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Vedolizumab for thetreatment of ulcerative colitisExpert Rev. Clin. Pharmacol. 7(4), 423–430 (2014)
Svend T Rietdijk andGeert R D’Haens*Academic Medical Center,
Meibergdreef 9, 1105 AZ Amsterdam,
The Netherlands
*Author for correspondence:
Tel.: +31 205 663 893
Ulcerative colitis is a chronic inflammatory disease of the large intestine that often develops inthe young. A few new treatment options have become available in the past decade, butmanagement of a large proportion of patients still remains challenging because of sideeffects, unresponsiveness and cost. A novel strategy targeting trafficking of immune cells tothe sites of inflammation involves reducing expression or binding of adhesion molecules tointegrins. Natalizumab was the first therapeutic antibody blocking infiltration of leukocytes,but because of lack of selectivity to the gut and associated risk of progressive multifocalleukoencephalopathy, it will probably never be tested in ulcerative colitis. In this article wediscuss molecules that block leukocyte trafficking to inflamed bowel that have been tested inulcerative colitis. Because of favourable efficacy and safety data, we will review thedevelopment, pharmacology and clinical data of vedolizumab, a gut-selective a4b7 antibody,in depth.
KEYWORDS: a-4 • b-7 • inflammatory bowel disease • MAdCAM-1 • progressive multifocal leukoencephalopathy
• ulcerative colitis • vedolizumab
Ulcerative colitis (UC) is a chronic inflamma-tory disease that affects the mucosal surface ofthe large bowel. It usually presents withabdominal pain, tenesmus and bloody diarrheain adolescents and adults and affects males andfemales at similar rates [1]. The course of thedisease varies greatly between patients but typi-cally alternates between periods of relapsingand remission. The annual incidence in NorthAmerica and Western Europe ranges from19 to about 24/100,000 people, with lowerrates in the Middle East and Asia [2]. Whilethere is little data from sub-Saharan Africa andSouth America, the incidence seems to belower in these continents except for specificmore developed regions such as SouthAfrica [2]. Apart from genetics, the main reasonfor the difference in incidence rates betweenthese areas of the world is thought to besought in increased hygiene and sanitation thatresult in reduced bacterial load and parasiticexposure [3].
The initial diagnosis of UC should bemade based on endoscopy with the typicalfindings being diffusely inflamed, friable orbleeding mucosa extending from directlyabove the anal verge. In many cases, the dis-ease involves only the rectum (i.e., ‘proctitis’),while it can involve a larger portion and is
then known as left-sided colitis, or the wholecolon (i.e., ‘pancolitis’). The extent of involvedcolon is important to ascertain and documentbecause topical treatments have to be ade-quately delivered to the sites of inflammation.In some cases, the disease can extend proxi-mally, and this is important to consider incases where rectally administered therapy losesefficacy in a patient.
For decades, the initial medical treatmentfor inflammatory bowel disease (IBD) has con-sisted of sulfasalazine and glucocorticoids [4].While steroids are excellent at inducingremission, maintenance therapy is problematicbecause the disease may become refractory andextensive side effects invariably develop. Ami-nosalicylates (5-ASA) derived from sulfasala-zine have much fewer side effects and areeffective at both inducing and maintainingremission in UC [5]. Because of this favorableprofile, optimal 5-ASA treatment is recom-mended, using oral and/or rectally adminis-tered preparations, with the choice of productdepending on the disease severity and localiza-tion. Oral and/or topical corticosteroid prepa-rations (budesonide or beclomethasone) areadded if symptoms persist. Once remission hasbeen attained, steroids can be tapered and5-ASA is further used as maintenance therapy.
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Unless there is isolated distal disease (proctitis), remission isusually maintained with oral, slow-release 5-ASA prepara-tions. In case of exacerbations, re-escalation of oral and topi-cal 5-ASA therapy (often the combination) is recommendedto control disease. If multiple induction courses or steroidsare needed, introduction of thiopurine maintenance therapyis recommended [4,6].
In severe UC cases that are refractory to relatively high dosesof oral prednisolone, rapid step up of treatment is recom-mended consisting of hospital admission for intravenous pred-nisolone and close monitoring of clinical parameters such asstool frequency, abdominal pain and fever. This is crucial inthe evaluation of response, which must take place within3–5 days. If there is no improvement, then treatment withinfliximab or cyclosporine is needed in an attempt to avoidcolectomy [4,6].
Thiopurines have been moderately effective in the mainte-nance treatment of UC, with less than 25% of patientsattaining steroid-free remission after 16 weeks of treat-ment [7]. No prospective trials have looked, however, at theadditional benefit of therapeutic drug monitoring in thissetting.
Oral tacrolimus is an effective treatment for moderate-to-severe UC, with almost 80% of patients with mucosal healingwhen high trough concentrations are reached (10–15 ng/ml)[8]. The problem with prolonged tacrolimus treatment, how-ever, is the relatively high risk of potentially irreversible renalinsufficiency. Methotrexate is a treatment that is currently notrecommended for UC, but a prospective trial is currently ongo-ing in France (METEOR). Finally, granulocyte monocyte/macrophages apheresis is frequently being used in Japan, but aprospective sham controlled was entirely negative so further useof this treatment remains questionable [9].
The introduction of anti-TNF antibodies has been a turn-ing point in the treatment of IBD with infliximab the firstanti-TNF agent shown to be effective in induction andmaintenance of remission [10]. Adalimumab, a subcutane-ously administered human anti-TNF antibody, is also effec-tive for the treatment of UC although initial results showeda more modest effect [11,12]. A limiting factor is, however,that anti-TNF agents are costly and therefore unavailable incertain countries. Additionally, some insurance companies ornational health services, such as that in the UK, only reim-burse anti-TNF therapy for the induction of remission [13].
Due to more effective immunosuppressive therapies, such ascyclosporine and infliximab, the rates of acute colectomiesappear to have declined. Interestingly, though, the rates ofcolectomy 5 years after diagnosis have remained above 10%,presumably because there is insufficient maintenance of remis-sion [14]. Although a colectomy can be a definitive and wel-come solution for the patient with severe or prolongedcomplaints, it should still be seen as a failure of medical treat-ment and a less desirable outcome given the postoperative riskof pouchitis, bowel obstruction, pouch failure, fertility prob-lems and decreased potency in male patients.
BackgroundThe molecular and cellular processes that lead to the develop-ment of UC are not clearly understood, but the end result isan overly active immune system. The majority of availabletherapies aim at suppression of the proinflammatory media-tors in this immune system. While corticosteroids have apotent anti-inflammatory action, the side effects ‘outside’ theimmune system limit their long-term use. Due to insightsinto the pathways that cause or propagate inflammation,emerging therapies have been developed to target the cells orproteins involved with a higher degree of selectivity [15,16].While there are still a number of candidate pathways to beexplored [15,17], several novel strategies have already provedsuccessful. The most successful targeted therapy to date hasbeen that of anticytokine antibodies directed against theproinflammatory cytokine TNF-a. By blocking the actions ofTNF-a, there is less induction of other proinflammatorycytokines, inflammatory cell recruitment and endothelial per-meability [18,19]. In addition, cross-linking of membrane-bound TNF-a causes apoptosis that may deplete pathogeniccells [20,21]. While the available anti-TNF antibodies inflixi-mab and adalimumab have been proven effective, new andmodified antibodies have been developed to reduce immuno-genicity and improve stability. One of them is golimumab, asubcutaneously administered anti-TNF-a, which was gener-ated in a human IgG transgenic mouse and selected on itshigh binding affinity [22]. Its increased stability also allowslonger intervals between injections (4 weeks) than adalimu-mab. Golimumab was successfully tested in integrated phaseII and III induction trials, as well as follow-on studies ofmaintenance therapy [23,24].
A new class of anti-inflammatory compounds also provedsuccessful in clinical trials with tofacitinib, a selective inhibi-tor of the Janus kinase family of kinases. These kinases medi-ate the signal transduction activity involving the receptors formultiple cytokines, and their inhibition results in the disrup-tion of a number of innate and adaptive immune responses[25]. In an 8-week Phase II trial of patients with moderatelyor severely active UC, treatment with tofacitinib resulted insignificant improvements in clinical and endoscopic responseand remission [26].
A completely new approach, which is the focus of thisreview, targets the trafficking of effector lymphocytes to the siteof inflammation. In the physiological situation, the recruitmentof immune cells to infected or damaged tissue is crucial formounting an adequate inflammatory response. This responseresults in bacterial killing, usually after phagocytosis, which issometimes antibody mediated, as well as the killing of virallyinfected cells by cytotoxic T cells. In some cases, however,inflammation is rather inappropriate, which is a hallmark ofIBD. T cells are one of the cell types that are crucial in thedevelopment of UC and can relocate to the intestinal mucosa.One mechanism by which this is done is through signals pro-vided by damaged tissue and other immune cells in the formof chemokines that provide a gradient for T cells to move
Drug Profile Rietdijk & D’Haens
424 Expert Rev. Clin. Pharmacol. 7(4), (2014)
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along when in close approximation to inflammation. Anotherexample has come to be known as gut homing because, as thename implies, it involves T cells that return to the gut afterundergoing imprinting. Imprinting is a process that occurswhen naıve T cells encounter antigen-presenting cells, usuallyin lymphoid organs, and are presented with an antigen theyrecognize and which, in turn, allows them to mature [27]. Inthe case of gut-homing lymphocytes, imprinting results in thesurface expression of the a4b7 integrin on the lymphocytecell membrane.
a4b7 consists of two chains, a4 and b7, which bind toMAdCAM-1 and to a lesser extent to VCAM-1 and fibronec-tin [28–31]. MAdCAM-1 is present on vascular endothelial surfa-ces in the lamina propria and Peyer’s patches and thus alsoinfers intestinal specificity [32–34]. An interesting exception isthe expression of MAdCAM-1 in the liver of patients withautoimmune hepatitis and primary sclerosing cholangitis(PSC), a chronic progressive cholestatic liver disease highlyassociated with UC [35].
The interaction of a4b7 and MAdCAM-1 results in lym-phocyte rolling, followed by firm adhesion and enables the cellsto translocate and infiltrate the tissue that this endothelium islocated in [36]. It is this process that natalizumab, etrolizumab,PF-00547,659, alicaforsen and vedolizumab were all developedto target.
Natalizumab is an antibody that was raised against humana4 and thereby binds a4b7 as well as a4b1. As mentionedabove, a4b7-expressing cells home to the gut, whilea4b1-expressing cells are able to translocate into both thegastrointestinal tract and the central nervous system (CNS)through their binding to VCAM-1. Natalizumab was testedin Crohn’s disease as well as multiple sclerosis and found tobe efficacious in both conditions [37–43]. There are, however,major issues regarding safety because of the development ofmultiple cases of progressive multifocal leukoencephalopathy(PML), a life-threatening infection that results after the reac-tivation of the JC virus, presumably due to reduced lympho-cyte patrolling in the brain [44]. Although natalizumab isapproved for the treatment of Crohn’s disease in the USA, itis unlikely that it will be evaluated in UC because of saferalternatives. Currently, natalizumab can only be used inCrohn’s disease, without concomitant immunosuppression,in patients who are not JC virus carriers (<50% of thepopulation).
Etrolizumab is an anti-b7 antibody, and therefore bindsa4b7 and aEb7. It showed a favorable safety profile and earlyindication of clinical activity in a Phase I trial of severeUC [45]. Preliminary results of a Phase II trial involving124 patients were presented at the most recent Digestive Dis-ease Week [46]. After three doses, both dosing regimens of etro-lizumab were associated with higher rates of clinical remissionthan placebo at 10 weeks. Additionally, etrolizumab continuedto demonstrate safety and tolerability. These results are of greatinterest, particularly because vedolizumab also binds b7, albeitonly in complex with a4 [47].
An alternative way of blocking the a4b7 interaction withthe endothelium is by binding and blocking its endothelialcounterpart MAdCAM-1, which is the target of the antibodyPF-00547,659. This antibody was tested in a preliminary trialto assess safety and efficacy in UC [48]. While the results werenot significant, they were considered somewhat favorable andfurther trials are ongoing both in UC and CD.
Another strategy aiming to block the transmigration of leu-kocytes into inflamed tissue is inhibition of the expression ofICAM-1 on endothelial cells. ICAM-1 is the ligand forLFA-1 (also known as aLb2 or CD11a-CD18) and thoughexpressed on a number of cells and tissues, it also mediates leu-kocyte adhesion to the endothelium [49,50]. ICAM-1 is inducedin inflammatory conditions such as IBD [51] and in order toreduce its expression, a 20-mer antisense nucleotide namedalicaforsen was developed and evaluated in clinical trials. Theresults with the subcutaneous formulation were somewhat dis-appointing in UC, but a recent meta-analysis suggested thatenemas are effective in distal disease and may even surpass theeffect of mesalazine during prolonged use [52–55]. In addition,the drug is currently being evaluated for chronic pouchitis aftera small open-label trial showed efficacy [56].
ChemistryIt is important to note that during the development of vedoli-zumab, a number of experiments and clinical trials were doneusing antibodies that are similar, but not identical to the cur-rent vedolizumab. While the antigen-binding sites haveremained unchanged, the rest of the antibody has been modi-fied [57–59]. The humanized anti-a4b7 antibodies LDP-02,MLN-02 and vedolizumab were all derived from Act1, amouse anti-human a4b7 antibody. Act-1 is was found to bindthe heterocomplex of the human a4 chain with theb7 chain [60–62]. The crystal structure of its Fab fragment witha4b7 shows that Act-1/vedolizumab recognizes a disulfide-bonded loop that projects from the b7 chain when in complexwith a4 [47].
Initially, LDP-02 (later known as MLN-02 or MLN-002)was generated by replacing the coding sequence of most of theantibody with a human IgG sequence. After some clinical trialswith this antibody, in order to reduce immunogenicity, theproduction process was altered using Chinese hamster ovarycells for the antibody now known as vedolizumab [63].
PharmacodynamicsWhile there is extensive data on expression of a4b7, panels oftissues were systematically screened by histology for the reactiv-ity of vedolizumab [57]. Binding was restricted to mononuclearinfiltrates in the gastrointestinal tract and bladder, as wellmononuclear cells in lymphoid tissue and the lumens of bloodvessels. More detailed examination of peripheral blood subsetswas performed by flow cytometry where the authors showedthat vedolizumab binds a clear subset (~ 25%) of the memoryCD4 cells, demonstrating high levels of a4b7. Amongthe remaining populations examined, vedolizumab bound at
Vedolizumab for the treatment of UC Drug Profile
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low-to-intermediate levels to the majority of naıve CD4 andNK cells, approximately 50% of CD8 cells and to almost all Bcells, eosinophils and basophils. A small subset of monocytesand neutrophils stained at low levels. These results suggest that,while many cells bind a small amount of vedolizumab, there isa subset of gut-homing memory CD4 cells that express highlevels of a4b7, which form the target of vedolizumab.
The specificity of vedolizumab was also examined by exclud-ing the binding to cells transfected with the integrins aEb7and a4b1 because they each share a chain with a4b7 [57]. Inorder to test whether the binding of vedolizumab did in factblock interaction with MAdCAM-1, cells were exposed to aMAdCAM-1 fusion protein after incubation with vedolizumaband a dose-dependent inhibition was shown. Interestingly,vedolizumab inhibited the adhesion a4b7 to MAdCAM-1 andfibronectin but not to VCAM-1. This suggests that there couldbe limited or even no interference in lymphocyte trafficking tothe CNS, which is of great importance, as this is the mecha-nism responsible for decreased immune surveillance that canresult in PML.
In vivo evidence of the selectivity of vedolizumab was pro-vided in a primate model of multiple sclerosis, experimentalautoimmune encephalomyelitis, which showed that natalizu-mab inhibited leukocyte infiltration to the CNS and therebyprevented experimental autoimmune encephalomyelitis, whilevedolizumab had no effect [59]. Further evidence for this wasgathered in healthy volunteers where it was shown that intra-venous vedolizumab did not affect the T cell phenotype incerebrospinal fluid [64].
Taken together, these in vitro and in vivo data may explainwhy there have been no cases of PML in vedolizumab-treatedpatients to date [63,65–69].
Pharmacokinetics & metabolism
In a dose-ranging study performed by Parikh et al., pharma-cokinetic studies were performed with three different dosesof vedolizumab [63]. Patients received an induction schemeof 2, 6 or 10 mg/kg on days 1, 15 and 29 followed by oneinfusion at day 85 (after an additional 8 weeks). Serum-levelkinetics were approximately dose dependent and did notchange after repeated infusions. The saturation of a4b7 wasexamined by flow cytometry and showed complete blockingfor all doses and time points. After the last dose, however,there was an earlier rise of unsaturated a4b7 in the 2 mg/kggroup. This near-complete saturation of a4b7 was alsofound in a trial examining long-term effects, with patientsreceiving 2 or 6 mg/kg as maintenance therapy with 8-weekintervals [69]. The dose ranging trial was not primarilydesigned to demonstrate differences in efficacy between theseparate doses, but rather to examine pharmacokinetics suchas half-life, which was between 15 and 22 days [63]. Theseresults provided the basis for the recently published largetrials in UC and CD, which were performed with doses of300 mg (which for most patients would be somewherebetween 2 and 6 mg/kg) every 4 or 8 weeks [67,68].
Clinical trials of anti-a4b7
Act-1
Act-1, the mouse antibody from which vedolizumab wasderived, was initially tested in a small number of Cotton-topTamarins [70]. These primates develop chronic colitis whenbred in captivity [71]. In an experiment in which four animalsreceived Act-1, there was a striking improvement in symptomsas well as histological inflammation compared with controlanimals.
LDP-02
The first studies in humans were reported only in abstractform in 2000 and revealed the results of a double-blind,placebo-controlled trial of LDP-02, the first humanized formof Act-1 [65]. The four treatment groups were small (n = 5)and patients received a single dose of 0.15 mg/kg sc. or 0.15,0.5 or 2.0 mg/kg iv. Eight patients received placebo. Theauthors noted that saturation of a4b7 lasted for at least amonth after the single dose and concluded that LDP-02 waswell tolerated. A response was seen in 5 of 20 patients in thetreatment groups, which was comparable to placebo (2 of 8),and a complete clinical and endoscopic remission were onlyseen in the 0.5 mg/kg group (2 of 5).
MLN-02
In a subsequent phase II trial with humanized Act-1, at thatpoint known as MLN-02, significant efficacy was demonstratedin a placebo-controlled phase II trial of patients with moder-ately active UC [66]. Patients were randomized into threegroups to receive either placebo or MLN-02 (0.5 mg or2.0 mg/kg of body weight). The treatment consisted of onlytwo infusions with a 4-week interval and upon analysis at6 weeks, the two groups that had received MLN-02 showedclinical remission rates of 33 and 32% versus 13% in the pla-cebo group. There was also more endoscopic remission, definedby a Baron score of 0, in the treatment groups (28 and 12%)versus 8% in the placebo group. One drawback of this trialwas that 44% of patients receiving MLN-02 developed antihu-man antibodies although it was unknown whether theseantibodies neutralized the biological effect of the drug. Theissue was addressed by altering the production process ofMLN-02 by using Chinese hamster ovary cells, resulting in theproduct since known as vedolizumab. In a phase III trial, only3.7% of patients developed antihuman (i.e., antivedolizumab)antibodies, of which 1% were persistent [67].
Vedolizumab
In an initial study with vedolizumab, UC patients were ran-domized into three groups receiving vedolizumab (2, 6 or10 mg/kg) or placebo, and although analysis focused primarilyon pharmacology and safety, partial Mayo scores and fecal cal-protectin were determined [63]. There was a greater decrease infecal calprotectin and a higher proportion of patients with aclinical response in the vedolizumab groups, but the samplesize precluded statistical analysis.
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In order to test the efficacy of vedolizumab for the inductionof remission in active UC, 225 patients received two doses ofvedolizumab with a 2-week interval [67]. At week 6, clinical andendoscopic scores were compared with those of 149 patientswho had received placebo. Forty-seven percent of the patientsin the vedolizumab group had a clinical response, 17% reachedclinical remission and 41% showed mucosal healing on endos-copy (Mayo endoscopic score of 0 or 1). These results were allsignificantly better than in the placebo group (26, 5 and 25%,respectively). The patients who responded well to vedolizumabtreatment in this induction trial were included in a follow-uptrial that assessed whether vedolizumab was suitable for mainte-nance of remission.
In order to fulfill sample size requirements in the mainte-nance trial, an additional 521 patients were included to receiveopen-label vedolizumab as per the induction of remission pro-tocol. The response rates among this group (‘cohort 2’) weresimilar to those in the double-blind induction trial (clinicalresponse 44%, clinical remission 19%, mucosal healing 37%),and 252 cohort 2 patients who responded were included inaddition to the 121 patients carried over from the inductiontrial. Patients were then randomized to receive vedolizumabevery 4 weeks (q4wk, n = 125) or every 8 weeks (q8wk,n = 122), or placebo (n = 126). These patients were alsorequired to taper their corticosteroids according to a protocol-ized schedule, and in addition, patients enrolled in the USAalso had to discontinue immunosuppressive medication.
The analysis clearly demonstrated steroid-sparing effects ofvedolizumab, while the placebo patients had an increased ste-roid usage after week 18. At the end of the maintenance phase(52 weeks), the patients receiving vedolizumab showed higherrates of glucocorticoid-free remission (45 and 31% in the q4wkand q8wk groups, respectively) than the placebo group (14%).The rates of clinical remission were 45, 42 and 16% in theq4wk, q8wk and placebo groups, respectively, and correspond-ing rates of mucosal healing were 56, 52 and 20%.
Taken together, this large Phase III program demonstratedthat vedolizumab was effective for both induction and mainte-nance of remission in patients with moderately to severelyactive UC.
There were no discernable differences in adverse eventsbetween the vedolizumab and placebo groups in this trial, andthis is in line with the other studies performed with vedolizu-mab and its predecessors. Most importantly, not a single caseof PML has occurred [63,65–69]. In a recent trial of vedolizumabin CD, a higher percentage of adverse events, including seriousinfections, was found in the group of patients who were treatedwith vedolizumab [68]. There was an increase in respiratorytract, as well as other infections, but these were not specified,and it is not clear why these findings differed from those in thepatients with UC.
Owing to the gut-specific nature of vedolizumab, intestinalinfections could be expected, but only one case of salmonellawas reported among the 37 patients receiving vedolizumab inthe long-term dose-ranging study [69]. We would, however,
remain vigilant with patients living in, or travelling to, thetropics. Although they are not widely in use, there is a theoreti-cal concern that oral vaccines could be less effective in patientsreceiving vedolizumab.
ConclusionUC develops after infiltration of leukocytes homing to the gutbased on expression of surface molecules such as a4b7. Vedoli-zumab was developed, in a few steps, from an antibody thatbinds the heterodimer a4b7 and not its individual chains inde-pendently of each other. It is, therefore, specific for gut-homingleucocytes, and blocks their migration to the gut mucosa. Thefirst humanized anti-a4b7 antibodies were shown effective inthe treatment of UC, but many subjects developed antibodiesagainst these proteins after which alterations were made todecrease immunogenicity, ultimately resulting in vedolizumab.Clinical trials performed with vedolizumab up to Phase IIIwere successful, with less drug-binding antibodies found thanwith previous versions of the molecule.
Expert commentaryVedolizumab will likely be the first gut-specific inhibitor ofleukocyte migration available for the treatment of patients withIBD. While the exact mechanism of action of many existingdrugs for UC remains incompletely understood, vedolizumabwas introduced into clinical trials only after the importance ofa4b7 in T cell homing to the gut was demonstrated. Thisemphasizes the importance of basic science in the developmentof new targets and is a good example of a translation of labora-tory findings into medicines that are of benefit to patients.While we have focused on UC, patients with Crohn’s diseasemay also benefit from this treatment [68].
Five-year reviewAn issue that should be addressed in further research withvedolizumab is optimal dosing. While pharmocodynamicanalysis showed almost complete saturation of a4b7, itremains to be determined whether this is imperative for inhi-bition of cellular adhesion and migration. Another diseasethat may, in theory, benefit from vedolizumab is PSC, anUC-associated inflammatory disease of the liver with a poorprognosis. Because of the expression of MAdCAM-1 on theliver endothelium of patients with PSC, and other evidencethat supports the aberrant migration of gut-homing leuko-cytes to the liver, we see a rationale for examining vedolizu-mab in PSC.
Similar exploratory efforts appear attractive for the treatmentof pouchitis and for the prevention of postoperative recurrenceof Crohn’s disease.
Financial & competing interests disclosure
G D’Haens has served as speaker, consultant and/or principal investigator
for Abbvie, Centocor, MSD, Pfizer, UCB, Takeda, TEVA, Millenium,
Jansen, Boerhinger Ingelheim, Elan, Ferring, DrFALK Pharma, Shire,
Cosmo, AstraZeneca, Vifor, Tillotts, Otsuka, Photopill, GivenImaging,
Vedolizumab for the treatment of UC Drug Profile
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GSK, PDL, Amgen, AM Pharma, Galapagos, Versant, Novonordisk, Nor-
gine, Giuliani. S Rietdijk has served as a speaker for Tillots and MSD
and was a visiting scientist and received research funding from Millenium
Pharmaceuticals, a Takeda company. 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.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Vedolizumab is a monoclonal antibody directed against the a4b7 integrin on the cell membrane of gut-homing lymphocytes.
• The a4b7 integrin binds to MAdCAM-1 which is almost exclusively expressed in the gastrointestinal tract and which is absent in the
central nervous system. No cases of progressive multifocal leukoencephalopathy have been reported during treatment with vedolizumab.
• Vedolizumab was effective and safe in patients with moderate-to-severe ulcerative colitis, both as induction and as maintenance
treatment. Durable clinical response and mucosal healing at 1 year were observed in more than 50% of patients who had initially
responded to an induction treatment.
• The efficacy of 4 weekly and 8 weekly vedolizumab treatment appeared comparable.
• Vedolizumab allowed complete corticosteroid withdrawal in more than one-third of the patients.
• The safety profile of vedolizumab in clinical trials was comparable to that of placebo. In particular, no increased incidence in
gastrointestinal or opportunistic infections was observed.
• Vedolizumab has received positive regulatory opinions in Europe and the USA for use in ulcerative colitis. It may also offer a useful
treatment option for Crohn’s disease and pouchitis.
References
1. Rogers BH, Clark LM, Kirsner JB. The
epidemiologic and demographic
characteristics of inflammatory bowel
disease: an analysis of a computerized file of
1400 patients. J Chronic Dis 1971;24:
743-73
2. Molodecky NA, Soon IS, Rabi DM, et al.
Increasing incidence and prevalence of the
inflammatory bowel diseases with time,
based on systematic review.
Gastroenterology 2012;142:46-54.
e42-quize30
3. Koloski N-A, Bret L, Radford-Smith G.
Hygiene hypothesis in inflammatory
bowel disease: a critical review of the
literature. World J Gastroenterol 2008;14:
165-73
4. Talley NJ, Abreu MT, Achkar J-P, et al. An
evidence-based systematic review on medical
therapies for inflammatory bowel disease.
Am J Gastroenterol 2011;106(Suppl 1):
S2-25.quizS26
5. Feagan BG, Macdonald JK. Oral
5-aminosalicylic acid for induction of
remission in ulcerative colitis. Cochrane
Database Syst Rev 2012;10:CD000543
6. Dignass A, Lindsay JO, Sturm A, et al.
Second European evidence-based consensus
on the diagnosis and management of
ulcerative colitis part 2: current
management. J Crohns Colitis 2012;6(10):
991-1030
7. Panaccione R, Ghosh S, Middleton S, et al.
Combination therapy with infliximab and
azathioprine is superior to monotherapy
with either agent in ulcerative colitis.
Gastroenterology 2014;146(2):392-400
8. Ogata H, Matsui T, Nakamura M, et al.
A randomised dose finding study of
oral tacrolimus (FK506) therapy in
refractory ulcerative colitis. Gut 2006;55:
1255-62
9. Sands BE, Sandborn WJ, Feagan B, et al.
A randomized, double-blind,
sham-controlled study of granulocyte/
monocyte apheresis for active ulcerative
colitis. Gastroenterology 2008;135:
400-9
10. Rutgeerts P, Sandborn WJ, Feagan BG,
et al. Infliximab for induction and
maintenance therapy for ulcerative colitis. N
Engl J Med 2005;353:2462-76
11. Sandborn WJ, Van Assche G, Reinisch W,
et al. Adalimumab induces and maintains
clinical remission in patients with
moderate-to-severe ulcerative colitis.
Gastroenterology 2012;142:257-65.e1-3
12. Reinisch W, Sandborn WJ, Hommes DW,
et al. Adalimumab for induction of clinical
remission in moderately to severely active
ulcerative colitis: results of a randomised
controlled trial. Gut 2011;60:780-7
13. NICE. Available from: www.nice.org.uk
14. Frolkis AD, Dykeman J, Negron ME, et al.
Risk of surgery for inflammatory bowel
diseases has decreased over time:
a systematic review and meta-analysis of
population-based studies. Gastroenterology
2013;145:996-1006
15. Danese S. New therapies for inflammatory
bowel disease: from the bench to the
bedside. Gut 2012;61:918-32
16. Rietdijk ST, D’Haens GR. Recent
developments in the treatment of
inflammatory bowel disease. J Dig Dis
2013;14:282-7
17. Lowenberg M, D’Haens G. Novel
targets for inflammatory bowel disease
therapeutics. Curr Gastroenterol Rep
2013;15:311
18. Tracey D, Klareskog L, Sasso EH, et al.
Tumor necrosis factor antagonist
mechanisms of action: a comprehensive
review. Pharmacol Ther 2008;117:244-79
19. Wong M, Ziring D, Korin Y, et al.
TNFalpha blockade in human diseases:
mechanisms and future directions. Clin
Immunol 2008;126:121-36
20. Hove ten T, van Montfrans C,
Peppelenbosch MP, van Deventer SJH.
Infliximab treatment induces apoptosis of
lamina propria T lymphocytes in Crohn’sdisease. Gut 2002;50:206-11
21. Van den Brande JMH, Braat H,
van den Brink GR, et al. Infliximab but not
etanercept induces apoptosis in lamina
propria T-lymphocytes from patients with
Crohn’s disease. Gastroenterology 2003;124:
1774-85
22. Shealy D, Cai A, Staquet K, et al.
Characterization of golimumab, a human
monoclonal antibody specific for human
tumor necrosis factor alpha. MAbs 2010;2.
[Epub ahead of print]
Drug Profile Rietdijk & D’Haens
428 Expert Rev. Clin. Pharmacol. 7(4), (2014)
Exp
ert R
evie
w o
f C
linic
al P
harm
acol
ogy
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Uni
vers
ity o
f Q
ueen
slan
d on
06/
18/1
4Fo
r pe
rson
al u
se o
nly.
23. Sandborn WJ, Feagan BG, Marano C, et al.
Subcutaneous golimumab induces clinical
response and remission in patients with
moderate-to-severe ulcerative colitis.
Gastroenterology 2014;146(1):85-95
24. Sandborn WJ, Feagan BG, Marano C, et al.
Subcutaneous golimumab maintains clinical
response in patients with moderate-to-severe
ulcerative colitis. Gastroenterology 2014;
146(1):96-109
25. Ghoreschi K, Jesson MI, Li X, et al.
Modulation of innate and adaptive immune
responses by tofacitinib (CP-690,550).
J Immunol 2011;186:4234-43
26. Sandborn WJ, Ghosh S, Panes J, et al.
Tofacitinib, an oral Janus kinase inhibitor,
in active ulcerative colitis. N Engl J Med
2012;367:616-24
27. Mora JR, Bono MR, Manjunath N, et al.
Selective imprinting of gut-homing T cells
by Peyer’s patch dendritic cells. Nature
2003;424:88-93
28. Andrew DP, Berlin C, Honda S, et al.
Distinct but overlapping epitopes are
involved in alpha 4 beta 7-mediated
adhesion to vascular cell adhesion
molecule-1, mucosal addressin-1,
fibronectin, and lymphocyte aggregation.
J Immunol 1994;153:3847-61
29. Strauch UG, Lifka A, Gosslar U, et al.
Distinct binding specificities of integrins
alpha 4 beta 7 (LPAM-1), alpha 4 beta 1
(VLA-4), and alpha IEL beta 7. Int
Immunol 1994;6:263-75
30. Newham P, Craig SE, Seddon GN, et al.
Alpha4 integrin binding interfaces on
VCAM-1 and MAdCAM-1. Integrin
binding footprints identify accessory binding
sites that play a role in integrin specificity.
J Biol Chem 1997;272:19429-40
31. Day ES, Osborn L, Whitty A. Effect of
divalent cations on the affinity and
selectivity of alpha4 integrins towards the
integrin ligands vascular cell adhesion
molecule-1 and mucosal addressin cell
adhesion molecule-1: Ca2+ activation of
integrin alpha4beta1 confers a distinct
ligand specificity. Cell Commun Adhes
2002;9:205-19
32. Streeter PR, Berg EL, Rouse BT, et al.
A tissue-specific endothelial cell molecule
involved in lymphocyte homing. Nature
1988;331:41-6
33. Berlin C, Berg EL, Briskin MJ, et al. Alpha
4 beta 7 integrin mediates lymphocyte
binding to the mucosal vascular addressin
MAdCAM-1. Cell 1993;74:185-95
34. Briskin MJ, McEvoy LM, Butcher EC.
MAdCAM-1 has homology to
immunoglobulin and mucin-like adhesion
receptors and to IgA1. Nature 1993;363:
461-4
35. Grant AJ, Lalor PF, Hubscher SG, et al.
MAdCAM-1 expressed in chronic
inflammatory liver disease supports mucosal
lymphocyte adhesion to hepatic
endothelium (MAdCAM-1 in chronic
inflammatory liver disease). Hepatology
2001;33:1065-72
36. Bargatze RF, Jutila MA, Butcher EC.
Distinct roles of L-selectin and integrins
alpha 4 beta 7 and LFA-1 in lymphocyte
homing to Peyer’s patch-HEV in situ: the
multistep model confirmed and refined.
Immunity 1995;3:99-108
37. Gordon FH, Lai CW, Hamilton MI, et al.
A randomized placebo-controlled trial of a
humanized monoclonal antibody to
alpha4 integrin in active Crohn’s disease.Gastroenterology 2001;121:268-74
38. Ghosh S, Goldin E, Gordon FH, et al.
Natalizumab for active Crohn’s disease. NEngl J Med 2003;348:24-32
39. Sandborn WJ, Colombel J-F, Enns R, et al.
Natalizumab induction and maintenance
therapy for Crohn’s disease. N Engl J Med
2005;353:1912-25
40. Targan SR, Feagan BG, Fedorak RN, et al.
Natalizumab for the treatment of active
Crohn’s disease: results of the ENCORE
Trial. Gastroenterology 2007;132:
1672-83
41. Rudick RA, Stuart WH, Calabresi PA, et al.
Natalizumab plus interferon beta-1a for
relapsing multiple sclerosis. N Engl J Med
2006;354:911-23
42. Polman CH, O’Connor PW, Havrdova E,
et al. A randomized, placebo-controlled trial
of natalizumab for relapsing multiple
sclerosis. N Engl J Med 2006;354:899-910
43. Miller DH, Khan OA, Sheremata WA,
et al. A controlled trial of natalizumab for
relapsing multiple sclerosis. N Engl J Med
2003;348:15-23
44. Hellwig K, Gold R. Progressive multifocal
leukoencephalopathy and natalizumab. J
Neurol 2011;258:1920-8
45. Rutgeerts PJ, Fedorak RN, Hommes DW,
et al. A randomised phase I study of
etrolizumab (rhuMAb b7) in moderate to
severe ulcerative colitis. Gut 2013;62:
1122-30
46. Lin KK, Mahadevan U. Etrolizumab:
anti-b7-a novel therapy for ulcerative colitis.
Gastroenterology 2014;146:307-9
47. Yu Y, Zhu J, Mi L-Z, et al. Structural
specializations of a(4)b(7), an integrin that
mediates rolling adhesion. J Cell Biol
2012;196:131-46
48. Vermeire S, Ghosh S, Panes J, et al. The
mucosal addressin cell adhesion molecule
antibody PF-00547,659 in ulcerative colitis:
a randomised study. Gut 2011;60:1068-75
49. Rothlein R, Dustin ML, Marlin SD,
Springer TA. A human intercellular
adhesion molecule (ICAM-1) distinct from
LFA-1. J Immunol 1986;137:1270-4
50. Dustin ML, Springer TA. Lymphocyte
function-associated antigen-1 (LFA-1)
interaction with intercellular adhesion
molecule-1 (ICAM-1) is one of at least
three mechanisms for lymphocyte adhesion
to cultured endothelial cells. J Cell Biol
1988;107:321-31
51. Nakamura S, Ohtani H, Watanabe Y, et al.
In situ expression of the cell adhesion
molecules in inflammatory bowel disease.
Evidence of immunologic activation of
vascular endothelial cells. Lab Invest
1993;69:77-85
52. Schreiber S, Nikolaus S, Malchow H, et al.
Absence of efficacy of subcutaneous
antisense ICAM-1 treatment of chronic
active Crohn’s disease. Gastroenterology2001;120:1339-46
53. Yacyshyn BR, Chey WY, Goff J, et al.
Double blind, placebo controlled trial of the
remission inducing and steroid sparing
properties of an ICAM-1 antisense
oligodeoxynucleotide, alicaforsen (ISIS
2302), in active steroid dependent Crohn’sdisease. Gut 2002;51:30-6
54. Yacyshyn B, Chey WY, Wedel MK, et al.
A randomized, double-masked,
placebo-controlled study of alicaforsen, an
antisense inhibitor of intercellular adhesion
molecule 1, for the treatment of subjects
with active Crohn’s disease. ClinGastroenterol Hepatol 2007;5:215-20
55. Vegter S, Tolley K, Wilson Waterworth T,
et al. Meta-analysis using individual patient
data: efficacy and durability of topical
alicaforsen for the treatment of active
ulcerative colitis. Aliment Pharmacol Ther
2013;38:284-93
56. Miner P, Wedel M, Bane B, Bradley J. An
enema formulation of alicaforsen, an
antisense inhibitor of intercellular adhesion
molecule-1, in the treatment of chronic,
unremitting pouchitis. Aliment Pharmacol
Ther 2004;19:281-6
57. Soler D, Chapman T, Yang L-L, et al. The
binding specificity and selective antagonism
of vedolizumab, an
anti-alpha4beta7 integrin therapeutic
antibody in development for inflammatory
Vedolizumab for the treatment of UC Drug Profile
informahealthcare.com 429
Exp
ert R
evie
w o
f C
linic
al P
harm
acol
ogy
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Uni
vers
ity o
f Q
ueen
slan
d on
06/
18/1
4Fo
r pe
rson
al u
se o
nly.
bowel diseases. J Pharmacol Exp Ther
2009;330:864-75
58. Fedyk ER, Wyant T, Yang L-L, et al.
Exclusive antagonism of the a4 b7 integrin
by vedolizumab confirms the gut-selectivity
of this pathway in primates. Inflamm Bowel
Dis 2012;18:2107-19
59. Haanstra KG, Hofman SO,
Lopes Estevao DM, et al. Antagonizing the
a4b1 integrin, but not a4b7, inhibitsleukocytic infiltration of the central nervous
system in rhesus monkey experimental
autoimmune encephalomyelitis. J Immunol
2013;190:1961-73
60. Lazarovits AI, Moscicki RA, Kurnick JT,
et al. Lymphocyte activation antigens. I.
A monoclonal antibody, anti-Act I, defines
a new late lymphocyte activation antigen.
J Immunol 1984;133:1857-62
61. Schweighoffer T, Tanaka Y, Tidswell M,
et al. Selective expression of integrin alpha
4 beta 7 on a subset of human CD4+
memory T cells with Hallmarks of
gut-trophism. J Immunol 1993;151:717-29
62. Tidswell M, Pachynski R, Wu SW, et al.
Structure-function analysis of the
integrin beta 7 subunit: identification of
domains involved in adhesion to
MAdCAM-1. J Immunol 1997;159:
1497-505
63. Parikh A, Leach T, Wyant T, et al.
Vedolizumab for the treatment of active
ulcerative colitis: a randomized controlled
phase 2 dose-ranging study. Inflamm Bowel
Dis 2012;18:1470-9
64. Milch C, Wyant T, Xu J, et al.
Vedolizumab, a monoclonal antibody to the
gut homing a4b7 integrin, does not affect
cerebrospinal fluid T-lymphocyte
immunophenotype. J Neuroimmunol
2013;264:123-6
65. Feagan BG, McDonald J, Greenberg G,
et al. An ascending dose trial of a
humanized A4B7 antibody in ulcerative
colitis (UC). Gastroenterology 2000;
118(4, Suppl 2):A874
66. Feagan BG, Greenberg GR, Wild G, et al.
Treatment of ulcerative colitis with a
humanized antibody to the
alpha4beta7 integrin. N Engl J Med
2005;352:2499-507
67. Feagan BG, Rutgeerts P, Sands BE, et al.
Vedolizumab as induction and maintenance
therapy for ulcerative colitis. N Engl J Med
2013;369:699-710
68. Sandborn WJ, Feagan BG, Rutgeerts P,
et al. Vedolizumab as induction and
maintenance therapy for Crohn’s disease.N Engl J Med 2013;369:711-21
69. Parikh A, Fox I, Leach T, et al. Long-term
clinical experience with vedolizumab in
patients with inflammatory bowel disease.
Inflamm Bowel Dis 2013;19:1691-9
70. Hesterberg PE, Winsor-Hines D,
Briskin MJ, et al. Rapid resolution of
chronic colitis in the cotton-top tamarin
with an antibody to a gut-homing integrin
alpha 4 beta 7. Gastroenterology 1996;111:
1373-80
71. Madara JL, Podolsky DK, King NW, et al.
Characterization of spontaneous colitis in
cotton-top tamarins (Saguinus oedipus) and
its response to sulfasalazine.
Gastroenterology 1985;88:13-19
Drug Profile Rietdijk & D’Haens
430 Expert Rev. Clin. Pharmacol. 7(4), (2014)
Exp
ert R
evie
w o
f C
linic
al P
harm
acol
ogy
Dow
nloa
ded
from
info
rmah
ealth
care
.com
by
Uni
vers
ity o
f Q
ueen
slan
d on
06/
18/1
4Fo
r pe
rson
al u
se o
nly.
