Faculty Bibliography

Most physicians believe that the drugs they prescribe will work in their patients and thus have made little preparation for alternative strategies in the event of failure. In the treatment of inflammatory bowel disease (IBD), achieving a remission rate of 20% to 30% or a response rate of 50% to 60% is highly acceptable. This review focuses primarily on placebo-controlled trials that evaluated 'usual' treatments for IBD in terms of induction and maintenance of remission, and identifies the 'gaps' (ie, the percentage of patients lacking any benefit) in currently available treatments for IBD. Approximately, 40% to 60% of patients will not benefit from the available treatments, indicating a considerable unmet need for new, more effective therapies

BACKGROUND: Natalizumab, a humanized monoclonal IgG(4) antibody to alpha4 integrin, was investigated as a treatment of active Crohn's disease (CD). The safety of natalizumab given in combination with infliximab has not previously been studied. METHODS: Seventy-nine adult patients with active CD (Crohn's Disease Activity Index [CDAI] score > or = 150) despite ongoing infliximab treatment were randomized 2:1 to receive 3 intravenous infusions of natalizumab (300 mg; n = 52) or placebo (n = 27) every 4 weeks. Patients received infliximab (5 mg/kg) every 8 weeks for at least 10 weeks before randomization and throughout the study. The primary objective was to assess the short-term safety and tolerability of natalizumab in patients concurrently receiving infliximab. Secondary and tertiary objectives included measures of efficacy, health-related quality of life (HRQoL), and effects on inflammatory markers. A subset of patients also participated in a pharmacokinetic/pharmacodynamic (PK/PD) analysis of the effects of concurrent treatment. RESULTS: Incidence of adverse events (AEs) was similar in the treatment groups. AEs frequently reported in both groups were headache, CD exacerbation, nausea, and nasopharyngitis. No patient had a hypersensitivity-like reaction to natalizumab, whereas 4 patients (5%) experienced reactions to infliximab. Two patients (4%) developed anti-natalizumab antibodies; 10 patients (14%) developed anti-infliximab antibodies. The mean CDAI score decreased with natalizumab plus infliximab but was unchanged with infliximab alone (-37.7 versus +3.5; P = 0.084). Patients in both groups showed small increases in HRQoL (P = 0.811). No drug-drug interactions were noted. CONCLUSIONS: The combination of natalizumab plus infliximab was well tolerated. Several positive trends suggested that treating patients not in remission with infliximab plus natalizumab had greater efficacy than treatment with infliximab alone

Leukocytapheresis has reemerged as a novel "nondrug" approach in the treatment of inflammatory bowel disease. The technique involves the extracorporeal passage of peripheral blood through a column of cellulose diacetate beads (Adacolumn) or a nonwoven polyester fiber filter (Cellsorba). The benefits accrued from the filtered extraction of granulocytes, monocytes (Adacolumn), and lymphocytes (Cellsorba) appear greater than the simple extraction of these cells. There appears to be an immunologic modulation of leukocytes and dendritic cells and a diminished response to proinflammatory cytokines. Unfortunately, blinded placebo-controlled trials are lacking. Nevertheless, the aggregate clinical experience detailed in this review suggests a relatively safe and attractive alternative to current inflammatory bowel disease therapies. Randomized, controlled sham trials are in progress.

OBJECTIVE: A residue-free sodium phosphate tablet (RF-NaP) was formulated that lacks microcrystalline cellulose, which can appear as a whitish residue in the colon. A multicenter, randomized, investigator-blinded study was conducted to compare the colon-cleansing efficacy of 40 or 32 tablets of RF-NaP with the marketed 40-tablet NaP treatment regimen. METHODS: Eight hundred sixteen patients were randomized prior to colonoscopy to receive either 40 tablets (60 g) of NaP or RF-NaP or 32 tablets (48 g) of RF-NaP. Colon cleansing was assessed using a 4-point scale based on retained 'colonic contents.' The primary end point was overall colon-cleansing response rate to treatment (score of excellent/good) versus nonresponse (fair/inadequate). RESULTS: Seven hundred four patients were included in the efficacy analysis. The overall colon-cleansing response rates were comparable among treatment arms (94.5%, 97.0%, and 95.3% for NaP, RF-NaP 40, and RF-NaP 32 tablets, respectively). Ascending colon-cleansing response rates for RF-NaP 40 (95.7%) and 32 tablets (93.6%) were significantly better than for NaP tablets (88.5%, p < 0.03 for both). Patients treated with RF-NaP 32 tablets experienced less pronounced changes in electrolyte levels and fewer adverse events (138/239, 58%) compared with patients receiving NaP (161/238, 68%, p= 0.07) and RF-NaP 40 tablets (156/236, 66%, p= 0.03). The most common adverse events reported were abdominal distention, nausea, abdominal pain, and vomiting. CONCLUSIONS: Based on the safety, efficacy, and patient preferences, the 32-tablet RF-NaP regimen was superior to the 40-tablet RF-NaP and NaP regimen for colon cleansing prior to colonoscopy

BACKGROUND: Intestinal inflammation associated with Crohn's disease is characterized by a type 1 helper T cell response and elevated levels of interleukin (IL)-12. We report our clinical experience with a novel oral IL-12/IL-23 inhibitor (STA 5326) for the treatment of active Crohn's disease. MATERIALS AND METHODS: We conducted an open-label, dose-escalating trial of the orally delivered small molecule immunomodulator STA 5326 in 73 patients with active Crohn's disease (Crohn's disease activity index [CDAI] 220-450, inclusive). Five cohorts of patients were treated for up to 4 weeks with 14 mg twice a day (bid), 35 mg daily (qd), 28 mg bid, 35 mg bid, or 70 mg qd. The endpoints of the study included safety and improvement in clinical activity measured by the CDAI and the Crohn's disease endoscopic index of severity. RESULTS: STA 5326 was well tolerated. Reported adverse events were similar across dose cohorts. The most common (>15%) drug-related adverse events observed were dizziness, nausea, headache, and fatigue. Clinical activity at day 28/29 was observed at qd doses of 28 mg and above for the clinical endpoints of response and remission: 70 points or greater decrease in CDAI (range 42%-82% of patients); 100 points or greater decrease in CDAI (range 38%-64% of patients), and CDAI <150 (range 15%-36%). CONCLUSIONS: Oral qd dosing of STA 5326 for 4 weeks was well tolerated in doses up to 70 mg qd in patients with active moderate to severe Crohn's disease. Clinical activity was observed at qd doses of 28 mg and above