Biological Therapies of Inflammatory Bowel Disease

[David in Seattle]

Biological Therapies of Inflammatory Bowel Disease (Excellent review article)

Aiping Bai; Zhikang Peng
Immunotherapy. 2010;2(5):727-742. © 2010 Future Medicine Ltd.

Abstract and Introduction
Abstract

Inflammatory bowel disease (IBD) is characterized by increasing morbidity and, if suboptimally treated, poor prognosis. Recent evidence strongly suggests that dysfunctional immune responses play an important role in the pathogenesis of IBD. Therefore, immunologically downregulating the overactivated innate and adaptive immune responses may be a better approach to treat IBD than currently used pharmaceutical therapies. In recent years, many new biological therapies have been developed. These therapies are shown to be effective for inducing remission, preventing complications, improving life quality of the patients, and reducing hospitalization and surgical rates. This article introduces and discusses these new biological agents that have been used effectively in clinic for IBD patients.
Introduction

Inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis, is a lifelong disease occurring early in life. The incidence and prevalence of IBD markedly increased in recent years, and IBD is considered to be one of the most prevalent gastrointestinal diseases.[1,2] Estimates indicate that IBD affected approximately 1.0–1.5 million Americans,[3] and approximately 10–15% of IBD patients present later in life. Recent estimates from a population-based, multiple province-wide study in Canada indicate that approximately 0.5% of Canadians have IBD, and incidence rates across the country are among the highest in the world.[4]

Although the etiology of IBD remains unclear, it is strongly suggested that dysregulated immune responses play an important role in the development of IBD.[5] After exposure to the abundant intestinal bacterial antigens or environmental factors, innate immune cells such as dendritic cells and macrophages in intestinal mucosa are activated, leading to the overproduction of chemokines and proinflammatory cytokines such as TNF, IL-12 and IL-23.[6,7] Innate immune cells, together with these proinflammatory cytokines, including IL-12 and IL-23, stimulate T-helper (Th) cell activation and differentiation into Th1 cells and IL-17-producing Th17 cells.[8] Both of these T cells are highly expressed in the inflamed mucosa of IBD patients.[9,10] Meanwhile, these cytokines induce the expression of adhesion molecule receptors in endothelial cells, which together with chemokines, further initiate leukocyte migration to sites of inflammation.[11] Thus, the aggregated leukocytes and cytokines contribute in maintaining the uncontrolled inflammatory response, eventually leading to the intestinal tissue damage found in IBD.[12,13] Downregulating overactivated innate and adaptive immune responses can successfully ameliorate IBD, as indicated by clinical and experimental research.[14–17]

Current nonsurgical treatments of IBD mainly include the administration of corticosteroids, 5-aminosalicylic acid (5-ASA) preparations, and immune-suppressive drugs such as azathioprine. However, only 50% of patients achieve sustained remission with these drugs and the treatment may cause many side effects, including the well-known toxicity of corticosteroids and cytopenia caused by azathioprine.[18,19] Recently, biological therapies that target immune pathways have been emerged as a new and effective therapeutic approach for the treatment of immune dysfunction-mediated diseases. They include administration of monoclonal antibodies (mAbs) against cytokines and those that influence immune responses such as certain small molecules, helminth ova and stem cells. As IBD is an immunological disease, biological therapy targeting excessive cytokines and immune responses in inflamed mucosa should be a highly promising approach to treatment. To date, many new biological agents acting as therapeutic modifiers have emerged as important new treatments. Here we introduce these new biological agents that have been used effectively in clinic for IBD patients (Table 1).

 

[David in Seattle]

Biotherapies
Monoclonal Antibodies to Cytokines

The technique of blocking overproduced endogenous cytokines that are involved in the pathogenesis of IBD by using human or humanized mAbs to cytokines has been emerging as an effective therapy in the treatment of IBD.

Monoclonal Antibodies Targeting TNF TNF is an important proinflammatory cytokine during the development of IBD, which not only modulates immune cell proliferation, but also upregulates adhesion molecules, and induces apoptosis of intestinal cells including epithelia.[20,21] Inhibition of TNF production initiated by TNF antibody can lead to amelioration of intestinal inflammation, as shown by experimental colitis and clinical trials.[20,21] Currently, the following mAbs to TNF, which have been clinically used and approved by the US FDA for treatment of IBD, will be discussed here: infliximab, adalimumab and certolizumab pegol (CDP870). CDP571 and soluble TNF receptors including etanercept and onercept seem to have no prospective of development in IBD treatment and, therefore, will be not discussed in this article.

Infliximab Infliximab is a chimerical human/murine monoclonal IgG1 antibody, binding with high affinity both to the soluble and the transmembrane form of human TNF. Infliximab can quickly form stable complexes with human TNF, which leads to the loss of biological activity by TNF.[22] Currently, infliximab is administered to IBD patients as an intravenous infusion at a dose of 5 mg/kg bodyweight at weeks 0, 2 and 6, followed by 5-mg/kg infusions every 8 weeks for maintenance.[23] As a conventional treatment, infliximab has been demonstrated to provide clinical benefit, reduce signs and symptoms of disease and improve quality of life.[24] In a placebo-controlled trial,[25] 13 patients with steroid-refractory Crohn's disease were treated with a single infusion of infliximab (5–20 mg/kg), and five were treated with placebo. Total histological activity score was reduced significantly in both ileitis and colitis after infliximab, with a virtual disappearance of the neutrophils and a reduction of mononuclear cells. Mucosal architecture returned to normal in four patients with infliximab treatment at 4 weeks. Signs of active inflammation nearly disappear accompanied by a profound downregulation of mucosal inflammatory mediators including ICAM-1 and TNF.[25]

A 12-week multicenter, double-blind, placebo-controlled trial of cA2 (infliximab) in 108 patients with moderate-to-severe Crohn's disease who were resistant to treatment was conducted.[26] Patients were randomly assigned to receive a single 2-h intravenous infusion of either placebo or cA2 in a dose of 5, 10 or 20 mg/kg. At 4 weeks, 81% of the patients given 5 mg/kg, 50% of those given 10 mg/kg and 64% of those given 20 mg/kg had had a clinical response, compared with 17% of patients in the placebo group (p < 0.001 for the comparison of the cA2 group as a whole with placebo). In total, 33% of the patients given cA2 went into remission (defined as a score below 150 on the Crohn's Disease Activity Index [CDAI], compared with 4% of the patients given placebo (p = 0.005). At 12 weeks, 41% of the cA2-treated patients had had a clinical response, compared with 12% of the patients in the placebo group (p = 0.008). The rates of adverse effects were similar in the groups.

The study of benefits of maintenance infliximab therapy was performed in the A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long Term Treatment Regimen (ACCENT) I randomized controlled trial.[27] A total of 573 patients with active Crohn's disease received a 5-mg/kg intravenous infusion of infliximab at week 0. After assessment of responses at week 2, patients were randomly assigned repeat infusions of placebo at weeks 2 and 6 and then every 8 weeks thereafter until week 46 (group I), repeat infusions of infliximab 5 mg/kg at the same time points (group II), or infliximab 5 mg/kg at weeks 2 and 6 followed by 10 mg/kg (group III). In total, 335 patients responded to a single infusion of infliximab within 2 weeks. At week 30, 23 out of 110 group I patients were in remission, compared with 44 out of 113 group II (p = 0.003) and 50 out of 112 group III (p = 0.0002) patients. The patients in groups II and III combined were more likely to sustain clinical remission than patients in group I (odds ratio: 2.7, 95% CI: 1.6–4.6). Throughout the 54-week trial, the median time to loss of response was 38 weeks (interquartile range [IQR]: 15 to >54) and more than 54 weeks (21 to >54) for groups II and III, respectively, compared with 19 weeks (10–45) for group I (p = 0.002 and p = 0.0002, respectively). Infliximab safety was consistent with that seen in other trials of infliximab in Crohn's disease and rheumatoid arthritis.

Two randomized, double-blind, placebo-controlled studies – the Active Ulcerative Colitis Trials (ACT) 1 and 2 – evaluated the efficacy of infliximab for induction and maintenance therapy in adults with ulcerative colitis.[23] In each study, 364 patients with moderate-to-severe active ulcerative colitis received placebo or infliximab (5 or 10 mg/kg bodyweight) intravenously at weeks 0, 2 and 6 and then every 8 weeks through week 46 (in ACT 1) or week 22 (in ACT 2). In ACT 1, 69% of patients who received infliximab 5 mg and 61% of those who received 10 mg had a clinical response at week 8, compared with 37% of those who received placebo (p < 0.001 for both comparisons with placebo). In ACT 2, 64% of patients who received infliximab 5 mg and 69% of those who received 10 mg had a clinical response at week 8, compared with 29% of those who received placebo (p < 0.001 for both comparisons with placebo). In both studies, patients who received infliximab were more likely to have a clinical response at week 30 (p ≤ 0.002 for all comparisons).

Recently, follow-up ACT-1 and -2 randomized, double-blind, placebo-controlled studies further evaluated infliximab induction and maintenance therapy in moderately to severely active ulcerative colitis with more population, and found that patients with moderately to severely active ulcerative colitis treated with infliximab were less likely to undergo colectomy than those receiving placebo.[28] A total of 728 patients received placebo (244 subjects) or infliximab (5 or 10 mg/kg, 242 subjects for each) intravenously at weeks 0, 2 and 6, then every 8 weeks through week 46 (ACT-1) or 22 (ACT-2). In total, 87% of patients had complete colectomy follow-up; 13% of patients had a median follow-up of 6.2 months. The cumulative incidence of colectomy through 54 weeks was 10% for infliximab and 17% for placebo (p = 0.02). Compared with placebo, fewer ulcerative colitis-related hospitalizations and surgeries/procedures per 100 patient-years of treatment occurred with infliximab therapy: 40 versus 20 (p = 0.003) and 34 versus 21 (p = 0.03), respectively. Serious adverse effects occurring in infliximab-treated patients included serious infections (19 out of 484), tuberculosis (one out of 484), and malignancy (one out of 484).

Infliximab has also been used as an effective maintenance therapy for Crohn's disease patients with fistulas.[29] In a multicenter, double-blind, randomized, placebo-controlled trial, the efficacy of infliximab maintenance therapy was evaluated in 306 adult patients with Crohn's disease and one or more draining abdominal or perianal fistulas of at least 3 months' duration. They concluded that patients with fistulizing Crohn's disease who had a response to induction therapy with infliximab had an increased likelihood of a sustained response over a 54-week period if infliximab treatment was continued every 8 weeks. Then, a follow-up ACCENT II trial was conducted to study the long-term treatment of rectovaginal fistulas in Crohn's disease,[30] in which 282 patients were involved. Together, they concluded infliximab was effective in short-term closure of rectovaginal fistulas and maintenance treatment was more effective than placebo in prolonging rectovaginal fistula closure.

Adalimumab Adalimumab is a fully human anti-TNF antibody that binds with a high affinity and specificity to human soluble TNF.[31] Adalimumab has demonstrated efficacy for induction and maintenance of remission in patients with moderate-to-severe Crohn's in clinical trials, and also an effective treatment in case of failure or loss of response of infliximab. In addition, adalimumab has demonstrated steroid-sparing properties and the ability to reduce hospitalizations and improve quality of life.[32] Owing to its clinical efficacy and the convenience of self-administration (self-injection), adalimumab is expected to have a significant effect on the management of Crohn's disease.[33] In a multicenter, prospective, open-label, observational, 52-week study,[34] 50 patients with luminal and/or fistulizing Crohn's disease received an induction dose of adalimumab (160 mg at baseline followed by 80 mg at week 2). Of the 36 patients with luminal Crohn's disease, 83% achieved clinical response (≥70-point reduction in CDAI score) and 42% achieved clinical remission (CDAI score <150) at week 4. Of the 22 patients with fistulizing disease, five experienced fistula remission (complete closure of all fistulas that were draining at baseline), and nine experienced fistula improvement (≥50% decrease in the number of fistulas that were draining at baseline) at week 4. Of the 19 adverse effects, 13 were mild and no serious or infectious adverse effects occurred. The study provided the evidence that adalimumab may be an effective alternative in patients with luminal and/or fistulizing Crohn's disease who have lost response to, or become intolerant of, infliximab.

 

[David in Seattle]

The effects of adalimumab maintenance treatment on the risks of hospitalization and surgery in Crohn's disease were determined in the Candesartan in Heart Failure – Assessment of Reduction in Mortality and Morbidity (CHARM) study.[35] A total of 778 patients with Crohn's disease were randomized to placebo, adalimumab 40 mg every other week or adalimumab 40 mg weekly, all after an 80-mg/40-mg adalimumab induction regimen. Both 3- and 12-month hospitalization risks were significantly lower for patients who received adalimumab. Hazard ratios for all-cause hospitalization were 0.45, 0.36 and 0.40 for the adalimumab every other week, weekly, and combined groups, respectively (all p < 0.01 vs placebo). Hazard ratios for Crohn's disease-related hospitalization were 0.50, 0.34 and 0.42, respectively (all p < 0.05). Cox model estimates demonstrated adalimumab every other week and weekly maintenance therapies were associated with 52 and 60% relative reductions in 12-month, all-cause hospitalization risk, and 48 and 64% reductions in 12-month risk of Crohn's disease-related hospitalization. The combined adalimumab group was associated with 56% reductions in both all-cause and Crohn's disease-related hospitalization risks. Fewer Crohn's disease-related surgeries occurred in the adalimumab every other week, weekly, and combined groups compared with placebo (0.4, 0.8 and 0.6 vs 3.8 per 100 patients; all p < 0.05).

Certolizumab Certolizumab pegol (CDP 870) is a mAb combining the Fab fragment of human anti-TNF antibody with polyethylene glycol.[36] The combination with polyethylene glycol resulted in prolonged serum half-life to approximately 2 weeks, which permits less frequent dosage.[37] Certolizumab is administered subcutaneous and has been approved by the US FDA for remission maintenance of Crohn's disease. Certolizumab improves quality of life and reduces clinical disease activity of Crohn's disease.[38] The dose for the induction of remission is 400 mg subcutaneously at weeks 0, 2 and 4. The dose for maintenance of remission is 400 mg subcutaneously administered every 4 weeks. The safety profile is comparable with other anti-TNF agents, and the major adverse effects are related to infections.[39]

A placebo-controlled, Phase II study found that, certolizumab 400 mg was effective and well tolerated in patients with active Crohn's disease.[40] In the study, 292 patients with moderate-to-severe Crohn's disease received subcutaneous certolizumab 100, 200 or 400 mg or placebo (74, 72, 73 or 73 subjects, respectively) at weeks 0, 4 and 8. All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7%, p = 0.033; 200 mg, 30.6%, p = 0.026; 400 mg, 33.3%, p = 0.01). At all time points, the Clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; p = 0.006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; p = 0.278). Patients with baseline C-reactive protein (CRP) levels of 10 mg/l or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; p = 0.005) owing to a lower placebo response rate than patients with CRP levels of less than 10 mg/l. Another randomized, double-blind, placebo-controlled trial demonstrated that, compared with placebo, induction and maintenance therapy with certolizumab pegol was associated with a modest improvement in response rates for moderate-to-severe Crohn's disease.[41] In the trial, 660 patients with moderate-to-severe Crohn's disease were randomly assigned to receive either certolizumab pegol 400 mg (331 subjects) or placebo (329 subjects) subcutaneously at weeks 0, 2 and 4 and then every 4 weeks. Among patients with a baseline CRP level of at least 10 mg/l, 37% of patients in the certolizumab group had a response at week 6, compared with 26% in the placebo group (p = 0.04). At both weeks 6 and 26, the corresponding values were 22% and 12%, respectively (p = 0.05). In the overall population, response rates at week 6 were 35% in the certolizumab group and 27% in the placebo group (p = 0.02); at both weeks 6 and 26, the response rates were 23 and 16%, respectively (p = 0.02). At weeks 6 and 26, the rates of remission in the two groups did not differ significantly (p = 0.17).

 

[David in Seattle]

Monoclonal Antibodies to IL-12/IL-23 p40 Subunit IL-12 and -23 have been implicated in the pathogenesis of Crohn's disease.[42] In the presence of IL-12, comprised by p40 and p35 subunits, naive CD4+ T cells differentiate to Th1 type cell, and produce IFN-γ to mediate cellular immunity.[43] IL-12 and IFN-γ act in a positive-feedback loop, leading to the excessive Th1 immune response developed in Crohn's disease.[44] Targeting IL-12 by mAbs is an effective treatment for the intestinal inflammation in animal model of Crohn's disease,[45] which provides the evidence for IL-12 antibody for clinical use. In the presence of IL-23, a heterodimer of the same p40 subunit as IL-12 and a unique p19 subunit, with IL-6 and TGF-β, naive CD4+ T cells adopt a Th17 cell profile, characterized by the production of IL-17A, IL-17F, IL-22 and IL-21 to induce TNF production and mediate cellular immunity.[46,47] In clinical trials for Crohn's disease, the IL-12/IFN-γ and the IL-23/IL-17 pathways have been targeted by the mAbs ABT-874 and ustekinumab, which are against the subunit p40 shared by IL-12 and IL-23.

ABT-874 ABT-874/J695 (Wyeth Research and Abbott Laboratories) is a recombinant, exclusively human-sequence, full-length IgG1 antibody genetically modified to recognize IL-12 p40 protein. A double-blind trial evaluated the safety and efficacy of ABT-874 in 79 patients with active Crohn's disease.[14] Patients were randomized to receive seven weekly subcutaneous injections of ABT-874 1 or 3 mg/kg bodyweight or placebo, with either a 4-week interval between the first and second injection (cohort 1) or no interruption between the two injections (cohort 2). After 7 weeks of uninterrupted treatment with ABT-874 3 mg/kg, higher response rates were achieve compared with placebo (75 vs 25%; p = 0.03). At 18 weeks of follow-up, the difference in response rates was no longer significant (69 vs 25%; p = 0.08). Differences in remission rates between the group receiving ABT-874 3 mg/kg and the placebo group in cohort 2 were not significant at either the end of treatment or the end of follow-up (38 and 0%, respectively, at both times; p = 0.07). There were no significant differences in response rates among the groups in cohort 1.

Ustekinumab Ustekinumab is a human mAb that specifically binds the p40 subunit that is shared by IL-12 and IL-23. Ustekinumab prevents IL-12 and IL-23 from binding their cell-surface receptor complexes, thereby blocking the Th1 and Th17 inflammatory pathways.[48] In a double-blind, cross-over trial, 104 patients with moderate-to-severe Crohn's disease (population 1) received subcutaneous placebo at weeks 0–3, then ustekinumab at weeks 8–11 (26 subjects); subcutaneous ustekinumab at weeks 0–3, then placebo at weeks 8–11 (25 subjects); intravenous placebo at week 0, then ustekinumab at week 8 (27 subjects); or intravenous ustekinumab at week 0, then placebo at week 8 (26 subjects).[49] Clinical response rates for the combined groups receiving ustekinumab and placebo were 53 and 30% (p = 0.02), respectively, at weeks 4 and 6, and 49 and 40% (p = 0.34), respectively, at week 8. In a subgroup of 49 patients who previously received infliximab (neither primary nor secondary nonresponders), clinical response to ustekinumab was significantly greater than with the group administered placebo (p < 0.05) through week 8. Furthermore, an open-label trial[49] evaluated the effects of four weekly subcutaneous injections (n = 14) or one intravenous infusion (n = 13) of ustekinumab in 27 patients who were primary or secondary nonresponders to infliximab (population 2). The clinical responses at week 8 to subcutaneous and intravenous ustekinumab were 43 and 54%, respectively.
Cytokines

Inflammatory bowel disease is characterized by the imbalance of proinflammatory cytokines and inhibitory cytokines in inflamed intestine tissues, with a dominance of proinflammatory cytokines, such as TNF, IL-1β and IL-6, but deficiency of inhibitory cytokines such as IL-10 and IL-11.[50] Supplement with these inhibitory cytokines has been shown to have beneficial effects for IBD patients.

IL-10 IL-10 has numerous inhibitory effects on inflammatory mediator synthesis by monocytes, macrophages, neutrophils, T and B cells, mast cells and eosinophils.[51] The importance of IL-10 for regulation of mucosal inflammation has been investigated in several clinical trials. In a nonplacebo-controlled trial, genetically modified Lactococcus lactis (LL-Thy12) was used as an effective approach for topical delivery of IL-10, in which the thymidylate synthase gene was replaced with a synthetic sequence encoding mature human IL-10.[52] Ten patients with Crohn's disease received ten capsules with 1 × 1010 colony-forming units of LL-Thy12 twice daily for 7 days, while then patients received placebo. Treatment with LL-Thy12 was safe because only minor adverse effects were present, and a decrease in disease activity was observed.

However, another double-blind, controlled trial showed no evidence of prevention of endoscopic recurrence of Crohn's disease by Tenovil (IL-10).[53] Patients with Crohn's disease who underwent curative ileal or ileocolonic resection and primary anastomosis were randomized within 2 weeks after surgery to receive subcutaneous Tenovil 4 µg/kg once daily (n = 22) or 8 µg/kg twice weekly (n = 21), or placebo (n = 22). An ileocolonoscopy was performed after 12 weeks of treatment. In total, 11 out of 21 patients in the placebo group had recurrent lesions compared with 17 out of 37 patients in the Tenovil group. The incidence of severe endoscopic recurrence was similar in both groups (9%).

IL-11 IL-11 is a pleiotropic cytokine of mesenchymal cell origin with thrombopoietic capacity.[54] It exhibits potent anti-inflammatory activity on macrophages and T cells by inhibiting the secretion of proinflammatory cytokines,[55] and has shown beneficial effects on intestinal mucosa in several animal models of IBD.[56] Some trials have reported the clinical use of recombinant human IL-11 (rhIL-11) in maintaining Crohn's disease remission. A multicenter, double-masked, placebo-controlled, dose-escalation study was performed for patients with active Crohn's disease.[57] In the study, 76 patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16 or 40 µg/kg/week administered two- or five-times weekly for 3 weeks. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 µg/kg/week as two- or five-times weekly doses and 16 µg/kg/week as five-times weekly doses than patients receiving placebo (p < 0.05). Patients receiving 16 µg/kg/week had the highest clinical response rates, with a response observed in 42% of patients receiving five-times weekly doses and 33% of patients receiving two-times weekly doses, compared with 7% of patients receiving placebo.

 

[David in Seattle]

Blockade of Leukocyte Migration

Establishing a blockade of interactions between adhesion molecules on circulating leukocytes and their endothelial cell receptors can decrease the migration of these cells to sites of inflammation, thereby decreasing intestinal inflammation.[58,59] To date, there are three targeting therapies in clinical trials including natalizumab (mAb to integrin α4 subunit), MLN-02 (mAb to integrin α4β7) and alicaforsen (antisense oligodeoxynucleotide to ICAM-1).

Natalizumab Natalizumab, a humanized mAb against α4 integrin, inhibits leukocyte adhesion and migration into inflamed tissue, and has been used in a clinical trial for Crohn's disease treatment. In a randomized placebo-controlled trial,[60] 509 patients with moderately to severely active Crohn's disease were randomized (1:1) to receive natalizumab 300 mg or placebo intravenously at weeks 0, 4 and 8. Response at week 8 sustained through week 12 occurred in 48% of natalizumab-treated patients and 32% of patients receiving placebo (p < 0.001). Sustained remission occurred in 26% of natalizumab-treated patients and 16% of patients receiving placebo (p = 0.002). Week 4 response rates were 51% for natalizumab and 37% for placebo (p = 0.001). Responses remained significantly higher at subsequent assessments (p < 0.001) in natalizumab-treated patients.

Two controlled trials were initiated to evaluate natalizumab as induction and maintenance therapy in patients with active Crohn's disease.[61] In the first trial, 905 patients were randomly assigned to receive natalizumab 300 mg or placebo at weeks 0, 4 and 8. The natalizumab and placebo groups had similar rates of response (56 and 49%, respectively; p = 0.05) and remission (37 and 30%; p = 0.12) at 10 weeks. In the second trial, 339 patients who had a response to natalizumab in the first trial were randomly reassigned to receive natalizumab 300 mg or placebo every 4 weeks through week 56. Continuing natalizumab in the second trial resulted in higher rates of sustained response (61 vs 28%; p < 0.001) and remission (44 vs 26%; p = 0.003) through week 36 than did switching to placebo.

Progressive multifocal leukoencephalopathy (PML) was reported to have developed in 3 patients treated with natalizumab.[62,63] Owing to the risk of PML, Natalizumab is available only through a special restricted distribution program termed the MS-TOUCH® prescribing program.

MLN02 MLN02, a humanized mAb, specifically recognizes integrin α4β7 heterodimer but does not crossreact with the individual component monomers.[64] This characteristic should convey specificity for the vasculature of the gut. A multicenter, double-blind, placebo-controlled trial was performed to study the effect of MLN02 in the induction of clinical and endoscopic remission in patients with active ulcerative colitis.[65] A total of 181 patients were randomized to receive MLN02 0.5 mg/kg bodyweight (58 patients), 2.0 mg/kg (60 patients), or an identical-appearing placebo (63 patients), intravenously on day 1 and day 29. Clinical remission rates at week 6 were 33, 32 and 14% for the group receiving MLN02 0.5 mg/kg, the group receiving 2.0 mg/kg, and the placebo group, respectively (p = 0.03). The corresponding proportions of patients who improved by at least three points on the ulcerative colitis clinical score were 66, 53 and 33% (p = 0.002). In total, 28% of patients receiving 0.5 mg/kg and 12% of those receiving 2.0 mg/kg had endoscopic evident remission, compared with 8% of those receiving placebo (p = 0.007).

Alicaforsen Alicaforsen (ISIS 2302; Isis Pharmaceuticals, Inc., CA, USA), a first-generation antisense oligodeoxynucleotide, is a highly selective inhibitor of ICAM-1 expression. ICAM-1 is an inducible transmembrane glycoprotein constitutively expressed at low levels on vascular endothelial cells and on a subset of leukocytes.[66] ICAM-1 serves multiple functions in the propagation of inflammatory processes; the best characterized are the facilitation of leukocyte migration from the intravascular compartment to the extravascular space at sites of inflammation.[67] ICAM-1 expression in endothelial cells can be highly induced by proinflammatory cytokines such as TNF and IL-1β,[68] and it had been found that ICAM-1 was overexpressed by IBD patients.[69] Thus, antisense to ICAM-1 has been studied for use as a therapy for IBD. One trial evaluated the safety, pharmacokinetics and clinical efficacy of alicaforsen at 250–350 mg in Crohn's disease.[70] A total of 22 patients with active Crohn's disease were assigned randomly to two alicaforsen treatment groups: 300 or 350 mg, infused intravenously three-times a week for 4 weeks. Nine patients experienced clinical remission; 53% of the evaluable subjects receiving more than three infusions experienced remission (18% at week 8; 29% at week 12). The overall response, using a minimum decrease of 70 in the CDAI, was 41–47% for the evaluable group, at weeks 8 and 12. The infusion-related reaction profile consisted of fever, chills, headache, nausea, emesis or arthralgias, typically occurring 2–4 h after completion of the first infusion.

However, another randomized, double-masked, placebo-controlled study failed to demonstrate efficacy of alicaforsen for Crohn's disease treatment.[71] In total, 331 subjects with active Crohn's disease were treated with either alicaforsen (221 subjects) or placebo (110 subjects) administered via 2-h intravenous infusion three-times a week for 4 weeks. Alicaforsen treatment failed to demonstrate statistical significance as a measure of its primary outcome (alicaforsen 33.9% vs placebo 34.5%; p =0.89). In addition, no statistical differences in response were observed between alicaforsen and placebo in subjects who were previously treated with anti-TNF therapy or had baseline fistulizing disease.
Anti-T-cell Activation

Under normal conditions, T-cell activation by antigen-presenting cells requires two signals: one signal is mediated by the interaction of the T-cell receptor complex, which includes CD4 and CD3, with the antigenic peptides presented by MHC molecules on the surface of antigen-presenting cells.[72,73] The second signal, the costimulatory signal, is antigen nonspecific and is provided by the interaction between costimulatory molecules expressed on the membrane of antigen-presenting cells and the T cell such as B7- CD28 and CD40-CD40L.[74] Activation of T cells without costimulation will make T cells fail to proliferate in response to the priming of antigen-presenting cells, and render T cells resistant to further stimulation,[75] then induce T-cell anergy, T-cell deletion or the development of immune tolerance.[76,77] Inhibiting T-cell activation by targeting stimulatory molecules is an effective way to induce immune tolerance, and appears as a new exploratory treatment for IBD.

Anti-CD3 Monoclonal Antibodies Visilizumab (HuM291, Nuvion) is a humanized IgG2 mAb that specifically binds to the invariant CD3e chain of the T-cell receptor expressed on human T cells. It was engineered to reduce FcR binding by incorporating two amino acid substitutions at positions 234 and 237 in the CH2 domain of the antibody's Fc region.[78] As a result of these changes in the Fc region, visilizumab elicits a substantially diminished cytokine release, complement fixation and T-cell activation compared with the FcR-binding of OKT3 of resting human peripheral blood mononuclear cells in vitro.[79] In an open-label Phase I study,[80] 32 subjects with ulcerative colitis received visilizumab treatment intravenously on 2 consecutive days. On day 30, 84% of patients demonstrated a clinical response, 41% achieved clinical remission and 44% achieved endoscopic remission. A total of 45% of patients did not require salvage therapies or colectomy during the first year postdose. All patients exhibited a rapid decrease in circulating CD4+ T-cell counts, which returned to baseline values by day 30 in 26 of 30 evaluable patients (86%).

In another randomized trial,[81] 73 patients with ulcerative colitis received intravenous visilizumab 5, 7.5, 10 or 12.5 µg/kg/day for 2 consecutive days in stage I, and 33 patients received visilizumab 5 µg/kg/day for 2 days in Stage II. The rates of symptomatic response at day 15 in the 5-, 7.5-, 10- or 12.5-µg/kg dose groups were 71, 70, 50 and 61%, respectively, in stage I and in 54% in stage II. The symptomatic remission rates were 35, 5, 22 and 11% in stage I and 18% in stage II. The rates of clinical response at day 30 in the 5-, 7.5-, 10- or 12.5-µg/kg dose groups were 71, 65, 50 and 67%, respectively, in stage I and 55% in stage II. The clinical remission rates were 6, 5, 0 and 11% in stage I and 6% in stage II. All patients experienced adverse effects including abdominal abscess, cytomegalovirus infection, atrial fibrillation, herpes zoster and esophageal candidiasis.

Recently, visilizumab administration was reported to be associated with a cytokine-release syndrome (CRS) and transient elevation of hepatic enzymes in some patients with Crohn's disease.[82] Those patients with CRS could be predisposed due to an aberrant expression of adhesion molecules in the liver that promotes CRS upon engagement of the T-cell receptor.

 

[David in Seattle]

Anti-CD40 Monoclonal Antibodies One costimulatory pathway of T-cell activation involves the interaction between CD40 and CD40L.[83] Chimerical 5D12 (Ch5D12) is a molecularly engineered human IgG4 antibody containing the variable domains of the heavy and light chains of 5D12 and was constructed to reduce the potential for immunogenicity and to enhance the in vivo half-life of the 5D12 mAb when used in humans.[84] In an open-label, dose-escalation Phase I/IIa study,[85] Ch5D12 was administrated to 18 patients with moderate-to-severe Crohn's disease. Ch5D12 plasma concentrations increased dose dependently after infusion. Two patients developed an anti-Ch5D12 antibody response. Overall response and remission rates were 72 and 22%, respectively, with no evidence for a dose-response effect. Treatment with Ch5D12 reduced microscopic disease activity and intensity of the lamina propria cell infiltrate, but did not alter percentages of circulating T and B cells. Ch5D12 was well tolerated, although some patients experienced headache, muscle aches or joint pains, which may have been related to the study drug.

Anti-CD25 Monoclonal Antibodies CD25 (IL-2 receptor) is a membrane receptor expressed by activated T lymphocytes. IL-2 is a cytokine produced by T cells that induces lymphocyte proliferation and differentiation and its overproduction is associated with a variety of immune disorders.[86] Blocking IL-2 receptor has been shown to be an effective therapy for ulcerative colitis.[87] Daclizumab (Zenapax) is a humanized IgG1 mAb to CD25 (IL-2R), and has been used for the treatment of ulcerative colitis in clinical trials. A randomized, double-blind, placebo-controlled trial was conducted to evaluate the efficacy of daclizumab induction therapy in patients with active ulcerative colitis.[88] A total of 159 patients with moderate ulcerative colitis were randomized to receive induction therapy with daclizumab 1 mg/kg intravenously at weeks 0 and 4, or 2 mg/kg intravenously at weeks 0, 2, 4 and 6, or placebo. A total of 2% of patients receiving daclizumab 1 mg/kg (p = 0.11 vs placebo) and 7% of patients receiving 2 mg/kg (p = 0.73) were in remission at week 8, compared with 10% of those who received placebo. Response occurred at week 8 in 25% of patients receiving daclizumab 1 mg/kg (p = 0.04) and in 33% of patients receiving 2 mg/kg (p = 0.30) versus 44% of those receiving placebo.
Growth Factors

There are some growth factors including growth hormone, granulocyte–macrophage colony-stimulating factor (GM-CSF) and EGF, which have been used in clinical trials.

Growth Hormone Growth hormone is a peptide hormone secreted by the pituitary gland that stimulates growth and cell reproduction. Growth hormone can also enhance the uptake of amino acids and electrolytes by the intestines,[89] decrease intestinal permeability and increase intestinal protein synthesis.[90] Preliminary studies suggested that growth hormone may be active in Crohn's disease. In a randomized, placebo-controlled trial, 37 patients with moderate-to-severe active Crohn's disease were randomized to self-administered injections of growth hormone (19 patients) or placebo (18 patients, but three patients withdrew) for 4 months. At baseline, the mean (±standard deviation) score on the CDAI was somewhat higher among the patients in the growth hormone group than among the patients in the placebo group (287 ± 134 vs 213 ± 120; p = 0.09). At 4 months, the CDAI score had decreased by a mean of 143 ± 144 points in the growth hormone group, compared with a decrease of 19 ± 63 points in the placebo group (p = 0.004). Side effects in the growth hormone group included edema (in ten patients) and headache (in five patients) and usually resolved within the first month of treatment.[91]

Granulocyte–Macrophage Colony-stimulating Factor Also known as sargramostim, GM-CSF is a hematopoietic growth factor, which was reported to stimulate intestinal immune cells and enhance innate immune defences. Innate immune deficiency may be central to the pathogenesis of Crohn's disease and, furthermore, GM-CSF may have clinical utility in the treatment of Crohn's disease through regulation or activation of the innate immunity, conferring therapeutic benefits.[92,93] In a randomized, placebo-controlled trial, 124 patients with moderate-to-severe active Crohn's disease were assigned to receive sargramostim 6 µg/kg/day or placebo subcutaneously for 56 days.[94] At the end of treatment (day 57), no significant difference was observed in the rate of a clinical response between the sargramostim and placebo groups (54 vs 44%; p = 0.28). However, significantly more patients in the sargramostim group than in the placebo group reached at least 100-point clinical response (48 vs 26%; p = 0.01) and of remission (40 vs 19%; p = 0.01). The rates of either type of clinical response and of remission were significantly higher in the sargramostim group than in the placebo group on day 29 of treatment and 30 days after treatment. Mild-to-moderate injection-site reactions and bone pain were observed commonly in the patients undergoing sargramostim treatment.

Recently, the tolerability, pharmacokinetics, safety and efficacy of sargramostim were assessed in Japanese patients with active Crohn's disease.[95] The study included two steps. Step 1 was an open-label, Phase I study of sargramostim administered subcutaneously for 4 weeks, with an optional 8-week extension. Step 2 was an open-label, Phase I–II study of the tolerability and pharmacokinetics of subcutaneously sargramostim over 4 weeks and of 8-week efficacy and safety. Six patients participated in step 1, and five in step 2. Serum concentrations of sargramostim peaked within 1 h of administration, and mean terminal half-life was 2 h. Maximal serum concentrations increased with the dose. Mean accumulation ratios were 0.998 in step 1 and 0.673 in step 2. One of the six patients in the step-1 extension and none of the five in step 2 achieved a clinical response. A notable decrease of clinical response was observed in the extension and step 2. Drug-related adverse effects included injection-site reaction, pyrexia, back pain and bone pain.

EGF EGF, a potent mitogenic peptide produced by salivary glands, has been shown to be a potent stimulant of the healing response including cell migration (restitution) and cell proliferation,[96] both of which are important in re-establishing epithelial continuity. EGF also reduces injury and stimulates repair in animal models of small intestinal and colonic injury.[97,98] In a randomized, double-blind clinical trial,[99] 12 patients with mild-to-moderate left-sided ulcerative colitis received daily enemas of EGF in inert carrier and 12 received daily enemas with carrier alone for 14 days. After 2 weeks of treatment, ten of the 12 patients receiving EGF enemas were in remission, compared with one of 12 in the control group (83 vs 8%; p < 0.001). At the 2-week assessment, disease-activity scores, sigmoidoscopic score and histologic scores were all significantly better in the EGF group than in the placebo group (p < 0.01 for all comparisons). This benefit was maintained at 4 weeks and at 12 weeks. For clinical use, the potential malignancy risk of EGF should be considered.
Small Molecules

Recently, except for conventional drugs including mesalamine, azathioprine/6-mercaptopurine and methotrexate, a lot of small molecules that target specific immune responses have been studied for the treatment of IBD. These include inhibitors of MAPK and NF-κB, and the ligands of PPARγ.

Inhibitors of MAPK MAPK is a kinase that regulates the expression of TNF and other proinflammatory cytokines,[100] while p38 MAPK plays an important regulatory role.[101] Blocking p38 MAPK activity by the specific inhibitors such as BIRB 796 and RDP58 may offer a novel therapeutic approach for the treatment of IBD.

BIRB 796 BIRB 796 is a peptide that belongs to the family of the N-pyrazole-N-naphthly urea class that selectively inhibits p38 MAPK signal, and thus, downregulates the production of proinflammatory cytokines including TNF, IL-6 and IL-8.[102] In a multicenter trial, 284 patients with moderate-to-severe Crohn's disease were assigned randomly to receive placebo, or four doses of BIRB 796 twice daily for 8 weeks.[103] No clinical efficacy was observed for BIRB 796 in comparison with placebo. A significant, dose-dependent decrease of CRP level was observed transiently with BIRB 796 after 1 week with a return to baseline level over time. The efficacy of BIRB 796 for IBD treatment needs to be further elucidated by more multicenter trials.

RDP58 RDP58, a novel anti-inflammatory D-amino acid decapeptide, has been shown to decrease proinflammatory cytokine production by lamina propria mononuclear cells from IBD patients and experimental colitis mice, by disrupting cell signaling at the pre-MAPK–MyD88–IRAK–TRAF6 protein complex.[104] Two parallel multicenter, double-blind, randomized studies were conducted to evaluate the efficacy of RDP58 in patients with ulcerative colitis.[105] In the first trial, 34 patients with active ulcerative colitis were randomized to receive placebo (n = 13) or RDP58 100 mg (n = 21). After 4 weeks, treatment success on RDP58 100 mg was 29% versus 46% on placebo (p = 0.46), but there were no significant differences in sigmoidoscopy or histology score. In the second trial, 93 ulcerative colitis patients received placebo (n = 30), RDP58 200 mg (n = 31), or RDP 300 mg (n = 32). After 4 weeks, treatment success on the higher doses of RDP58 (200 and 300 mg) was 71 and 72%, respectively, versus 43% on placebo (p = 0.016). Improvements in sigmoidoscopy scores (41% on 200 mg and 46% on 300 mg versus 32% on placebo) did not reach significant difference, but histology scores improved significantly (p = 0.002) versus placebo.

 

[David in Seattle]

Curcumin: Inhibitor of NF-κB Curcumin is the principal curcuminoid of the popular Indian turmeric, the spice that gives food an exotic yellow color. Curcumin has been shown to have a broad spectrum of pharmacologic actions in neoplastic, neurological, cardiovascular, pulmonary and metabolic diseases.[106] In the past few years, curcumin has been reported to mediate anti-inflammatory effects through the downregulation of inflammatory transcription factors such as the NF-κB, and proinflammatory cytokines including TNF, IL-1β and IL-6.[107] NF-κB functions as crucial regulators of inflammatory and immune responses as well as of cell survival. It was identified as one of the key regulators in immune responses of IBD, by promoting the expression of various proinflammatory genes, and influencing the course of mucosal inflammation.[107] By inhibiting NF-κB activation and CD4+ T-cell infiltration into the colonic mucosa, curcumin was demonstrated to prevent murine experimental colitis.[108] Recently, curcumin has been studied in a randomized, double-blind, multicenter trial for the prevention of ulcerative colitis relapse.[109] In total, 89 patients with quiescent ulcerative colitis were assigned to receive curcumin plus sulfasalazine or mesalamine treatment (45 patients), or placebo plus sulfasalazine or mesalamine (44 patients) orally for 6 months. Except for seven patients who were protocol violators, two of 43 patients who received curcumin, relapsed during 6 months of therapy, whereas eight of 39 patients in the placebo group relapsed (p < 0.040). Recurrence rates evaluated on the basis of intention to treat showed significant difference between curcumin and placebo (p < 0.049).[109]

Rosiglitazone: The Ligand of PPARγ PPARγ are members of the nuclear hormone receptor superfamily of transcription factors, which include α, β and γ subtypes. The γ subtype of PPARs (PPARγ) is highly expressed by adipose tissue and the colonic epithelium,[110] and its ligands, the thiazolidinedione antidiabetic drugs such as rosiglitazone, have potential anti-inflammatory properties.[111] Treatment with PPARγ ligands, widely used to treat Type 2 diabetes mellitus, has been shown to downregulate proinflammatory cytokine production including TNF and IL-1β, inhibit inflammatory cell infiltration and reduce colonic inflammation in murine models of colitis.[112–114] Treatment with PPARγ ligand has been proposed as a novel therapeutic treatment for ulcerative colitis.

In a multicenter, randomized, double-blind clinical trial, 105 patients with mild-to-moderately active ulcerative colitis were orally administered rosiglitazone or placebo for 12 weeks. In total, 23 patients treated with rosiglitazone and 12 patients treated with placebo achieved clinical response (p = 0.04), and remission was achieved in nine patients treated with rosiglitazone and one patient treated with placebo (p = 0.01).[115]
Hematopoietic Stem-cell Transplantation

Autologous hematopoietic stem-cell transplantation (HSCT) has immune-suppressive effects and leads to immunoablation. After transplantation, stem cells regenerate a new and antigen-naive immune system similar to the normal ontogeny of the immune system during fetal development, and thus, ablate aberrant disease-causing immune cells,[116] which is the reason HSCT has been used in some trials for Crohn's disease treatment.

In 2003, one study demonstrated that HSCT research for severe Crohn's disease appeared warranted. In the study, stem cells were isolated from the peripheral blood, and enriched by CD34+ selection. Two patients with severe Crohn's disease were treated by intense immune suppression and HSCT. Since HSCT treatment, patients have remained in remission for 1 year.[117] A Phase I HSCT study in 12 patients with refractory Crohn's disease demonstrated that after HSCT treatment, 11 of 12 patients entered a sustained remission (CDAI <150). After a median follow-up of 18.5 months, only one patient has developed a recurrence of active Crohn's disease, which occurred 15 months after HSCT.[118]

Hematopoietic stem-cell transplantation also presents a good alternative of conventional therapies. In a recent study, four patients with active moderate–severe Crohn's disease refractory or intolerant to multiple drugs including infliximab, were enrolled and received HSCT treatment. After 3 months, clinical remission was achieved in all patients, and complete endoscopic remission was achieved in two out of three patients. After a median follow-up of 16.5 months, three out of four patients maintained both clinical and endoscopic remission, despite withdrawal of all drugs, and complete fistula closure was observed in all affected patients. No deaths or life-threatening infection occurred. Unexpected adverse effects included a perianal abscess after mobilization in one patient, pleural and pericardial effusions in another and BK virus-related macrohematuria in another. All rapidly resolved with conservative treatment.[119]
Helminth Ova

In experimental models of murine colitis, helminth ova has been demonstrated to induce various regulatory-type T-cell subsets and also cytokines such as IL-10 and TGF-β in the gut that limit effector T-cell growth and function.[120] These effects of once ever-present helminth ova have been reported as novel management for IBD patients, as they can alter host mucosal and systemic immunity.

Trichiuris suis ova is the popular treatment for clinical trials. In an open-label study, 29 patients with active Crohn's disease ingested 2500 live T. suis ova every 3 weeks for 24 weeks, and disease activity was monitored by CDAI. At week 24, 23 patients responded and 21 out of 29 remitted.[121] In another randomized, double-blind, placebo-controlled trial, 2500 T. suis ova was administered orally once every 2 weeks to 30 patients with active ulcerative colitis, while placebo was administered orally for 24 patients.[122] After 12 weeks of therapy, improvement according to the intent-to-treat principle occurred in 13 out of 30 patients with ova treatment compared with four out of 24 patients receiving placebo (p < 0.04).

 

[David in Seattle]

Selection & Safety of Biological Therapies in Inflammatory Bowel Disease

Biological therapies of IBD are considered as selections following standard treatments, which include 5-ASA preparations, glucocorticosteroids and immunosuppressive agents. Indications for biological therapies in Crohn's disease are as follows:[123]

* Induction therapy in patients with moderate or severe disease activity who do not respond to conventional treatment with 5-ASA preparations, glucocorticosteroids and/or immunosuppressive agents;
* Induction therapy in patients with fistulas, present despite appropriate standard therapy (antibiotic therapy, immunosuppression, surgical drainage);
* Maintenance treatment in patients who responded to the induction therapy.

In ulcerative colitis, biological therapies are recommended as below:

* Induction therapy in patients with active ulcerative colitis who did not respond to standard treatment (5-ASA preparations, glucocorticosteroids and immunosuppressive agents);
* Maintenance treatment in patients who responded to induction therapy.

While biological therapies have been increasingly used in clinical trials in recent years, their safety has also been emphasized. These therapies have a number of safety issues that differ from the adverse reactions induced by sulfasalazine, mesalamines, steroids and even azathioprine. Among biological therapies of IBD, only mAbs, including infliximab, certolizumab, adalimumab and natalizumab, are approved by the FDA for clinical treatment of IBD, and, therefore, the side effects of these mAbs are well studied and have been described in each mAb study previously discussed. In summary, the most common adverse effects are as follows:[123–127]

* Acute and delayed transfusion reactions, which occurred in approximately 20–30% of patients receiving infliximab and 20% of those receiving adalimumab;[124,125]
* The development of antibodies against the infused mAbs, which reduces clinical effectiveness of the therapy and occurred in up to 61% of the patients receiving infliximab;[125]
* Delayed reactions or serum disease-like reactions, which occurred in approximately 2% of patients receiving infliximab;[124]
* Other rare side effects, which include lupus-like syndrome, reactivation tuberculosis, bacterial and fungal infections such as aspergillosis, histoplasmosis, cryptococcosis, candidosis, listeriosis, pneumocystosis, increased activity of liver enzymes (visilizumab), cardiovascular insufficiency, hepatosplenic lymphoma, leukoencephalopathy (natalizumab) and development of cancer such as lymphomas.

Future Perspective

New findings in IBD genetics have advanced our understanding of IBD pathogenesis in recent years,[128,129] providing evidence of the interaction between genes and environment in IBD. The improved understanding of IBD pathogenesis should lead to new alternatives for inhibiting inflammation mediators or pathways, different therapeutics for various disease phenotypes and eventually to personalized treatment. At the same time, some novel strategies, such as gene therapy-based approaches and autologous HSCT, have been providing new clues for the discovery of IBD pathogenesis, and should also be emphasized as new therapeutic options in the future.

Sidebar
Executive Summary

* Numerous biological agents are currently available for the treatment of patients with inflammatory bowel disease (IBD).
* These agents have shown to be good promising alternatives, or supplements to, our current treatment for IBD patients, especially for those patients refractory to conventional drugs.
* Biological therapies have provided new strategies to discontinue or reduce the doses of the treatment of glucocorticosteroids and immunosuppressives, shorten the hospitalization period, avoid surgical treatment, elongate the remission period and improve the quality of life in IBD patients.
* Among these biotherapies, only a few agents are currently approved by the US FDA. These include infliximab, adalimumab and certolizumab pegol. More clinical trials need to be carried out in order to find new agents as routine treatments for IBD patients.
* Considering the efficacy, indication and side effects of biological agents, clinicians should be aware of the mechanisms of the biotherapies to maximize the effectiveness of the bioagents, and minimize and monitor the problems associated with side effects.

 

[David in Seattle]

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[David in Seattle]

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[David in Seattle]

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