You Can Never Stop a Biologic

Scott D Lee MDAssociate Professor of Medicine

Director, Clinical Inflammatory Bowel Diseases ProgramUniversity of Washington

Seattle, WAMarch 23rd, 2013

General Considerations in IBD Patients Started and Maintained on Biologics

Diagnosed with moderate to severe diseaseAt risk for complications of IBDHave had significant improvementDiscontinued or on significantly less steroids

Do not have related limiting side effectsHave not develop contraindication

CancerActive infectionDemyelinating disease

Week 54 Remission after Response to InfliximabDiscontinued vs Continued Therapy

Series10

10

20

30

40

50

15%

28%

38%

Single Dose(n=102)

5 mg/kgq 8 wks(n=104)

10 mg/kgq 8 wks(n=105)

Prop

ortio

n of

Pat

ient

s (%

) P<0.001

P=0.021

ACCENT I

Remission defined as: CDAI <150 points

Week 54 Steroid Free Remission After Response to Infliximab

Discontinued vs Continued Therapy

Series10

5

10

15

20

25

30

35

40

11%

25%

34%

Single Dose 5 mg/kgq 8 wks

10 mg/kgq 8 wks

Prop

ortio

n of

Pat

ient

s (%

)

P=0.005P=0.059 P=NS

6/54 14/56 18/53

ACCENT I

ACCENT I Infliximab Antibody FormationDiscontinued vs Continued Therapy

Proportion of Patients with ATI*Through Week 54

Series10

10

20

30

40

50

38

11 816

7 4

No immunomodulators (n=362) With immunomodulators (n=152)

Prop

ortio

n of

Pat

ient

s (%)

Episodic Strategy

Maintenance q 8 weeks10 mg/kg

Maintenance q 8 weeks5 mg/kg

P=0.003

P=0.42P=0.42

Hanauer S, et al., Clin Gastroenterol Hepatol. 2004;2:542–553.

Baert F, et al. N Engl J Med. 2003;348:601-608.

Duration of Response by Antibody Level

Antibody Formation and Effect on Response with Episodic Treatment with InfliximabD

ays

of R

espo

nse 37% of Patients

(n=46)

140

120

100

40

20

0

80

60

Negative 1.7 - 7.9g/mL

8.0 - 20.0g/mL

>20.0g/mL

71 days of clinical response to Infliximab therapy

35 days of clinical response to Infliximab therapy

63% of Patients(n=79)

Episodic Strategy5 mg/kg Scheduled Strategy

10 mg/kg Scheduled StrategyCombined Schedule Strategy

Num

ber o

f Hos

pita

lizat

ions

pe

r 100

Pat

ient

s

Rutgeerts P et al. Gastroenterology. 2004;126:402-413.

Week 54

P=0.047 P=0.023 P=0.014

0

10

20

30

40

50

Continued Therapy Is Associated with Fewer Hospitalizations

ACCENT I

Continued Therapy Is Associated With Fewer Intra-Abdominal Surgeries

Prop

ortio

n of

Pat

ient

s W

ith S

urge

ries

Rutgeerts P et al. Gastroenterology. 2004;126:402-413.

Week 54

P = 0.04 P = 0.07 P = 0.01

0

10

20

30

40

50

Episodic Strategy5 mg/kg Scheduled Strategy

10 mg/kg Scheduled StrategyCombined Schedule Strategy

ACCENT 1

UC Response and RemissionIFX Discontinued vs Continued Therapy

Response

Rutgeerts P. N Engl J Med. 2005;353:2462-2476.

†P<0.001

††

† ‡

3730

69

5262

51

0102030405060708090

100

8 Weeks 30 Weeks

Perc

ent o

f Pat

ient

s

Placebo infusions 5 mg/kg infliximab 10 mg/kg infliximab

‡P<0.01

Perc

ent o

f Pat

ient

s

Remission

†

‡†

†

15 16

393432

37

05

101520253035404550

8 Weeks 30 Weeks

ACT 1

AZA Placebo

Sustained remission up to month 18NRI

p= 0.5

0

25

50

75

100

% p

atie

nts

LOCFp= 0.2

67,757,1

0

25

50

75

100

% p

atie

nts

44,138,1

0

25

50

75

100

125

150

2 3 4 5 6 7 8 9 10 11 12 13

P< 0.01

Visit number

Mea

n C

DA

I

Early Use of AZA After First Steroid Induction

P= 0.07

Sans M. Gastroenterology 2011 (Abstract)

EFFICACY OF AZA THERAPY

Week 50 Steroid Free Remission AZA vs IFX vs Dual Therapy

SONIC

All Randomized Patients (N=508)*

p<0.001

p=0.028 p=0.035

41/170 59/169 78/169

Colombel JF et al. NEJM 2010.

Mucosal Healing at Week 26AZA vs IFX vs Dual Therapy

SONIC

16

30

44

0

20

40

60

80

100

Prop

ortio

n of

Pat

ient

s (%

)

AZA + placebo IFX + placebo IFX+ AZA

p<0.001

p=0.023 p=0.055

18/109 28/93 47/107

Mucosal Healing Predicts Sustained Clinical Remission in Early CD

.

* P < 0.05; ** P < 0.01 (Fischer’s exact)Baert FJ, et al. Gastroenterology 2010

Simple endoscopic score 0 Simple endoscopic score 1-9%

of p

atie

nts *****

0

20

40

60

80

100

Remission at year 3+4

Remission offsteroids at year 3+4

Remission offsteroids at year 3+4

and noflare during year

3+4

Mucosal Healing is Predictive of Sustained Remission

Beaugerie et al, Lancet 2009;7:374.

Risk of Lymphoma Associated with Immunomodulators

19,486 IBD patients 30.1% currently receiving thiopurines 14.4% discontinued thiopurines 55.5% never exposed to thiopurines

Receiving thiopurines vs. never exposedHR 5.28 (2.01-13.9)

Exposure Rate per 10,000 pt-years 95% CI

Current use 9 .0 5.0-14.9Discontinued 2.0 0.2-7.2Never exposed 2.6 1.0--5.7

RISK OF THERAPY - MALIGNANCY

8905 patients representing 20,602 pt-years of exposure 13 Non-Hodgkin lymphomas 6.1/10,000 pt years

This HR is very similar to SIR with thiopurines Mean age 52, 62% male 10/13 exposed to IM* (This is really a risk of combo Rx)

Lymphoma SIR does not appear increase with addition of anti-TNF Lymphoma SIR appears to be dependent on thiopurine use

NHL rate per 10,000 SIR 95% CI

SEER all ages 1.9 - -IM alone 6.1 3.23 -Anti-TNF + IM vs SEER 6.1 3.23 1.5-6.9Anti-TNF+ IM vs IM alone 6.1 1.7 0.5-7.1

*not reported in 2Siegel et al, CGH 2009;7:874.

Meta-Analysis Of Lymphoma Rate Associated With Anti-TNF Agents

RISK OF THERAPY - MALIGNANCY

Anti-TNF Meta-Analysis And Malignancies

Peyrin-Biroulet et al CGH 2008;6:664.

Controls Anti-TNF-0.14% (-0.4-0.2, P=0.39)

Risk difference

Difference in effect: treatment minus placebo (CI 95%)

RISK OF THERAPY - MALIGNANCY

Conclusions

Discontinued biologic vs continued use leads to: Higher recurrence rates of disease activityLower likelihood of steroid free remission Increased risk of antibody formationAntibody formation leads to loss of response

Continued biologic therapy vs Thiopurines is: More effective maintenance therapyThiopurines appear to be the primary risk of lymphomaResults in higher rates of mucosal healing

Once biologic therapy it should not be stopped as the risks outweigh the benefits

A transition to thiopurines as maintenance is less effective and potentially higher risk