What are the Unmet in the of IBD? - etouches 1 What are the Unmet Needs in the Management of IBD? Shane Devlin, MD, FRCPC Inflammatory Bowel Disease Group The University of Calgary

23/06/2014

1

What are the Unmet Needs in the

Management of IBD?

Shane Devlin, MD, FRCPCInflammatory Bowel Disease Group

The University of Calgary

Some Real Cases: #1

• 32 yo male with pan UC.• Grumbling phenotype with 8 BM per day with blood

75% of the time, modestly elevated CRP• Poor quality of life• No clinical or endoscopic response to dose

escalated infliximab, weekly adalimumab and now failing golimumab

Some Real Cases: #2

• 42 yo female with ileal and pan colonic CD• Prior ileo-cecal resection in 2009• Induction and maintenance infliximab in 2010• Developed delayed type hypersensitivity reaction

to infliximab in 2012• Switched to adalimumab with incomplete

response, but recently developed severe psoriaform lesions that are not responding to topical or UV therapy

23/06/2014

2

Some Real Cases: #3

• 78 yo male patient• Multiple comorbidities• Newly diagnosed steroid dependent pan ulcerative

colitis, non responsive to 5-ASA

Anti‐TNF in IBD: A Historical Timeline

1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown

2009 Sonic 2009 COMMIT

2010Postop

2009EXTEND


1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

Episodic Combination Therapy

23/06/2014

3


1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

Maintenance Combination Therapy


1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

Monotherapy? (esp. Humira)


1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

HSTCL…Monotherapy?

23/06/2014

4


1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

Earlier Use


1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

Combo TherapyMucosal HealingAnti TNF for UC


2014 and Beyond

‐TDM

‐Golimumab and Adalimumab for UC

1995

1997

2002

1999

20041998IFX

2007

2006ADA

2008Topdown


2010Postop

2009EXTEND

Combo TherapyMucosal HealingInfliximab for UC

23/06/2014

5

y

Maximize the Use of Anti‐TNF

Therapy

Yet….We have unmet needs

• IBD is a serious, systemic disease• Primary non-response• Inadequate response• Secondary loss of response due to a variety of

mechanisms• Intolerance due to adverse events• Ongoing steroid use

The Requirement for Colectomy in IBD

remains Higher than we’d like

4.9%

11.6%15.6%16.3%

33.3%

46.6%

0

10

20

30

40

50

1‐year 5‐year 10‐year

Colectomy rate

U

C

Colectomy rates in meta‐analysis of 30 population‐based studies

Frolkis et al. Gastroenterology 2013;Online:doi 10.1053/j.gastro.2013.07.041

23/06/2014

6

UC Negatively Impacts Patient

Quality of LifePatients & physicians differ in their

perception of disease severity

5

8

11

2

45

0

5

10

15

Mild Moderate Severe

Estimated # disease flares/y

Patients

Physicians

• 62% say their disease made it difficult to lead a normal life

• Only 42% believed that remission means living without symptoms

Rubin et al. Inflamm Bowel Dis 2009; 15:581‐8

Colectomy and IPAA Is Not

OptimalPostoperative problems are

frequent

• Pouchitis: 46%1

• Female infertility: 48%2

o (vs. 15% in medically-treated UC)

• Other complications1

o Sexual dysfunction, pouch leakage, abscess formation, fistula formation, small bowel ileus, anastomotic stenosis, and fecal incontinence

Functional outcomes after colectomy1

1. Ferrante et al. Inflamm Bowel Dis 2008; 14:20‐8; 2. Waljee et al. Gut 2006; 55:1575‐8

51%

25%

19%

14%

35%

0

10

20

30

40

50

60

>5 BM/day >2 BM/nightPeri‐anal sorenessDietary restrictionsMedication

Patients (%)

y

Disease with Serious

Complications

Probability of developing penetrating or stricturing complicationin CD patients (N=2,002)

Cosnes et al. Inflamm Bowel Dis 2002;8:244‐50

23/06/2014

7

Mortality in UC

Mortality rates in meta-analysis of 10 population-based studies

• Greater risk of dying during the first years of follow-up, and in patients with extensive colitis vs. general population

o 17% of all deaths were UC-related mortality

o Higher rates of mortality from GI diseases, nonalcoholic liver diseases, pulmonary embolisms, and respiratory diseases

Jess et al. Am J Gastro 2007;102:609‐17

CD Associated with Increased

Mortality Risk

Overall

Bewtra et al. Inflamm Bowel Dis 2013; 19:599‐613

Standardized mortality rates (SMR) in population‐based cohort studies

• Each year, 114 deaths in Canada are attributed to CD and UC

1.39 (95%CI 1.18, 1.64)

Primary and Inadequate Response

23/06/2014

8

*P<.05NS=not significant.

We are not successful in inducing remission

with a significant proportion of patients

n 57 60 328 331 74 75 76 25 27 28

Tx Pbo CzP400mg

Pbo CzP400 mg

Pbo ADA80/40 mg

ADA160/80

mg

Pbo INF5 mg/kg

INF10 mg/kg

Delta 20 8 12 24 44 21

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.

Overall induction of remission ~30–50%

0

20

40

60

80

100

4

25

* NS48

Certolizumabpegol1

7

27*

11

*19

*NS

1224

36

Pa

tie

nts

(%

)

Certolizumapegol2 Adalimumab3 Infliximab4

6 Month Data

CD, Crohn’s disease.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.

Overall maintenance of remission in CD

~25–30%

Infliximab – ACCENT I2Certolizumab pegol – PRECISE 21

Adalimumab – CHARM3

28.618.3

64.147.9

30.7

0

20

40

60

80

100

Open-LabelInductionWeek 6

Week 26Remission

NetRemissionWeek 26

Pat

ien

ts (

%) Pbo CzP

21.012.3

58.5

39.022.8

0

20

40

60

80

100

Pat

ien

ts (

%) Pbo IFX

17.0 9.9

58.0

40.0

23.2

0.0

20.0

40.0

60.0

80.0

100.0

Pat

ien

ts (

%)

Pbo ADACertolizumab pegol – PRECISE 14

18.329.5

0

20

40

60

80

100

Pat

ien

ts (

%)

Pbo CzP


Week 30Remission

NetRemissionWeek 30

NetRemissionWeek 26


Week 26Remission

NetRemissionWeek 26

Sustained remission at 12

months in UC

8 7 2

23 21 1526 20 23

0

20

40

60

80

100

Remission at weeks 8 and 30 Remission at weeks 8, 30 and 54 Remission at weeks 8 and 30

Infliximab: ACT1 and 21*

Placebo Infliximab 5 mg Infliximab 10 mg

ACT1 ACT2

p=0.001

p<0.001

Pat

ien

ts (

%)

p=0.002

p=0.002

p<0.001

p<0.001

9.2 1018.5

29.5

0

20

40

60

80

100

Remission at week 8 Remission at week 52

Adalimumab: ULTRA12,3†

*Clinical remission was defined as a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point.†Non-responder imputation (NRI) analyses, Week 8; mNRI analyses, Week 52.amNRI (modified NRI): did not count patients who dose escalated (and were in remission) as failures (post-hoc analyses). Clinical remission: Mayo score ≤2 with no individual subscore >1.1. Rutgeerts P, et al. N Engl J Med 2005;353:2462–76. 2. Reinisch W, et al. J Crohns Colitis 2011;5:S10; 3. Reinisch W, et al. Gut 2011;60:780–7.

Adalimumab 80/40 Adalimumab 160/80

Overall maintenance of remission in UC

~15–25%

All randomised

Pat

ien

ts (

%)

23/06/2014

9

Sandborn WJ, et al. Gastroenterology 2013 Epub ahead of print. DOI: 10.1053/j.gastro.2013.05.048

24.1

36.5 40.4

PlaceboN=54

Golimumab50 mg q4w

N=52

Golimumab100 mg q4w

N=57

18.427.8

22.9

PlaceboN=87

Golimumab50 mg q4w

N=79

Golimumab100 mg q4w

N=83

0

20

40

60

80

100

Per

cen

t o

f su

bje

cts

Secondary:Durable clinical remissionat both Week 30 and 54 in

patients in remission Week 0

Secondary:Corticosteroid-free

remission rates through Week 30 and 54

p=0.073p=0.365

p=0.299p=0.464

GolimumabWeek 54Primary and major secondary endpoints among randomised responders

Vedolizumab in UC Primary and Secondary

Outcomes Through 52 Weeks, ITT Population

%

26.1 29.1 32.8 28.5 32.0 36.3 11.8 15.3 17.6 31.4

******

**

**

***

*** ***

***

*

***

*P<0.05. **P<0.01. ***P<0.0001

n: 72 70 73

Feagan, B.G. et al Gastroenterology 2012; Volume 142, Issue 5, Suppl 1, Pg S-160-S-161

Vedolizumab in CD Primary and Secondary

Outcomes at 52 Weeks

Patie

nts,

%

17.4 14.7 13.4 15.3 7.2 2.015.9 12.9

Primary Outcome

Secondary Outcomes

§

†P<0.01 vs placebo; ‡P<0.05 vs placebo§

Mean % vs VDZ/PBO

VDZ/PBOVDZ/VDZ Q8WVDZ/VDZ Q4W

Sandborn WJ. et al. American J Gastro.107: 2012: Abstract 1550.

23/06/2014

10

Secondary Loss of Response

1. Hanauer SB, et al. Lancet 2002;359:1541–9.2. Colombel JF, et al. Gastroenterology 2007;132:52–65.3. Lichtenstein GR, et al. Clin Gastroenterol Hepatol 2010;8:600–9.

Patients Attenuate Over Time

ACCENT I1

CDAI 7054 weeks

CHARM2

CDAI 7054 weeks

PRECiSE 2&33

CDAI 10080 weeks

6 12 18

Months

6 12 18

Months

6 12 18

Months

52% 38% 54% 43% 61% 54%

Anti-TNF

Placebo

Anti-TNF

Placebo

Anti-TNF

Placebo

Patients

with Prior Anti‐TNF Use

34%

48%

31%

42%

1014

0

10

20

30

40

50

60

Prior anti‐TNF (N=237) No prior anti‐TNF (N=262)

Patients in remission* (%) Adalimumab 40 mg

weekly

CHARM: Remission* rates with adalimumab at week 56, by prior anti‐TNF use (N=778)

Colombel et al. Gastroenterology 2007; 132:52‐65

*Remission defined as CDAI <150

23/06/2014

11

Outcomes of maintenance

therapy with 3rd anti‐TNFRetrospective, single-center cohort study (N=664) of CD patients on maintenance anti-TNF therapy

examining long-term outcomes by number of prior anti-TNFs (1, n=444; 2, n=178; 3, n=42)

• Two thirds of patients on long-term anti-TNF maintenance therapy remained on 1st agent • Patients on their 1st or 2nd anti-TNF had similar long-term outcomes. Those on their third anti-TNF

agent had significantly worse disease control and higher healthcare utilisation

HBI, Harvey-Bradshaw Index; SIBDQ, Short Inflammatory Bowel Disease Questionnaire.Perera et al. Gastroenterology 2012; 142(Suppl):S-357. DDW 2012; Abstract Sa1910.

Ave

rag

e sc

ore

SIBDQ HBI

Number of anti-TNFs receivedNumber of anti-TNFs received

Ave

rag

e sc

ore

2.93.9

5.2

0

10

1 2 3

50.9 47.940.3

0

100

1 2 3

Sometimes we need to stop therapy

y y

Uncommon but Remains a Relevant

Concern

Adverse Event Events/100 pt‐y (N=3401.9 p‐y)

Any SAE 34.4

Serious infection 6.6

Malignant neoplasms 1.3

Opportunistic infections 2.0

Congestive heart failure <0.1

Demyelinating disorder 0.2

Lupus‐like syndrome 0.2

Any fatal adverse event 0.1 (4 patients)

Colombel et al. Inflamm Bowel Dis 2009;15:1308‐19.

Adverse events of interest in patients treated with adalimumab in 6 global clinical trials (N=3160)

• Most common infectious SAEs were: abscess 2.5%, GI infection (excluding abscess) 1.0%, and pulmonary infection 0.9%

23/06/2014

12

Infection and TNF Antagonists

• TREAT registry n > 6,000, f/u > 5yrs

• Factors independently associated with serious infections (Descending order of risk) : • Disease activity mod‐severe (HR = 2.24, 95% CI = 1.57, 3.19; P < 0.001),

• Narcotic analgesic treatment (HR = 1.98, 95% CI = 1.44, 2.73; P < 0.001)

• Prednisone therapy (HR = 1.57, 95% CI = 1.17, 2.10; P = 0.002)

• Infliximab treatment (HR = 1.43, 95% CI = 1.11, 1.84; P =

0.006).

Lichtenstein GR. Am J Gastroenterol. 2012 Sep;107(9):1409‐22.

Our Best Treatment With Earlier Use and

Combination Therapy

All randomised patients (N=508)*

p<0.001

p=0.028 p=0.035

41/170 59/169 78/169

*Patients who did not enter the Study Extension were treated as non-respondersColombel JF, et al. N Eng J Med 2010; 362:1383-95.

Fewer than half are in remission and off of steroidsIn most anti TNF trials, the rate of SFR at one year is around 25‐30%

In Summary…

• IBD is a serious systemic condition with significant potential complications

• Anti TNF therapy has, and will continue to markedly enhance our ability to treat patients with a view to affecting a longer term change in disease course

• However, more than 10 years of wide-spread use has taught us the limitations and heightened our awareness of a need for alternative therapies

• Loss of response, continued steroid use, systemic effects remain relevant concerns

• There is considerable room to improve upon as we continue to strive for the safest and most efficacious treatments for our patients with IBD.

Documents

What are the Unmet in the of IBD? - etouches 1 What are the Unmet Needs in the Management of IBD? Shane Devlin, MD, FRCPC Inflammatory Bowel Disease Group The University of Calgary