Literature Review

1. Literature Review Peter R. McNally, DO, FACP, FACGLone Tree, Colorado

2. Title: Adalimumab Induction Therapy for Crohn’s Disease Previously Treated with Infliximab. Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, et al. Annals of Internal Medicine. 2007;146:829-838.

3. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. Introduction • Tumor Necrosis factor (TNF) is an important pro inflammatory cytokine seen in Crohn’s disease. Infliximab is a chimeric, anti-TNF monocolonal antibody that is effective in inducing and maintaining clinical remission in Crohn’s patients. Loss of efficacy, need for dose escalation, or infusion reactions with infliximab have been reported in upto 40% of cases (Hanauer SB, et al. Lancet. 2002;359:1541-9). • Adalimumab is a new phage derived purely human TNF antagonist that has been shown to be effective in Crohn’s patients that are naive to and some patients that have lost response to or are intolerant to Infliximab. • Sandborn WJ, et al conducted a prospective randomized placebo controlled trial of adalimumab for Crohn patients intolerant to or unresponsive to Infliximab.

4. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. Aim • Determine if Adalimumab is more effective than placebo in inducing remission among patients that are intolerant or resistant to Infliximab therapy. • Study Eponym: GAIN • Gauging • Adalimumab Efficacy in • Infliximab • Non-Responders

5. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. GAIN Study Design: • Design: • 4-week, randomized, double-blind, placebo-controlled trial. • Subjects: • 325 adults with Moderate to severe Crohn’s disease (CDAI 220–450). • All intolerant to or loss of response to Infliximab • Stopped infliximab at least 8 weeks prior to the study • Stable dose concurrent treatment allowed • Treatment arms: • Adalimumab: 160 mg at Week 0 and 80 mg at Week 2 • Placebo at Weeks 0 and 2

6. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. GAIN Study Design: • Measurements: • CDAI • Fall > 70 points (moderate improvement) • Fall > 100 points (significant improvement) • Remission = CDAI < 150 points • Evaluation Time Points • T-2 weeks, T0, T1, T2, & T4 weeks

7. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. GAIN: Study Subjects

8. GAIN: Baseline Disease Characteristics Baseline differences between treatment groups were not statistically significant. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

9. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. Mean CDAI score at each visit

10. GAIN: Efficacy Outcomes Wk 4 * † * % of Patients 12/166 34/159 56/166 82/159 41/166 61/159 *P<0.001, †P<0.01, both vs. placebo. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

11. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838. GAIN Trial Results Time CDAI ScoreResponse Rates 4 wk CDAI Placebo Adalimumab p-value > 70 ↓ 34% 52% > 100 ↓ 25% 38% <150 (remission) 7% 21% <0.001 Remission in Adalimumab group 21% or a Δ 14.2% (95% CI, 6.7 to 21.6 percentage points)

12. GAIN: Prior Response to Infliximab Differences in prior response to infliximab were not statistically significant. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

13. GAIN: Patient Disposition Differences between treatment groups were not statistically significant. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

14. GAIN: Efficacy Outcomes at Week 4 * † * % of Patients 12/166 34/159 56/166 82/159 41/166 61/159 *P<0.001, †P<0.01, both vs. placebo. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

15. * * 21 21 % of Patients 6 7 6 4 Week GAIN: Remission Rates: CDAI<150 *P<0.001 vs. placebo. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

16. † † 52 52 * % of Patients 35 34 33 21 Week Response Rate 70-Point CDAI Decrease (CR-70) *P<0.005, †P<0.001, both vs. placebo Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

17. 6/84 16/73 6/82 18/86 Week 4 Remission by Baseline Immunosuppressant (IMM) Use Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

18. Week 4 Remission by Infliximab History % of Patients 7/87 15/77 5/95 21/95 0/21 3/19 Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

19. 2/58 10/48 10/101 21/105 Wk 4 Remission by Baseline HACA* to Infliximab *Human anti-chimeric antibodies (HACAs). Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

20. Conclusions • 52% of Crohn’s pts no longer responsive to Infliximab at 5mg/kg clinically improved (↓ CDAI > 70 points) on Adalimumab 160/80mg and 21% of pts went into remission by 4wks. - Response to Adalimumab was not influenced by presence of HACA (+) or co-therapy with IMM. • This study does NOT show that Infliximab “non- responders” will have long term response to Adalimumab. • This trial did NOT directly compare efficacy of Infliximab & Adalimumab. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.

21. Reviewer Comments • Infliximab “non responders” are seen in up to 40% of Crohn’s patients within a year of treatment. This study provides important information that Adalimumab is a valuable alternative for these patients. • Expect 52% of Crohn’s pts that are Infliximab “non-responders” to experience improvement in CDAI > 70 pts after 4 wk of Adalimumab 160/80 mg and 21% of pts will go into remission. Sandborn WJ, et al. Ann Intern Med. 2007;146:829-838.