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A Practical Approach to Anti-TNFs in IBD 2020
William J. Sandborn MDProfessor and Chief, Division of GastroenterologyDirector, UCSD IBD Center
Anti-TNFs in IBD 2020
• Comparative efficacy within class and out of class• Immunogenicity• Therapeutic drug monitoring and dose escalation
ReactiveProactive
• Combination therapy• Hospitalized patients• CD perianal fistulas• Prevention of postoperative recurrence of CD• Biosimilars• Toxicity
Comparative Efficacy Within Class and Out of Class
Infliximab for Active Crohn’s Disease: Infliximab for Active Crohn’s Disease: Remission at Week 4Remission at Week 4
Targan N Engl J Med 1997
Clinical remission defined as a CDAI score < 150.
Systematic review with network meta-analysis: first-line induction pharmacotherapy for moderate-severe Crohn’s disease
Singh S, Sandborn WJ. Alimentary Pharmacology & Therapeutics 2018.
Systematic review with network meta-analysis: second-line induction pharmacotherapy for moderate-severe Crohn’s disease
Singh S, Sandborn WJ. Alimentary Pharmacology & Therapeutics 2018.
Rutgeerts P, Sandborn WJ, et al. N Engl J Med 2005;353:2462-2476.
Proportion of Patients with a Clinical Response (Panel A), in Clinical Remission (Panel B), and with Mucosal Healing (Panel
C) at Week 8 in ACT 1 and ACT 2 After Treatment with Infliximab for Moderate to Severe Ulcerative Colitis.
Systematic review with network meta-analysis: first-line pharmacotherapy for moderate-severe ulcerative colitis
Singh S, Sandborn WJ. Alimentary Pharmacology & Therapeutics 2018;47:162-175.
Systematic review with network meta-analysis: second-line pharmacotherapy for moderate-severe ulcerative colitis
Singh S, Sandborn WJ. Alimentary Pharmacology & Therapeutics 2018;47:162-175.
Vedolizumab Versus Adalimumab for Active Ulcerative Colitis
• 769 patients were randomised to VDZ (n = 383) or ADA (n = 386) for 52 weeks
• Clinical remission at week 52 was 31.3% for VDZ and 22.5% for ADA (P = 0.0061)
• Mucosal healing at Week 52 was 39.7% for VDZ and 27.7% for ADA (P = 0.0005)
• Exposure-adjusted rates of infections were 33.5% and 43.5% in patients treated with VDZ and ADA
Perc
ent o
f pat
ient
s
P=0.195
Sands B. New Engl J Med 2019
P=0.0061
Immunogenicity
§ Study design: prospective, cohort study
§ N=125 with refractory CD§ Median follow-up: 36 mo§ Efficacy
§ Negative correlation between concentration of ATI and duration of response to infliximab (P<0.001)
Baert F, et al. N Engl J Med 2003;348:601-8.
Dura
tion
of re
spon
se (d
ays) P<0.001
Higher Serum Antibodies to Infliximab (ATI) Level is Associated with a Shortened Duration of Response
in Patients with Crohn’s Disease
Duration of Response Based onATI Concentrations
35
71
Immunogenicity of TNF AntagonistsPatients With Detectable Antibodies to a TNF Antagonist
Patients, %
Episodic Maintenance Scheduled Maintenance
IMS- IMS+ IMS- IMS+
Infliximab1 (CD 5 mg/kg)(CD 10 mg/kg)
38% 16%11%8%
7%4%
Infliximab2 (UC 5 mg/kg)(UC 10 mg/kg)
19% 9%
2% 4%
Certolizumab3 (PRECiSE I) 10% 4%
Certolizumab4 (PRECiSE II) 12% 2%
Adalimumab5 (RA, all doses) 12% 1%
Adalimumab6 (CLASSIC II) 4% 0%
IMS = immunosuppressant.1. Hanauer et al. Clin Gastroenterol Hepatol. 2004;2(7):542-553; 2. Data on file, Centocor (Sandborn et al. DDW 2007 Poster and abstract T1273); 3. Sandborn WJ, et al. N Engl J Med. 2007;357:228-238; 4. Schreiber S, et al. N Engl J Med. 2007;357:239-250; 5. Summary of Product Characteristics for adalimumab. Abbott Laboratories. July 2007; 6. Sandborn WJ, et al. Gut. 2007;56:1232-1239.
No data
24% 8%
No data
Therapeutic Drug Monitoring and Dose Escalation
• Reactive• Proactive
Afif W, Sandborn WJ. Am J Gastroenterol 2010;105:1133-9.
Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or Sub-therapeutic Infliximab Concentrations
Response to test Complete/partial response (%) P value
Detectable HACA Increase infliximab 1/6 (17) P<0.004
Change anti-TNF 11/12 (92)
Subtherapeutic concentration Increase infliximab 25/29 (86) P<0.016
Change anti-TNF 2/6 (33)
Elevating Infliximab Concentration from Sub-Therapeutic Levels is Effective in Regaining Response
in HACA (-) Patients
Treatment algorithm in patients with clinical symptoms (infliximab and HACA concentrations)
1Patients should have endoscopic or radiologic imaging2This strategy may be preferableHACA, human anti-chimeric antibody; TNF, tumor necrosis factor
Afif W. Am J Gastroenterol 2010
Monitoring Infliximab Values and Antibodies: Utility
DESIGN§ Randomized, multicenter, controlled,
12-wk, single-blind studyOBJECTIVE§ Assess utility of monitoring of drug
and related Ab to optimize IFX therapies
§ CD pts, 2° failure IFX (N=69)§ IFX dose intensification 5 mg/kg q 4
wks (n=36) or tx based on serum [IFX] or IFX Ab values (n=33)
OUTCOMES§ 70% pts w/2° failure: + [IFX] and
undetectable Ab at time of failure § 20% pts: + IFX Ab, sub-therapeutic [IFX]§ 4% pts: undetectable IFX Ab, sub-
therapeutic [IFX]§ 6% pts: + [IFX], + IFX Ab
OUTCOMES
Steenholdt C, et al. Gut. 2014.
Treatment algorithm for patients with Crohn’s disease (CD) with secondary loss of response to infliximab (IFX). Ab=antibody; IV=intravenously; sc=subcutaneously; TNF=tumor necrosis factor
ACT 1+2: Proportions of Patients with Ulcerative Colitis Achieving Efficacy Endpoints by Serum Infliximab
Concentrations
Prop
ortio
n of
pat
ient
s (%
)
<21.3 <0.11≥21.3 –< 33.0
≥0.11-<2.4
≥33.0 –< 47.9
≥2.4-<6.8> 47.9 > 6.8
Adedokum OJ, Sandborn WJ, Reinisch W. Gastroenterology 2014.
Modeled exposure–response relationship between serum adalimumabconcentration and efficacy at Week 8 in ulcerative colitis: logistic regression
model from ULTRA-2
Logistic regression model predictions from ULTRA-2 study1
100
75
50
25
00 10 20 30 40 50
ADA concentration (µg/mL)
Patie
nts
(%)
Clinical remission100
75
50
25
00 10 20 30 40 50
ADA concentration (µg/mL)
Patie
nts
(%)
Clinical response
1. Mostafa NM, et al. Gastroenterology 2013;144(5 Suppl. 1):S225–6ADA, adalimumab
ITT analysis set. aAdjusted by stratification factors. Central reviewer scoring of endoscopy results was used for all efficacy assessments. Rectal bleeding subscore (RBS) and stool frequency subsccore (SFS) components of Mayo were based on entries into a patient's diary on the 5 days prior to each study visit and averaged.
Clinical remission per Full Mayo score: Full Mayo score ≤2 with no subscore >1
37/340 68/512
Standard induction dosing
Higher induction dosing
Patie
nts
(%)
p=0.273
∆=2.5a
Panes J, Sandborn WJ. UEGW 2019 Abstract
Endoscopic improvement
Fecalcalprotectin <150
IBDQresponse
Clinicalresponse
Endoscopicremission
15992 11567 342207 241136 6734
p=0.182
p=0.283
p=0.063
p=0.034*
p=0.162
Efficacy of standard dose versus high dose induction with adalimumab in ulcerative colitis: secondary endpoints
*Clinical response endpoint had nominal p-value ≤0.05. ITT analysis set. Endpoints are in ranked order from left to right. Endoscopic improvement: endoscopic subscore of 0 or 1; fecal calprotectin: <150 mg/kg; IBDQ response: increase ≥16 from baseline; clinical response: decrease from baseline in Full Mayo score ≥3 points and ≥30% from baseline, PLUS a decrease in RBS ≥1 or an absolute RBS ≤1; endoscopic remission: endoscopic subscore of 0. Central reviewer scoring of endoscopy results was used for all efficacy assessments.
Standard induction dosing (n=340)Higher induction dosing (n=512)
Patie
nts
(%)
Panes J, Sandborn WJ. UEGW 2019 Abstract
Observed exposure–response relationship between serum adalimumabconcentration and efficacy at Week 8 in ulcerative colitis in SERENE relative
to logistic regression model from ULTRA-2
SERENE-UC higher induction dosing regimen only
Logistic regression model predictions from ULTRA-2 study1
SERENE-UC observed data (SD)
100
75
50
25
00 10 20 30 40 50
ADA concentration (µg/mL)
Patie
nts
(%)
Clinical remission100
75
50
25
00 10 20 30 40 50
ADA concentration (µg/mL)
Patie
nts
(%)
Clinical response
1. Mostafa NM, et al. Gastroenterology 2013;144(5 Suppl. 1):S225–6 ADA, adalimumab
Panes J, Sandborn WJ. UEGW 2019 Abstract
Combination Therapy
Efficacy of Combination Therapy: SONIC
Colombel JF, Sandborn WJ, et al. N Engl J Med. 2010;362):1383-1395
Hospitalized Patients
Proportion of surgical patients and time to operation in acute severe ulcerative colitis
Järnerot G, Gastroenterology 2005;128:1805–1811
Cyclosporin Versus Infliximab in Acute Severe Ulcerative Colitis Refractory to Intravenous Steroids
Primary Endpoint: Treatment Failure
p=0.4960% 54%
0%
20%
40%
60%
80%
100%
Cys (n=55) IFX (n=56)
Difference Cys vs. IFX failure rates: -6.4% (95%CI: - 24.8 to 12.0%)
Laharie D. Lancet2012
Crohn’s Disease Perianal Fistulas
Infliximab: Complete Fistula Closure in CD
0
20
40
60
80
100
Infliximab5 mg/kg
Infliximab10 mg/kg
Placebo
Treatment Group
% P
atie
nts
With
Com
plet
e Cl
osur
e of
All
Fist
ulae
55%
38%
4/3113%
17/31 12/32
Present DH et al. N Engl J Med. 1999;340:1398.
p=0.001
p=0.04
Complete response defined as all fistulae closed for 2 consecutive visits (at least 1 mo)
Prevention of Postoperative Recurrence of Crohn’s Disease
Infliximab for prevention of Crohn’s disease postoperative recurrence: endoscopic recurrence before or at week 76
Biosimilars
Innovator Infliximab (IFX) versus CT-P13 Biosimilar for Active Rheumatoid Arthritis: Mean (±SD) Serum Concentrations Versus Time By Treatment
34
180 360 540 720 900 1080 1260 1440
Note: Values below the lower limit of quantification (LLoQ) have been set equal to LLoQ.
Park W, et al. Ann Rheum Dis. 2013;72:1605-1612.
Kim YH, et al. Congress of the European Crohn’s and Colitis Organisation (ECCO)2017. DOP061.
Efficacy measure
Inflectra(infliximab-dyyb)
(n=105)
Originator IFX(n=101)
PCDAI-70 response,n (%) [95% CI]
75 (71.4)[61.8-79.8]
76 (75.2)[65.7-83.3] 0.56
CDAI-100 response,n (%) [95% CI]
65 (61.9)[51.9-71.2]
65 (64.4)[54.2-73.6] 0.77
Clinical remission,n (%) [95% CI]
45 (42.9)[33.2-52.9]
45 (44.6)[34.7-54.8] 0.83
Results after 6 weeks of therapy
Abbreviations: CDAI, Crohn’s Disease Activity Index; CI, confidence interval.
Randomized, Controlled Trial of Inflectra (infliximab-dyyb) in CD
Toxicity
Safety ConsiderationsInfliximab Adalimumab Golimumab Vedolizumab Tofacitinib Ustekinumab
Granulomatous infection + + + - ? -
Serious infection + + + - + -
Herpes zoster - - - - + -
Non-Hodgkin’s lymphoma + + + - ?+ -
Demyelination + + + - - -
Hyperlipidemia - - - - + -
DVT/PE - - - - + -
Lymphoma Risk in IBD Stratified by Medication Use• French national databases• >189,000 IBD patients• Lymphoma incidence by use of
medication• 2/3 of lymphoma occurred in
patients not on thiopurines or anti-TNF therapy
• Lymphoma risk with thiopurine and anti-TNF monotherapy are similar
• Absolute risk of lymphoma remains very low
Lemaitre M et al, JAMA 2017;318:1679-86
RR, 2.6RR, 2.4
RR, 6.1
Before Anti-TNF and After 21 Years of Anti-TNF
With Sidney Truelove, Green College,Oxford University, 1996 (pre-anti-TNF)
With family in 2019 (post-anti-TNF)
Conclusions• Anti-TNF remains an important 1st line therapy for CD• Vedolizumb has become an important 1st line therapy for UC• Anti-TNF switching as 2nd line therapy is not highly effective• Anti-TNF therapy is substantially immunogenic, and is optimally
administered as combination therapy• Reactive and proactive therapeutic drug monitoring can be useful,
but the SERENE data suggest that dose escalation may be less effective than we thought
Conclusions• Anti-TNF therapy with infliximab remains the go to drug for
hospitalized patients• Anti-TNF therapy with infliximab (and other anti-TNF agents)
remains the go to drug for perianal fistulas• Anti-TNF therapy remains the go to drug class for prevention of
post operative recurrence of Crohn’s disease• Biosimilar anti-TNF agents appear to be similarly effective to the
branded agents• Anti-TNF therapy has substantial infection and lymphoma risks,
and highly effective agents without these risks are needed