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