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Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis Matilda Hagan MD
ab
a
& Raymond K Cross MD MS
a 1
University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA b 2
Institute for Digestive Health and Liver Disease, Mercy Medical Center, Baltimore, MD, USA Published online: 03 Jul 2015.
Click for updates To cite this article: Matilda Hagan MD & Raymond K Cross MD MS (2015) Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis, Expert Opinion on Drug Safety, 14:9, 1473-1479 To link to this article: http://dx.doi.org/10.1517/14740338.2015.1063612
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Drug Safety Evaluation
Expert Opinion on Drug Safety 2015.14:1473-1479.
Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis 1.
Introduction
2.
Mechanism of action
3.
Clinical applications
4.
Safety evaluation
5.
Conclusion
6.
Expert opinion
Matilda Hagan & Raymond K Cross† †
University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine, Baltimore, MD, USA
Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials. Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug. Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile. Keywords: anti-adhesion molecule, anti-integrin, Crohn’s disease, inflammatory bowel disease, natalizumab, ulcerative colitis, vedolizumab Expert Opin. Drug Saf. (2015) 14(9):1473-1479
1.
Introduction
Inflammatory bowel diseases (IBD) consisting of ulcerative colitis (UC) and Crohn’s disease (CD) are chronic gastrointestinal disorders of unknown etiology, characterized by chronic intestinal inflammation with periods of active disease and remissions. For moderate-to-severe disease, the mainstays of therapy are corticosteroids, immune suppressants such as azathioprine, 6-mercaptopurine, methotrexate and anti-TNF inhibitors (anti-TNF) to include infliximab, adalimumab, certolizumab pegol and golimumab. The choice of therapy primarily depends on disease severity; biologic therapy is generally reserved for patients unresponsive or intolerant to conventional therapy. However, recent studies have demonstrated that anti-TNF therapy alone or in combination with an immune suppressant is the most effective strategy for management of moderate-to-severe IBD [1,2]. The advent of anti-TNF therapy has significantly improved medical therapy for the management of CD and UC; however, there is an unmet need for additional medical therapies to manage CD and UC. The main reasons being, despite their efficacy, 30 -- 40% of patients may have primary non-response to anti-TNF therapy or may develop secondary loss of response with estimated rate of 23 -- 46% either due to increased drug clearance or development of neutralizing antibodies [3-5]. Additionally, patients may develop side effects of therapy resulting in discontinuation of treatment. As such development of medications with alternative mechanism of action is paramount. Cell surface adhesion molecules have been implicated in the inflammatory pathway resulting in IBD. The integrins are heterodimeric cell surface glycoproteins expressed on most leukocytes consisting of an a and b subunit pair which upon interaction with its ligand modulate signaling pathways. The a4 integrins are 10.1517/14740338.2015.1063612 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name (generic name) Phase Indication
Vedolizumab FDA-approved Treatment of adults with moderate-tosevere Crohn’s disease or ulcerative colitis who have been unresponsive to, intolerant of, or have lost response to anti-TNF inhibitors and or immune suppressants or are steroid-dependent. Intravenous infusion
Route of administration Chemical structure Molecular formula is C6528H10072N1732O2042S42 Mechanism Monoclonal antibody that binds to and of action inhibits interactions between a4b7 integrin on leukocytes and its ligand mucosal addressin cell adhesion molecule-1 present on gut vascular endothelium [22-24] Pivotal trials
thought to facilitate the adhesion and migration of leukocytes to sites of inflammation in the intestines and play a vital role in the maintenance of inflammation [6,7]. Animal studies using monoclonal antibodies to antagonize the a4 integrins alone or in combination with b7 (a4b7) integrins resulted in resolution of spontaneous acute and chronic colitis similar to UC seen in cotton-top tamarins [8,9]. Additional support for this approach came from the use of monoclonal antibody to antagonize the interaction between the b7 subunit and its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) resulting in reduction of inflammation in T-cell-mediated colitis in severe combined immunodeficiency mice [10]. Natalizumab is a recombinant humanized IgG4 monoclonal antibody which binds the a4 integrin subunit and broadly antagonizes the interactions of a4b1 and vascular cell adhesion molecule-1 (VCAM-1) as well as a4b7 and MAdCAM-1 thus inhibiting leukocyte adhesion and subsequent migration into the brain and gut respectively. Multiple randomized, placebo-controlled trials have demonstrated the efficacy of natalizumab in induction and maintenance of clinical remission and response in moderate-to-severe CD [11-15]. Natalizumab offered the promise of a much needed alternative to anti-TNF inhibitors for management of CD. Unfortunately, after initial approval by the FDA for the treatment of multiple sclerosis in 2004, natalizumab was withdrawn from the market after reports of three patients developing progressive multifocal leukoencephalopathy (PML) after being treated with natalizumab [16]. PML is thought to occur in patients treated with natalizumab as a result of decreased immune surveillance of the John Cunningham (JC) virus attributable to blockade of a4b1 in 1474
the blood--brain barrier. Additional attributable risk factors for the development of PML include natalizumab treatment duration of ‡ 2 years, prior exposure to immunosuppressant, and JC virus antibody seropositive [17]. Following a safety review, the FDA reapproved natalizumab in 2006 under a special prescribing program as monotherapy for MS (Biogen Idec Inc., TYSABRI [natalizumab] Injection Full Prescribing Information, 2013, Biogen Idec Inc.: Cambridge, MA). Natalizumab gained approval for the treatment of CD in 2008 under a strict monitoring program, Tysabri Outreach: Unified Commitment to Health Registry. The use of natalizumab in clinical practice has been limited in light of the safety concerns. A second cell adhesion molecule inhibitor, vedolizumab (Takeda) (Box 1) designed to be gut-selective unlike natalizumab is now available on the market for treatment of CD and UC. The aim of this article is to review the safety and effectiveness of vedolizumab in the treatment of CD and UC. Additionally, it will review the mechanism of action of the drug and lastly address where vedolizumab can be positioned in our current algorithm in the treatment of CD and UC. 2.
Mechanism of action
Vedolizumab (previously known as LDP-02, MLN02 and MLN0002) is a humanized, gut-selective immunoglobulin G1 monoclonal antibody that binds to and blocks interactions between a4b7 integrin on select group of leukocytes and its ligand MAdCAM-1 present on gut vascular endothelium [18]. Vedolizumab does not bind nor affect the interaction of a4b1 integrin with VCAM-1 thus migration of leukocytes to the CNS is not affected with resultant lower to no risk of PML. The initial version of vedolizumab was derived from a NS0 mouse myeloma cell line and was shown to be efficacious in CD and UC. However, it was highly immunogenic with 44% of subjects developing clinically significant titers of human antihuman antibodies [19,20]. The current version of vedolizumab, designed to be less immunogenic than its predecessors, was derived from a Chinese hamster ovary cell-based system without alteration of the antigen recognition sequence [18]. A Phase II dose ranging study performed to evaluate the safety, efficacy and pharmacology of the new version of vedolizumab demonstrated that the Cmax and AUC increased with increasing dose in a linear manner. The mean elimination half-life was 15 -- 22 days across the dose range tested. Additionally, targeted a4b7 receptors were nearly 100% saturated after dosing and the maximum effect was > 95% at all doses in the presence of detectable serum concentrations of vedolizumab. The investigators were unable to evaluate dose or concentration response owing to the near-complete saturation of a4b7 receptors [18]. Population pharmacokinetic data suggest similar pharmacokinetic in CD and UC. Additionally, at a dose of 300 mg intravenous infusion the half-life of 25.5 day is longer than the other available biologics. In population pharmacokinetic
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analysis, the covariates of age, fecal calprotectin, CD activity index score, partial Mayo score, concomitant immunomodulator use, anti-drug antibody status and prior TNF-a antagonist therapy status had no clinically significant influence on vedolizumab pharmacokinetics. However, linear clearance of vedolizumab increased with decreasing albumin concentrations and body weight positively correlated with vedolizumab linear clearance [21].
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3.
Clinical applications
Currently, vedolizumab is indicated for the treatment of adults with moderate-to-severe CD and UC who have been unresponsive to, intolerant of, or have lost response to antiTNF inhibitors and or immune suppressants or are steroiddependent. Vedolizumab was approved by the FDA in May 2014 and has also been approved by the European Medicines Agency and Health Canada. Evidence to support approval came from multiple randomized, multicenter, blinded, placebo-controlled trials evaluating the safety and efficacy of vedolizumab in CD and UC. For the treatment of CD, an initial Phase III trial by Sandborn et al. evaluated the safety and efficacy of vedolizumab in achieving and maintaining response and remission in patients with moderate-to-severely active CD who had previously failed or were intolerant to conventional therapy with corticosteroids, immune suppressant or anti-TNF. In this trial, 368 patients were randomized to vedolizumab 300 mg or placebo infusion at week 0 and 2 with assessment of clinical response and remission at week 6. In the open-label arm of the study, 747 subjects received vedolizumab at week 0 and 2 with assessment of clinical response at week 6. The primary end point of clinical response at week 6 was not achieved in this trial. The other primary end point was met with 15% of vedolizumab-treated patients achieving clinical remission compared to 7% of placebotreated patients (p = 0.02). In a parallel maintenance trial, 461 responders to vedolizumab at week 6 were randomized to vedolizumab 300 mg infusion every 8 weeks or every 4 weeks, or placebo through week 52. The primary end point of clinical remission at week 52 was achieved with significantly more vedolizumab-treating patients maintaining clinical remission compared to placebo (39% vedolizumab every 8 weeks, 36% vedolizumab every 4 weeks, 22% placebo [p < 0.001]) [22]. As seen in clinical trials of other biologics, patients with prior exposure to anti-TNF had lower remission and response rates compared with anti-TNF naı¨ve patients. A second Phase III induction trial was conducted to assess the safety, efficacy and tolerability of vedolizumab in moderate-to-severely active CD patients with prior failure to one or more anti-TNF. Three hundred and fifteen (76%) of the 416 randomized patients had previous failure of 1 or more TNF antagonists. Vedolizumab-treated patients were given 300 mg of vedolizumab at week 0, 2 and 6. The primary end point of clinical remission at week 6 was not achieved in this trial. However, a secondary end point at week 10 was
achieved with more patients in the vedolizumab group achieving clinical remission compared with the placebo group (26.6 vs 12.1%; p = 0.001) [23]. This supports the hypothesis that for the treatment of CD, response to induction therapy may require longer than the 6-week time point evaluated in prior clinical trials. This observation was also noted in patients treated with natalizumab and may owe to the mechanism of action of these drugs. A Phase III multicenter, randomized, double-blind, placebo-controlled study, evaluating the safety and efficacy of vedolizumab for UC was also performed. Two hundred and twenty-five patients were randomized to vedolizumab 300 mg or placebo infusion at week 0 and 2. Similar to the CD trial, there was an open-label cohort where an additional 521 patients received vedolizumab at 0 and 2. At week 6, clinical response (primary outcome) was achieved in 47.1% of patients treated with vedolizumab compared to 25.5% of patients treated with placebo (p < 0.001). Similarly, rates of clinical remission were 16.9 and 5.4% in vedolizumab and placebo-treated patients respectively at week 6 (p = 0.001). Vedolizumab-treated patients also had higher rates of mucosal healing at week 6 compared to placebo-treated patients. Responders from both cohorts (n = 373) were randomized to vedolizumab 300 mg every 4 or 8 weeks or placebo through week 52. At week 52, vedolizumab-treated patients were more likely to maintain clinical remission (41.8% vedolizumab every 8 weeks, 44.8% vedolizumab every 4 weeks, and 15.9% placebo, p < 0.001) mucosal healing (51.6, 56 and 19.8%, p < 0.001) and corticosteroid-free remission (31.4, 45.2 and 13.9%, p < 0.001) [24]. As previously observed with biologic therapy, anti-TNF exposed patients had lower response rates compared with anti-TNF naı¨ve patients. A recent meta-analysis of the six key randomized controlled trials supports the efficacy of vedolizumab. For induction therapy, treatment with vedolizumab was associated with achieving clinical remission compared to placebo with a risk ratio (RR) of 1.88 (95% CI [1.45, 2.43]) [25]. This effect was present within subgroups of IBD as well (UC RR = 2.23, 95% CI [1.35, 3.68] and CD RR = 1.71, 95% CI [1.25, 2.34]). Vedolizumab use was also associated with superior disease-specific response rates to induction therapy compared to placebo (UC, RR = 1.82, 95% CI [1.43, 2.31]; CD, RR = 1.46, 95% CI [1.18, 1.81]). Similarly, vedolizumab maintenance therapy was associated with improved rates of clinical remission compared to placebo (RR = 2.06; 95% CI [1.47, 2.88]). While there is no headto-head comparison with natalizumab, a meta-analysis by Chandar et al. suggests that Vedolizumab and Natalizumab have comparable efficacy in induction and maintenance of remission in CD [5]. Overall, there is a strong pool of data to support use of vedolizumab for management of moderate-to-severe CD and UC.
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4.
Safety evaluation
In light of the safety concerns associated with natalizumab, vedolizumab was designed primarily to overcome the major safety concern of PML associated with natalizumab. The safety of vedolizumab has been extensively evaluated in multiple trials. In the initial trial of MLN02 in the treatment of UC (n = 181) there were no significant difference in adverse effects in the treatment groups (MLN02 dose 0.5 or 2.0 mg/kg) compared with placebo. The most common reported adverse event was worsening of UC. Serious adverse events (SAEs) were reported in 18 out of 118 patients in the vedolizumab groups and 6 of 63 in the placebo group. Three main adverse effects of interest were observed in vedolizumabtreated patients. One woman developed hives and angioedema at second infusion and was found to have positive human anti-human antibodies; a second patient developed primary cytomegalovirus infection which resolved without antiviral therapy; a third patient developed lobar pneumonia 3 days after spinal surgery. Other serious side effects reported include exacerbation of colitis, nausea and vomiting, and degenerative disk disease. There were no reported deaths or cancer [19]. In a subsequent study evaluating use of MLN0002 in the treatment of CD, no significant differences in adverse events were noted in vedolizumab-treated compared to placebotreated patients. The most commonly reported adverse event was worsening of CD. SAEs were reported in 37/127 patients in the vedolizumab compared with 19/58 in the placebo group [20]. The reported events (Table 1) were similar to that observed in the prior study with UC. As with the prior study, the serious infection rate was low. In a Phase II study by Parikh and colleagues evaluating vedolizumab for treatment of UC, two serious adverse reactions were reported in 37 patients. A patient with preexisting osteoporosis had a compression fracture and a second patient with chronic gastroduodenitis had an exacerbation of gastroduodenitis. One patient treated with vedolizumab experienced an elevation of aspartate aminotransferase levels to 1.8 times the upper limit of normal (ULN) and alanine aminotransferase levels to 3.3 times the ULN on day 15 which normalized by day 29. Commonly reported adverse events were otherwise similar to earlier publications and included headache, nasopharyngitis, cough and exacerbation of underlying IBD. There was no infusion reactions reported in this study. None of the nine patients in the placebo group reported a serious adverse event. Patients were monitored for PML and there was note of one patient with positive serum JC virus DNA; however no cases of PML were reported [18]. In the large Phase III trial to assess the efficacy and safety of vedolizumab to induce and maintain remission in CD (n = 1115), adverse events were higher in vedolizumab-treated 1476
patients. Notably, 100 vedolizumab-treated patients (12.3%) developed nasopharyngitis compared to 24 placebo-treated patients (8%). Additionally, there was a higher rate of SAEs in vedolizumab-treated patients compared to placebo (199/814 vs 46/301, respectively). There were four cancers diagnosed in patients treated with vedolizumab; one breast cancer during induction therapy, a basal cell skin cancer, a squamous cell skin cancer and a carcinoid of the appendix. One placebo-treated patient was diagnosed with ovarian cancer. One patient treated with vedolizumab developed latent tuberculosis. Five deaths were reported, four of which were in vedolizumab-treated patients; CD with sepsis, intentional overdose of prescription drugs, myocarditis and septic shock. Only one death occurred in placebo-treated patients (bronchopneumonia). No cases of PML were observed [22]. The observation of higher incidence of adverse events associated with treatment of vedolizumab for CD was not observed in a second CD induction study. The overall rates of adverse events were low and were similar between groups. Only 2% of patients in both groups discontinued treatment secondary to adverse effects. Two vedolizumab-treated patients reported SAEs; anal abscess and urinary tract infection. Conversely, no placebo-treated patients developed serious infections. One malignancy of ependymoma was reported in a vedolizumabtreated patient. There were no deaths and no cases of PML [23]. On the other hand, rates of adverse events were similar between vedolizumab and placebo-treated patients in the large induction and maintenance trial in UC (n = 895). There were no significant differences in SAEs and serious infections between the groups. One death occurred in a vedolizumabtreated patient from acute coronary syndrome. There were three infusion reactions. Commonly reported adverse events were similar to the profile seen in other publications [24]. Additionally, a Cochrane systematic review by Mosli et al. confirms that the incidence of adverse effects, withdrawal of therapy secondary to adverse effects and serious adverse effects of vedolizumab is comparable to placebo in the treatment of UC [26]. In a meta-analysis of six randomized, controlled trials, vedolizumab was associated with higher rates of SAEs compared to placebo-treated patients (RR of 1.21; 95% CI [1.00, 1.46]). The effect was slightly more pronounced when a fixed effects model was employed in the CD subgroup (RR of 1.31; 95% CI [1.04, 1.66]). Treatment with vedolizumab was not associated with a higher rate of serious infection compared to placebo treatment (RR = 1.17; 95% CI [0.51, 2.69]). Conversely, vedolizumab was associated with a higher rate of nasopharyngitis compared to placebo (RR = 1.42; 95% CI [1.09, 1.83]). This association was not present in the subgroup of patients with UC [25]. Although comparable adverse events have been noted with vedolizumab compared to placebo, it is notable that Clostridium difficile and CMV colitis rates were higher in vedolizumab treated group compared with placebo [27].
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Table 1. Common adverse events reported in patients treated with vedolizumab. Nasopharyngitis Headache Nausea Arthralgia Vomiting Aphthous stomatitis
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5.
Abdominal pain Fatigue Upper respiratory infections Back pain Pyrexia
Conclusion
Vedolizumab is effective for the induction and maintenance of remission for patients with UC and CD. It appears to be well tolerated with an excellent side effect profile and offers a reasonable alternative to our current available therapies for management of moderate-to-severe IBD. Importantly, rates of serious infection and malignancy are low and not greater than those observed in placebo-treated patients. Also, the published trials report a low rate of immunogenicity associated with vedolizumab use. The safety profile of vedolizumab appears to be comparable to those observed in short-term trials of other biologic therapies. These results are encouraging but should be interpreted with caution until long-term reports of safety emerge from Phase IV registries and clinical practice. 6.
Expert opinion
Currently, as the only alternative anti-integrin therapy to natalizumab, vedolizumab has a more favorable side effect profile largely attributable to the very low to nil risk of PML due to the gut selectivity of the drug. It has been shown in healthy volunteers that vedolizumab does not affect CSF T-lymphocyte immune phenotype [28] supporting the theory that vedolizumab is selective in inhibiting trafficking of leukocytes to the intestines minimizing the risk of PML. As with other rare adverse effects (serious infection, opportunistic infection, autoimmune phenomena and malignancy) of medications, cases of PML may emerge with use of vedolizumab in larger populations. However, several thousand patients have been treated, some for 2 years or more, with no reports of PML. Use of concomitant immune suppressant was prohibited with natalizumab owing to increased risk of PML associated with prior exposure to immunosuppressant. Some patients in the clinical trials of vedolizumab were on concomitant immunosuppressant without any reported increased risk of SAEs in this subgroup. Although not demonstrated in the existing trials, it is likely that concurrent use of an immune suppressant with vedolizumab will be associated with a higher relative risk of serious and opportunistic infection. However, we anticipate that the absolute risk of such infections will be quite low. Some have suggested that because of the gutselectivity of vedolizumab, it should be considered first-line
for treatment of patients with IBD. The National Institute for Health and Care Excellence recommends use of vedolizumab in patients naı¨ve to or intolerant to anti-TNF [29]. However, we caution that more evidence is needed. We await long-term safety data post-marketing to determine if uncommon to rare adverse events are identified after vedolizumab treatment. So where does vedolizumab fit into our current treatment algorithm? It is approved for use in patients not responsive to, intolerant of or ineligible for anti-TNF therapy. In our practice, we typically follow the FDA-approved indications for use of vedolizumab. Although the efficacy of vedolizumab has been established in both UC and CD, rates of response and remission are not superior to conventional therapy. Head-to-head trials are needed in biologic naı¨ve patients with IBD to determine if vedolizumab is superior to antiTNF; however, such studies are unlikely to be performed. In addition, because the safety profile of anti-TNF therapy is well known and unlikely to change at this point in time, we await long-term safety data before concluding that vedolizumab is safer than conventional therapy. If vedolizumab is positioned after anti-TNF treatment has failed, should vedolizumab be given after the first, second or third anti-TNF? We recommend evaluating all patients with primary or secondary loss of response to anti-TNF therapy to confirm the presence of active disease. In those with confirmed active disease, we advocate for drug and anti-drug antibody levels if commercially available. For patients with adequate drug levels with or without anti-drug antibodies, transition to vedolizumab is appropriate. The ability to assess drug and anti-drug antibody levels is an advantage to anti-TNF use. Other considerations include the slow onset of action of vedolizumab. We do not recommend use of vedolizumab for severely ill patients with UC and CD, especially hospitalized patients unless concurrent therapy with an induction agent such as corticosteroids is being used. Combining vedolizumab with a rapidly acting agent such as corticosteroids (or immune suppressants such as cyclosporine and tacrolimus) to improve short-term response followed by vedolizumab maintenance is intriguing. The efficacy and safety of these approaches will need to be assessed. Methods to optimize patients with partial and/or loss of response to vedolizumab needs to be addressed. For example, can an extra dose of vedolizumab be given after induction (at week 10) to induce a response/remission? Can vedolizumab dosing be adjusted in patients losing response to treatment (shorten infusion to every 6 or 4 weeks)? Lastly, should costs be considered when selecting therapy for patients with moderate-to-severe IBD? An analysis comparing adalimumab and vedolizumab in patients with CD and UC demonstrated that the cost per responder was more than twice as high for vedolizumab compared to adalimumab ($406,629 vs $197,902) [30]. Conversely, a study recently presented at the American Gastroenterological Association’s Digestive Diseases Week demonstrated that vedolizumab was the dominant strategy compared to anti-TNF agents
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and conventional therapy in treatment-naı¨ve patients with UC [31]. We anticipated that vedolizumab use will expand in the treatment of IBD and will replace natalizumab in the treatment paradigm except in the situation where a patient has concurrent MS. If favorable long-term efficacy and safety data emerge, it is likely that vedolizumab will be used firstline in treatment of IBD. It is also likely that as personalized medicine evolves, improved diagnostic tests will be developed to help providers and patients select the most efficacious and safe treatment. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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25.
Sands BE, Feagan BG, Rutgeerts P, et al. Effects of vedolizumab induction therapy for patients with Crohn’s disease in whom tumor necrosis factor antagonist treatment failed. Gastroenterology 2014;147(3):618-27 This clinical trial demonstrated that three-dose induction with vedolizumab resulted in improvement in induction of remission in patients with treatment refractory Crohn’s disease. Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med 2013;369(8):699-710 This is the pivotal clinical trial demonstrating the effectiveness and safety of vedolizumab in induction and maintenance of remission in patients with treatment refractory ulcerative colitis. Wang MC, Zhang LY, Han W, et al. PRISMA-efficacy and safety of vedolizumab for inflammatory bowel diseases: a systematic review and meta-
analysis of randomized controlled trials. Medicine (Baltimore) 2014;93(28):e326 26.
27.
Mosli MH, MacDonald JK, Bickston SJ, et al. Vedolizumab for Induction and maintenance of remission in ulcerative colitis: A cochrane systematic review and meta-analysis. Inflamm Bowel Dis 2015;21(5):1151-9 Dulai PS, Mosli M, Khanna R, et al. Vedolizumab for the treatment of moderately to severely active ulcerative colitis. Pharmacotherapy 2015;35(4):412-23
28.
Milch C, Wyant T, Xu J, et al. Vedolizumab, a monoclonal antibody to the gut homing alpha4beta7 integrin, does not affect cerebrospinal fluid T-lymphocyte immunophenotype. J Neuroimmunol 2013;264(1-2):123-6
29.
Bryant RV, Sandborn WJ, Travis SP. Introducing vedolizumab to clinical practice: who, when, and how? J Crohns Colitis 2015;9(4):356-66
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Liu YK. Comparison of cost per responder and remitter in patients with inflammatory bowel disease in the United States: An indirect comparison of Adalimumab and Vedolizumab. Am J Gastroenterol 2014;109:S479-9
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Jansen JP. Cost per clinical outcomes with biologics for the treatment of moderately to severely active Ulcerative Colitis. Gastroenterology 2015;148(4):S1-2
Affiliation Matilda Hagan1,2 MD & Raymond K Cross†1 MD MS † Author for correspondence 1 University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA E-mail: [email protected] 2 Institute for Digestive Health and Liver Disease, Mercy Medical Center, Baltimore, MD, USA
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Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis Matilda Hagan MD
ab
a
& Raymond K Cross MD MS
a 1
University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA b 2
Institute for Digestive Health and Liver Disease, Mercy Medical Center, Baltimore, MD, USA Published online: 03 Jul 2015.
Click for updates To cite this article: Matilda Hagan MD & Raymond K Cross MD MS (2015) Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis, Expert Opinion on Drug Safety, 14:9, 1473-1479 To link to this article: http://dx.doi.org/10.1517/14740338.2015.1063612
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Drug Safety Evaluation
Expert Opinion on Drug Safety 2015.14:1473-1479.
Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis 1.
Introduction
2.
Mechanism of action
3.
Clinical applications
4.
Safety evaluation
5.
Conclusion
6.
Expert opinion
Matilda Hagan & Raymond K Cross† †
University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine, Baltimore, MD, USA
Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials. Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug. Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile. Keywords: anti-adhesion molecule, anti-integrin, Crohn’s disease, inflammatory bowel disease, natalizumab, ulcerative colitis, vedolizumab Expert Opin. Drug Saf. (2015) 14(9):1473-1479
1.
Introduction
Inflammatory bowel diseases (IBD) consisting of ulcerative colitis (UC) and Crohn’s disease (CD) are chronic gastrointestinal disorders of unknown etiology, characterized by chronic intestinal inflammation with periods of active disease and remissions. For moderate-to-severe disease, the mainstays of therapy are corticosteroids, immune suppressants such as azathioprine, 6-mercaptopurine, methotrexate and anti-TNF inhibitors (anti-TNF) to include infliximab, adalimumab, certolizumab pegol and golimumab. The choice of therapy primarily depends on disease severity; biologic therapy is generally reserved for patients unresponsive or intolerant to conventional therapy. However, recent studies have demonstrated that anti-TNF therapy alone or in combination with an immune suppressant is the most effective strategy for management of moderate-to-severe IBD [1,2]. The advent of anti-TNF therapy has significantly improved medical therapy for the management of CD and UC; however, there is an unmet need for additional medical therapies to manage CD and UC. The main reasons being, despite their efficacy, 30 -- 40% of patients may have primary non-response to anti-TNF therapy or may develop secondary loss of response with estimated rate of 23 -- 46% either due to increased drug clearance or development of neutralizing antibodies [3-5]. Additionally, patients may develop side effects of therapy resulting in discontinuation of treatment. As such development of medications with alternative mechanism of action is paramount. Cell surface adhesion molecules have been implicated in the inflammatory pathway resulting in IBD. The integrins are heterodimeric cell surface glycoproteins expressed on most leukocytes consisting of an a and b subunit pair which upon interaction with its ligand modulate signaling pathways. The a4 integrins are 10.1517/14740338.2015.1063612 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
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Box 1. Drug summary.
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Drug name (generic name) Phase Indication
Vedolizumab FDA-approved Treatment of adults with moderate-tosevere Crohn’s disease or ulcerative colitis who have been unresponsive to, intolerant of, or have lost response to anti-TNF inhibitors and or immune suppressants or are steroid-dependent. Intravenous infusion
Route of administration Chemical structure Molecular formula is C6528H10072N1732O2042S42 Mechanism Monoclonal antibody that binds to and of action inhibits interactions between a4b7 integrin on leukocytes and its ligand mucosal addressin cell adhesion molecule-1 present on gut vascular endothelium [22-24] Pivotal trials
thought to facilitate the adhesion and migration of leukocytes to sites of inflammation in the intestines and play a vital role in the maintenance of inflammation [6,7]. Animal studies using monoclonal antibodies to antagonize the a4 integrins alone or in combination with b7 (a4b7) integrins resulted in resolution of spontaneous acute and chronic colitis similar to UC seen in cotton-top tamarins [8,9]. Additional support for this approach came from the use of monoclonal antibody to antagonize the interaction between the b7 subunit and its ligand mucosal addressin cell adhesion molecule-1 (MAdCAM-1) resulting in reduction of inflammation in T-cell-mediated colitis in severe combined immunodeficiency mice [10]. Natalizumab is a recombinant humanized IgG4 monoclonal antibody which binds the a4 integrin subunit and broadly antagonizes the interactions of a4b1 and vascular cell adhesion molecule-1 (VCAM-1) as well as a4b7 and MAdCAM-1 thus inhibiting leukocyte adhesion and subsequent migration into the brain and gut respectively. Multiple randomized, placebo-controlled trials have demonstrated the efficacy of natalizumab in induction and maintenance of clinical remission and response in moderate-to-severe CD [11-15]. Natalizumab offered the promise of a much needed alternative to anti-TNF inhibitors for management of CD. Unfortunately, after initial approval by the FDA for the treatment of multiple sclerosis in 2004, natalizumab was withdrawn from the market after reports of three patients developing progressive multifocal leukoencephalopathy (PML) after being treated with natalizumab [16]. PML is thought to occur in patients treated with natalizumab as a result of decreased immune surveillance of the John Cunningham (JC) virus attributable to blockade of a4b1 in 1474
the blood--brain barrier. Additional attributable risk factors for the development of PML include natalizumab treatment duration of ‡ 2 years, prior exposure to immunosuppressant, and JC virus antibody seropositive [17]. Following a safety review, the FDA reapproved natalizumab in 2006 under a special prescribing program as monotherapy for MS (Biogen Idec Inc., TYSABRI [natalizumab] Injection Full Prescribing Information, 2013, Biogen Idec Inc.: Cambridge, MA). Natalizumab gained approval for the treatment of CD in 2008 under a strict monitoring program, Tysabri Outreach: Unified Commitment to Health Registry. The use of natalizumab in clinical practice has been limited in light of the safety concerns. A second cell adhesion molecule inhibitor, vedolizumab (Takeda) (Box 1) designed to be gut-selective unlike natalizumab is now available on the market for treatment of CD and UC. The aim of this article is to review the safety and effectiveness of vedolizumab in the treatment of CD and UC. Additionally, it will review the mechanism of action of the drug and lastly address where vedolizumab can be positioned in our current algorithm in the treatment of CD and UC. 2.
Mechanism of action
Vedolizumab (previously known as LDP-02, MLN02 and MLN0002) is a humanized, gut-selective immunoglobulin G1 monoclonal antibody that binds to and blocks interactions between a4b7 integrin on select group of leukocytes and its ligand MAdCAM-1 present on gut vascular endothelium [18]. Vedolizumab does not bind nor affect the interaction of a4b1 integrin with VCAM-1 thus migration of leukocytes to the CNS is not affected with resultant lower to no risk of PML. The initial version of vedolizumab was derived from a NS0 mouse myeloma cell line and was shown to be efficacious in CD and UC. However, it was highly immunogenic with 44% of subjects developing clinically significant titers of human antihuman antibodies [19,20]. The current version of vedolizumab, designed to be less immunogenic than its predecessors, was derived from a Chinese hamster ovary cell-based system without alteration of the antigen recognition sequence [18]. A Phase II dose ranging study performed to evaluate the safety, efficacy and pharmacology of the new version of vedolizumab demonstrated that the Cmax and AUC increased with increasing dose in a linear manner. The mean elimination half-life was 15 -- 22 days across the dose range tested. Additionally, targeted a4b7 receptors were nearly 100% saturated after dosing and the maximum effect was > 95% at all doses in the presence of detectable serum concentrations of vedolizumab. The investigators were unable to evaluate dose or concentration response owing to the near-complete saturation of a4b7 receptors [18]. Population pharmacokinetic data suggest similar pharmacokinetic in CD and UC. Additionally, at a dose of 300 mg intravenous infusion the half-life of 25.5 day is longer than the other available biologics. In population pharmacokinetic
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analysis, the covariates of age, fecal calprotectin, CD activity index score, partial Mayo score, concomitant immunomodulator use, anti-drug antibody status and prior TNF-a antagonist therapy status had no clinically significant influence on vedolizumab pharmacokinetics. However, linear clearance of vedolizumab increased with decreasing albumin concentrations and body weight positively correlated with vedolizumab linear clearance [21].
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3.
Clinical applications
Currently, vedolizumab is indicated for the treatment of adults with moderate-to-severe CD and UC who have been unresponsive to, intolerant of, or have lost response to antiTNF inhibitors and or immune suppressants or are steroiddependent. Vedolizumab was approved by the FDA in May 2014 and has also been approved by the European Medicines Agency and Health Canada. Evidence to support approval came from multiple randomized, multicenter, blinded, placebo-controlled trials evaluating the safety and efficacy of vedolizumab in CD and UC. For the treatment of CD, an initial Phase III trial by Sandborn et al. evaluated the safety and efficacy of vedolizumab in achieving and maintaining response and remission in patients with moderate-to-severely active CD who had previously failed or were intolerant to conventional therapy with corticosteroids, immune suppressant or anti-TNF. In this trial, 368 patients were randomized to vedolizumab 300 mg or placebo infusion at week 0 and 2 with assessment of clinical response and remission at week 6. In the open-label arm of the study, 747 subjects received vedolizumab at week 0 and 2 with assessment of clinical response at week 6. The primary end point of clinical response at week 6 was not achieved in this trial. The other primary end point was met with 15% of vedolizumab-treated patients achieving clinical remission compared to 7% of placebotreated patients (p = 0.02). In a parallel maintenance trial, 461 responders to vedolizumab at week 6 were randomized to vedolizumab 300 mg infusion every 8 weeks or every 4 weeks, or placebo through week 52. The primary end point of clinical remission at week 52 was achieved with significantly more vedolizumab-treating patients maintaining clinical remission compared to placebo (39% vedolizumab every 8 weeks, 36% vedolizumab every 4 weeks, 22% placebo [p < 0.001]) [22]. As seen in clinical trials of other biologics, patients with prior exposure to anti-TNF had lower remission and response rates compared with anti-TNF naı¨ve patients. A second Phase III induction trial was conducted to assess the safety, efficacy and tolerability of vedolizumab in moderate-to-severely active CD patients with prior failure to one or more anti-TNF. Three hundred and fifteen (76%) of the 416 randomized patients had previous failure of 1 or more TNF antagonists. Vedolizumab-treated patients were given 300 mg of vedolizumab at week 0, 2 and 6. The primary end point of clinical remission at week 6 was not achieved in this trial. However, a secondary end point at week 10 was
achieved with more patients in the vedolizumab group achieving clinical remission compared with the placebo group (26.6 vs 12.1%; p = 0.001) [23]. This supports the hypothesis that for the treatment of CD, response to induction therapy may require longer than the 6-week time point evaluated in prior clinical trials. This observation was also noted in patients treated with natalizumab and may owe to the mechanism of action of these drugs. A Phase III multicenter, randomized, double-blind, placebo-controlled study, evaluating the safety and efficacy of vedolizumab for UC was also performed. Two hundred and twenty-five patients were randomized to vedolizumab 300 mg or placebo infusion at week 0 and 2. Similar to the CD trial, there was an open-label cohort where an additional 521 patients received vedolizumab at 0 and 2. At week 6, clinical response (primary outcome) was achieved in 47.1% of patients treated with vedolizumab compared to 25.5% of patients treated with placebo (p < 0.001). Similarly, rates of clinical remission were 16.9 and 5.4% in vedolizumab and placebo-treated patients respectively at week 6 (p = 0.001). Vedolizumab-treated patients also had higher rates of mucosal healing at week 6 compared to placebo-treated patients. Responders from both cohorts (n = 373) were randomized to vedolizumab 300 mg every 4 or 8 weeks or placebo through week 52. At week 52, vedolizumab-treated patients were more likely to maintain clinical remission (41.8% vedolizumab every 8 weeks, 44.8% vedolizumab every 4 weeks, and 15.9% placebo, p < 0.001) mucosal healing (51.6, 56 and 19.8%, p < 0.001) and corticosteroid-free remission (31.4, 45.2 and 13.9%, p < 0.001) [24]. As previously observed with biologic therapy, anti-TNF exposed patients had lower response rates compared with anti-TNF naı¨ve patients. A recent meta-analysis of the six key randomized controlled trials supports the efficacy of vedolizumab. For induction therapy, treatment with vedolizumab was associated with achieving clinical remission compared to placebo with a risk ratio (RR) of 1.88 (95% CI [1.45, 2.43]) [25]. This effect was present within subgroups of IBD as well (UC RR = 2.23, 95% CI [1.35, 3.68] and CD RR = 1.71, 95% CI [1.25, 2.34]). Vedolizumab use was also associated with superior disease-specific response rates to induction therapy compared to placebo (UC, RR = 1.82, 95% CI [1.43, 2.31]; CD, RR = 1.46, 95% CI [1.18, 1.81]). Similarly, vedolizumab maintenance therapy was associated with improved rates of clinical remission compared to placebo (RR = 2.06; 95% CI [1.47, 2.88]). While there is no headto-head comparison with natalizumab, a meta-analysis by Chandar et al. suggests that Vedolizumab and Natalizumab have comparable efficacy in induction and maintenance of remission in CD [5]. Overall, there is a strong pool of data to support use of vedolizumab for management of moderate-to-severe CD and UC.
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4.
Safety evaluation
In light of the safety concerns associated with natalizumab, vedolizumab was designed primarily to overcome the major safety concern of PML associated with natalizumab. The safety of vedolizumab has been extensively evaluated in multiple trials. In the initial trial of MLN02 in the treatment of UC (n = 181) there were no significant difference in adverse effects in the treatment groups (MLN02 dose 0.5 or 2.0 mg/kg) compared with placebo. The most common reported adverse event was worsening of UC. Serious adverse events (SAEs) were reported in 18 out of 118 patients in the vedolizumab groups and 6 of 63 in the placebo group. Three main adverse effects of interest were observed in vedolizumabtreated patients. One woman developed hives and angioedema at second infusion and was found to have positive human anti-human antibodies; a second patient developed primary cytomegalovirus infection which resolved without antiviral therapy; a third patient developed lobar pneumonia 3 days after spinal surgery. Other serious side effects reported include exacerbation of colitis, nausea and vomiting, and degenerative disk disease. There were no reported deaths or cancer [19]. In a subsequent study evaluating use of MLN0002 in the treatment of CD, no significant differences in adverse events were noted in vedolizumab-treated compared to placebotreated patients. The most commonly reported adverse event was worsening of CD. SAEs were reported in 37/127 patients in the vedolizumab compared with 19/58 in the placebo group [20]. The reported events (Table 1) were similar to that observed in the prior study with UC. As with the prior study, the serious infection rate was low. In a Phase II study by Parikh and colleagues evaluating vedolizumab for treatment of UC, two serious adverse reactions were reported in 37 patients. A patient with preexisting osteoporosis had a compression fracture and a second patient with chronic gastroduodenitis had an exacerbation of gastroduodenitis. One patient treated with vedolizumab experienced an elevation of aspartate aminotransferase levels to 1.8 times the upper limit of normal (ULN) and alanine aminotransferase levels to 3.3 times the ULN on day 15 which normalized by day 29. Commonly reported adverse events were otherwise similar to earlier publications and included headache, nasopharyngitis, cough and exacerbation of underlying IBD. There was no infusion reactions reported in this study. None of the nine patients in the placebo group reported a serious adverse event. Patients were monitored for PML and there was note of one patient with positive serum JC virus DNA; however no cases of PML were reported [18]. In the large Phase III trial to assess the efficacy and safety of vedolizumab to induce and maintain remission in CD (n = 1115), adverse events were higher in vedolizumab-treated 1476
patients. Notably, 100 vedolizumab-treated patients (12.3%) developed nasopharyngitis compared to 24 placebo-treated patients (8%). Additionally, there was a higher rate of SAEs in vedolizumab-treated patients compared to placebo (199/814 vs 46/301, respectively). There were four cancers diagnosed in patients treated with vedolizumab; one breast cancer during induction therapy, a basal cell skin cancer, a squamous cell skin cancer and a carcinoid of the appendix. One placebo-treated patient was diagnosed with ovarian cancer. One patient treated with vedolizumab developed latent tuberculosis. Five deaths were reported, four of which were in vedolizumab-treated patients; CD with sepsis, intentional overdose of prescription drugs, myocarditis and septic shock. Only one death occurred in placebo-treated patients (bronchopneumonia). No cases of PML were observed [22]. The observation of higher incidence of adverse events associated with treatment of vedolizumab for CD was not observed in a second CD induction study. The overall rates of adverse events were low and were similar between groups. Only 2% of patients in both groups discontinued treatment secondary to adverse effects. Two vedolizumab-treated patients reported SAEs; anal abscess and urinary tract infection. Conversely, no placebo-treated patients developed serious infections. One malignancy of ependymoma was reported in a vedolizumabtreated patient. There were no deaths and no cases of PML [23]. On the other hand, rates of adverse events were similar between vedolizumab and placebo-treated patients in the large induction and maintenance trial in UC (n = 895). There were no significant differences in SAEs and serious infections between the groups. One death occurred in a vedolizumabtreated patient from acute coronary syndrome. There were three infusion reactions. Commonly reported adverse events were similar to the profile seen in other publications [24]. Additionally, a Cochrane systematic review by Mosli et al. confirms that the incidence of adverse effects, withdrawal of therapy secondary to adverse effects and serious adverse effects of vedolizumab is comparable to placebo in the treatment of UC [26]. In a meta-analysis of six randomized, controlled trials, vedolizumab was associated with higher rates of SAEs compared to placebo-treated patients (RR of 1.21; 95% CI [1.00, 1.46]). The effect was slightly more pronounced when a fixed effects model was employed in the CD subgroup (RR of 1.31; 95% CI [1.04, 1.66]). Treatment with vedolizumab was not associated with a higher rate of serious infection compared to placebo treatment (RR = 1.17; 95% CI [0.51, 2.69]). Conversely, vedolizumab was associated with a higher rate of nasopharyngitis compared to placebo (RR = 1.42; 95% CI [1.09, 1.83]). This association was not present in the subgroup of patients with UC [25]. Although comparable adverse events have been noted with vedolizumab compared to placebo, it is notable that Clostridium difficile and CMV colitis rates were higher in vedolizumab treated group compared with placebo [27].
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Table 1. Common adverse events reported in patients treated with vedolizumab. Nasopharyngitis Headache Nausea Arthralgia Vomiting Aphthous stomatitis
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Abdominal pain Fatigue Upper respiratory infections Back pain Pyrexia
Conclusion
Vedolizumab is effective for the induction and maintenance of remission for patients with UC and CD. It appears to be well tolerated with an excellent side effect profile and offers a reasonable alternative to our current available therapies for management of moderate-to-severe IBD. Importantly, rates of serious infection and malignancy are low and not greater than those observed in placebo-treated patients. Also, the published trials report a low rate of immunogenicity associated with vedolizumab use. The safety profile of vedolizumab appears to be comparable to those observed in short-term trials of other biologic therapies. These results are encouraging but should be interpreted with caution until long-term reports of safety emerge from Phase IV registries and clinical practice. 6.
Expert opinion
Currently, as the only alternative anti-integrin therapy to natalizumab, vedolizumab has a more favorable side effect profile largely attributable to the very low to nil risk of PML due to the gut selectivity of the drug. It has been shown in healthy volunteers that vedolizumab does not affect CSF T-lymphocyte immune phenotype [28] supporting the theory that vedolizumab is selective in inhibiting trafficking of leukocytes to the intestines minimizing the risk of PML. As with other rare adverse effects (serious infection, opportunistic infection, autoimmune phenomena and malignancy) of medications, cases of PML may emerge with use of vedolizumab in larger populations. However, several thousand patients have been treated, some for 2 years or more, with no reports of PML. Use of concomitant immune suppressant was prohibited with natalizumab owing to increased risk of PML associated with prior exposure to immunosuppressant. Some patients in the clinical trials of vedolizumab were on concomitant immunosuppressant without any reported increased risk of SAEs in this subgroup. Although not demonstrated in the existing trials, it is likely that concurrent use of an immune suppressant with vedolizumab will be associated with a higher relative risk of serious and opportunistic infection. However, we anticipate that the absolute risk of such infections will be quite low. Some have suggested that because of the gutselectivity of vedolizumab, it should be considered first-line
for treatment of patients with IBD. The National Institute for Health and Care Excellence recommends use of vedolizumab in patients naı¨ve to or intolerant to anti-TNF [29]. However, we caution that more evidence is needed. We await long-term safety data post-marketing to determine if uncommon to rare adverse events are identified after vedolizumab treatment. So where does vedolizumab fit into our current treatment algorithm? It is approved for use in patients not responsive to, intolerant of or ineligible for anti-TNF therapy. In our practice, we typically follow the FDA-approved indications for use of vedolizumab. Although the efficacy of vedolizumab has been established in both UC and CD, rates of response and remission are not superior to conventional therapy. Head-to-head trials are needed in biologic naı¨ve patients with IBD to determine if vedolizumab is superior to antiTNF; however, such studies are unlikely to be performed. In addition, because the safety profile of anti-TNF therapy is well known and unlikely to change at this point in time, we await long-term safety data before concluding that vedolizumab is safer than conventional therapy. If vedolizumab is positioned after anti-TNF treatment has failed, should vedolizumab be given after the first, second or third anti-TNF? We recommend evaluating all patients with primary or secondary loss of response to anti-TNF therapy to confirm the presence of active disease. In those with confirmed active disease, we advocate for drug and anti-drug antibody levels if commercially available. For patients with adequate drug levels with or without anti-drug antibodies, transition to vedolizumab is appropriate. The ability to assess drug and anti-drug antibody levels is an advantage to anti-TNF use. Other considerations include the slow onset of action of vedolizumab. We do not recommend use of vedolizumab for severely ill patients with UC and CD, especially hospitalized patients unless concurrent therapy with an induction agent such as corticosteroids is being used. Combining vedolizumab with a rapidly acting agent such as corticosteroids (or immune suppressants such as cyclosporine and tacrolimus) to improve short-term response followed by vedolizumab maintenance is intriguing. The efficacy and safety of these approaches will need to be assessed. Methods to optimize patients with partial and/or loss of response to vedolizumab needs to be addressed. For example, can an extra dose of vedolizumab be given after induction (at week 10) to induce a response/remission? Can vedolizumab dosing be adjusted in patients losing response to treatment (shorten infusion to every 6 or 4 weeks)? Lastly, should costs be considered when selecting therapy for patients with moderate-to-severe IBD? An analysis comparing adalimumab and vedolizumab in patients with CD and UC demonstrated that the cost per responder was more than twice as high for vedolizumab compared to adalimumab ($406,629 vs $197,902) [30]. Conversely, a study recently presented at the American Gastroenterological Association’s Digestive Diseases Week demonstrated that vedolizumab was the dominant strategy compared to anti-TNF agents
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and conventional therapy in treatment-naı¨ve patients with UC [31]. We anticipated that vedolizumab use will expand in the treatment of IBD and will replace natalizumab in the treatment paradigm except in the situation where a patient has concurrent MS. If favorable long-term efficacy and safety data emerge, it is likely that vedolizumab will be used firstline in treatment of IBD. It is also likely that as personalized medicine evolves, improved diagnostic tests will be developed to help providers and patients select the most efficacious and safe treatment. Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers.
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R Cross has received consulting, educational and research Grants, participation in advisory boards from Abbvie; Consulting, Educational Grants, participation in advisory boards from Janssen; Consulting and educational grants from Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. maintenance therapy for Crohn’s disease. N Engl J Med 2005;353(18):1912-25
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Affiliation Matilda Hagan1,2 MD & Raymond K Cross†1 MD MS † Author for correspondence 1 University of Maryland, Division of Gastroenterology and Hepatology, Department of Medicine, 100 North Greene Street, Lower Level, Baltimore, MD 21201, USA E-mail: [email protected] 2 Institute for Digestive Health and Liver Disease, Mercy Medical Center, Baltimore, MD, USA
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