Biological therapy for ulcerative colitis

Infliximab

Infliximab was the first agent to receive FDA approval for induction and maintenance therapy in UC [10]. It is a chimeric, monoclonal antibody against TNF-α, which binds to both soluble and membrane-bound forms of TNF-α [4]. It is only available for administration as an intravenous infusion.

The efficacy of infliximab in the treatment of UC has been demonstrated in both open-label and randomized, controlled trials [10–20]. Two large, multi-center, randomized, double blinded, placebo-controlled trials—the Active Ulcerative Colitis Trials 1 and 2 (ACT 1 and ACT 2, respectively)—have provided evidence of the efficacy of infliximab in UC patients [10]. Both of these trials included 364 ambulatory patients with moderate-to-severe UC (defined as a total Mayo Score of 6–12 and a Mayo Endoscopy Subscore of ≥2) who had failed to respond to—or were intolerant to—conventional treatment with corticosteroids or immunomodulators (azathioprine or 6-mercaptopurine) [21]. ACT2 also included patients previously treated with 5-aminosalicylate agents. Patients were randomized to receive either placebo or infliximab infusion (5 or 10 mg/kg) at weeks 0, 2 and 6, and then every 8 weeks until week 46 in ACT1 and week 22 in ACT2. Clinical response was defined as a reduction in the Mayo Score by at least 3 points and at least 30%. Clinical remission was defined as a total Mayo Score of ≤2 points with no sub-score exceeding 1. The total duration of follow-up was 54 weeks in ACT1 and 30 weeks in ACT2. The patients in the infliximab group experienced significantly higher rates of clinical response and clinical remission at weeks 8, 30 and 54 than the placebo group in both clinical trials. The rates of adverse events in the infliximab and placebo groups were comparable.

The efficacy of infliximab increases further when used in combination with azathioprine. In a recent double-blinded, placebo-controlled trial, 239 anti-TNF-α therapy-naïve patients with moderate-to-severe UC were randomized to receive either (i) intravenous infusions of infliximab (5 mg/kg dose) at weeks 0, 2, 6, and 14, plus daily oral placebo capsules or (ii) oral azathioprine (2.5 mg/kg daily) plus placebo infusions on the infliximab schedule or (iii) combination therapy with both drugs [22]. Significantly more patients achieved corticosteroid-free clinical remission in the infliximab + azathioprine group, than either therapy alone.

A meta-analysis of five randomized, controlled trials, examining the efficacy of infliximab in the treatment of moderate-to-severe UC, showed that infliximab therapy was associated with a higher rate of induction of remission than placebo [23].

Infliximab has also been used for the treatment of chronic pouchitis, which is a common complication after proctocolectomy with ileal pouch anal anastomosis surgery for UC; however, experience with the use of infliximab in this setting is currently limited to case reports and series [24–31]. Although results from these studies suggest a promising role for infliximab, further data from larger randomized trials are need to demonstrate its guaranteed efficacy in pouchitis patients.

Adalimumab

Adalimumab is a fully humanized monoclonal antibody against TNF-α which is administered subcutaneously. It was approved by the FDA in 2012 for the treatment of moderate-to-severe UC in adults after its efficacy was demonstrated in several randomized and non-randomized studies [32–37]. Because of the subcutaneous route of administration, it can be self-administered by patients at home, thus avoiding the high cost and inconvenience of hospital visits for intravenous infusions.

Two large, randomized, controlled trials demonstrated the efficacy of adalimumab for the induction and maintenance of remission in UC patients. These were the UC Long-Term Remission and Maintenance with Adalimumab 1 and -2 trials (ULTRA 1 and ULTRA 2, respectively) [35, 38].

ULTRA 1 was an 8-week, multicenter, randomized, double-blinded, placebo-controlled trial investigating the use of adalimumab as induction therapy in patients with moderate-to-severe UC despite conventional therapy [35]. In this trial, 576 patients were randomized to receive either placebo or one of two different regimens of adalimumab: (i) regimen 160/80: adalimumab 160 mg at week 0; 80 mg at week 2; 40 mg at weeks 4 and 6 or (ii) regimen 80/40: adalimumab 80 mg at week 0; 40 mg at weeks 2, 4 and 6, while concurrently receiving stable treatment with oral corticosteroids or immunomodulators. At the end of 8 weeks, patients receiving adalimumab 160/80 were nearly twice as likely to achieve clinical remission as those receiving placebo (18.5% vs. 9.2%; P = 0.031). There was no significant difference in remission rates between patients receiving adalimumab 80/40 and placebo (10% vs. 9.2%; P = 0.833). Simultaneously, patients receiving adalimumab 160/80 showed significantly greater improvements in nutrition and inflammatory markers than the placebo group.

This study was followed by ULTRA 2, which was a 52-week study assessing the efficacy of adalimumab as maintenance therapy in UC patients [38]. This trial included 494 patients with moderately-to-severely active UC for the last 3 months despite concurrent treatment with corticosteroids or immunomodulator drugs. Patients were also stratified, based on whether they had previously been treated with TNF-antagonists or were anti-TNF therapy-naïve. The patients were randomized to receive either placebo or adalimumab (160 mg at week 0; 80 mg at week 2 and then 40 mg every 2 weeks starting week 4). A significantly higher proportion of patients in the treatment group achieved clinical remission at 8 weeks and remained in clinical remission at the end of 52 weeks, than was seen in the placebo group. Clinical response rates were also higher at weeks 8 and 52 in the treatment group, as compared with the placebo group. Importantly, on sub-group analysis, adalimumab was found to be effective at week 8 only in the anti-TNF therapy-naïve patients. In patients who had received anti-TNF therapy prior to their participation in the trial, clinical remission rates at week 8 were similar in the treatment and placebo arms.

An open-label extension study to ULTRA 1 and 2 is currently under way, to assess the long-term efficacy of adalimumab in UC patients [39]. Preliminary results suggest that the efficacy of adalimumab was sustained for up to 3 years for the treatment of moderate-to-severe UC.

Golimumab

Golimumab is a fully humanized monoclonal antibody against TNF-α and is the latest anti-TNF agent to receive FDA approval for treatment of moderate-to-severe ulcerative colitis. Similarly to adalimumab, it is administered subcutaneously and can therefore be self-administered by patients at home. Data regarding the efficacy of golimumab in UC comes mainly from two large, double-blinded, randomized, controlled trials, the Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment, which was divided into Subcutaneous and Maintenance phases (PURSUIT-SC and PURSUIT-M, respectively) [40, 41]. The PURSUIT-SC trial investigated the efficacy of golimumab as induction therapy, whereas PURSUIT-M studied its efficacy as maintenance therapy for moderate-to-severe UC.

PURSUIT-SC was an integrated phase-II and phase-III trial, in which 1064 anti-TNF therapy-naïve patients with moderate-to-severe UC (Mayo Score: 6–12; Mayo Endoscopic Subscore: ≥2) despite conventional therapy were included [40]. Of these, 774 were in phase III. The phase II trial data indicated that higher doses of golimumab [(i) 200 mg followed by 100 mg and (ii) 400 mg followed by 200 mg given subcutaneously 2 weeks apart] were associated with a higher rate of clinical response and remission than lower doses (100 mg followed by 50 mg given subcutaneously 2 weeks apart). There was no significant difference in the rate of adverse events between the different dose regimens. After the dose-finding phase-II trial, 774 patients were randomized to receive subcutaneous doses of (i) golimumab 400 mg followed by 200 mg, (ii) golimumab 200 mg followed by 100 mg or (iii) placebo at weeks 0 and 2, respectively. The primary and secondary endpoints were measured at week 6 and were defined similarly to the ACT1 and ACT2 trials [10]. The results of the study showed that patients treated with golimumab, with both the 400/200 mg and 200/100 mg regimens, exhibited higher clinical response and clinical remission rates than with placebo. The rates of adverse events were significantly lower in the golimumab arm than that in the placebo arm.

The subsequent PURSUIT-M trial included the same participants as PURSUIT-SC, to study the efficacy of golimumab as maintenance therapy [41]. In PURSUIT-M, 464 patients who had responded to golimumab induction therapy in PURSUIT-SC were randomized to receive placebo or golimumab (50 mg or 100 mg) every 4 weeks for 52 weeks. Patients who had responded to placebo continued to receive it and all non-responders were given 100 mg golimumab. After 54 weeks, patients receiving golimumab experienced higher rates of clinical response than patients who received placebo. In addition, patients who received a 100 mg dose of golimumab had significantly higher rates of clinical remission at 54 weeks, compared with patients receiving placebo or 50 mg dose. Adverse events and infections occurred more frequently in the golimumab group than in the placebo group.

Certolizumab pegol

Certolizumab pegol is the first pegylated, humanized monoclonal antibody against TNF-α. In fact, it contains only the antigen binding fragment (Fab) of the monoclonal antibody which has been conjugated to polyethylene glycol and does not contain the crystallizable (Fc) or tail portion of the antibody [42]. These unique characteristics afford some special properties to certolizumab pegol. Firstly, PEGylation of the antibody leads to an increase in its circulating half-life and improvement in bioavailability and pharmacokinetics, thereby permitting a minimum dosing interval of 2 weeks [43]. Also, as a result of PEGylation, the preferential penetration of certolizumab pegol into the inflamed tissue (over the non-inflamed tissue) is increased [44]. Secondly, due to the absence of the Fc portion, certolizumab pegol does not induce complement-dependent cytotoxicity or antibody-dependent cell-mediated cytotoxicity in vitro [45]. Lack of the Fc region also prevents trans-placental transfer of certolizumab pegol during pregnancy [46].

Certolizumab pegol has been shown to be effective in the treatment of CD and was approved by the FDA for this indication [42, 47]; however, its efficacy in the management of UC patients is currently under investigation in a phase II clinical trial [48].

Vedolizumab

Vedolizumab is a humanized monoclonal antibody that selectively binds to α4β7 integrin, which is located exclusively on the surface of gut-homing leukocytes [50–52]. By binding to the α4β7 integrin, it selectively blocks the adhesion and trans-endothelial migration of leukocytes in the gut without interfering with lymphocyte migration in the nervous system, thereby leading to a reduction in the inflammatory response in IBD patients. It is administered intravenously.

The efficacy of vedolizumab in the treatment of UC has been demonstrated in the GEMINI 1 trial [52]. This was a phase III, multicenter, double-blind, placebo-controlled study that integrated two different trials: for induction and maintenance therapies. The trial of induction therapy included 374 patients who were randomized to receive placebo or vedolizumab (300 mg at weeks 0 and 2). In addition, to meet the sample size requirements of the maintenance trial, a second group of 521 patients was enrolled, who received open-label vedolizumab at weeks 0 and 2, with responders at week 6 subsequently entering into the maintenance trial. All patients had moderate-to-severe UC (Mayo Score: 6–12 with endoscopy sub-score ≥2) and had failed to respond to previous therapy with at least one agent, including corticosteroids, immunomodulators and TNFα antagonists. The results of the induction trial showed that a significantly greater number of patients who received vedolizumab achieved clinical response and clinical remission at the end of 6 weeks, than those with placebo.

For the maintenance trial, patients from either above group who had a response to vedolizumab were randomized to receive either vedolizumab or placebo every 4 or 8 weeks. At the end of 52 weeks, patients receiving vedolizumab were significantly more likely to have clinical remission and clinical response than with placebo, including those who had previously failed anti-TNF therapy. Additionally, patients in the treatment group were less likely to require corticosteroids and had greater improvements in quality of life scores than those in the placebo group. There was no significant difference in efficacy between the two vedolizumab regimens. Also, the rate of adverse events was similar in the treatment and placebo groups and no cases of PML were observed during the 52 week follow-up.

Vedolizumab was recently approved by the FDA for the treatment of adults with moderate-to-severe UC [53]. An open-label study to determine the long-term efficacy and safety of vedolizumab in the treatment of UC and CD is also currently in progress [54].

PF-547659

PF-547659 is an investigational monoclonal antibody against MAdCAM-1 (addressin), which is the extracellular ligand for α4β7 integrin. It inhibits adhesion and trans-endothelial migration of leukocytes by suppressing the interaction of leukocytes with vascular endothelium, similarly to vedolizumab. Favorable results were observed in a preliminary study in UC patients and further trials are in progress [55].

Alicaforsen

Alicaforsen is another anti-adhesion molecule that reduces lymphocyte migration. It is an anti-sense oligonucleotide, causing decreased synthesis of endothelial adhesion molecule ICAM-1. A recent meta-analysis of four phase II studies in UC suggests that alicaforsen is effective for the treatment of moderate-to-severe UC, especially in patients with distal disease [56]. In an open-label trial of 12 patients, an enema formulation of alicaforsen was also shown to be effective for the treatment of chronic pouchitis in patients with underlying UC [57].