Review Article: New Drugs and Therapeutic Approaches for the Management of UC

[David in Seattle]

Review Article: New Drug Formulations, Chemical Entities and Therapeutic Approaches for the Management of Ulcerative Colitis

S.C. Ng; M.A Kamm

Alimentary Pharmacology & Therapeutics. 2008;28(7):815-829. © 2008 Blackwell Publishing

Abstract and Introduction
Abstract

Background: Treatment options for ulcerative colitis (UC) are expanding with the development of novel drug formulations and dosing regimens and new chemical entities. Although the goals of medical therapy for UC remain unchanged, that is to induce and to maintain remission, focus has also centred on improving patient compliance, modifying the natural course of disease and healing the mucosa.
Aim: To examine novel formulations, new chemical entities and novel therapeutic approaches to the management of UC.
Methods: Searches for all studies related to UC treatment in Medline and abstracts from major national and international meetings published in the last 10 years.
Results: 5-Aminosalicylic acids (5-ASA) remain the standard first-line treatment for patients with mild to moderately active UC. New formulations with altered delivery, and new dosing regimens have demonstrated possible improvements in efficacy compared with historically available preparations and dosing patterns. Once-daily dosing, micropellet formulations, and high-dose tablets offer enhanced efficacy and improved compliance. 5-ASA is now recognized as a ligand for peroxisome proliferator-activated receptor-γ (PPAR-γ) and it has a role as a chemo-preventive agent in long-standing UC. New colonic release corticosteroid formulations help to limit systemic toxicity; turmeric, tacrolimus and infliximab have shown promising results. New anti-inflammatory targeted therapies include an anti-CD3 antibody, selective integrin blockers, anti-IL-2 antibody and PPAR-γ agonists.
Conclusion: The evolution of novel oral 5-ASA formulations and dosage regimens, and recent development of new molecules have expanded the therapeutic armamentarium of UC.
Introduction

Traditional therapy for the drug management of ulcerative colitis (UC) has involved the use of 5-aminosalicylic acid (5-ASA) compounds, corticosteroids and thiopurines [azathioprine and mercaptopurine (MP)]. There is a substantial evidence base supporting their use in this setting.[1–3] This review does not aim to review that evidence. In contrast, a range of therapies is emerging, which offer the prospect of improved dosing and compliance with traditional molecules, or new molecules and therapeutic approaches, which may offer disease control in patients unresponsive to, or intolerant of, standard therapies. This review aims to examine some of these developments.

The source material for this review was obtained from searches for all studies related to the treatment of UC published over the last 10 years in (i) Medline and (ii) abstracts from major international and national meetings. In contrast to published guidelines, this review is not intended as a systematic review, or as an evaluation of the merits of different levels of evidence. Rather, it is intended as a selection of the most relevant publications that demonstrate points of therapeutic importance, therapeutic advance over existing treatment regimens, or novel therapeutic approaches.

For a detailed systematic review, we refer readers to the recent European Crohn's and Colitis Organisation (ECCO) guidelines. Their recently published European Consensus on management of UC involved systematic literature searches, grading of the quality of evidence and a final consensus reached by discussion among experts.[1-3]

5-aminosalicylic Acid

5-ASA [mesalazine (mesalamine)] remains the first-line therapy for patients with mild to moderately active UC, based on an extensive and long history of efficacy and safety.[4] It is effective in inducing and maintaining remission.[5] 5-ASA acts topically but is absorbed in the small intestine; hence a number of mechanisms have been developed that allow delivery of 5-ASA to the large bowel mucosa.[6] Differences in drug delivery may account for the variability in efficacy and tolerability among different formulations.[7,8]

Controlled-release mesalazine (Pentasa) releases 5-ASA slowly throughout the entire gastrointestinal tract, where approximately 30% of the drug is absorbed before reaching the colon; pH-dependent mesalazine formulations (Asacol, Mezavant XL) rely on an enteric coating that dissolves when the pH level reaches 7 or higher in the terminal ileum. Azo-bonded 5-ASA prodrugs, which include sulphasalazine, olsalazine and balsalazide, rely on anaerobic bacteria in the colon to enzymatically release the active drug and deliver almost 100% of the drug directly to the colon.[9] Table 1 shows currently available 5-ASA formulations and their mechanisms of delivery.

Novel 5-ASA Formulations

Despite the effectiveness of 5-ASA, up to 60% of patients do not take their medications as prescribed.[10] Patients who are non-adherent, most commonly single young men or those taking multiple concomitant medications, have a fivefold increased risk of disease relapse compared with patients who take at least 80% of their prescribed dose.[11] Patient non-adherence may be in part because of multiple tablet, multiple daily dosing regimens.
Multi-matrix (MMX) Mesalazine (1.2 g Tablet)

Recent developments in this field have focused on the development of new higher-dose formulations and improved dosing regimens. MMX mesalazine (Multi Matrix System, Lialda, US; Mezavant XL; UK and Ireland, Mezavant rest of Europe; Shire Pharmaceuticals Inc., Wayne, PA, USA) comprises a tablet coated with a gastro-resistant pH-dependent polymer film that breaks down at pH ≥ 7, containing 1.2 gm mesalazine embedded in a matrix, which disintegrates slowly over 24 h as the tablet moves through the large bowel. It has been approved by the US Food and Drug Administration for the induction of remission in patients with active mild-to-moderate UC, and by the European authorities for the induction and maintenance of remission.

Two randomized clinical trials evaluated the efficacy of MMX mesalazine in patients with active UC. In both studies, the primary endpoint was strictly-defined clinical and endoscopic remission. In the double-blind, randomized, placebo-controlled, multi-centre study by Kamm et al., 343 patients with active mild to moderate UC were randomized to MMX mesalazine 2.4 g once daily, MMX mesalazine 4.8 g once daily, Asacol (Procter & Gamble, Cincinnati, OH, USA) 0.8 g three times daily, or placebo for 8 weeks. The primary end point was the proportion of patients in strictly-defined clinical remission [modified UC disease activity index (DAI) of ≤ 1 with rectal bleeding and stool frequency scores of 0] and endoscopic remission (endoscopic score of 0 or 1, no mucosal friability and one point or more point reduction in sigmoidoscopy score from baseline). A significantly greater proportion of patients who received one of the two MMX mesalazine doses (2.4 g/day, 40.5%; 4.8 g/day, 41.2%) achieved clinical and endoscopic remission compared with placebo (22.1%) at 8 weeks, whereas the clinical and endoscopic remission rate for Asacol (32.6%) was not significantly different compared with placebo.[12]

 

[David in Seattle]

In the study by Lichtenstein et al., 280 patients with mild to moderately active UC were randomized to MMX mesalazine 2.4 g/day twice daily, MMX mesalazine 4.8 g/day once daily, or placebo. At 8 weeks, clinical and endoscopic remission was achieved in 34% of patients who had MMX mesalazine 2.4 g/day twice daily, in 29% who had MMX mesalazine 4.8 g/day once daily, and in 13% of placebo-treated patients. Both MMX mesalazine doses had statistically significant beneficial effects compared with placebo and most of the improvement in the MMX mesalazine-treated patients occurred within 2 weeks.[13]

In a randomized comparison evaluating the efficacy of MMX for the maintenance of remission in UC, MMX mesalazine 2.4 g/day given once daily was equally effective to 1.2 g given twice daily.[14] Comparing once- vs. twice-daily dosing, 89% vs. 93% of patients maintained clinical remission, and 64% vs. 69% maintained clinical and endoscopic remission, at 1 year. Treatment was effective in both left-sided and extensive disease,[15] and in patients with a history of frequent relapse.[16]

The current licensed dose of MMX mesalazine for the induction of remission in patients with active, mild-to-moderate UC is two–four 1.2 g tablets administered once daily. The recommended dose for the maintenance of remission is 2.4 g once daily.[17,18]
Increase Dose Per Tablet or Per Sachet

Asacol (800mg Tablet). Earlier clinical trials comparing the efficacy between 1.6 g/day and 4.8 g/day of pH-dependent delayed-release mesalazine (Asacol) in patients with mild to moderately active UC showed no differences in efficacy between the two mesalazine doses.[19,20]

Recently, the ASCEND (Assessing the Safety and Clinical Efficacy of a New Dose of 5-ASA) I and II trials utilized a new 800-mg tablet formulation of Asacol, comparing 4.8 g/day of delayed-release mesalazine (Asacol; Procter & Gamble) with 2.4 g/day in 386 patients with mild to moderately active UC.[21] The primary endpoint was the proportion of patients in each treatment group that achieved overall improvement ('treatment success' defined as either complete remission or a clinical response to therapy). Significantly, more patients with moderately active UC treated with 4.8 g/day responded compared with patients who had 2.4 g/day at 6 weeks (72% vs. 59%). However, there was no significant difference in response between treatment groups in the patients with mildly active disease. The recent ASCEND III study confirmed the clinical benefit of delayed-release mesalazine 4.8 g/day in patients with moderately active UC; the therapeutic advantage of this higher dose compared with 2.4 g/day was most evident in patients with previous use of oral mesalazine and rectal therapies.[22]
Micropellets

Micropellet formulations of 5-ASA such as Pentasa or Salofalk granules allow large doses in a format preferred by some patients. They have also been tested for efficacy on a once-per-day basis. Preclinical pharmacokinetic studies that examined the amount of 5-ASA release from pellets (Pentasa) compared with conventional tablets in healthy volunteers showed similar systemic exposure and similar release of active drug in the terminal ileum and ascending colon.[23,24]

Pentasa (Once Daily 2g Tablet). In a recent multicentre investigator-blinded randomized controlled trial, patients with mild to moderate UC in remission were randomized to 2 g mesalazine granules sachet (Pentasa) once daily or 1 g mesalazine granules sachet twice daily. At 1 year, 74% and 64% of patients in the once-daily and twice-daily groups, respectively, maintained clinical and endoscopic remission. Once daily dosing was clinically superior to, and had a higher compliance than twice daily dosing.[25]

Farup et al. compared the efficacy of an equal dose of a prolonged-release granule formulation of mesalazine (4 g daily; Pentasa sachet) divided into twice daily vs. four times daily. with that of prolonged-release mesalazine tablets 0.5 g four times daily in patients with mild to moderately active UC. In this 8-week open label study, 4 g mesalazine given as prolonged-release granules twice and four times daily was at least as effective as prolonged-release tablets four times daily. Granules were as effective as tablets, and twice-daily dosing was as effective as more frequent dosing. The reduced dose frequency and lower pill burden were preferred by patients.[26]

The pharmacokinetic profile of 5-ASA for pentasa sachets administered 4 g once daily was also similar to that of 2 g given twice daily.[27]
Micropellet Mesalazine Sachets

The efficacy of a new mesalazine micropellet formulation (Merckle GmbH, Ulm, Germany) was compared with that of the tablet formulation (Claversal 500, Merckle GmbH) at a dose of 3 g/day, taken as 1.5 g sachet twice daily. Micropellets formulation showed non-inferiority in terms of clinical remission at 8 weeks compared with conventional tablet formulations. Similarly, patients expressed a preference for less frequent dosing with the micropellet formulation.[28]

These studies demonstrate that 5-ASA granules (micropellets) are as effective as tablet formulations, and that reduced dosing frequency (once daily or twice daily) has similar efficacy to more frequent dosing.
Salofalk (3g Granules)

In a phase 3 trial, once-daily dosing of 3 g mesalazine (Salofalk granules; Falk Pharma, Freiburg, Germany) was as effective as three-times daily dosing of 1 g mesalazine for the treatment of active UC.[29]
Once Daily 1g 5-ASA Suppositories

In addition, a once-daily suppository formulation of 5-ASA is now available and has been shown to be an effective option for the induction of remission in UC patients with disease limited to the distal colon.[30]

Rectal 5-ASA has also been shown to be superior to placebo for the maintenance of remission of distal UC.[31-34] In a double-blind placebo-controlled multi-centre trial, 95 patients with ulcerative proctitis were randomized within 2 weeks of remission to receive Pentasa 1 g suppositories three times per week or placebo for 1 year or until relapse. The relapse rates were significantly lower in the Pentasa arm than the placebo arm at 3, 6 and 9 months but not at 12 months.

A meta-analysis has demonstrated superiority of rectal 5-ASA over placebo for maintenance of remission in UC at 1 year (OR 15.2, 95% CI 4.7–55.9).[35]
Combination Therapy

In patients with left sided UC of mild to moderate severity, combined oral (>2 g/day) and topical 5-ASA therapy is more effective than either oral or rectal therapy alone.[36] Therefore, if a patient is not responding to oral or rectal therapy alone, combined therapy should be instituted. Combined therapy also enhances the benefit in patients with extensive mild to moderately active UC.[37]

New Data on the Mode of Action of 5-ASA
Peroxisome Proliferator-activated Receptors-γ (PPAR-γ)

The putative anti-inflammatory actions of 5-ASA include the modulations of inflammatory cytokine secretion,[38] the reduction of transcriptional activity of NK-κB and the inhibition of leucotrienes and prostaglandins.[39] 5-ASA has also been demonstrated to have a chemopreventive effect through several other mechanisms including the reduction of oxidative stress, inhibition of cell proliferation and the promotion of apoptosis.[40]

Recent data suggest that 5-ASA acts at least in large part through the activation of the PPAR-γ nuclear receptors. These receptors are expressed at high levels in colonic epithelial cells, where their expression appears to be at least in part stimulated by the gut bacteria.[41] PPAR-γ is involved in the control of inflammation, cell proliferation, apoptosis and metabolic functions.[40] Recent data identifying PPAR-γ as the key receptor for 5-ASA have been based on functional, pharmacological and chemical lines of evidence.[42] These results have been validated in vivo in a mouse model of inflammatory bowel disease (IBD) using organ cultures of human colonic tissue.[43] Targeting PPAR-γ through a variety of ligands provides a mechanistic basis for the development of other compounds, which may modify inflammatory activity and neoplastic risk.

Alternative Possible Effect Via PPAR-γ
Rosiglitazone

Thiazolidinedione ligands for PPAR-γ, widely used to treat type-2 diabetes mellitus, have been proposed as novel therapies for UC. In a multi-centre, randomized, double-blind placebo-controlled clinical trial, 105 patients with mild to moderately active UC were randomized to oral rosiglitazone 4 mg or placebo twice daily for 12 weeks. The primary endpoint was clinical response defined as a reduction in the Mayo DAI of two or more points. After 12 weeks of therapy, 44% of patients treated with rosiglitazone and 23% of patients treated with placebo achieved clinical response, and 17% treated with rosiglitazone and 2% treated with placebo achieved clinical remission. Endoscopic remission was uncommon in either of the treatment arm. Clinical improvement was evident as early as 4 weeks after starting the treatment.[44]

A recent study assessed the therapeutic effects of the combined use of rosiglitazone and 5-ASA in mild or moderately active UC. Twenty-one patients were assigned to additional treatment with rosiglitazone 4 mg/day (4 mg/tablet; GlaxoSmithKline Pharmaceutical Co. Ltd, Beijing, China) and 21 to no additional treatment. Both groups received 5-ASA 2 g/day (500 mg granules; Beaufour Ipsen Pharmaceutical Co. Ltd, Tianjin, China). Clinical remission was defined as a final DAI score of ≤ 2 and partial remission was defined as a reduction in the DAI of ≥ 2 and final score ≥ 3. Clinical remission was achieved in 15 patients in the treatment group (71%) and 12 patients in the control group (57%); partial remission was achieved in five patients (24%) and four patients (19%) in the treatment group and control group, respectively, after 4 weeks of treatment.[45]

 

[David in Seattle]

Corticosteroids

Glucocortosteroid therapy is a well established and effective treatment for patients with active UC, but their use is associated with systemic side effects.[46-48]
Controlled-release Beclomethasone Dipropionate (Clipper)

Beclomethasone dipropionate (BDP) is a second-generation steroid with topical effects and minimal systemic activity.[49] An oral controlled release preparation of BDP (Clipper; Chiesi Pharmaceuticals, Parma, Italy) has an acid-resistant film coating (Eudragit-L100/55) that dissolves at pH < 6, releasing the active drug in the distal small bowel and colon.[50] Campieri et al. demonstrated that BDP has equivalent efficacy to 5-ASA in the treatment of extensive and left sided active UC.[51]

A double-blind placebo-controlled trial evaluated the efficacy of BDP added to 5-ASA in the treatment of extensive or left sided active UC. One hundred and nineteen patients were randomized to receive BDP (5 mg daily) or placebo; all patients received oral 5-ASA (3.2 g daily). More patients in the BDP plus 5-ASA group achieved clinical remission than the placebo and 5-ASA group after 4 weeks of treatment (58.6% vs. 34.4%, P = 0.008).[52]

Biancone et al. showed in a controlled trial that BDP liquid enema, BDP foam enema, mesalazine liquid enema and mesalazine foam have comparable tolerability and efficacy in mildly active distal UC.[53]
Oral Prednisolone Metasulfobenzoate (Predocol)

In a double-blind randomized study, Rhodes et al. compared the efficacy and safety of a sparingly absorbed formulation of prednisolone metasulfobenzoate (predocol) with a conventional tapering course of oral prednisolone in 181 patients with active UC. Fifty-nine patients were randomized to Predocol 40 mg/day for 6 months, 61 patients to Predocol 60 mg/day for 6 months, and 61 patients to oral prednisolone 40 mg/day for 2 weeks, tapered to zero after 8 weeks, followed by placebo until 6 months. Remission rates at 2 months were 46%, 28% and 41% respectively (P = 0.13). Remission rates at 6 months also did not differ significantly between the treatment arms. Predocol 40 mg/day had markedly fewer side effects than a conventional tapering prednisolone regimen.[54]
MMX Budesonide

D'Haens et al. studied the safety and efficacy of budesonide MMX 9 mg in patients with active left-sided UC. Thirty-six patients were treated with budesonide MMX 9 mg extended release tablets (Cosmo Technologies Ltd, Dublin, Ireland) for 8 weeks or placebo (blinded phase) for 4 weeks followed by budesonide MMX 9 mg for 4 weeks. Eight of 17 patients (47%) in the budesonide group and five of 15 patients (33%) in the placebo group responded, defined as a reduction in colitis activity index (CAI) of at least 50% or a CAI ≤ 4. There was no significant suppression of the adrenocortical function in patients who had budesonide compared with those who had placebo.[55]

Biological Therapies

A range of biological drugs have been evaluated recently for their therapeutic effect in treating patients with UC. Positive clinical trials include antitumour necrosis factor (anti-TNF)-α antibodies, anti-CD3 antibodies, and antiadhesion molecules.
Infliximab

Infliximab, a chimeric monoclonal antibody to TNF-α, has been used for the treatment of UC. Two large randomized placebo-controlled trials, the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2), evaluated the efficacy of infliximab for the induction and maintenance of remission in 728 adult out-patients with moderate to severely active UC treated up to 54 weeks. Infliximab demonstrated double the remission rate compared with placebo. Approximately one-third of patients in each trial had steroid refractory disease. The primary endpoint for both trials was a clinical response at week 8 defined as a decrease from baseline in total Mayo DAI of three or more points, out of a possible maximum of 12 points. For both the ACT 1 and two studies, the clinical response at 8 weeks was significantly higher in patients who had infliximab (5 and 10 mg/kg) compared with placebo. Clinical and endoscopic improvement was reported in approximately 60–70% of the treated population, compared with approximately 40% in the placebo-treated group. Remission rates were substantially higher in infliximab-treated patients. Infliximab was also associated with significant reductions in UC-related hospitalizations and surgical procedures.[56] Further analysis of the ACT 1 and 2 trials demonstrated that infliximab was associated with a reduction in colectomy (hazard ratio 0.57, 95% CI 0.37–0.89) during the trial, but whether this benefit is maintained remains unclear.[57]

In patients with moderate to severe UC refractory to corticosteroids and/or immunomodulators, a systematic review which included all treated out-patients and in-patients concluded that infliximab is effective in inducing clinical remission, clinical response, promoting mucosal healing and reducing the rates of short-term colectomy.[58] The ECCO guidelines also support the use of infliximab in resistant disease.[3]

Further studies are needed to confirm the long-term efficacy of infliximab in UC and to address whether early use of infliximab prevents colectomy in the long term.[59,60]

Infliximab has a proven role in patients with acute severe UC, although the magnitude of the clinical effect remains to be determined in larger studies. In a multicentre placebo-controlled trial, patients with moderately severe to severe UC unresponsive to at least 3 days of intravenous steroids were randomized to infliximab 5 mg/kg or placebo. Significantly less patients who had infliximab (29%) required colectomy at 90 days compared with patients who had placebo (67%), although this study involved a relatively small sample size.[61]

The Scottish Society of Gastroenterology Infliximab group, in a retrospective survey, showed that approximately one-third of patients with acute severe UC treated with infliximab underwent urgent colectomy during the acute admission.[62] In the largest study of fuliminant colitis treated with infliximab published to date, an Italian group treated 83 patients with severe steroid-refractory UC. Fifteen per cent of patients underwent colectomy within 2 months; 58 patients avoided colectomy at a median of 23 months follow-up. In the short term, two or more infusions were more effective than a single infusion.[63] Investigators from Oxford showed that approximately half the patients with refractory UC treated in their cohort came to a colectomy at a median of 140 days after their first infusion.[64]

The biological therapies do carry a particular risk profile that should be considered. Of the 484 patients in the ACT trials who received infliximab, 17 serious adverse events occurred. Eight patients developed pneumonia, one tuberculosis, one histoplasmosis (who later died), and there were four cases of malignancy (likely pre-existing but presented during the study period) and three neuropathies (two optic neuritis and one multifocal motor disease).[56] In the retrospective series of 39 patients of acute UC treated with infliximab, Lees et al. reported one death secondary to Pseudomonas pneumonia and one patient had post-operative fungal septicaemia.[62]
Adalimumab

Adalimumab is a humanized anti-TNF agent administered subcutaneously. Current trials are in progress to evaluate the efficacy in the treatment of UC. In a small open-label study, 10 patients with UC who had previously responded to infliximab but subsequently lost response or became intolerant to the drug were treated with adalimumab. Three patients experienced clinical improvement, and one was in remission, at week 4.[65]
Visilizumab (Anti-CD3 Antibody)

Visilizumab is a humanized immunoglobulin G2 monoclonal antibody that binds specifically to human CD3 expressed on T cells, thereby inducing T-cell apoptosis. Phase I and II studies with visilizumab demonstrated clinical benefit in patients with severe UC refractory to intravenous steroids.[66] In the open-label phase IB study, 32 subjects with active UC refractory to intravenous steroids were treated with intravenous visilizumab at a dose of 10 or 15 µg/kg. On day 30, 84% of patients showed a clinical response, 41% achieved clinical remission and 44% achieved endoscopic remission. Forty-five per cent of patients did not require salvage therapies or colectomy during the first year postinfusion. Side effects consisted of transient infusion-related cytokine release symptoms including chills, headache, pyrexia and arthralgia. There was a transient decrease in circulating T-cell levels. There were no serious infections.[67] At the time of writing the further development of this compound was under review.
Alpha-4-integrin Blockade

Alpha-4 integrins facilitate leucocyte migration across vascular endothelium at the sites of inflammation. The development of monoclonal antibodies that inhibit or block alpha-4 integrins permitted the targeting of lymphocyte trafficking into the intestine as a novel therapeutic intervention.[68] The Efficacy of Natalizumab as Active Crohn's Therapy trial demonstrated the efficacy of natalizumab (Tysabri; Elan Pharmaceuticals, San Diego, CA, USA, and Biogen Idec, Cambridge, MA, USA), a recombinant humanized monoclonal antibody against alpha-4 integrin, in active Crohn's disease (CD).[69] The benefit of natalizumab will need to be weighed against the risk of serious adverse events such as progressive multifocal leucoencephalopathy. In UC, a pilot study was conducted to assess the safety and efficacy of a single infusion of 3 mg/kg of natalizumab in 10 patients with active UC. Five and one patient achieved good clinical response at 2 and 4 weeks, respectively.[70]

 

[David in Seattle]

Natalizumab is available for use under a restricted license in the US, for patients with CD who are resistant to other therapies. It is not licensed for use in Europe.

A more gut-selective humanized antibody to the alpha-4 beta7 integrin (MLN02; Millennium Pharmaceuticals, Cambridge, MA, USA) has been evaluated in a multi-centre, double-blind, placebo-controlled trial of 181 patients with active UC. Patients were randomized to receive two intravenous infusions of MLN02 0.5 mg/kg, 2 mg/kg or placebo on days 1 and 29. At week 6, clinical remission rates were 33%, 32% and 14%, respectively. More patients treated with MLN02 achieved endoscopic remission than patients on placebo.[71] Short-term results are promising but long-term data are required for its use in UC.
Anti-interleukin IL-2 Receptor Antibody (Daclizumab)

An uncontrolled pilot study demonstrated that daclizumab (Protein Design Labs, Inc., Fremont, CA, USA), a humanized monoclonal antibody to the IL-2 receptor (CD25), may be effective for the treatment of active UC.[72] A subsequent randomized, double-blind, placebo-controlled trial compared induction therapy with intravenous daclizumab 1 mg/kg, 2 mg/kg or placebo in 159 patients with moderately active UC. Daclizumab was not superior to placebo in inducing clinical response or remission at 8 weeks.[73]

Other Anti-inflammatory Chemical Entitites Evaluated in UC
Ciclosporin and Tacrolimus

Ciclosporin and tacrolimus (FK506) are different types of molecules that act via a similar mechanism of calcineurin inhibition. They are both effective in patients with UC intolerant of or resistant to conventional immunosuppressants including azathioprine and MP.[74-78]

Ciclosporin is most commonly used in patients admitted to hospital with acute severe UC refractory to steroids. Following a response to intravenous ciclosporin, oral ciclosporin is used as a bridging therapy to azathioprine. In the first randomized controlled trial, 11 patients with acute severe UC were randomized to ciclosporin (4 mg/kg) and nine patients to placebo. Two of 11 patients in the ciclosporin group and nine of nine in the placebo group failed to respond. Three of 11 and four of nine patients had a colectomy in the ciclosporin and placebo groups, respectively and the follow-up was less than a month.[79] In a second trial, 15 patients with acute UC were randomized to ciclosporin and 15 to intravenous methylprednisolone. Five of 15 patients in the ciclosporin and seven of 15 in the methyprednisolone group failed to respond. At 1 year, seven of nine responders in the ciclosporin group were still in remission compared with four of eight in the steroids group and the colectomy rates were similar in both groups.[80] A Cochrane review that included only these two trials concluded that there is limited evidence that ciclosporin was more effective than standard treatment in acute UC.[81]

Recent data suggest that long-term failure rates after ciclosporin salvage therapy are relatively high.[82] Campbell et al. showed that 90% of patients had relapsed after 3 years, and 58% had undergone colectomy after 7 years.[83] In the second retrospective cohort study by Actis et al., 60% of patients with steroid-refractory colitis responded to ciclosporin and of the initial responders, 60% and 35% were colectomy-free at 1 and 7 years, respectively. These figures improved to 80% and 60%, respectively in the subset of patients treated with azathioprine.[84] In a study (published in abstract form) assessing the long-term follow-up of patients with severe steroid-refractory UC who had intravenous ciclosporin, 86% had an initial response. Forty-five per cent of initial patients were colectomy-free at a mean of 75 months. Life analysis predicted a 15.5 year colectomy-free survival rates of 39% overall; this was the highest in patients who had AZA/MP (49%) compared with those who did not (17%).[85]

Tacrolimus has tended to be used predominantly for out-patients with chronic active disease resistant to other therapies. The only controlled trial of tacrolimus in UC randomized 20 patients with active resistant disease to each treatment arm: low trough level (5–10 ng/mL whole blood), high trough level (10–15 ng/mL whole blood), or placebo. At the end of 2 weeks treatment, there was a 68.4% improvement rate in the high trough level group, 38.1% in the low trough level group, and 10% in the placebo group. Twenty per cent of patients in the tacrolimus group achieved remission and 78.9% had mucosal healing.[86,87]

Several other studies have evaluated the efficacy of tacrolimus but most of these were retrospective and uncontrolled. The long-term colectomy rate in these patients remains unclear. In our experience, oral tacrolimus can be effective in patients with UC refractory to conventional therapy in the short to medium term. In one study, 19 patients with IBD were treated. Three of six patients with UC resistant to azathioprine, MP or infliximab achieve clinical remission over a median treatment duration of 5 months.[66]

Fellerman et al. reported 38 patients with refractory UC or indeterminate colitis who were treated with oral tacrolimus. Eighteen of 38 patients improved within 2 weeks and a complete remission was achieved in 13 patients after 1 month. The overall colectomy rate was 34% over 16 months.[88] Baumgart demonstrated a favourable outcome in their retrospective series of 31 patients. Twenty-eight patients (90.3%) responded and 20 patients (64.5%) went into remission at 1 year follow-up. The response to tacrolimus was superior in UC compared with CD (74% vs. 17% respectively).[89]
Tumeric

Curcumin is a biologically active phytochemical substance present in turmeric and has been shown to diminish inflammation in animal models of colitis.[90,91] To assess the efficacy of curcumin as maintenance therapy in UC, 89 patients with quiescent UC were randomized to sulfasalazine or mesalazine with the addition of curcumin (1 g b.d.) or placebo for 6 months. Of 82 patients who completed the study, two of 43 patients (5%) in the curcumin group and eight of 39 patients (21%) had relapsed at 6 months.[92]
Omega-3 Fatty Acids (Fish Oils)

A recent Cochrane review showed that the current data do not allow for a definitive conclusion regarding the efficacy of fish oil in the treatment of UC.[93]
RDP58

RDP58 (Nasdaq: GENZ) is a novel anti-inflammatory D-amino acid decapeptide that inhibits the synthesis of proinflammatory cytokines including TNF-α, interferon γ and IL-12. In a double-blind placebo-controlled trial, significantly more patients with mild to moderately active UC who had RDP58 responded to treatment compared with those who had placebo.[94]
OPC-635 (Tetomilast)

Tetomilast is a thiazole compound that inhibits leucocyte phosphodiesterase-4 and several proinflammatory pathways including superoxide production, protease secretion and cytokine formation. In a placebo-controlled phase II clinical trial in 186 patients with mild to moderately active UC, clinical improvement at 8 weeks with oral tetomilast (OPC-635; Otsuka Pharmaceutical Company Ltd, Tokushima, Japan) 25 mg, 50 mg, or placebo daily did not differ significantly between the three groups: tetomilast 25 mg (52%), tetomilast 50 mg (39%) and placebo (35%). Although remission was achieved in more patients on tetomilast, the differences were not statistically significant. Post hoc analysis suggested that patients who had a higher DAI at study entry had the best response as compared with placebo.[95]
Interferon (IFN)-β

IFN-α or -β has been used in the treatment of UC.[96,97] In a small controlled trial, 18 patients with moderately active UC were randomized to IFN-β-1a (Rebif; Serono, Geneva, Switzerland), 22 µg three times/week subcutaneously with dose increase to 44 µg and then to 88µg if no response, or placebo. Clinical response was achieved in five of 10 patients (50%) in the IFN-β-1a group and in one in seven (14%) in the placebo group. Remission was reported in three of 10 patients (33%) in the IFN-β-1a group and in none in the placebo group. Most adverse reactions associated with IFN-β-1a were influenza-like symptoms or injection site reactions, and were mild or moderate in severity. The number of patients was too small to draw definite conclusions.[98]
Leucocytapheresis

Leucocytapheresis involves extracorporeal removal of activated leucocytes via an absorptive system and is widely used in Japan for the treatment of active UC. Two systems are available, which include cellulose acetate beads (Adacolumn; Otsuka Pharmaceuticals) or a polyester fibre filter (Cellsorba; Asahi Medical Company, Tokyo, Japan).

Several observational studies and two randomized trials have reported the effectiveness of leucocytapheresis in active UC, with a response rate ranging from 60% to 90%.[99] Leucocytapheresis is a relatively safe procedure and represents a possible effective therapy in some patients with UC. A recent randomized controlled trial comparing leucocytapheresis with sham apheresis has been completed but not reported.

 

[David in Seattle]

Changing Gut Flora
Probiotic Bacterial Therapy

Escherichia Coli Nissle 1917. Most studies examining the efficacy of probiotics in UC have focused on the maintenance of disease remission. In a double-blind, double dummy study comparing mesalazine (1.5 g/day) to an oral preparation of E. coli Nissle 1917 (5 × 1010 viable bacteria) for 3 months in 120 patients with inactive UC, E. coli Nissle 1917 was equivalent to mesalazine in maintaining remission (84% vs. 89%).[100] In a larger longer-term study, 327 patients with inactive UC were randomized to mesalazine (1.5 g/day) or E. coli Nissle 1917 for 12 months. Remission rates were 64% in the mesalazine group and 55% in the E. coli Nissle 1917 group at 12 months. E. coli Nissle 1917 appears to be as effective as mesalazine in maintaining remission in UC.[101]

Rembacken et al. conducted a single centre randomized double-blind double dummy study of E. coli Nissle in 116 patients with active UC, to assess both the treatment of acute disease and the maintenance of remission. All patients received a 1 week course of gentamicin (80 mg three times daily), tapering oral prednisolone or hydrocortisone enemas, and were randomized to either mesalazine (2400 mg/day) or E. coli Nissle strain 1917 (1 × 1010 viable bacteria). Forty-four patients in the mesalazine group (75%) and 39 patients (68%) in the E. coli group attained remission. In the subsequent maintenance study, patients who achieved remission within 3 months were maintained on either mesalazine or E. coli for up to 12 months. Relapse was frequent in both groups: 67% in the E. coli Nissle Group and 73% in the mesalazine group relapsed, demonstrating relatively poor efficacy for both treatments.[102,103]

VSL#3. VSL#3 is a high-dose mixed probiotic preparation containing eight different species of bacteria (four lactobacillus, three bifidobacteria and one streptococcus). Few studies have assessed the role of probiotics in the treatment of active UC. In an open-label study, 34 ambulatory patients with mild to moderately active UC who had failed mesalazine therapy were treated with VSL#3 (3600 billion bacteria daily) for 6 weeks. Fifty-three per cent of the VSL#3-treated patients achieved remission and a further 24% had a response. At least two of the bacterial species incorporated in the probiotic product reached the target colonic sites.[104]

A recent randomized double-blind placebo-controlled trial published in abstract form assessed the efficacy of VSL#3 in the treatment of 147 adult patients with mild to moderately active UC. Patients were randomized to VSL#3 3600 bacteria per day or placebo for 12 weeks. Significantly more patients on VSL#3 (42%) showed an improvement in Ulcerative Colitis Disease Acitivity Index (UCDAI) by 50% at 6 and 12 weeks compared with placebo (18%). There was a significant reduction in stool frequency, rectal bleeding score, mean endoscopic score and physician's global assessment score both at 6 and 12 weeks.[105]

In a small open-label study, 20 patients with UC who were intolerant or allergic to 5-ASA were treated with VSL#3 (1 × 1012 bacteria; 3 g/day) for 12 months. At 1 year, 15 of 20 treated patients remained in remission. Faecal concentrations of Streptococcus salivarius ssp. thermophilus, lactobacilli and bifidobacteria increased significantly in all treated patients, compared to their basal level.[106]

Saccharomyces Boulardii. The nonpathogenic yeast, S. boulardii has been found to be beneficial in the maintenance treatment of CD,[107] and this has now been tested in the treatment of acute UC. In a pilot study, 25 patients with acute mild to moderately active UC, who were intolerant of corticosteroids, received open-label S. boulardii (750 mg/day) for 4 weeks. All patients were maintained on mesalazine prior to and during the study. Seventeen of 25 patients (68%) achieved remission. This remission rate is similar to those described for E. coli Nissle 1917 and VSL#3.[108]

Probiotic Containing-fermented Milk. In a randomized controlled study, the effects of fermented milk that contained live Bifidobacterium breve and bifidum and Lactobacillus acidophilus were examined in 21 patients with inactive UC. After 12 months, 73% treated with fermented milk, and 10% on placebo, were in clinical remission. However, there were no significant differences in colonoscopic findings at 1 year.[109]

A recent Cochrane review of all randomized-controlled trials of the use of probiotics in UC showed that probiotics added to standard therapy may provide modest benefits in terms of reduction of disease activity in patients with mild to moderately active UC. Whether probiotics are as effective in patients with severe and more extensive disease and whether they can be used as an alternative to existing therapies remain to be fully investigated.[110]
Helminths - Trichuris Suis

Helminths have been shown to diminish inflammation and improve colitis in animal models. An open-label study demonstrated that 79% of patients with active CD responded at 24 weeks.[111] A recent double-blind randomized placebo-controlled trial from the University of Iowa assessed the efficacy of the helminth T. suis in the treatment of active UC. Fifty-four patients were randomized to 2500 T. suis ova or placebo orally every 2 weeks for 12 weeks. The primary efficacy measure was clinical improvement defined as a reduction of UCDAI of ≥ 4, and the secondary endpoint was clinical remission defined as a UCDAI of ≤ 2. At week 12, improvement according to the intention-to-treat principle was seen in 43% on treatment compared with 17% who had placebo (P = 0.04).[112] However, relatively few patients were in clinical and endoscopic remission.

 

[David in Seattle]

Epithelial Restitution and Enhanced Barrier Function
Epidermal Growth Factor

Growth factors including transforming growth factor-β, epidermal growth factor and keratinocyte growth factor, play an important role in regulating the integrity of the colonic mucosa and preserving epithelial barrier function in the gastrointestinal tract.[113] Apart from barrier protection, they are involved in immune regulation, cell migration and wound healing.[114] A small controlled trial showed that the addition of epidermal growth factor enemas to oral 5-ASA in 24 patients with mild to moderately active UC produced significant improvement in both clinical and endoscopic scores. After 2 weeks, 10 of 12 patients who received epidermal growth factor enemas achieved remission compared with one of 12 patients who had placebo enemas.[115] This clinical efficacy needs to be confirmed, and the potential effects of mucosal carcinogenesis need to be addressed in future studies.

In contrast, Sandborn et al. showed no significant benefit of a recombinant keratinocyte growth factor-2 (intravenous repifermin 1–50 µg/kg) compared with placebo in the treatment of active UC.[116]
Barrier Function

An impaired phospholipid barrier function with exposure to colonic commensal bacteria may lead to mucosal inflammation in UC. Phosphatidylcholine has been shown to have anti-inflammatory properties in murine models of colitis.[117,118] In a phase IIa proof of concept study, 60 patients with chronic active, nonsteroid dependent UC were randomized to retarded release phosphatidylcholine-rich phospholipids at a dose of 6 g or placebo over 3 months. Fifty-three per cent of phosphatidylcholine-treated patients achieved clinical remission compared with 10% placebo-treated patients. Clinical improvement, defined as a reduction in DAI of 50% or more, was seen in 90% of the phosphatidylcholine group compared with 10% in placebo-treated patients.[119] Phosphatidylcholine also reduced corticosteroid dependence. Eighty per cent of patients with chronic steroid-refractory UC discontinued steroid therapy without disease exacerbation, compared with 10% on placebo.[120] The same group has recently established in a randomized controlled dose finding study that the lowest effective dose of retarded release phosphatidylcholine for patients with nonsteroid treated ulcerative pancolitis was 1 g daily.[121]

Conclusion

New 5-ASA formulations including high-dose tablets and micropellet formulations, with less frequent administration, have demonstrated efficacy in active mild to moderate colitis and in the maintenance of remission. These new dosing regimes are likely to improve compliance, although this remains to be tested in clinical practice.

The discovery of 5-ASA as a topical ligand for the PPAR-γ receptor expressed by colonic epithelial cells paves the way for the development of new molecules specifically targeting this receptor. Such molecules have potential therapeutic benefit in treating active inflammation, and in preventing inflammation and neoplastic transformation.

Data regarding the effects of growth factors provide clinical evidence that direct epithelial repair may be therapeutically effective in the management of UC. Evidence of benefit also comes from chemical mucosal barrier enhancement, which may act to prevent exposure of the epithelial barrier to luminal contents. Alternatively, altering the bacterial milieu using probiotics or parasitic infection may also be effective therapies; the latter of these remains experimental. Simple chemicals with anti-inflammatory activity, such as turmeric, may be therapeutically effective.

A variety of new biotechnologically engineered therapies that target a spectrum of inflammatory molecules are in development, including anti-CD3 antibodies (Visiluzumab), anti-IL2 receptor antibody (daclizumab) and molecules that selectively block leucocyte migration and recruitment (MLN02). Although the efficacy and safety of these new treatments require further evaluation in a larger patient population, they may potentially be added as new therapies into the treatment armamentarium of UC.

 

[David in Seattle]

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[gibby]

interesting reading!
i am hopefully going to be entered into a clinical trial on thursday for the use of synbiotic treatment which is not unlike the probiotic type studies such as VSL etc that have been mentioned above, which is to treat and heal the mucosa in the colon, hopefully stalling my colectomy! if i get put on the drug that is, and not the placebo! currently flaring and i have to be unwell enough to be put on it, which is really odd, the first time i have ever called up my GI at a flare and told i dont need steroids to treat my flare cos i need to be ill on thursday to get on the trial! wish me luck x good to see they are still searching for new things!

 

[ssv]

Thanks David. Some great information there.

Good luck with the trial Gibby. Keep us updated with how it goes.

 

[David in Seattle]

Thanks David. Some great information there.

Good luck with the trial Gibby. Keep us updated with how it goes.

Glad you guys found it of interest