See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/274570504

Vedolizumab for Induction and Maintenance of Remission in Ulcerative Colitis: A Cochrane Systematic Review and Meta-analysis ARTICLE in INFLAMMATORY BOWEL DISEASES · APRIL 2015 Impact Factor: 5.48 · DOI: 10.1097/MIB.0000000000000396 · Source: PubMed

DOWNLOADS

VIEWS

12

26

8 AUTHORS, INCLUDING: Mahmoud H Mosli

Stephen J Bickston

Robarts Research Institute

Virginia Commonwealth University

32 PUBLICATIONS 40 CITATIONS

74 PUBLICATIONS 1,245 CITATIONS

SEE PROFILE

SEE PROFILE

Available from: Mahmoud H Mosli Retrieved on: 23 June 2015

COCHRANE REVIEW

Vedolizumab for Induction and Maintenance of Remission in Ulcerative Colitis: A Cochrane Systematic Review and Meta-analysis Mahmoud H. Mosli, MBBS, MSc,* ,† John K. MacDonald, MA,* Stephen J. Bickston, MD,‡ Brian W. Behm, MD,§ David J. Tsoulis, MD,* Jianfeng Cheng, MD, PhD,jj Reena Khanna, MD,* and Brian G. Feagan, MD, MSc*

Background: We performed a systematic review to evaluate the efficacy and safety of vedolizumab for induction and maintenance of remission in ulcerative colitis. Methods: A literature search to June 2014 identified all applicable randomized trials. Outcome measures were clinical and endoscopic remission, clinical and endoscopic response, quality of life, and adverse events. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome. Study quality was evaluated using the Cochrane risk of bias tool. The GRADE criteria were used to assess the quality of the evidence.

Main Results: Four studies (606 patients) were included. The risk of bias was low. Pooled analyses indicated that vedolizumab was significantly superior to placebo for induction of remission (RR ¼ 0.86, 95% CI, 0.80–0.91), clinical response (RR ¼ 0.82, 95% CI, 0.75–0.91), endoscopic remission (RR ¼ 0.82, 95% CI, 0.75–0.91), and for achieving remission at 52 weeks in week 6 responders (RR ¼ 2.73, 95% CI, 1.78–4.18). GRADE analyses suggested that the overall quality of the evidence was high for induction of remission and moderate for maintenance therapy (due to sparse data consisting of 246 events). No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo.

Conclusions: Vedolizumab is superior to placebo as induction and maintenance therapy for ulcerative colitis. Future studies are needed to define longterm efficacy and safety of this agent. (Inflamm Bowel Dis 2015;21:1151–1159) Key Words: ulcerative colitis, inflammatory bowel disease, a4b7, MAdCAM-1, vedolizumab, therapy

U

lcerative colitis (UC) is a chronic idiopathic inflammatory disease of the colon characterized by abdominal pain and bloody diarrhea. Management includes use of 5aminosalicylates, corticosteroids, and thiopurines (azathioprine or 6-mercaptopurine). In recent years, tumor necrosis factor

alpha (TNF-a) antagonists, including infliximab, adalimumab, and golimumab, have been used to manage patients with an inadequate response to conventional therapy.1,2 However, many patients fail treatment with these agents and require colectomy. Furthermore, corticosteroids, thiopurines, and TNF-a antago-

Received for publication January 20, 2015; Accepted February 11, 2015. From the *Robarts Clinical Trials, Robarts Research Institute, Western University, London, ON, Canada; †Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; ‡Center for Inflammatory Bowel Diseases, Richmond, Virginia; §UVA Digestive Health Center of Excellence, University of Virginia Health Systems, Charlottesville, Virginia; and jjCarolinas Medical Center, University of North Carolina Charlotte Campus, Charlotte, North Carolina. S. J. Bickston’s institution has received grant funding from Janssen for the PREVENT clinical trial. This activity is outside of the submitted work. B. W. Behm’s institution received funding to be a site for the GEMINI clinical trials. B. G. Feagan is an author of 3 manuscripts that were included in this review. He has received fee(s) from Abbott/AbbVie, Amgen, AstraZeneca, Avaxia Biologics Inc., Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, JnJ/Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, Tillotts Pharma AG, UCB Pharma for Board membership; fee(s) from Abbott/AbbVie, ActoGeniX, Albireo Pharma, Amgen, AstraZeneca, Avaxia Biologics Inc., Axcan, Baxter Healthcare Corp., Boehringer Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene, Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, GiCare Pharma, Gilead, Given Imaging Inc., GSK, Ironwood Pharma, Janssen Biotech (Centocor), JnJ/ Janssen, Kyowa Hakko Kirin Co Ltd., Lexicon, Lilly, Merck, Millennium, Nektar, Novo Nordisk, Pfizer, Prometheus Therapeutics and Diagnostics, Protagonist, Receptos, Salix Pharma, Serono, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, Tillotts, UCB Pharma, Vertex Pharma, Warner Chilcott, Wyeth, Zealand, and Zyngenia for consultancy; and lecture fee(s) from Abbott/ AbbVie, JnJ/Janssen, Takeda, Warner Chilcott, and UCB Pharma. R. Khanna has received fee(s) from AbbVie for Board membership and fee(s) from Takeda for consultancy. All of these activities are outside the submitted work. The other authors have no conflicts of interest to disclose. Reprints: Brian G. Feagan, MD, MSc, Robarts Clinical Trials, Western University, P.O. Box 5015, 100 Perth Drive, N6A 5K8, London, ON, Canada (e-mail: brian. [email protected]). Copyright © 2015 Crohn’s & Colitis Foundation of America, Inc. DOI 10.1097/MIB.0000000000000396 Published online 3 April 2015.

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

2015

www.ibdjournal.org |

1151

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Mosli et al

nists are systemic immunesuppressives that are associated with an increased risk of serious infection. Thus, development of alternative approaches to medical management is a research priority. Adhesion molecules play a vital role in the pathogenesis of UC by regulating white blood cell trafficking to the gut. Consequently, integrins and other adhesion molecules have been extensively studied as therapeutic targets in inflammatory bowel disease (IBD).3 Specifically, agents directed toward the a4b7 integrin, which is found on a minority of circulating T lymphocytes, have been comprehensively evaluated in both preclinical studies and randomized controlled trials.4 The major ligand of a4b7, mucosal addressin-cell adhesion molecule-1 (MAdCAM-1), which is selectively expressed on the endothelium of the intestinal vasculature, is up-regulated in areas of active inflammation.4–7 Therefore, targeting a4b7 with monoclonal antibodies might interfere with recruitment of lymphocytes into intestinal tissue and ameliorate the pathological immune response of IBD. Previous experience with natalizumab (Tysabri, comarketed by Elan [Dublin, Ireland] and Biogen [Cambridge, MA]) therapy for Crohn’s disease (CD) has validated this approach. Natalizumab, a humanized IgG-4 monoclonal antibody directed toward the a4 integrin, is effective for both induction and maintenance of remission in CD.8–10 However, the development of progressive multifocal leukoencephalopathy (PML), a serious infection of the central nervous system caused by the John Cunningham (JC) virus, in patients receiving long-term natalizumab therapy raised critical concerns regarding the safety of integrin inhibition. Given the highly selective nature of the a4b7/MAdCAM-1 interaction, it was reasonable to hypothesize that targeting this mechanism would not affect systemic immunity and thus avoid the risk of PML. A vital distinction between the 2 approaches is that antibodies directed specifically toward a4b7 should not affect the a4b1/VCAM interactions that are essential for T-cell mediated immune surveillance against JC virus infection in the central nervous system. Vedolizumab (Takeda, Tokyo, Japan), a humanized monoclonal IgG-1 antibody specific for a shared epitope of the a4b7 heterodimer, does not bind to either of the component monomers. As a result, the antibody does not affect a4b1-VCAM interactions that globally regulate lymphocyte trafficking in the systemic circulation. Initial studies in the cotton-top tamarin model of colitis showed that a murine antibody (ACT1) directed against a4b7 was effective.11 This observation led to development of a humanized a4b7 antibody (MLN02) that was evaluated in phase II clinical trials for the treatment of both UC12 and CD.13 Promising data from these studies led to a phase III development program that assessed vedolizumab, a reformulated version of MLN02,14 for the treatment of both diseases. This systematic review and meta-analysis, which is based on a previously published Cochrane review,15 summarizes current evidence regarding the use of vedolizumab as an induction and maintenance agent for UC.

1152

| www.ibdjournal.org

2015

TABLE 1. Search Strategies PubMed #1. (singl* OR doubl* OR tripl* OR trebl* OR blind* OR mask* OR placebo* OR single-blind* OR double-blind* OR triple-blind* OR random* OR (controlled clinical)) #2. ((ulcerat* AND colitis) OR proctocolitis OR proctosigmoiditis OR rectocolitis OR rectosigmoiditis OR proctitis) #3. (MLN-02 OR MLN02 OR (MLN 02) OR LDP-02 OR LDP02 OR (LDP 02) OR MLN0002 OR MLN-0002 OR (MLN 0002) OR LDP0002 OR LDP-0002 OR (LDP 0002) OR vedolizumab) #4. (anti-alpha4* OR (anti alpha4*) OR antialpha4* OR (alpha4beta7 antibod*)) #5. (#1 AND #2) #6. (#3 OR #4) #7. (#5 AND #6) EMBASE and MEDLINE 1. random$.tw. 2. factorial$.tw. 3. (crossover$ or cross over$ or crossover$).tw. 4. placebo$.tw. 5. single blind.mp. 6. double blind.mp. 7. triple blind.mp. 8. (singl$ adj blind$).tw. 9. (double$ adj blind$).tw. 10. (tripl$ adj blind$).tw. 11 assign$.tw. 12. allocat$.tw. 13. crossover procedure/ 14. double blind procedure/ 15. single blind procedure/ 16. triple blind procedure/ 17. randomized controlled trial/ 18. or/1–17 19. (exp animal/or animal.hw. or nonhuman/) not (exp human/or human cell/or (human or humans).ti.) 20. 18 not 19 21. ulcerative colitis.mp. or exp ulcerative colitis/ 22. (proctocolitis or proctosigmoiditis or rectocolitis or rectosigmoiditis or proctitis).mp. 23. 21 or 22 24. 20 and 23 25. vedolizumab.mp. or exp vedolizumab/26. (MLN-02 or MLN02 or “MLN 02” or LDP-02 or LDP02 or “LDP 02” or MLN0002 or MLN-0002 or “MLN 0002” or LDP0002 or LDP-0002 or “LDP 0002”).mp. 27. (anti-alpha4* or “anti alpha4*” or antialpha4* or “alpha4beta7 antibod*”).mp. 28. 25 or 26 or 27 29. 24 and 28 CENTRAL #1. (ulcerat* and colitis) or proctocolitis or proctosigmoiditis or rectocolitis or rectosigmoiditis or proctitis #2. MLN-02 or MLN02 or (MLN 02) or LDP-02 or LDP02 or (LDP 02) or MLN0002 or MLN0002 or (MLN 0002) or LDP0002 or LDP-0002 or (LDP 0002) or vedolizumab #3. anti-alpha4* or (anti alpha4*) or antialpha4* or (alpha4beta7 antibod*) #4. #2 or #3 #5. #1 and #4 IBD/FBD group specialized register “MLN*” “OR LDP*” OR “vedo*” OR “alpha4* OR “anti-alpha*” OR antialpha*

MATERIALS AND METHODS Search Strategy PubMed, MEDLINE, EMBASE, CENTRAL (Cochrane Library), and the Cochrane IBD/FBD group specialized trials register were searched from inception to June 15, 2014. Review articles and conference proceedings were also searched to identify additional studies. The search strategies are reported in Table 1.

Eligibility Randomized controlled trials where either MLN02 or vedolizumab was compared with placebo or a control medication were considered for inclusion. Only trials that evaluated adult patients (.18 yr of age) with active or quiescent UC, as defined by conventional clinical, histological, or endoscopic criteria were considered eligible.

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Vedolizumab for Remission in UC

Outcomes The primary outcome measures were (1) the proportion of patients who failed to achieve clinical remission at week 6 and (2) the proportion of patients who responded to therapy at week 6 who achieved clinical remission at week 52. Secondary outcomes were the proportion of patients who failed to have a clinical response at week 6, failure to enter endoscopic remission at week 6, failure to have an endoscopic response at week 6, failure to achieve endoscopic remission at week 52, disease-specific quality of life, development of antidrug antibodies (ADAs), adverse events (AEs), withdrawal due to AEs and serious AEs.

Methods of the Review Publications identified by the search strategy were independently assessed by 2 authors (D.J.T. and J.K.M.), and potentially relevant studies were selected for full-text review and assessed for eligibility based on the previously described inclusion criteria. Extracted data consisted of patient demographics such as age, disease distribution, disease duration, concomitant medications, the type of disease activity scoring instrument used, treatment and control modalities, the number of subjects randomized into each treatment group, outcome data, the duration of treatment and follow-up, and the number of subjects lost to follow-up. The methodological quality of the included studies was assessed using the Cochrane risk of bias tool,16 which assesses sequence generation (i.e., method of randomization); allocation concealment; appropriate blinding; incomplete outcome reporting (i.e., the investigators had determined methods of dealing with attrition); selective outcome reporting (i.e., the investigators reported all a priori outcomes), and other sources of bias (i. e., any other feature of the study that could have increased the risk of bias). The studies were judged to be of high, low, or unclear risk of bias based on these factors. The overall quality of the evidence supporting the primary outcomes was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria. Evidence from randomized controlled trials was considered to be of high quality but could be downgraded due to: risk of bias, indirect evidence, inconsistency (unexplained heterogeneity), imprecision in data, and publication bias. The overall quality of evidence supporting each outcome was determined and classified as high quality (i.e., further research is very unlikely to change our confidence in the estimate of effect); moderate quality (i.e., further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate); low quality (i.e., further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate); and very low quality (i.e., we are very uncertain about the estimate).17,18

Statistical Analysis The Cochrane collaboration software Review Manager (RevMan 5.3) was used the data analysis on an intention-to-

FIGURE 1. Flow diagram of assessment of studies identified by the literature search.

treat basis whereby dropouts or withdrawals were considered treatment failures. We calculated the risk ratio (RR) and corresponding 95% confidence interval (CI) for each dichotomous outcome using the authors of the included studies specified definitions of clinical remission, clinical response, and endoscopic response and endoscopic remission. Data from individual trials were pooled for meta-analysis if the interventions, patient groups, and outcomes were sufficiently similar (determined by consensus). Where appropriate meta-analysis of data was performed using a fixed-effects model.

RESULTS Description of Studies The literature search conducted on June 15, 2014 identified 103 records. Searching conference abstracts identified 6 additional studies. After duplicates were removed, a total of 82 studies remained for review of titles and abstracts. Two authors (D.J.T. and J.K.M.) independently reviewed the titles and abstracts of these trials, and 32 studies were selected for full-text review (Fig. 1). Twelve reports of 7 studies were excluded. Twenty www.ibdjournal.org |

2015

1153

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Mosli et al

TABLE 2. Characteristics of Included Studies Study

No. Patients

Country, No. Centers

Interventions

No. Infusions

Duration of Study

Methods

Feagan et al14

29

1 country 1 center

1

30 d

Double-blind

Feagan et al12

181

1 country 20 centers

2

8 wk

Double-blind

Feagan et al19,a

374

2

6 wk

Double-blind

Feagan et al19,b

373

34 countries 211 centers 34 countries 211 centers

6 13

52 wk

Double-blind

Parikh et al20,a

47

VDZ, 0.15 mg/kg SC (n ¼ 5) VDZ, 0.15 mg/kg IV (n ¼ 5) VDZ, 0.5 mg/kg IV (n ¼ 5) Placebo (n ¼ 8) VDZ, 0.5 mg/kg (n ¼ 58) VDZ, 2 mg/kg (n ¼ 60) Placebo (n ¼ 63) VDZ, 300 mg (n ¼ 225) Placebo (n ¼ 149) VDZ, every 8 wk (n ¼ 122) VDZ, every 4 wk (n ¼ 125) Placebo (n ¼ 126) VDZ, 2 mg/kg (n ¼ 13) VDZ, 6 mg/kg (n ¼ 14) VDZ, 10 mg/kg (n ¼ 11) Placebo (n ¼ 9)

4

253 d

Double-blind

2 countries 11 centers

a

Induction of remission study. Maintenance of remission study. IV, intravenously; SC, subcutaneously; VDZ, vedolizumab. b

reports of 4 studies met the predefined inclusion criteria and were included in the review (Table 2).12,14,19,20 Feagan et al14 was a randomized double blind ascending dose safety and efficacy trial that assessed MLN02 therapy in 29 patients with moderate to severe UC. Participants received a single dose of MLN02 at various dose levels or placebo and were monitored for 30 days. One patient was excluded before randomization for not meeting inclusion criteria, which included a minimum score of 5 on the Mayo Clinic score, greater than or equal to 3 bowel movements per day and signs of active disease on endoscopy. Outcomes after 30 days were final Mayo Clinic scores, clinical remission (Mayo Clinic score of zero), and endoscopic response (a 2-grade improvement in the modified Baron score).14 Feagan et al12 enrolled 181 adult patients with active UC in a 6-week induction trial. Disease activity was quantified using the ulcerative colitis clinical score (UCCS)14 and the modified Baron score.21 Active disease was defined as a UCCS of 5 to 9 points, with a score of at least 1 on either stool frequency or rectal bleeding, and a modified Baron score of at least 2 on sigmoidoscopic examination with active disease extending a minimum of 25 cm from the anal verge. Exclusion criteria included patients currently or recently treated with topical therapy, corticosteroids, or immunosuppressives. Patients were randomized to MLN02 at doses of 0.5 mg/kg (n ¼ 58) or 2 mg/kg (n ¼ 60), or identical placebo (n ¼ 63). Patients received study drug or placebo intravenously on days 1 and 29. The primary outcome was the proportion of patients in clinical remission at week 6, defined as a UCCS of 0 or 1, and a modified Baron score of 0 or 1 with

1154

| www.ibdjournal.org

2015

no evidence of rectal bleeding. Secondary outcomes were the proportion of patients with a clinical response (defined as an improvement of 3 points or more on the UCCS), endoscopic remission, and AEs. Disease-related quality of life was assessed using the inflammatory bowel disease questionnaire (IBDQ).22 For the purpose of this analysis, endpoints were pooled across the 2 studied doses of vedolizumab. Parikh et al20 randomized 47 patients from 11 centers to either vedolizumab at a dose of 2 mg/kg (n ¼ 13), 6 mg/kg (n ¼ 14), or 10 mg/kg (n ¼ 11); or placebo (n ¼ 9). Study drug was given on days 1, 15, 29, and 85. The primary goal of the trial was to assess the clinical pharmacology and safety of a new formulation of MLN02 (vedolizumab). Efficacy was considered a secondary outcome. Pharmacological evaluations included measurement of serum vedolizumab concentrations, receptor saturation in peripheral blood lymphocytes, and ADAs. In addition to usual monitoring for AEs, particular attention was paid to detection of symptoms/signs of PML. In distinction to the phase II study performed by Feagan et al, this study did not include endoscopic evaluations and used the partial Mayo score (PMS),23 to evaluate baseline disease activity and as an outcome measure. Remission was defined as a PMS of 2 points or less with no subscore greater than 1. Remission was only reported in a post hoc subgroup of patients with active disease (PMS of 4 to 7). Response was defined as a decrease of 2 points or more and a greater than 25% decrease in the PMS compared with baseline, along with a decrease in the rectal bleeding subscore of 1 point or more or an absolute subscore of 0 or 1 for rectal bleeding.20 For the

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Vedolizumab for Remission in UC

TABLE 3. Methodological Quality of Included Studies Study Feagan et al14 Feagan et al12 Feagan et al19 Parikh et al20

Sequence Generation

Allocation Concealment

Low riska Uncleara Low riska Uncleara

Low riskb Unclearb Low riskb Low riskb

Blinding Low Low Low Low

riskc riskc riskg riskc

Incomplete Outcome Data

Selective Outcome Reporting

Low riskd Low riskf Low riskh Low riski

Low Low Low Low

riske riske riske riske

a

Computer-generated. Centralized randomization. c Double-blind identical placebo. d No withdrawals. e All expected outcomes reported. f Drop-outs balanced across groups with similar reasons for withdrawal. g Double blind, neither the investigators nor the patients were aware of the treatment assignment. h The number of subjects who withdrew during the induction phase were 14 and 7 in the placebo and VDZ groups, respectively. i One patient withdrew from the placebo group and 1 patient withdrew from the vedolizumab 2 mg/kg group. b

purpose of this analysis, endpoints were pooled across all studies doses of vedolizumab. In a phase III induction trial, Feagan et al19 randomly assigned 374 patients to receive 300 mg intravenous doses of vedolizumab at weeks 0 and 2 (n ¼ 225) or placebo (n ¼ 149). Notably, approximately 40% of the enrolled patients had failed previous treatment with a TNF-a antagonist. The primary outcome was clinical response at week 6, defined as a decrease in Mayo score by 3 or more and a 30% decrease from the baseline score and a decrease in the rectal bleeding subscore of 1 or greater or an absolute rectal bleeding subscore of 1 or less at week 6. Secondary outcomes were clinical remission (MCS of less than 2 and no subscale scores greater than 1) and mucosal healing (Mayo endoscopic subscore of #1).19 In the maintenance phase of the trial, patients in either cohort who demonstrated a clinical response to vedolizumab at week 6 underwent rerandomization and were assigned to either continue receiving vedolizumab every 4 or 8 weeks or to be switched to placebo for a total period of 52 weeks. The primary outcome for maintenance therapy was the presence of clinical remission at week 52 in patients who had responded to vedolizumab therapy at week 6. The risk of bias assessment is summarized in Table 3. All 4 studies were considered to be of high methodological quality and

were rated as being of low risk of bias for all of the items that were assessed.

Meta-analysis of Induction Data: Comparison of Vedolizumab with Placebo Induction of Clinical Remission A pooled analysis of 4 induction studies (n ¼ 606 patients) showed a statistically significant difference in clinical remission rates favoring vedolizumab therapy over placebo.12,14,19,20 After an induction phase of 4 to 6 weeks of therapy, 77% (293/382) of vedolizumab patients failed to enter clinical remission compared with 92% (205/224) of placebo patients (RR ¼ 0.86; 95% CI, 0.80–0.91; Fig. 2). No significant heterogeneity was detected for this comparison (P ¼ 0.57, I2 ¼ 0%).

Induction of Clinical Response A pooled analysis of 3 studies (n ¼ 601 patients) showed a statistically significant difference in clinical response rates favoring vedolizumab over placebo.12,19,20 After 6 weeks of treatment 48% (183/380) of vedolizumab patients failed to have a clinical response compared with 72% (159/221) of placebo patients (RR ¼ 0.68; 95% CI, 0.59–0.78; Fig. 3). No significant heterogeneity was detected for this comparison (P ¼ 0.64, I2 ¼ 0%).

FIGURE 2. Vedolizumab versus placebo: Failure to induce clinical remission. www.ibdjournal.org |

2015

1155

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Mosli et al

FIGURE 3. Vedolizumab versus placebo: Failure to induce clinical response.

Induction of Endoscopic Remission

Development of ADAs

The pooled analysis examining endoscopic remission included 3 studies and 583 patients and showed a statistically significant difference in endoscopic remission rates favoring vedolizumab over placebo.12,14,19 Sixty-eight percent (246/363) of vedolizumab patients failed to achieve endoscopic remission compared with 81% (178/220) of placebo patients (RR ¼ 0.82; 95% CI, 0.75–0.91). No significant heterogeneity was detected for this comparison (P ¼ 0.27, I2 ¼ 24%). Feagan et al,14 also reported endoscopic response as an outcome. No statistically significant difference in failure to achieve endoscopic response was found between vedolizumab and placebo patients. In both groups, 75% of patients failed to have an endoscopic response (RR ¼ 1.00; 95% CI, 0.62–1.61).

Development of a humoral response to MLN02 was associated with decreased efficacy.12,20 Feagan et al12 reported that 44% (52/188) of patients assigned to MLN02 developed detectable ADAs at week 8. Patients with high ADA titers (greater than 1:125; 24% (28/118)) had a remission rate similar to placebo patients (12% versus 14%, respectively).12 In these patients, the a4b7 binding site on CD4+CD45RO+ T cells was unsaturated. In contrast, only 11% (4/37) of patients who received vedolizumab in the study of Parikh et al20 had detectable ADAs. One of the primary differences between the vedolizumab formulations used in the 2 studies was the cell line used to produce the antibody. The formulation used in Feagan et al12 was produced in an NSO mouse myeloma cell line, whereas Parikh et al20 used product derived from a Chinese hamster ovary (CHO) cell-based system. Comparing the 2 studies, patients who received the NSO mouse myeloma cell-derived antibody had a significantly higher chance of developing ADAs compared with patients who received the CHO cell-derived product (RR ¼ 4.08; 95% CI, 1.58–10.51). Pooled data from Feagan et al19 and Sandborn et al19,24 (patients with both UC and CD) showed that administration of concomitant immunosuppressive therapy was associated with decreased immunogenicity. ADAs were detected in 3% (1/32) of patients who received concomitant immunosuppressive therapy compared with 18% (44/247) of those who received vedolizumab monotherapy.

Clinical and Endoscopic Remission at 52 Weeks Feagan et al19 reported on clinical and endoscopic relapse at 52 weeks (n ¼ 373 patients) as outcomes. There was a statistically significant difference in clinical remission rates at 52 weeks favoring vedolizumab over placebo. Forty-three percent (107/247) of patients who continued to receive vedolizumab every 4 or 8 weeks were in remission at 52 weeks compared with 16% (20/126) of patients who were switched to placebo (RR ¼ 2.73; 95% CI, 1.78–4.18). There was a statistically significant difference in endoscopic remission rates at 52 weeks favoring vedolizumab over placebo. Fifty-four percent (133/ 247) of patients who continued to receive vedolizumab were in endoscopic remission at 52 weeks compared with 20% (25/ 126) of patients who were switched to placebo (RR ¼ 2.71; 95% CI, 1.88–3.93).

IBDQ Scores Feagan et al12 reported significantly higher IBDQ scores in patients after vedolizumab induction therapy in comparison with patients assigned to placebo. After 6 weeks of treatment, the mean IBDQ score was 171.5 in the vedolizumab group compared with 162.5 in placebo treated patients (P ¼ 0.03). Feagan et al19 reported that the proportion of patients with a total IBDQ score .170 (remission) was higher with vedolizumab at weeks 6 and 52 compared with placebo (P , 0.005), and higher proportions of vedolizumab patients had clinically meaningful increases in IBDQ from baseline (weeks 6 and 52) compared with placebo.

1156

| www.ibdjournal.org

2015

Adverse Events Two studies reported the proportion of patients who experienced at least 1 AE.19,20 Parikh et al20 collected safety data up to day 253. Safety data from the study of Feagan et al19 included the full safety population for both the induction (6 wk) and maintenance phases (52 wk, n ¼ 895). A pooled analysis (n ¼ 941 patients) found no statistically significant difference in the incidence of AEs between vedolizumab and placebo patients. Seventy-nine percent (521/657) of vedolizumab patients experienced at least 1 AE compared with 80% (227/284) of placebo patients (RR ¼ 1.00; 95% CI, 0.93–1.07). Two of the studies reported on withdrawals due to AEs as an outcome.19,20 Parikh et al20 reported that no patients withdrew due to AEs. A pooled analysis (2 studies, 941 patients) demonstrated no statistically significant difference in withdrawal due to AEs. In this analysis, 6% of vedolizumab patients withdrew due

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Vedolizumab for Remission in UC

to AEs compared with 7% of placebo patients (RR ¼ 0.86; 95% CI, 0.51–1.47).19,25 A pooled analysis of 3 studies,12,19,20 including 1122 patients showed that the likelihood of serious AEs was not significantly increased in patients assigned to vedolizumab. Twelve percent (97/775) of vedolizumab patients had a serious AE compared with 12% (43/347) of placebo patients (RR ¼ 1.02; 95% CI, 0.73–1.42). Serious AEs reported in the study of Feagan et al12 included exacerbations of colitis, angioedema with an infusion reaction, infection, and degenerative disk disease. Parikh reported 2 serious AEs in the vedolizumab group including compression fractures of the thoracic vertebrae in one patient and gastroduodenitis in another patient. Frequently reported AEs in Feagan et al12 included worsening UC, nausea, headache, frequent bowel movements, fatigue, nasopharyngitis and abdominal pain. The most commonly reported AE in the study of Feagan et al14 was headache. In the study of Feagan et al,12 3 AEs that occurred during vedolizumab administration included one patient who developed an infusion reaction with hives and angioedema, one patient who developed a primary cytomegalovirus infection,

and one patient who developed postoperative pneumonia after spine surgery. The patient who developed the infusion reaction was positive for ADAs (1:125). Commonly reported AEs in the study of Parikh et al20 included headache, worsening UC, upper respiratory tract infection, and nasopharyngitis. Parikh et al20 reported 2 incidents of pyrexia but no allergic reactions to the medication. No systemic opportunistic infections or neoplasms were reported.20 Commonly reported AEs in the study of Feagan et al19 included worsening UC, headache, nasopharyngitis, arthralgia, upper respiratory tract infection, nausea, cough, anemia, abdominal pain, fatigue, and influenza. There were no reports of PML in any of the 4 studies.12,14,19,20

Quality of the Evidence The GRADE criteria were used to assess the overall quality of the evidence reported (Table 4). The outcomes clinical remission, endoscopic remission, and AEs were rated as high quality. The outcomes clinical improvement, clinical relapse, endoscopic relapse, and serious AEs were downgraded to moderate quality due to sparse data (i.e., less than 400 events).

TABLE 4. Summary of Findings Table Illustrative Comparative Risksa (95% CI)

Outcomes Failure to induce clinical remission Failure to induce clinical response Failure to maintain endoscopic remission Clinical remission at 52 wk Endoscopic remission at 52 wk Adverse events Serious adverse events

Assumed Risk

Corresponding Risk

Control

Vedolizumab Versus Placebo

Relative Effect (95% CI)

No. of Participants (Studies)

915 per 1000b

787 per 1000 (732–833)

0.86 (0.80–0.91)

606 (4 studies)

4444 high

720 per 1000b 809 per 1000b

490 per 1000 (425–562) 663 per 1000 (607–736)

0.68 (0.59–0.78) 0.82 (0.75–0.91)

601 (3 studies) 583 (3 studies)

444⊝ moderatec 4444 high

1000b 1000b 1000b 1000b

434 per 1000 (283–665) 537 per 1000 (372–778) 799 per 1000 (743–855) 122 per 1000 (87–172)

2.73 2.71 1.00 1.01

373 (1 study) 373 (1 study) 941 (2 studies)f 1122 (3 studies)f

444⊝ moderated 444⊝ moderatee 4444 high 444⊝ moderateg

159 198 799 121

per per per per

(1.78–4.18) (1.88–3.93) (0.93–1.07) (0.72–1.42)

Quality of the Evidence (GRADE)

Vedolizumab versus placebo for induction and maintenance of remission in UC. Patient or population: patients with moderately to severely active UC; Settings: outpatients; Intervention: vedolizumab versus placebo. GRADE working group grades of evidence. a The basis for the assumed risk (e.g., the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). b Control group risk estimates come from control arm of meta-analysis, based on included trials. c Sparse data (342 events). d Sparse data (127 events). e Sparse data (158 events). f Includes full safety population from Feagan et al19 (induction and maintenance phase). g Sparse data (136 events). CI, Confidence interval; RR, risk ratio; High quality, further research is very unlikely to change our confidence in the estimate of effect; Moderate quality, further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate; Low quality, further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate; Very low quality, we are very uncertain about the estimate.

www.ibdjournal.org |

2015

1157

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

Mosli et al

DISCUSSION This meta-analysis shows that vedolizumab is superior to placebo as induction and maintenance therapy for UC. Although vedolizumab was not demonstrated to have a significant effect on endoscopic response (RR ¼ 1.00; 95% CI, 0.24–4.14), only 1 inadequately powered study evaluated this outcome.14 In the largest study of vedolizumab,19 both anti-TNF-a exposed and antiTNF-a–naive patients were studied. Evidence for efficacy was present in both of these subpopulations. An important finding of this systemic review was that vedolizumab therapy was not associated with a greater incidence of AEs, withdrawals due to AEs or serious AEs relative to placebo. Vedolizumab is more selective than previous integrin antagonists because it specifically blocks the a4b7 integrin26,27 and does not interfere with VCAM–a4b1 mediated interactions. The clinical relevance of this difference will undergo further appraisal as additional safety evidence accumulates from prospective safety registries and practice experience. Although patient risk profiling for AEs from drug treatment has not been well studied for any IBD therapy, patients with UC at higher risk of serious infection, such as the elderly or those with chronic diseases such as chronic obstructive pulmonary disease might be better treated with vedolizumab than with TNF-a antagonists, immunosuppressives, or corticosteroids. This possibility requires additional prospective evaluation. PML is a rare infection of the brain that is usually seen in severely immunocompromised patients, which is caused by the JC virus.28 Bloomgren et al28 investigated the risk of PML among patients receiving natalizumab and reported a total of 212 cases of in 99,571 exposed patients (2.1 cases per 1000 patients). Forty-six of these patients (22%) died. Three risk factors were identified for the development of PML: previous use of immunosuppressants, increased length of therapy (especially beyond 2 years), and presence of anti-JC virus antibodies. It is important to note that all of the PML cases with samples available for analysis (n ¼ 54) tested positive for anti-JC virus antibodies. Risk stratification based on the aforementioned factors can be used in selection of patients for natalizumab therapy.9 Concerns over the potential for vedolizumab-associated PML prompted Parikh et al29 to develop a specific case detection protocol that was included in the phase III development program. No case of PML occurred in any of the studies included in this review.12,14,19,20 Vedolizumab likely has little or no risk of PML because lymphocyte trafficking to the central nervous system is not impaired.30 Accordingly, testing for anti-JC virus antibodies in patients receiving vedolizumab is not recommended. Furthermore, no cases of PML have been observed in the entire vedolizumab development program that has evaluated more than 3000 patients who have received treatment for up to 6 years. A Poisson regression model predicted with 95% confidence that based on this experience at least 3 cases of PML would have been observed with 95% certitude if the PML risk for vedolizumab was the same as that for natalizumab.31

1158

| www.ibdjournal.org

2015

Immunogenicity is a potential problem for all monoclonal antibodies because the development of ADAs increases drug clearance and decreases efficacy. Although MLN02 therapy was associated with a high rate of ADAs, reformulation of the product seems to have reduced this risk.20 Parikh et al20 reported the development of ADAs in only 11% of patients who received CHO cell-derived vedolizumab. We compared the rates of ADAs between the formulations. Patients who received NSO mouse myeloma cell-derived MLN02 had a significantly higher chance of developing ADAs than patients who received CHO cellderived vedolizumab (RR ¼ 4.08; 95% CI, 1.58–10.51).19 Pooled data from the Feagan et al19 and Sandborn et al24 studies, which evaluated patients with both UC and CD, respectively, indicate that combination therapy with an immunosuppressive may prevent the formation of ADAs. The therapeutic index of vedolizumab when used in combination with immunosuppressives relative to vedolizumab monotherapy requires evaluation in large welldesigned trials. Although it is difficult to make a strong recommendation given the absence of controlled data, the authors’ opinion is that the benefits of combined therapy likely outweigh the risks. However, it has not escaped us that the coadministration of a systemic immunosuppressive such as azathioprine or methotrexate might diminish the safety benefit conveyed by a gut-selective mechanism of action. The methodological basis for these conclusions seems to be sound. The Cochrane risk of bias tool was used to assess the quality of the 4 included trials, and the possibility of bias was judged to be low. Furthermore, the overall quality of evidence supporting the primary outcome “failure to induce clinical remission” was rated as “high” using the GRADE criteria. This indicates that further research is unlikely to change our confidence in the point estimate of effect. Conversely, the overall quality of evidence supporting the maintenance outcome, the proportion of patients in remission at week 52 in week 6 vedolizumab responders, was rated as “moderate” using the GRADE criteria. This finding indicates that further research may change the point estimate of effect. The overall quality of evidence supporting the AE outcomes data (any AE and serious AEs) was rated as “moderate” using the GRADE criteria. However, further evaluation, particularly long-term data regarding the risk of enteric infection, is necessary to define the risk of the drug. Future research should also evaluate the relative efficacy and safety of vedolizumab compared with other treatments for UC, specifically the TNF-a antagonists, infliximab, adalimumab, and golimumab. Since no direct comparisons have been performed, it is difficult to make a recommendation as to the initial choice of biological therapy in biologic-naive patients. Since vedolizumab is effective in patients with UC who have failed treatment with a TNF-a antagonist, clinicians have a new option for management of these patients. No data are currently available regarding the efficacy of TNF-a antagonist therapy in patients who have failed vedolizumab. In conclusion, vedolizumab is significantly more effective than placebo as induction and maintenance therapy for UC. The

Inflamm Bowel Dis  Volume 21, Number 5, May 2015

rates of AEs in patients treated with this agent are consistent with a gut-selective mechanism of action. Future studies should compare vedolizumab with other active therapies such as TNF-a antagonists.

REFERENCES 1. Kornbluth A, Sachar DB; Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105:501–523; quiz 524. 2. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2006;CD005112. 3. Mosli MH, Rivera-Nieves J, Feagan BG. T-cell trafficking and antiadhesion strategies in inflammatory bowel disease: current and future prospects. Drugs. 2014;74:297–311. 4. Erle DJ, Briskin MJ, Butcher EC, et al. Expression and function of the MAdCAM-1 receptor, integrin alpha 4 beta 7, on human leukocytes. J Immunol. 1994;153:517–528. 5. 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;74:185–195. 6. Fong S, Jones S, Renz ME, et al. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Its binding motif for alpha 4 beta 7 and role in experimental colitis. Immunol Res. 1997;16:299–311. 7. Hamann A, Andrew DP, Jablonski-Westrich D, et al. Role of alpha 4integrins in lymphocyte homing to mucosal tissues in vivo. J Immunol. 1994;152:3282–3293. 8. MacDonald JK, McDonald JWD. Natalizumab for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2007;CD006097. 9. Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353:1912–1925. 10. Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007;132:1672–1683. 11. 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;111:1373–1380. 12. 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;352:2499–2507. 13. Feagan BG, Greenberg GR, Wild G, et al. Treatment of active Crohn’s disease with MLN0002, a humanized antibody to the alpha4beta7 integrin. Clin Gastroenterol Hepatol. 2008;6:1370–1377. 14. Brian G, Feagan JM, Gordon G, et al. An ascending dose trial of humanized A4B7 antibody in ulcerative colitis. Gastroenterology. 2000;118 (4 suppl 2):A874. 15. Bickston SJ, Behm BW, Tsoulis DJ, et al. Vedolizumab for induction and maintenance of remission in ulcerative colitis. Cochrane Database Syst Rev. 2014;8:CD007571. 16. Higgins JPT, Douglas AG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, eds. Cochrane Handbook

Vedolizumab for Remission in UC

17.

18.

19.

20.

21.

22.

23.

24.

25.

26.

27. 28.

29.

30.

31.

for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011. Available at: http://www.cochrane-handbook.org. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924–926. Schünemann HJOA, Vist GE, Higgins JPT, et al. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. The Cochrane Collaboration; 2011. Available at: http://www.cochrane-handbook.org. 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. 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;18:1470–1479. Baron JH, Connell AM, Lennard-Jones JE. Variation between observers in describing mucosal appearances in Proctocolitis. Br Med J. 1964; 1:89–92. Irvine EJ. Development and subsequent refinement of the inflammatory bowel disease questionnaire: a quality-of-life instrument for adult patients with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1999;28: S23–S27. Lewis JD, Chuai S, Nessel L, et al. Use of the noninvasive components of the Mayo score to assess clinical response in ulcerative colitis. Inflamm Bowel Dis. 2008;14:1660–1666. Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2013;369: 711–721. 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. 2011;18:1470–1479. ** An important phaseIIb study that provided significant insight into the pharmacological profile of vedolizumab. Fedyk ER, Wyant T, Yang LL, et al. Exclusive antagonism of the alpha(4) beta(7) integrin by vedolizumab confirms the gut-selectivity of this pathway in primates. Inflamm Bowel Dis. 2012;18:2107–2119. Milch CWT, Xu J. Vedolizumab does not reduce the CD4+: CD8+ ratio in the CSF of healthy volunteers. Gut. 2011;60:A407. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumabassociated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366:1870–1880. Parikh A, Fox I, Leach T, et al. Long-term clinical experience with vedolizumab in patients with inflammatory bowel disease. Inflamm Bowel Dis. 2013;19:1691–1699. 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;264:123–126. Colombel JF, Sands B, Hanauer S, et al. Long-term safety of vedolizumab for the treatment of ulcerative colitis or crohn’s disease. Am J Gastroenterol. 2013;108:S502–S503.

www.ibdjournal.org |

2015

1159