Adalimumab, a fully human IgG; monoclonal antibody, is being evaluated in CD and results of clinical studies are favorable. Preliminary studies have demonstrated that adalimumab may be effective even among patients who have lost response to, or were intolerant to, inflixi-mab.
CLASSIC I (Clinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease) was a randomized, double-blind, pla cebo-controlled, multicenter dose-ranging study that evaluated the efficacy of adalimumab induction therapy in 299 patients with moderate to severe CD who were nai've to anti-TNF therapy (Hanauer et al. 2006). Patients received induction treatment at Weeks 0 and 2 with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo and were followed to Week 4. Serum adalimumab concentrations increased proportionately with increasing dose. Adalimumab concentrations were similar at Weeks 2 and 4, indicating that the loading doses achieved stable levels by Week 2. Serum adalimumab concentrations achieved with the 160 mg/80 mg and 80 mg/40 mg doses were comparable to those achieved with long-term 40 mg weekly and 40 mg every other week (e.o.w.), respectively. Statistically significant rates of clinical remission (CDAI < 150 points) and clinical response (decrease in CDAI > 70 or >100 points from baseline, respectively) were achieved by adalimumab-treated patients at Week 4. The optimal induction dosing regimen in this study was 160 mg at Week 0 followed by 80 mg at Week 2. Adverse events occurred at similar frequencies in all four treatment groups, with the exception of injection site reactions that were more common among patients treated with adalimumab.
Patients who completed the CLASSIC I study were eligible to enroll in CLASSIC II, a two-cohort study (open-label and randomized arms) evaluating adalimumab in the maintenance of clinical remission in subjects with CD (Sandborn et al. 2005a). All patients entering CLASSIC II received open-label adalimumab 40 mg at Weeks 0 and 2. Fifty-five patients who were in remission at Weeks 0 (end of CLASSIC I) and 4 were randomized to receive adalimumab 40 mg e.o.w., 40 mg weekly, or placebo for up to 1 year. The remaining subjects not in remission at both Weeks 0 and 4 received open-label adalimumab 40 mg e.o.w. The adalimumab dose could be increased to 40 mg weekly for flare or persistent nonresponse. In the open-label cohort, the long-term efficacy and safety of adalimumab 40 mg e.o.w. therapy was assessed in 221 patients with moderate to severe CD. Data from Year 1 support maintenance of remission, with clinical remission rates of 43 %, and decreases in CDAI 70 or 100 points from baseline occurred in 69% and 61% of patients, respectively (Sandborn et al. 2005b). Among the 55 patients in the randomized cohort study, 83% receiving adalimumab 40 mg weekly, 68% receiving 40 mg e.o.w., and 39% receiving placebo maintained remission at 1 year.
Adverse events were mild to moderate in severity and similar to those observed in previous studies of patients with rheumatoid arthritis (Sandborn et al. 2005c).
CHARM (Crohn's Trial of the Fully Human Antibody Adalimumab for Induction and Remission Maintenance) (Colombel et al. 2006) was a randomized, double-blind, placebo-controlled, 56-week study designed to assess the efficacy and safety of two adalimumab dosing regimens in maintaining clinical remission at 26 and 56 weeks in patients with moderately to severely active CD (CDAI 220-450) who responded to open-label induction therapy with adalimumab at Week 4. A total of 854 patients received open-label induction with adalimumab 80 mg at Week 0 and adalimumab 40 mg at Week 2. At Week 4, patients were stratified by response status (CDAI decrease > 70 points from baseline) and randomized to receive placebo, ada-limumab 40 mg e.o.w., or adalimumab 40 mg weekly through Week 56. The coprimary endpoints were the percentage of Week 4 responders who achieved clinical remission (CDAI <150) at Weeks 26 and 56. The percentage of Week 4 responders in remission was significantly higher in the adalimumab 40 mg e.o.w. and 40 mg weekly treatment groups versus placebo at Week 26 (40%, 47%, and 17%, respectively, p <0.001 for each active treatment group vs. placebo) and at Week 56 (36%, 41%, and 12%, respectively; p <0.001 for each active treatment group vs. placebo). Both active treatment groups also achieved higher response rates (CDAI decreases of > 70 points and > 100 points from baseline) at Week 26 and Week 56 compared with placebo. Greater percentages of adalimumab-treated patients achieved steroid-free clinical remission at 26 and 56 weeks versus placebo. Complete fistula closure (no draining fistulas for > 2 consecutive visits) also was observed more frequently among adalimumab-treated patients versus those receiving placebo. Adalimumab was well tolerated, with a safety profile consistent with previous experience with this drug.
Adalimumab was also examined in infliximab failures. Approximately one-third of patients do not respond to infliximab (van Deventer 2003). Moreover, a proportion of patients lose response over time mostly due to the effect of antibodies to infliximab on the phar-macokinetics of the drug. Preliminary evidence in patients with CD suggests that adalimumab is clinically beneficial in patients who have lost response or who are intolerant to infliximab (Barthel et al. 2005; Papadakis et al. 2005; Sandborn et al. 2004a; Stallmach et al. 2004; Youdim et al. 2004). In one study of seven patients with CD who had allergic reactions to infliximab, patients who had active disease and who had a previous response to infliximab (n = 6) also responded to adalimumab, as evidenced by improvement in the Harvey-Bradshaw index (HBI) and inflammatory markers (Youdim et al. 2004). In a second study, 15 patients with CD who experienced an attenuated response to inflixi-mab were treated with an adalimumab 80 mg loading dose following by 40 mg e.o.w. for 6 months. Of the 13 patients who completed the study, 7 had a complete response (HBI of <4 and withdrawal of corticosteroids), 4 had a partial response (decrease of > 50% in HBI and reduction in corticosteroid dose), and 2 were nonresponders (Papadakis et al. 2005). In a third study of patients with CD who had lost responsiveness or developed intolerance to infliximab who were switched to adalimumab, clinical remission (CDAI <150) was achieved by 5 of 17 patients and a CDAI decrease of
> 70 was achieved by 10 of 17 patients at 12 weeks (Sandborn et al. 2004a). In all of these studies, adalimumab was generally well tolerated, without signs or symptoms of allergic reactions (Papadakis et al. 2005; Sandborn et al. 2004a; Youdim et al. 2004). These studies, although small, suggest that patients with CD who have lost their response to or are intolerant of inflixi-mab, may benefit from switching to adalimumab. Further studies of adalimumab are ongoing, including GAIN (Gauging Adalimumab Efficacy in Infliximab Non-responders), a double-blind, placebo-controlled study of adalimumab in patients who have lost response or are intolerant to infliximab.
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