Anne M. Robinson

Adalimumab Induces Deep Remission in Patients With Crohn's Disease

BACKGROUND & AIMS Patients with moderate to severe ileocolonic Crohns disease (CD) who received adalimumab induction and maintenance therapy had greater rates of mucosal healing than patients who received placebo after adalimumab induction therapy in a 52-week trial (EXTend the Safety and Efficacy of Adalimumab Through ENDoscopic Healing). We investigated whether this treatment also induced deep remission-a composite clinical and endoscopic end point. METHODS Rates of deep remission, defined as the absence of mucosal ulceration and CD Activity Index scores less than 150, were compared between patients given continuous adalimumab and those given only induction therapy followed by placebo. We assessed the relationships between deep remission and other outcomes among patients who received adalimumab. The outcomes of patients with deep remission were compared with those of patients with only the absence of mucosal ulceration or only clinical remission. RESULTS Rates of deep remission were 16% in patients given adalimumab vs 10% in those given placebo (P = .34) at week 12, and 19% vs 0% (P < .001) at week 52. Rates of deep remission were greatest among patients who received adalimumab and had CD for 2 years or less (33% at weeks 12 and 52). At week 52, patients who achieved deep remission at week 12 required significantly fewer adalimumab treatment adjustments, hospitalizations, and CD-related surgeries; had significantly less activity impairment; and had better quality of life and physical function compared with patients not achieving deep remission. Deep remission generally was associated with better outcomes than only an absence of mucosal ulceration; outcomes of patients with deep remission vs only clinical remission were similar. Deep remission was associated with estimated total cost savings of

Adalimumab safety in global clinical trials of patients with Crohn's disease.

10,360 (from weeks 12 through 52) compared with lack of deep remission. CONCLUSIONS In an exploratory study of patients with moderate to severe ileocolonic CD who received adalimumab induction and maintenance therapy, patients achieving deep remission appeared to have better 1-year outcomes than those not achieving deep remission. These findings should be validated in large, prospective trials. ClinicalTrials.gov number: NCT00348283.

Increased Risk of Malignancy With Adalimumab Combination Therapy, Compared With Monotherapy, for Crohn's Disease

Background: Adalimumab, a fully human anti‐tumor necrosis factor (anti‐TNF) monoclonal antibody, is approved for the treatment of Crohns disease (CD) in adults. We evaluated the overall safety profile of adalimumab in global clinical trials in patients with CD. Patients who participated in these trials, which included randomized induction and maintenance trials, Phase IIIb trials, and open‐label extension studies, had moderately to severely active CD and were evaluated for safety at regular intervals. Methods: Rates of adverse events of interest were assessed per 100‐patient‐years of adalimumab exposure. Standardized mortality rates and standardized incidence rates (for malignancies) were calculated using population‐matched data. As of April 15, 2008, 3160 patients with CD had been treated with adalimumab in clinical trials, representing 3401.9 patient‐years of adalimumab exposure. Results: Serious infection was the most frequently reported serious adverse event of interest in the CD trials; abscess (intraabdominal and gastrointestinal related) was the most common serious infection. Low incidences of malignancies, lymphomas, opportunistic infections (including tuberculosis), demyelinating disorders, and lupus‐like disorders were reported in the CD trials. The standardized mortality rate for adalimumab‐treated patients with CD, 0.44 (95% confidence interval [CI], 0.12–1.12), is less than the rate of 1.52 (95% CI, 1.32–1.74) reported in a recent meta‐analysis of patients with CD. Conclusions: The safety profile of adalimumab in patients with CD was similar to that of other TNF antagonists in CD populations, and the rates of adverse events were comparable to other approved indications for adalimumab spanning >10 years of clinical observation. No new safety signals were identified. (Inflamm Bowel Dis 2009)

Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease

BACKGROUND & AIMS Few studies have assessed the risk of malignancy from anti-tumor necrosis factor monotherapy or combination therapy for Crohns disease (CD). We determined the relative risk of malignancy in patients with CD who received adalimumab monotherapy, compared with the general population. We also compared the risk of malignancy associated with combination adalimumab and immunomodulator therapy with that of adalimumab monotherapy. METHODS We performed a pooled analysis of data from 1594 patients with CD who participated in clinical trials of adalimumab (CLASSIC I and II, CHARM, GAIN, EXTEND, and ADHERE studies; 3050 patient-years of exposure). We calculated rates of malignancy among patients; the expected rates of malignancy, based on the general population, were derived from the Surveillance, Epidemiology, and End Results registry and National Cancer Institute survey. RESULTS Compared with the general population, patients receiving adalimumab monotherapy did not have a greater than expected incidence of nonmelanoma skin cancer (NMSC) or other cancers, whereas those receiving combination therapy had a greater than expected incidence of malignancies other than NMSC (standardized incidence ratio, 3.04; 95% confidence interval [CI], 1.66-5.10) and of NMSC (standardized incidence ratio, 4.59; 95% CI, 2.51-7.70). Compared with patients receiving adalimumab monotherapy, those patients receiving combination therapy had an increased risk of malignancy other than NMSC (relative risk, 2.82; 95% CI, 1.07-7.44) and of NMSC (relative risk, 3.46; 95% CI, 1.08-11.06). CONCLUSIONS In patients with CD, the incidence of malignancy with adalimumab monotherapy was not greater than that of the general population. Co-administration of immunomodulator therapy and adalimumab was associated with an increased risk of NMSC and other cancers.

One-year maintenance outcomes among patients with moderately-to-severely active ulcerative colitis who responded to induction therapy with adalimumab: subgroup analyses from ULTRA 2

Background: Although tumor necrosis factor (TNF) antagonists are effective for the treatment of Crohns disease and ulcerative colitis, lack and loss of clinical response is a clinical challenge. Accordingly, the use of therapeutic drug monitoring has been proposed as a means to optimize treatment. This article reviews the mechanisms of and factors which influence clearance of biologics, the relationship between serum drug concentrations and antidrug antibody presence and treatment efficacy, and identifies areas for future research needs regarding the use of therapeutic drug monitoring in clinical practice. Methods: Publications regarding these topics were identified from literature searching and supplemented by review of gastroenterology meeting presentations and reference lists. Results: The clearance of monoclonal antibodies and pegylated antibody fragments is complex, and may be affected by demographic variables, concomitant medications, inflammatory burden, and immunogenicity, leading to high interpatient variability in plasma concentration of drug and clinical response. Several observational studies have demonstrated a relationship between anti‐TNF agent serum drug concentrations and/or antidrug antibody presence and various symptomatic and objective clinical endpoints. However, these relationships are not absolute, and although some algorithms for the use of therapeutic drug monitoring in clinical practice have been proposed, none have yet been validated in a prospective clinical trial. Conclusions: Further research to identify the most appropriate use of therapeutic drug monitoring is needed. (Inflamm Bowel Dis 2011;)

Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn’s disease

Patients with moderately‐to‐severely active ulcerative colitis (UC) are unlikely to continue anti‐TNF therapy in the absence of early therapeutic response.

Subgroup analysis of the placebo-controlled CHARM trial: Increased remission rates through 3 years for adalimumab-treated patients with early Crohn's disease

Aliment Pharmacol Ther 31, 1296–1309

Adalimumab produces clinical remission and reduces extraintestinal manifestations in Crohn's disease: results from CARE.

BACKGROUND AND AIMS We examined the impact of disease duration on clinical outcomes and safety in a post hoc analysis of a remission maintenance trial with adalimumab in patients with moderate to severe CD. METHODS Patients in the CHARM trial were divided into 3 disease duration categories: <2 (n=93), 2 to <5 (n=148), and ≥5 years (n=536). Clinical remission and response rates at weeks 26 and 56 were compared between adalimumab and placebo subgroups, and assessed through 3 years of adalimumab treatment in the ADHERE follow-on trial. Logistic regression assessed the effect of disease duration and other factors on remission and safety. RESULTS At week 56, clinical remission rates were significantly greater for adalimumab-treated versus placebo-treated patients in all 3 duration subgroups (19% versus 43% for <2 years; P=0.024; 13% versus 30% for 2 to <5 years; P=0.028; 8% versus 28% for ≥5 years, P<0.001). Logistic regression identified shorter duration as a significant predictor for higher remission rate in adalimumab-treated patients. Patients with disease duration <2 years maintained higher remission rates than patients with longer disease duration through 3 years of treatment. The incidence of serious adverse events in adalimumab-treated patients was lowest with disease duration <2 years. CONCLUSIONS Adalimumab was superior to placebo for maintaining clinical remission in patients with moderately to severely active CD after 1 year of treatment regardless of disease duration. Clinical remission rates through 3 years of treatment were highest in the shortest disease duration subgroup in adalimumab-treated patients, with a trend to fewer side effects.

Serum adalimumab concentration and clinical remission in patients with Crohn's disease.

Background: Data regarding the effectiveness of anti‐tumor necrosis factor (TNF) agents for resolution of extraintestinal manifestations (EIMs) are scarce. The CARE study evaluated clinical effectiveness, EIM resolution, and safety of adalimumab in a large pan‐European cohort of patients with moderate to severe Crohns disease (CD). Methods: In all, 945 patients with a Harvey–Bradshaw Index (HBI) ≥7 enrolled in this multicenter, open‐label phase IIIb trial. Patients received subcutaneous adalimumab, 160/80 mg at weeks 0/2, then 40 mg every other week. Dose adjustments were allowed for CD‐related concomitant medications (from week 8) and adalimumab (from week 12). Clinical endpoints were analyzed through week 20 for all patients, and after stratification by prior infliximab exposure and by reason for discontinuing infliximab (primary nonresponse [PNR] or other). Results: The remission rate (HBI <5) at week 20 was 52% (95% confidence interval, 49%–55%) overall, and was higher for infliximab‐naïve versus infliximab‐exposed patients (62% versus 42%, P < 0.001). Remission rates were similar for PNR (37%) and other reasons (43%; P = 0.278). Of 497 patients with baseline EIMs, 51% were free of EIM signs and symptoms at week 20. Serious infectious adverse events were reported in 5% of patients. Opportunistic infections and malignancies were rare (≤1%). There was one case of demyelinating disease, but no occurrences of lupus, tuberculosis, or death. Conclusions: In this large cohort of patients, adalimumab treatment resulted in rates of clinical remission and EIM resolution exceeding 50%, and substantial rates of effectiveness in patients who had PNR to infliximab. Adalimumab was well tolerated, with safety consistent with prior reports. (Inflamm Bowel Dis 2011)

Dosage adjustment during long-term adalimumab treatment for Crohn's disease: clinical efficacy and pharmacoeconomics.

Background:Drug concentration monitoring may be useful to guide therapeutic adjustments for anti–tumor necrosis factor agents in Crohns disease. The relationship between serum adalimumab concentrations and clinical outcomes was assessed using data from CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohns Disease (CLASSIC) I/II. Methods:Serum adalimumab concentrations at week 4 of CLASSIC I and weeks 4, 24, and 56 of CLASSIC II were compared by clinical remission status (yes/no). Logistic regression and Classification and Regression Tree analyses explored factors associated with remission at weeks 4, 24, and 56. Threshold analyses and receiver operating characteristic curves evaluated the relationship between serum concentrations and clinical remission/response. Results:Serum adalimumab concentrations for 275 patients were available. Median adalimumab concentrations were significantly higher in patients who achieved clinical remission than those who did not at week 4 of CLASSIC I (8.10 versus 5.05 µg/mL, P < 0.05). At all time points, adalimumab concentrations demonstrated considerable variability and overlap between patients with and without remission. With Classification and Regression Tree analyses, baseline Crohns Disease Activity Index, baseline C-reactive protein, and adalimumab concentrations were associated with early remission at week 4 of CLASSIC I and week 4 of CLASSIC II, but not at weeks 24 and 56. Receiver operating characteristic curves demonstrated low utility of cutoff thresholds to discriminate by clinical response/remission status. Conclusions:A positive association between serum adalimumab concentration and remission was identified at several time points. A threshold concentration reliably associated with remission was not identified. Further prospective evaluations are needed before recommendations for adalimumab concentration monitoring can be made.