An Update on Anti-TNF Agents in Ulcerative Colitis




Anti-tumor necrosis factor-α agents are key therapeutic options for the treatment of ulcerative colitis. Their efficacy and safety have been shown in large randomized controlled trials. The key evidence gained from these trials of infliximab, adalimumab, and golimumab is reviewed along with their effect on mucosal healing and long-term outcomes. Also reviewed are methods for optimizing their effectiveness, including therapeutic drug monitoring and treat-to-target strategies. Finally, remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials.


Key points








  • Large randomized controlled trials have demonstrated the efficacy of multiple anti- tumor necrosis factor (TNF) agents in delivering mucosal healing, reducing clinical disease activity, and improving long-term outcomes in patients with moderate-to-severe ulcerative colitis.



  • A head-to-head trial has shown that infliximab may be as effective as cyclosporin when used as rescue therapy in severe colitis.



  • Combining infliximab with an immunomodulator is more effective than infliximab alone in inducing a response in moderate-to-severe ulcerative colitis.



  • Therapeutic drug monitoring and dose optimization of anti-TNF agents can maximize their efficacy.






Introduction


The advent of biologic therapies has led to significant changes in treatment strategies for ulcerative colitis (UC). Before biologic therapies, options for treatment primarily consisted of the stepwise use of mesalamine, corticosteroids, and immunomodulators for disease of increasing severity. Mesalamine was used to achieve and maintain remission in mild-to-moderate cases with the addition of corticosteroids for those failing to respond or with severe disease. Patients with colitis refractory to intravenous (IV) corticosteroids received cyclosporin or underwent colectomy. Over the past decade, multiple clinical trials have shown the efficacy of anti-tumor necrosis factor-α (anti-TNF) therapies for these patients with moderate-to-severe UC. Therefore, anti-TNF agents are key tools in current treatment algorithms for both chronically active and acute severe UC.


The effectiveness of biologic agents has also changed treatment goals in UC, which is evident in the evolution of endpoints used for clinical trials and targets used in clinical practice. Conventional and established goals of treatment focused predominantly on achieving symptomatic remission. The cessation of corticosteroid use and achieving mucosal healing (MH) were secondary goals. However, in the era of anti-TNF agents with the ability to heal colonic mucosa when other drugs have failed, MH and steroid-free clinical remission have gained prominence as therapeutic targets.


In this update, data are reviewed from randomized controlled trials (RCTs) and comparative effectiveness research and the impact of anti-TNF agents on long-term disease outcomes and their safety data is assessed. In addition, ongoing research is discussed on the pharmacokinetics and pharmacodynamics of TNF-antagonists in UC. Also considered is what may lie ahead as it is aimed to maximize the benefit this group of drugs can deliver.




Introduction


The advent of biologic therapies has led to significant changes in treatment strategies for ulcerative colitis (UC). Before biologic therapies, options for treatment primarily consisted of the stepwise use of mesalamine, corticosteroids, and immunomodulators for disease of increasing severity. Mesalamine was used to achieve and maintain remission in mild-to-moderate cases with the addition of corticosteroids for those failing to respond or with severe disease. Patients with colitis refractory to intravenous (IV) corticosteroids received cyclosporin or underwent colectomy. Over the past decade, multiple clinical trials have shown the efficacy of anti-tumor necrosis factor-α (anti-TNF) therapies for these patients with moderate-to-severe UC. Therefore, anti-TNF agents are key tools in current treatment algorithms for both chronically active and acute severe UC.


The effectiveness of biologic agents has also changed treatment goals in UC, which is evident in the evolution of endpoints used for clinical trials and targets used in clinical practice. Conventional and established goals of treatment focused predominantly on achieving symptomatic remission. The cessation of corticosteroid use and achieving mucosal healing (MH) were secondary goals. However, in the era of anti-TNF agents with the ability to heal colonic mucosa when other drugs have failed, MH and steroid-free clinical remission have gained prominence as therapeutic targets.


In this update, data are reviewed from randomized controlled trials (RCTs) and comparative effectiveness research and the impact of anti-TNF agents on long-term disease outcomes and their safety data is assessed. In addition, ongoing research is discussed on the pharmacokinetics and pharmacodynamics of TNF-antagonists in UC. Also considered is what may lie ahead as it is aimed to maximize the benefit this group of drugs can deliver.




Infliximab


Infliximab (Remicade) is a chimeric IgG 1 monoclonal antibody that binds with high affinity and specificity to soluble TNF-α. This process prevents the proinflammatory cytokine binding to cell receptors and propagating the inflammatory cascade. Infliximab also mediates inflammatory processes by binding to membrane-bound TNF-α on inflammatory cells, thereby inducing apoptosis. Infliximab is administered as an IV infusion with weight-based dosing and a regimen that includes an induction phase followed by maintenance treatment.


The first randomized, placebo-controlled study of infliximab for UC was published in 2001. Described as a pilot study, it included just 11 patients with severely active, steroid-refractory UC (defined as a Truelove and Witts score >10 and Blackstone endoscopic grade of 3 or 4). Although the trial was not sufficient to draw meaningful conclusions, it provided an initial signal of the drug’s efficacy with response seen in 4 of the 8 patients treated, compared with none in the placebo group. This study was followed by several uncontrolled trials before a larger randomized, double-blind, placebo-controlled trial using only a single dose of 4 to 5 mg/kg of infliximab was carried out in Sweden. That study included 45 patients with moderate, severe, or fulminant colitis (based on the Seo or fulminant colitis index ) who were refractory to conventional therapies. Their results demonstrated the value of infliximab as a rescue therapy with 7 of 24 (29%) treated patients requiring colectomy at 3 months compared with 14 of 21 (67%) given placebo ( P = .017). The first RCT to implement an induction regimen of 5 mg/kg at 0, 2, and 6 weeks demonstrated the superiority of infliximab when compared with IV methylprednisolone.


Clinical Efficacy: Moderate-to-Severe Disease and Maintenance Therapy


Infliximab has also been evaluated for use in patients with ongoing moderate to severely active UC, despite conventional therapy. In 2005, infliximab became the first anti-TNF agent approved by the US Food and Drug Administration (FDA) for use in moderate-to-severe UC. A year later, this approval was extended to include maintenance, as well as induction therapy, and European approval was also granted. This evidence was generated in 2 large, randomized, placebo-controlled, double-blind trials : A ctive Ulcerative C olitis T rials 1 and 2 (ACT 1 and ACT 2). The 2 trials ran concurrently for 3 years at multiple sites over 4 continents. Each trial included 364 patients and studied the effect of infliximab given at doses of 5 or 10 mg/kg at weeks 0, 2, and 6 followed by maintenance treatment scheduled at 8 weekly intervals. Both studies included patients with moderate-to-severe disease activity (defined as a Mayo score >6, with an endoscopic subscore of ≥2) and their inclusion criteria regarding concomitant medications differed only slightly. Both included patients taking corticosteroids and/or thiopurines as well as those who were no longer taking them but had previously failed or had contraindications (or intolerance) to these medications in the past. In addition to these groups, ACT 2 also included 5-aminosalicylate drugs using the same criteria. Therefore, patients did not necessarily need to be receiving corticosteroids at baseline (61% and 51% were in ACT 1 and 2, respectively). Although the 2 studies had identical induction regimens, the duration of treatment and follow-up period differed. Patients were given maintenance treatment until week 46 in ACT 1 and followed until 56 weeks. In ACT 2, the corresponding time points were week 22 and 30. Clinical response at week 8 was the primary endpoint of the ACT trials. The authors defined this as a decrease from baseline in the total Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Both trials showed that patients treated with infliximab (at either dose) were significantly more likely to have a clinical response at week 8 and 30. The 2 dosing regimens delivered similar efficacy, and response rates at these time points in treated patients were greater than 60% at week 8 and greater than 47% at week 30. Placebo response rates were less than 38% and 30% at the corresponding time points. With its extended follow-up period, ACT 1 showed this response to be durable at week 54 with 45.5% and 44.3% of treated patients (5 mg/kg and 10 mg/kg, respectively) responding compared with 19.8% on placebo. Clinical remission rates followed a similar pattern to clinical response and the effect of infliximab was again significant. In ACT 1, remission rates at 54 weeks were 34.7%, 34.4%, and 16.5% of patients treated with infliximab 5 mg/kg, 10 mg/kg, or placebo, respectively ( P = .01).


Corticosteroid-Free Remission


Remission in the absence of corticosteroid treatment has become an important endpoint for clinical trials in UC. Of the 61% of patients in ACT 1 on steroids at baseline, the proportion in clinical remission following corticosteroid cessation at week 30 was significantly higher with infliximab 5 mg/kg than with placebo (24.3% vs 10.1%, respectively; P = .03). The durability of this effect was evident at week 54 when the corresponding corticosteroid-free remission rates were 25.7% versus 8.9%, respectively ( P = .006). Furthermore, at baseline, the median dose was 20 mg/d in all groups. By week 54, this had fallen to 5 mg/d in the group given infliximab 5 mg/kg, whereas it remained at 20 mg/d in the placebo group.


Mucosal Healing


MH is an outcome measure with important implications for remission rates, future steroid use, and risk of colectomy in UC. Evidence is growing that complete mucosal reconstitution or significant improvement of endoscopic appearance can have multiple clinical benefits. MH was defined in the trials as a Mayo endoscopic subscore of 0 or 1 following treatment. Analysis of data from ACT 1 using this definition showed that at all time points, 5 mg/kg infliximab was significantly superior to placebo in this regard. At week 8, 62% achieved MH on this dose compared with 33.9% on placebo. This difference was maintained at weeks 30 (50.4% vs 24.8%, respectively) and 54 (45.5% vs 18.2%, respectively) with all comparisons reaching statistical significance ( P <.001).


As debate is on-going regarding whether Mayo grade 1 (abnormal vascular pattern and some friability but no erosions, ulcerations, or active bleeding) should be included in the group achieving MH, subgroup analysis including only those with grade 0 (completely normal mucosa) has subsequently been carried out. Using this more stringent definition, MH was achieved in 22.3% of infliximab patients and 12.4% of placebo patients at week 8, and 32.2% and 15.7%, respectively, at week 54.


Hospitalizations, Colectomy, and Long-Term Efficacy


Hospitalization and colectomy rates from the ACT trials were studied in a post-hoc analysis, which included 630 (87%) of the original 728 patients. When assessed at week 54, the cumulative incidence of colectomy was 10% in the infliximab-treated group compared with 17% in the placebo group ( P = .02). Infliximab therefore delivers an absolute risk reduction of 7% for colectomy in patients with moderate-to-severe UC. In their post-hoc analysis, the authors also showed that infliximab halved the rate of hospital admissions compared with placebo. Through week 54, there were 40 hospitalizations per 100 patient-years (PY) in the placebo group and 20 per 100 PY with infliximab ( P = .003).


To assess the long-term efficacy, effect on quality of life (QoL), and safety of infliximab, a 3-year open-label extension to the ACT trials was carried out. Any patient participating in the original trials who could benefit from ongoing treatment, as deemed by the investigator (without specific criteria), was eligible for inclusion. Ongoing infliximab, given at 8 weekly intervals, was shown to deliver maintained clinical benefit and health-related QoL while reducing corticosteroid use.


Combination Therapy Versus Monotherapy


Panaccione and colleagues conducted the UC SUCCESS trial to compare the efficacy of infliximab monotherapy with the combination of infliximab and azathioprine. To compare these 2 approaches, they recruited 239 biologic-naïve patients with moderate-to-severe UC (Mayo score ≥6). Ninety percent were azathioprine-naïve and 10% had stopped azathioprine more than 3 months before trial entry. The original trial design had planned the enrollment of 600 patients to the first phase (described here) to allow 200 to subsequently enter a longer-term observational study in the second phase. However, enrollment was terminated prematurely by the sponsor, because of higher than expected serious infusion reactions with an intermittent infliximab regimen in an unrelated study of patients with psoriasis. Patients were randomized to 1 of 3 treatment arms: azathioprine and placebo; infliximab and placebo; infliximab and azathioprine. A standard induction regimen of 5 mg/kg infliximab and/or 2.5 mg/kg azathioprine was administered to the relevant groups and endpoints were judged at week 16. The primary endpoint investigated was steroid-free remission (defined as total Mayo score ≤2 with no subscore >1). In this regard, combination therapy performed significantly better than either infliximab (40% vs 22%, P = .017) or azathioprine (40% vs 24%, P = .032) alone. Patients on combination therapy were significantly more likely to achieve MH (endoscopic Mayo of 0 or 1) than those on azathioprine monotherapy. MH rates were 63% with combination therapy compared with 55% with infliximab monotherapy ( P = .295) and 37% with azathioprine monotherapy ( P = .001).


Safety


The TREAT (Crohn T herapy, R esource, E valuation, and A ssessment T ool) registry was designed specifically to investigate the long-term safety of anti-TNF therapy in patients with Crohn disease (CD). More than 5 years of data from this ongoing, prospective, observational study was published in 2012 and, although the study only includes patients with CD, results are certainly relevant to anti-TNF-treated patients with UC. Based on analysis of more than 6000 patients, the authors demonstrated no increase in mortality or neoplasia between patients receiving infliximab and those receiving other treatments only. Analysis of this data also confirmed the increased risk of serious infections that had been previously seen (hazard ratio 1.98; 95% confidence interval [CI] 1.11, 1.84; P = .006). It should be noted, however, that increased risk was not relative to cumulative infliximab dose because neither the number of infusions nor the dose escalation to 10 mg/kg significantly impacted it.


Of significant concern in the treatment of fulminant colitis with infliximab is its possible effect on postoperative complication rates among nonresponder who require colectomy. This group of patients are often already at increased risk of infectious complications owing to the use of immunomodulators and corticosteroids. A literature review and meta-analysis of trials have been conducted to examine this issue. Although the studies included are all retrospective, use different endpoints, and report mixed results, limited conclusions can be drawn. It seems that if the use of preoperative infliximab increases the risk of postoperative complications (infectious or otherwise) at all, the effect is minimal.


Clinical Efficacy: Rescue Therapy


Before infliximab, therapeutic options for patients with severe or fulminant colitis unresponsive to IV corticosteroids were only cyclosporin or colectomy. Given the risks for toxicity with cyclosporin, the benefit of infliximab in clinical trials of moderate-to-severe UC suggested a potential alternative for patients hospitalized with severe UC. However, until recently the 2 agents had not been compared in a head-to-head trial to assess their relative efficacy. This comparison was recently carried out in a study involving 27 centers in France and Belgium as part of a parallel, open-label, RCT. Patients experiencing a severe flare (defined as a Lichtiger score >10) with an insufficient response to IV corticosteroids received either cyclosporin (2 mg/kg/d for 1 week, followed by oral drug until day 98) or infliximab (5 mg/kg at 0, 2, and 6 weeks). All 115 patients included were naïve to the trial agents and those with a satisfactory response to either drug commenced azathioprine at day 7. The primary outcome was “treatment failure,” and the authors defined this as the absence of a clinical response at day 7, a relapse between day 7 and day 98, absence of steroid-free remission at day 98, a severe adverse event leading to treatment interruption, colectomy, or death. Failure of therapy was seen in 60% (35) of those receiving cyclosporin and 54% (31) given infliximab (absolute risk difference 6%, 95% CI −7 to 19; odds ratio 1.3, 95% CI 0.6–2.7). Roughly 85% of patients in both groups had a clinical response at day 7 measured by the Lichtiger score (a secondary endpoint). The proportion of severe adverse events was also similar among the 2 arms with 9 (16%) and 14 (25%) suffering these in the cyclosporin and infliximab groups, respectively. No deaths and few serious infections were reported. Overall, the authors concluded that treatment choice should be guided by physician and center experience. When considered in the context of the monitoring cyclosporin blood levels, the significant potential toxicity of cyclosporin, and the emerging evidence regarding the pharmacodynamics of infliximab, infliximab may soon become the rescue therapy of choice for many practitioners. The overriding practical issue in relation to cyclosporin is that its use is restricted to centers that can regularly monitor concentrations and have sufficient clinical experience in the use of drugs not routinely used in outpatient practices. Evidence has also emerged demonstrating that patients with severe, steroid-refractory colitis may fail to respond to infliximab because of accelerated clearance of the drug. Dose optimization with higher or more frequent doses may therefore improve response rates, an aspect that was not studied in the head-to-head comparison. This theory is supported by post-hoc analysis from the ACT 1 and 2 demonstrating that higher infliximab trough concentrations were associated with greater likelihood of response, remission, and MH than were low or absent trough concentrations.


It is also important to consider the patient who has a severe flair despite thiopurine maintenance therapy in whom there is no subsequent maintenance option if rescue cyclosporin is chosen and succeeds. Infliximab, therefore, has a significant advantage in this group. Further data regarding the efficacy and cost-effectiveness of each agent will be available when the UK-wide CONSTRUCT trial ( CO mparison of i N fliximab and cyclosporin in ST eroid R esistant U lcerative C olitis: a T rial) is completed in August 2014.




Adalimumab


After FDA approval of infliximab for induction and maintenance of UC, the next anti-TNF agent to achieve FDA approval for the treatment of UC was adalimumab (Humira). Adalimumab is a TNF-α targeted fully human monoclonal antibody. It is administered via the subcutaneous route and is FDA approved as therapy for moderate-to-severe CD as well. In addition, adalimumab is currently in use for the therapy for psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis. Initially, case reports and many small open-label studies showed efficacy in UC. Recently, a multicenter RCT, ULTRA1, was conducted to examine the efficacy of adalimumab in induction of clinical remission in moderate-to-severe UC. This phase III, randomized, double-blind, placebo-controlled study was conducted across 94 European and North American centers. Enrolled subjects were required to have a full Mayo score ranging from 6 to 12, with an endoscopic subscore of 2 to 3. Subjects were required to be anti-TNF naïve. Prior failure of oral corticosteroid and/or immunomodulator therapy with azathioprine or 6-mercaptopurine was required for study enrollment. Subjects were randomized to either placebo or induction with subcutaneous adalimumab 160/80 mg or 80/40 mg. This dosing selection was based on adalimumab dosing in the CHARM and CLASSIC-I CD trials and regulatory agency guidance. The 160/80 mg group received subcutaneous adalimumab 160 mg at week 0, 80 mg at week 2, followed by 40 mg at weeks 4 and 6. The 80/40 mg group received 80 mg at week 0 followed by 40 mg at weeks 2, 4, and 6.


The study’s primary endpoint was the proportion of subjects in clinical remission by week 8, defined as a composite Mayo score less than or equal to 2 with no individual subscore of 1 or more. At the study’s end, the adalimumab 160/80 mg group achieved clinical remission in 18.5% of subjects, which was double the placebo rate of 9.2% ( P = .031). The adalimumab 80/40 mg group reached a clinical remission rate that was similar to placebo at 10% ( P = .833). Furthermore, secondary endpoints revealed that the adalimumab 160/80 mg group did achieve greater rates of MH, clinical response, and improvement to less than or equal to 1 in all components of the Mayo score in comparison to placebo. Subanalyses revealed that subjects with a greater composite Mayo score on study entry, CRP more than or equal to 10 mg/L at baseline, and higher study entry weight achieved lower rates of remission than those with a lower Mayo score. The safety profile of adalimumab appeared to be comparable to that of placebo. Overall, the results of ULTRA1 conclude that adalimumab 160/80 mg is effective for induction of remission in moderate-to-severe UC subjects who are failing corticosteroids and/or thiopurines. The optimal dose regimen in UC may, however, not have been reached because the dose-response curve suggests that efficacy may be improved with doses more than the current standard dosing regimen.


Following ULTRA1, the ULTRA2 study was conducted as a phase III, randomized, double-blind, placebo-controlled trial to examine the efficacy of adalimumab in long-term maintenance of remission in moderate-to-severe UC. Before enrollment, subjects were required to have 3 months of active moderate-to-severe UC defined as a composite Mayo score of 6 to 12 and an endoscopic subscore of 2 or more. Subjects had moderate-to-severe UC despite corticosteroid or azathioprine/6-mercaptopurine. Concomitant 5-ASA therapy was allowed but not a requirement, and prior use of infliximab was permitted after a more than or equal to 8-week washout period. In total, 40% of subjects had prior anti-TNF exposure. Randomization to placebo or subcutaneous adalimumab 160 mg at week 0, 80 mg at week 2, and then 40 mg every other week was done in a 1:1 fashion. After week 12, subjects who showed poor response were able to enter the open-label phase using adalimumab 40 mg every other week. In addition, subjects were permitted to dose escalate to adalimumab 40 mg every week in the case of inadequate response to every other week dosing.


The study followed subjects for a total of 52 weeks with assessments of primary and secondary endpoints at weeks 8, 32, and 52. The primary endpoint of clinical remission was defined as a composite Mayo score less than or equal to 2 with no individual subscore greater than 1. By week 8, 16.5% of subjects who received adalimumab were in clinical remission, whereas the placebo remission rate was 9.3% ( P = .019). By week 52, remission rates were 17.3% and 8.5% in the adalimumab and placebo group, respectively ( P = .004). Secondary endpoints included clinical response and MH. Clinical response was defined as a decrease in Mayo score of more than or equal to 3 from baseline and a decrease in Mayo score more than or equal to 30% from baseline and decrease in rectal bleeding subscore more than or equal to 1 or an absolute score of 0 or 1. By week 8, the adalimumab group achieved clinical response in 50.4% of subjects compared with 34.6% in the placebo group ( P <.001). By week 52, the adalimumab group revealed response in 30.2% compared with 18.3% placebo response ( P = .002). MH was achieved by reaching an endoscopic subscore of 0 or 1. At week 8, 41.1% of subjects achieved MH compared with 31.7% on placebo ( P = .032). In comparison, by week 52, the adalimumab group achieved MH in 25% compared with 15.4% in the placebo group ( P = .009). Further subanalyses revealed that subjects who were anti-TNF naïve had a greater chance of achieving clinical remission at weeks 8 and 52 compared with the anti-TNF exposed group. Safety results were also comparable between the treatment and placebo groups.


An additional study analyzing the safety of adalimumab using a benefit-to-risk balance assessed the likelihood of achieving efficacy without serious adverse events in the intention-to-treat group. This analysis showed a favorable adverse event profile and overall positive benefit/risk balance when remission or response was achieved at weeks 8 and 52 in adalimumab-treated subjects. One notable difference between the ULTRA2 trial and the infliximab trials (ACT 1 and 2) is that the infliximab studies did not allow for rescue therapy. Another variation is that a significant portion of the ULTRA2 subjects had been exposed to anti-TNF, whereas all the infliximab study subjects were anti-TNF naïve at enrollment. These variations may explain in part the lower remission rates seen with adalimumab versus infliximab.


In summary, the ULTRA2 study results confirm findings from ULTRA1. Combined, these studies show that adalimumab 160 mg at week 0, 80 mg at week 2, followed by 40 mg every other week is effective in induction and maintenance of remission in moderate-to-severe UC.


To study the long-term safety of adalimumab, the PYRAMID registry was initiated in 2007. In common with the TREAT registry for infliximab, only patients with CD are included, but once again the results are also certainly of relevance to those on long-term adalimumab treatment of UC. Although not due for completion until 2015 with a planned 6-year study duration for each patient, an interim safety analysis was carried out at year 3. This study demonstrated very low rates of opportunistic infection (0.1 per 100 PY) as well as malignancy (0.6 per 100 PY) and lymphoma (<0.1 per 100 PY) with no new safety signals. At that point, more than 8000 PY had been studied with a median exposure to adalimumab of 19 months, suggesting that long-term treatment can be considered safe.

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Feb 26, 2017 | Posted by in GASTROENTEROLOGY | Comments Off on An Update on Anti-TNF Agents in Ulcerative Colitis

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