Journal Club: Biologic Agents in UC, Systematic Review and Network Meta-

analysis, by Danese et al. , Annals 2014

Barrett G. Levesque, MDAssistant Professor of Clinical Medicine

UC San Diego, IBD Center

Panel

• Larry Stitt, Robarts Biostatistician• Gopalan Rajamannar, Robarts Statistician• Dr. Siddharth Singh, Advanced Fellow in IBD,

Mayo Clinic, Rochester• Niels Vande Casteele, PharmD, PhD, Post-doc

UCSD, and KU Leuven, • Moderated by Dr. Barrett Levesque, Robarts

Associate Medical Director

Which is the best biologic option in UC?

Model Study name Statistics for each study Risk ratio and 95% CI

Risk Lower Upper ratio limit limit Z-Value p-Value

Ardizzone, 2006 2.714 1.304 5.650 2.669 0.008

Sood, 2002 1.721 0.963 3.073 1.834 0.067

Sood, 2003 0.677 0.306 1.500 -0.961 0.337

Sood, 2000 1.063 0.713 1.583 0.298 0.766

Jewell, 1974 1.778 0.893 3.541 1.636 0.102

Fixed 1.350 1.041 1.751 2.265 0.024

Random 1.416 0.936 2.144 1.646 0.100

0.01 0.1 1 10 100

Favours A Favours B

Background

A “second-look” meta-analysis, Levesque, Olkin Dig Dis Sci 2010

Background

A “second-look” meta-analysis, Levesque, Olkin Dig Dis Sci 2010

Model Study name Statistics for each study Log risk ratio and 95% CI

Log Standard Lower Upper risk ratio error Variance limit limit Z-Value p-Value

Ardizzone, 2006 0.999 0.374 0.140 0.265 1.732 2.669 0.008

Sood, 2002 0.543 0.296 0.088 -0.037 1.123 1.834 0.067

Sood, 2003 -0.390 0.406 0.165 -1.185 0.406 -0.961 0.337

Sood, 2000 0.061 0.203 0.041 -0.338 0.459 0.298 0.766

Jewell, 1974 0.575 0.352 0.124 -0.114 1.264 1.636 0.102

Fixed 0.300 0.133 0.018 0.040 0.560 2.265 0.024

-1.00 -0.50 0.00 0.50 1.00

Favours A Favours B

Background: Network Meta-analysis

Trial Designs in UC

R

Induction & maintenance (ACT I & II – “ treat right through”):

R

Maintenance in open label respondes (Golimumab):

R R

Induction & maintenance – “ re-reandomization” (vedolizumab):

Courtesy William Sandborn

ACT 1 and ACT 2: Clinical Remission

††

†

†P.002 vs placebo‡P.003 vs placebo

†

Rutgeerts et al. N Engl J Med. 2005 Dec 8;353(23):2462-76.

‡

‡

‡

‡

ACT 1 ACT 2

ULTRA 1: Clinical Remission at Week 8

ITT-A3 analysis set (NRI)Clinical remission: Mayo score ≤2 with no individual subscore >1

0

5

10

15

20

25

30

35M

ayo

sco

re r

emis

sio

n (

%)

Placebo

N=130

9.2%

ADA 80/40 mg

N=130

10.0%

ADA 160/80 mg

N=130

18.5%

N=390

*p=0.031, ADA 160/80 vs placebo

Reinisch W, et al. Gut, 2011; 60:780-787

Reinisch W et al. Gut doi:10.1136/gut.2010.221127

Aim:

Assess the comparative efficacy of biologic agents in (biologic naïve) adult UC.

Methodology*:

• Inclusion: Moderate to Severe UC**, RCT• Network Meta-Analysis (“WinBUGS”) of:

– Clinical Response (OR) – Mucosal Healing (OR) – Adverse Events

-{{Maintenance of Remission}}

*Registered on PROSPERO**Mayo Score 6-12, w/ endo 2-3

Measurements:

• Clinical Response:– Decrease MCS 30% AND decrease rectal

bleeding(RB) by 1 or more , or absolute RB (0,1)• Clinical Remission:

– MCS 2 or lower (subscores 1 or less) • Mucosal Healing

– Mayo endoscopic Score 0 or 1

Measurements:

• Serious Adverse Events:– death, hospital, persistent disability,life-

threatening• Any AE

Infectious AE• Serious Infections• TB• CHF

Results:

Clinical Response

Clinical Remission

Mucosal Healing

Comparing ADA vs IFX in induction of UC remission

Clinical Trial Reinisch et al. ACT 1

Anti-TNF Adalimumab (ADA)160/80 mg

Infliximab (IFX)5mg/kg

Activity index Mayo score Mayo score

Definition of remission Mayo score < 2, no subscore >1

Mayo score < 2, no subscore >1

Participants 130/group 121

Prior Anti-TNF therapy No No

Mean Mayo Score at trial entry

ADA 8.8 ± 1.6 IFX 8.5 ± 1.7

Placebo 8.7 ± 1.6 Placebo 8.4 ± 1.8

Age (yrs) median 36.5 (range 18-75) 42.4 ± 14.3

Disease duration (yrs) 6.1 5.9

Week 8 Clinical Response (%)

54.6

69.4

44.637.2

0

10

20

30

40

50

60

70

80

Reinisch (ADA) ACT 1 (IFX)

Anti-TNF Group

Placebo

Week 8 Remission (%)

18.5

38.8

9.2

14.9

0

5

10

15

20

25

30

35

40

45

Reinisch (ADA) ACT 1 (IFX)

Anti-TNF GroupPlacebo

Placebo arm is not just placebo• “a larger portion of the IFX patients (40-

60%) were on concomitant immunomodulator therapy at baseline compared to the ADA (30%), golimumab (20-30%) and vedolizumab (20%)”

Dulai P, Personal Communication

The ACT Studies: Proportions of Patients with Clinical Remission by Serum IFX Concentration Quartiles

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

%

26.3

37.0

43.943.1

P=0.0504

P<0.0001

Reinisch W. et al DDW 2012

Conclusion

• Biologics superior to “placebo” for induction, maintenance

• No direct Comparisons• Indirect Comparisons of approved dosing favors

infliximab for inducing clinical response• Limitations of endpoint timing, history of treatments, • Biologics were not optimized based on pK/pD• Question of best biologic, optimized or not, for

moderate to severe UC remains unanswered.• What is the best? Consider strategy w/ best Value