
do
sco
pic
R
esp
on
se*
(%)
Feagan et al. UEGW 2016
54
Summary
Emerging strategies are defining improved ways of managing patients with IBD
New therapies provide us with more choice and greater treatment flexibility
Our task is to use the right treatment in the right patient at the right time
– Explore the evidence base
– Understand best practice
– Optimise your first biologic
– Tailor treatment to patient needs