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

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Presentation on theme: "1 Literature Review Peter R. McNally, DO, FACP, FACG Lone Tree, Colorado."— Presentation transcript:

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

2 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:

3 3 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). 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. 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. Sandborn WJ, et al conducted a prospective randomized placebo controlled trial of adalimumab for Crohn patients intolerant to or unresponsive to Infliximab. Sandborn WJ, et al. Ann Intern Med. 2007;146:

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

5 5 GAIN Study Design: Design: Design: – 4-week, randomized, double-blind, placebo- controlled trial. Subjects: 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: Treatment arms: – Adalimumab: 160 mg at Week 0 and 80 mg at Week 2 – Placebo at Weeks 0 and 2 Sandborn WJ, et al. Ann Intern Med. 2007;146:

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

7 7 GAIN: Study Subjects CharacteristicsPlaceboN=166AdalimumabN=159 Men n (%) 65(39)50(31) Mean age (SD),y 37(12)39(12) Loss resp to infliximab n (%) 87(52)77(48) Acute Reaction Infliximab 63(38)68(43) Delay Reaction Infliximab 52(31)43(27) HACA60(38)50(33) Sandborn WJ, et al. Ann Intern Med. 2007;146:

8 8 PlaceboN= /80 mg N=159 Mean CDAI Score* Mean IBDQ Score † Median CRP <1 mg/dl 59%52% Steroids 73 (44%) 55 (35%) Immunosuppressants 85 (51%) 73 (46%) 5-ASAs 60 (36%) 45 (28%) Baseline differences between treatment groups were not statistically significant. GAIN: Baseline Disease Characteristics Sandborn WJ, et al. Ann Intern Med. 2007;146:

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

10 10 GAIN: Efficacy Outcomes Wk 4 * *P<0.001, † P<0.01, both vs. placebo. % of Patients * 34/15956/16682/15941/16661/15912/166 † Sandborn WJ, et al. Ann Intern Med. 2007;146:

11 11 GAIN Trial Results Time CDAI ScoreResponse Rates 4 wk CDAIPlacebo 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) Sandborn WJ, et al. Ann Intern Med. 2007;146:

12 12 PlaceboN= /80 mg N=159 Prior AE to infliximab 95 (57%) 95 (60%) Acute (  24 hr) 63 (38%) 68 (43%) Delayed 52 (31%) 43 (27%) Both 20 (12%) 15 ( 9%) Lost response, % 87 (53%) 77 (48%) Prior AE & lost response, % 21 (13%) 19 (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:

13 13 GAIN: Patient Disposition Differences between treatment groups were not statistically significant. PlaceboN= /80 mg N=159 Completed, n (%) 156 (94%) 155 (98%) Withdrawn, n (%) 10 (6%) 4 (3%) Primary Reason (n) Adverse event 42 Protocol violation 51 Lack of efficacy 00 Withdrew consent 11 Other00 Sandborn WJ, et al. Ann Intern Med. 2007;146:

14 14 GAIN: Efficacy Outcomes at Week 4 * *P<0.001, † P<0.01, both vs. placebo. % of Patients * 34/15956/16682/15941/16661/15912/166 † Sandborn WJ, et al. Ann Intern Med. 2007;146:

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

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

17 17 Week 4 Remission by Baseline Immunosuppressant (IMM) Use 6/8416/7318/866/82 Sandborn WJ, et al. Ann Intern Med. 2007;146:

18 18 Week 4 Remission by Infliximab History % of Patients 15/777/8721/955/950/213/19 Sandborn WJ, et al. Ann Intern Med. 2007;146:

19 19 Wk 4 Remission by Baseline HACA* to Infliximab 2/5810/4821/10510/101 *Human anti-chimeric antibodies (HACAs). Sandborn WJ, et al. Ann Intern Med. 2007;146:

20 20 Conclusions 1. 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. 2. This study does NOT show that Infliximab “non- responders” will have long term response to Adalimumab. 3. This trial did NOT directly compare efficacy of Infliximab & Adalimumab. Sandborn WJ, et al. Ann Intern Med. 2007;146:

21 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. 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. 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:


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