update on biologic therapy in 2015update on biologic...

Millie D. Long, MD

Update on Biologic Therapy in 2015Update on Biologic Therapy in 2015

September 12, 2015Millie D. Long MD, MPH, FACG

Assistant Professor of MedicineInflammatory Bowel Disease Center

University of North Carolina-Chapel Hill

Outline

• Crohn’s disease induction and maintenance– Role of combined therapy with anti-TNF

(Aza/6MP vs. MTX)( )– Comparative effectiveness with different anti-TNF– Recapturing response with a second anti-TNF– Anti-integrin therapy efficacy and timing

• Ulcerative colitis induction and maintenance– Role of combined therapy with anti-TNF (Aza/6MP)py ( )– Anti-integrin therapy efficacy and timing– Specific role of escalated anti-TNF

dosing in severe UC

ACG/VGS/ODSGNA Regional Postgraduate Course - Williamsburg Copyright 2015 American College of Gastroenterology

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Millie D. Long, MD

Anti-TNF Therapy + 6MP/Aza or MTX in Crohn’s Disease

SONIC: Corticosteroid-Free Clinical Remission at Week 26 and 50

p<0.001

p<0.02

p<0.04

p<0.001

p<0.006

p<0.03

*250/508 (55%) entered study extension at week 26, results assume patients not entering extension trial were not in remission in week 26

Colombel et al. 2010 N Engl J Med. 2010 Apr 15;362(15):1383-95


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Millie D. Long, MD

SONIC: Trough Levels at Week 46 on Mono –versus Combination Therapy

Colombel et al. 2010 N Engl J Med. 2010 Apr 15;362(15):1383-95

COMMIT (Methotrexate+ Infliximab (IFX) or IFX

Feagan et al. Gastroenterology. 2014 Mar;146(3):681-688.


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Millie D. Long, MD

Detectable p-value IFX Trough- p-value Antibody + p-value

COMMIT: IFX-Trough and IFX Antibody Levels

n=126 patients, 63 IFX+MTX, 63 IFX

IFXg

levelmg/ml

y

IFX+MTX 52%0.84

6.4<0.08

4%<0.01

IFX 44% 3.8 20%

Feagan et al. Gastroenterology. 2014 Mar;146(3):681-688.

• Disease duration SONIC vs COMMIT (2.2 years vs 9 years).

• Immunosuppression SONIC no previous immunosuppression vs COMMIT 25%

Differences SONIC and COMMIT

SONIC no previous immunosuppression vs COMMIT 25% previous exposure and failure of azathioprine

• Inclusion criterion SONIC: CDAI > 220 and need for steroids, COMMIT patient in

need for steroids (15-40mg) in the previous 4 weeks SONIC >70% prednisone naive at inclusion vs. COMMIT mean

dose of prednisone 22 mg • Trial Design• Trial Design SONIC: Dual therapy (IFX + AZA) vs COMMIT initial Steroid

taper which might have masked the effects of MTX


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Millie D. Long, MD

Comparative Effectiveness of Anti-TNF in Crohn’s disease

Anti-TNF Timeline in Crohn’s disease

InfliximabInfliximab AdalimumabAdalimumab CertolizumabCertolizumab

1998 2007 2008FDA approval for Crohn’s disease


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Millie D. Long, MD

Anti-TNF Timeline in Crohn’s disease

InfliximabInfliximab AdalimumabAdalimumab CertolizumabCertolizumab

1998 2007 2008FDA approval for Crohn’s disease

Anti-TNF Agents: Induction and Maintenanceof Remission in Crohn’s Disease –Network Meta-analysis

Overall Anti-TNF for Induction and Maintenance vs. Placebo• Induction Remission RR: 1.66, 95% CI: 1.17–2.36;

Maintenance of Remission RR: 1.78, 95% CI: 1.51–2.09 Induction therapy Comparison• Infliximab (IFX) non-significant superiority to adalimumab

(ADA) and certolizumab (CTZ)• ADA superior to CTZ (RR: 2.93 for ADA vs. CZP, 95% CI:

1.21– 7.75)

M i t Th C iMaintenance Therapy Comparison• Non-significant trends ADA>IFX>CTZ

Stidham et al. Aliment Pharmacol Ther. 2014 Jun;39(12):1349-62


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Millie D. Long, MD

Total number of subjects required for comparative efficacy RCTs between anti-TNF agents for Induction / Maintenance of remission

Comparative Effectiveness Trials of Anti-TNF Agents in Crohn’s Disease

of remission

Infliximab Certolizumab Adalimumab

Infliximab - 3272 / 558 4780 / 3076

Certolizumab 3272 / 558 - 104518 / 286

Adalimumab 4780 / 3076 104518 / 286Adalimumab 4780 / 3076 104518 / 286 -


Total number of subjects required for comparative efficacy RCTs between anti-TNF agents for Induction / Maintenance of remission

Comparative Effectiveness Trials of Anti-TNF Agents in Crohn’s Disease

of remission

Infliximab Certolizumab Adalimumab

Infliximab - 3272 / 558 4780 / 3076

Certolizumab 3272 / 558 - 104518 / 286

Adalimumab 4780 / 3076 104518 / 286Adalimumab 4780 / 3076 104518 / 286 -



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Millie D. Long, MD

Recapturing Response with a 2nd Anti-TNF in Crohn’s disease

325 patients loss of response/intolerance IFX

ADA week 0 (160 mg) + week 2 (80 mg)

Placebo week 0 and 2

Adalimumab Efficacy after Loss of Response/Intolerance to Infliximab (GAIN)

Outcome: Induction of remission Week 4

on (%

pat

ient

s)

p<0.001

Outcome: Induction of remission Week 4

Sandborn et al. Ann Intern Med. 2007 Jun 19;146(12):829-38.

Rem

issi

o


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Millie D. Long, MD

Variable Remission at week 4Placebo Adalimumab

Previous loss of response to IFX 8% 20%

Subgroup Analysis Adalimumab Efficacy after Loss of Response/Intolerance to Infliximab (GAIN)

Previous loss of response to IFX 8% 20%

Previous intolerance to IFX 5% 22%

Not receiving steroids at baseline 10% 15%

Receiving steroids at baseline 4% 33%

Negative IFX antibodies 8% 22%

Indeterminate IFX antibodies 25% 17%

Positive IFX antibodies 3% 22%

Sandborn et al. Ann Intern Med. 2007 Jun 19;146(12):829-38.

Week 4:

539 patients loss of response IFX

CTZ q 2 weeks

CTZ week 0,2 and 4 Response week 6

Certolizumab Efficacy after Loss of Response/Intolerance to Infliximab (WELCOME)

CTZ q 4 weeks

RSP: 43.3%REM: 25.4%

Week 6:RSP: 62.0%REM: 39.3%

Week 26:REM CTZ q 2 weeks: 30.4%REM CTZ q 4 weeks: 29.2%

Sandborn et al. Clin Gastroenterol Hepatol. 2010 Aug;8(8):688-695


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Millie D. Long, MD

Anti-Integrin Therapy inCrohn’s disease

Vedolizumab Therapy – Blocking Cell Adhesion in the Gut


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Millie D. Long, MD

Week 6 Week 52

Vedolizumab (VDZ) in Crohn’s Disease –Short and Long-Term Efficacy (GEMINI 2)

Induction of Remission Maintenance of Remission

p<0.02 p<0.2p<0.001

p<0.004 p<0.02p<0.04

Sandborn et al. N Engl J Med. 2013 Aug 22;369(8):711-21.

Remission Week 6 Remission Week 10

Vedolizumab Efficacy After Previous anti-TNF Antagonist Failure in Crohn’s Disease (GEMINI 3)

Sands et al. Gastroenterology. 2014 Sep;147(3):618-627

Approx. 5% higher efficacy at week 10 with concomitant steroids.No clinical effects for concomitant immunosuppression week 6 and week 10.


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Millie D. Long, MD

• Overall there seem to be no significant differences between the different anti-TNF’s in CD

• Combination therapy using infliximab and azathioprine/6-MP is superior to infliximab mono therapy

Summary Biologics in Crohn’s Disease (CD)

superior to infliximab mono-therapy• Adding Methotrexate to infliximab increases trough level and

decreases antibody formation, but no effect on 1 year clinical outcome

• No prospective data for combination therapy adalimumab or certolizumab + azathioprine/6-MP or MTX in IBD

• Vedolizumab is effective in CD, but has a delayed onset of clinical ffi f d t f i f i it f th bi tiefficacy, so far no data of inferiority of mono-therapy vs combination

therapy• Role for steroids with vedolizumab for induction of remission

Flare with severe activity1. Prednisone

Relapse

Algorithm for Induction and Maintenance of Remission in Crohn’s Disease

Flare with mild to moderate inflammatory activity

1. Budesonide (Entocort) Predictors of severe disease (perianal disease, young

• Azathioprine, 6-MP + anti-TNF agent (IFX)

• MTX + anti-TNF (IFX)?

• anti-TNF (ADA, CTZ) alone

• Vedolizumab (?)no remissionConsider surgery

( )2. (5-ASA) (?)

age, penetrating disease, isolated upper GI- disease) or second flare in 12 months.

Vedolizumab (?)

• Switch anti-TNF agent or Vedolizumab

No remission or loss of response

Induction and Maintenance regimen

Induction regimen


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Millie D. Long, MD

Anti-TNF in Ulcerative Colitis

Trial Clinical Remission Week 8 Delta Clinical Remission

Week 52 or 54 Delta

Placebo anti-TNF Placebo anti-TNF

Therapeutic Success anti-TNF Therapy in UC

ACT-1 (IFX) 15.0% 39.0% 24.0% 17.0% 35.0% 18%

ACT-2 (IFX) 6.0% 34.6% 28.6% - -

Ultra-1 (ADA) 9.2% 18.5% 9.3% - -

Ultra-2 (ADA) 9.3% 16.5% 7.2% 8.5% 17.3% 8.8%

Ultra-2 anti-TNF naïve 11.0% 21.3% 10.3% 11.4% 22.0% 10.6%

Pursuit (GOL) 6.3%* 18.7%* 12.4% 15.4%** 28.6%** 13.2%

**Week 30 and 54* Week 6

Rutgeerts et al. 2005, Reinisch et al. 2011, Sandborn et al. 2012; Sandborn et al. 2014


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Millie D. Long, MD

Infliximab Concentration and Clinical Outcome –ACT1 and ACT2 Study

Infliximab 5 mg/kg bodyweight week 0,2,6, IFX level week 8

Week 30p=0.0001

Week 54p=0.007

Week 8p=0.05

*Data presented for the 5 mg/kg groups in ACT 1 & ACT 2

<21.3 <0.11≥21.3-<33.0

≥33.0-<47.9

≥1.4-<3.6>47.9 >8.1

Reinisch W, et al. Presented at DDW; May 20, 2012. Abstract 566.

≥0.11-<2.4

≥2.4-<6.8 >6.8

≥3.6-<8.1<1.4

• Presence of antibodies to drug increases clearance • Lack of concomitant immunosuppression favors antibody

formation• High BMI increases clearance

Factors Influencing the Pharmacokinetics of Anti-TNF Agents

• High BMI increases clearance Probably only relevant for fixed dosed sc anti-TNF

• TNF –levels High baseline TNF may increase clearance

• Albumin Low albumin predictor of failure

• Fecal Excretion of IFX Hi h f l ti b di t f f il High fecal secretion may be a predictor of failure

Ordas et al. 2012; Brandse et al. DDW 2013


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Millie D. Long, MD

Infliximab, Azathioprine or Combination – UC SUCCESS Trial: Week 16 Results

Patients naïve to anti-TNF and AZA or >3 months stop of AZA before trial

p<0.001p<0.001

p<0.02

Patie

nts

(%) p<0.02

p<0.03

pp<0.03

Panaccione et al Gastroenterology. 2014 Feb;146(2):392-400.

Remission: Steroid-free + Mayo <2, Mucosal Healing: endoscopy 0 or 1

Anti-TNF Agents: Induction and Maintenanceof Remission in Ulcerative Colitis–Network Meta-analysis

Overall Anti-TNF for Induction and Maintenance vs. Placebo• Induction Remission RR 2.45, 95% CI: 1.72-3.47 • Maintenance of Remission RR: 2.00, 95% CI: 1.52-2.62

Induction therapy Comparison• Infliximab (IFX) with non-significant trends for superiority

over golimumab (GOL) and adalimumab (ADA)

Maintenance Therapy ComparisonMaintenance Therapy Comparison• Non-significant trends IFX >ADA/GOL

Stidham et al. Aliment Pharmacol Ther. 2014 Apr;39(7):660-71.


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Millie D. Long, MD

Total number of subjects required for comparative efficacy RCTs between anti-TNF agents for Induction / Maintenance

Comparative Effectiveness Trails of Anti-TNF Agents in Ulcerative Colitis

of remission

Infliximab Golimumab Adalimumab

Infliximab - 214 / 1870 174 / 204

Golimumab 214 / 1870 - 13562/ 420

Adalimumab 174 / 204 13562 / 420 -


Total number of subjects required for comparative efficacy RCTs between anti-TNF agents for Induction / Maintenance

Comparative Effectiveness Trails of Anti-TNF Agents in Ulcerative Colitis

of remission

Infliximab Golimumab Adalimumab

Infliximab - 214 / 1870 174 / 204

Golimumab 214 / 1870 - 13562/ 420

Adalimumab 174 / 204 13562 / 420 -

PRACTICAL SIZE; SHOULD BE PERFORMED



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Millie D. Long, MD

Anti-Integrin in Ulcerative Colitis

Delta: 18.4% Delta: 6.6% Delta: 26.8% Delta: 16.5%

Vedolizumab (VDZ)in UC – Clinical Response and Remission Week 6 Depending on Prior anti-TNF Exposure (GEMINI 1)

n=206n=145

Pat

ient

s (%

)

Feagan et al N Engl J Med. 2013 Aug 22;369(8):699-710.


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Millie D. Long, MD

Vedolizumab (VDZ) in UC – Clinical Remission, Corticosteroid-free Remission and Mucosal Healing Week 52 (GEMINI 1)

<0 0001 <0 05 <0 0001

895 patient included -373 patients responded at week 6 (42%) and were randomized

p<0.0001p<0.0001

p<0.05p<0.0001

p<0.0001p<0.0001

Pat

ient

s (%

)

Feagan et al N Engl J Med. 2013 Aug 22;369(8):699-710.

Therapeutic Pyramid in Ulcerative Colitis

Infliximab Cyclosporine Infliximab, Adalimumab, Golimumab, Vedolizumab

Azathioprine, 6-MP Vedolizumab (?)

Steroids, Budesonide (Uceris)

(severe inpatient UC as bridge to other

maintenance therapy)

, ( )

5-ASA’s


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Millie D. Long, MD

Severe Ulcerative Colitis

• Retrospective analysis of 50 patients (35 standard and 15

p=0.039

Accelerated Infliximab Regimen for Severe Acute UC

accelerated protocol)• Standard regimen of 5 mg/kg

at 0,2,6 weeks compared to accelerated (5 mg/kg for 3 doses over a median of 24 days)

Gibson DJ 2015


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Millie D. Long, MD

Accelerated Infliximab Regimen for Severe Acute UC

Changes in CRP Proportion colectomy-free

Gibson DJ 2015

Algorithm for Severe Ulcerative Colitis

Long MD 2009


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Millie D. Long, MD

Algorithm for Severe Ulcerative Colitis

Factors to consider that may influence the decision for accelerated infliximab dosing:

Clinical severityCRPAlbumin

Long MD 2009

Albumin

• Infliximab with highest remission/response rates of the anti-TNFs• Infliximab + azathioprine/6-MP is superior to infliximab monotherapy,

but there are no data for adalimumab or golimumab combination

Summary Biologics in Ulcerative Colitis (UC)

but there are no data for adalimumab or golimumab combination therapy

• Trough levels play a role in the efficacy of anti-TNF agents in UC• Vedolizumab is similarly effective when compared to anti-TNF

agents, but may have a more favorable side effect profile• ? should vedolizumab be combined with azathioprine/6-MP or MTX

to warrant long term efficacy• In severe UC accelerated dosing algorithms may improve short• In severe UC, accelerated dosing algorithms may improve short-

term colectomy rates, but prospective RCT’s are needed


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Millie D. Long, MD

Acknowledgements

• Hans H. Herfarth MD, PhD


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