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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0b013e318281f538
Original Clinical Articles

Long-term Clinical Experience with Vedolizumab in Patients with Inflammatory Bowel Disease

Parikh, Asit MD, PhD*; Fox, Irving MD*; Leach, Timothy MD*; Xu, Jing PhD*; Scholz, Catherine PharmD*; Patella, Michael MSM*; Feagan, Brian G. MD

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Author Information

*Millennium Pharmaceuticals, Inc, Cambridge, Massachusetts; and

Robarts Research Institute, University of Western Ontario, London, Ontario, Canada.

Reprints: Brian G. Feagan, MD, Robarts Research Institute, University of Western Ontario, 100 Perth Drive, London, Ontario, Canada N6A 5K8 (e-mail:

Supported by Millennium Pharmaceuticals, Inc, A Takeda Company.

Drs. A. Parikh, I. Fox, T. Leach, J. Xu, and C. Scholz, and Mr. M. Patella are employees of Millennium Pharmaceuticals, Inc, and stockholders of Takeda Pharmaceuticals. Dr. B. G. Feagan has received grant/research support from Millennium Pharmaceuticals, Inc.

The authors have no other conflicts of interest to disclose.

Writing support was provided by Brian G. Shearer, PhD, Takeda Pharmaceuticals North America, Deerfield, IL.

Received October 18, 2012

Accepted November 1, 2012

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Background: Vedolizumab, a gut-selective, anti-inflammatory monoclonal antibody, has shown preliminary efficacy in ulcerative colitis (UC) and Crohn's disease (CD). We report long-term experience with vedolizumab for active UC and CD.

Methods: After a placebo-controlled study, 38 patients with UC were randomized to a loading regimen of vedolizumab 2, 6, or 10 mg/kg on days 1, 15, and 43, followed by maintenance dosing every 8 weeks. Thirty-four vedolizumab-naive patients (15 UC; 19 CD) were randomized to vedolizumab 2, 6, or 10 mg/kg on the same schedule. Rollover patients were treated up to 630 days and treatment-naive patients were treated up to 547 days.

Results: Seventy-two patients were dosed; 52 (72%) completed the study. In exploratory analyses, 28 of 72 (39%; UC: 21 of 53, CD: 7 of 19) achieved clinical response and 42 of 72 (58.3%; UC: 38 of 53, CD: 4 of 19) achieved clinical remission. Mean partial Mayo scores declined from baseline through day 155 in both treatment-naive patients with UC (5.4 to 1.7, respectively) and rollover patients with UC (2.3 to 1.4, respectively), leveling off thereafter. Mean Crohn's Disease Activity Index scores decreased from 295 (baseline) to 238 at day 43, continued to trend downward through day 155, and remained below baseline through day 491. Mean Inflammatory Bowel Disease Questionnaire scores increased in all treatment groups. No deaths or systemic opportunistic infections were reported.

Conclusion: Vedolizumab every 8 weeks for up to 78 weeks had an adverse event profile similar to that previously observed. Mean disease activity indices (partial Mayo score and Crohn's Disease Activity Index score) improved with all 3 doses investigated.

The introduction of biological therapy has dramatically improved the treatment of inflammatory bowel disease. Recent studies have confirmed the importance of leukocyte trafficking in the pathogenesis of these diseases.1,2 The interaction between adhesion molecules on circulating leukocytes (integrins) and receptor cell adhesion molecules expressed on the surface of endothelial cells is regulated by highly specific mechanisms. Immune surveillance of the gastrointestinal tract is mediated in part by the interaction of the α4β7 integrin complex of memory T and B cells with its principal ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is primarily expressed on gut vascular endothelium.3,4 Vedolizumab (previous versions known as LDP-02, MLN02, and MLN0002) is an investigational humanized monoclonal antibody that exclusively targets the α4β7 integrin. In doing so, vedolizumab selectively inhibits migration of lymphocytes into the gut.5 The increased risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab has raised questions about the long-term safety of anti-integrin therapy in immune-mediated diseases6,7; however, it is hypothesized that the highly selective inhibition provided by vedolizumab should not result in the more generalized immune-suppressive effects and the associated risks of opportunistic infections. Nevertheless, long-term clinical experience with this monoclonal antibody has not been available.

Two randomized, placebo-controlled multicenter phase 2 trials have shown that an earlier version of vedolizumab has clinically relevant anti-inflammatory activity and results in clinical benefit in both ulcerative colitis (UC) and Crohn's disease (CD) as measured by disease activity indices.8,9 To date, serious and opportunistic infections have been infrequently observed with vedolizumab, and as of the writing of this manuscript, there have been no reported cases of PML.

The current investigation was an open-label extension study to assess the long-term pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, efficacy, and safety of vedolizumab in 3 groups of patients with UC and CD. The study was open to patients with UC who had previously participated in a phase 2 dose-ranging study (“rollover” patients) who could have received drug or placebo in that study. It was also open for direct enrollment of patients with active UC or CD who had not participated in the dose-ranging study (referred to as “treatment-naive” patients for simplicity).

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This phase 2 long-term safety extension study was conducted at 5 academic medical centers in Canada and 9 academic medical centers in the Russian Federation. The first patient was enrolled in December 2007; the last patient completed treatment in March 2010. The study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and its amendments. The protocol was approved by the investigational review/ethics board at each study center. All patients gave written informed consent.

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Patient Selection

Male and nonpregnant female patients (18–75 years old) were eligible to enroll in this open-label study. Rollover patients with UC had completed an 8-month dose-ranging study (Study C13002, NCT 01177228)10 and had tolerated the previous study treatment, either vedolizumab or placebo. Treatment-naive patients with UC were required to have had symptoms for a minimum of 2 months, in conjunction with endoscopic and/or histopathological documentation of UC extending proximal to the rectum, obtained within 36 months of screening, and a partial Mayo score (PMS) of 2 to 7. Patients with CD were required to have had symptoms for a minimum of 2 months, in conjunction with endoscopic, radiological, and/or histopathological documentation consistent with CD of the ileum and/or colon, obtained within 36 months of screening, and a Crohn's Disease Activity Index (CDAI) score of 220 to 450. Patients could have received concomitant treatment for UC or CD with oral 5-aminosalicylates; oral corticosteroids (up to a maximum of prednisone 30 mg/d, budesonide 9 mg/d, or equivalent); antibiotics; and/or azathioprine, 6-mercaptopurine, or methotrexate (patients with CD only). Treatment-naive patients were required to have maintained a stable dose of these concomitant therapies for 2 weeks immediately before the day 1 visit.

Exclusion criteria included an anticipated requirement for imminent surgical intervention; clinically significant laboratory abnormalities; treatment with cyclosporine, tacrolimus, infliximab, adalimumab or certolizumab pegol within 90 days before the screening visit; history of exposure to natalizumab; evidence of colorectal mucosal dysplasia or cancer on most recent surveillance colonoscopy; tube feeding or parenteral alimentation within 14 days before screening; and ostomies or known intestinal stenoses. Patients with a history or evidence of viral hepatitis, HIV, tuberculosis, or major medical disorders were also ineligible.

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Study Design

All treatment-naive patients were screened for eligibility during a 30-day period before enrollment. Rollover patients did not require a screening visit since the end-of-study data from the earlier phase 2 study was used to determine eligibility. At the initial visit, baseline disease activity was assessed using the CDAI score for patients with CD and the PMS for patients with UC.

During the enrollment period, pharmacologic modeling based on PK and PD data from preceding clinical studies predicted that vedolizumab doses of 2 mg/kg every 8 weeks and 6 mg/kg every 8 weeks would maintain a >95% trough level α4β7 receptor saturation in blood in >95% of the population, considered to represent a clinically important benchmark for target inhibition. Accordingly, a protocol amendment was implemented 5 months into the study while patients were still being enrolled. This amendment resulted in dose adjustment for 17 of the patients accrued to that point; vedolizumab dosing for 13 treatment-naive patients with UC and CD was reduced from 10 to 6 mg/kg and for 4 patients with UC from 6 to 2 mg/kg. Hence, the bulk of exposure in this study was derived at the doses administered under the revised dose regimen.

Each patient received an intravenous loading regimen of vedolizumab on days 1, 15, and 43, followed by maintenance dosing every 8 weeks for approximately 18 months (days 99, 155, 211, 267, 323, 379, 435, 491, and 547). Patients were assessed clinically for PK and PD parameters, as well as safety and disease activity at each of the scheduled study visits as described below. After the day 43 visit, patients on corticosteroids who had achieved a clinical response or had a Mayo score ≤2 or CDAI score ≤180 were to begin a corticosteroid tapering regimen. Beginning on day 491, subjects were permitted to withdraw for the purpose of enrolling in a vedolizumab phase 3 long-term safety extension study (results to be reported separately) before completing the final study visit on day 637. Subjects who did not choose this option were assessed for safety during a 90-day observation period.

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Clinical Pharmacology Assessments

Blood samples for PK and PD analyses were collected within 2 hours before dosing on days 1, 43, 99, 155, and 267. Vedolizumab plasma concentrations were determined using a validated direct capture assay (Quest Pharmaceutical Services, Newark, DE) with a lower detection limit of 0.00125 µg/mL (0.125 µg/mL in undiluted serum). The saturation and blockade of α4β7 receptors on peripheral blood lymphocytes were assessed by a validated flow cytometric assay, the MAdCAM-1+[CD4+CD45RO High] binding assay for α4β7 receptor blockade, and saturation.5 This assay quantitates the percentage of cells bearing α4β7 that are not saturated with vedolizumab at the time of sampling.

Immunogenicity was also assessed longitudinally on samples collected before dosing on days 1, 43, 155, 267, 379, and 491 and before study termination on day 637. Two dilutions of serum (1:5 and 1:50) were screened for the presence of human anti-human antibody (HAHA) using a biotinylated bridging assay and strepavidin-HRP (data on file; Millennium Pharmaceuticals, Inc, Cambridge, MA). All specimens that screened positive were further diluted to determine a final HAHA titer using standard techniques. If both screening dilutions were negative, the sample was considered negative. Positive specimens were tested for neutralizing ability using a flow cytometry binding competition assay (data on file; Millennium Pharmaceuticals, Inc).

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Efficacy Assessments

As this long-term extension study was not powered to evaluate specific efficacy-related hypotheses, all efficacy assessments were exploratory. The population of patients evaluable for efficacy had received at least one dose of study drug and had at least one postdose efficacy assessment available. Efficacy assessments were made at each clinic visit on days 1 (pre-dose), 43, 99, 155, 267, 379, 491, and 637. Since patients were permitted to enroll in a vedolizumab phase 3 long-term safety extension study beginning at day 491, efficacy results from this study are presented through day 491. The PMS, which does not incorporate an endoscopic assessment, was used to monitor changes in UC disease activity.11,12 The PMS consists of 3 components: rectal bleeding, stool frequency, and physician's global assessment, each scored from 0 to 3, with higher scores indicating more severe disease. Total scores range from 0 to 9. For UC, clinical response was defined as a decrease from baseline in the PMS of ≥2 points and a ≥25% decrease in the total score, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or an absolute subscore for rectal bleeding of 0 or 1. Clinical remission in UC was defined as a PMS of ≤2 with no individual subscore >1. The CDAI was used to monitor changes in CD activity.13,14 Clinical response in CD was defined as a decrease from baseline in the CDAI score of ≥70 points, whereas enhanced clinical response was defined as a decrease from baseline of ≥100 points. Clinical remission in CD was defined as an absolute CDAI score ≤150. The Inflammatory Bowel Disease Questionnaire (IBDQ) was used to monitor symptoms in both UC and CD patients throughout the treatment period. The IBDQ is a validated instrument for measuring health-related quality of life in patients with UC or CD. Scores on the IBDQ range from 32 to 224, with higher scores indicating better quality of life.15

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Safety Assessments

Adverse events (AEs) were assessed at each study visit (days 1 [predose and postdose], 15, 43, 99, 155, 211, 267, 323, 379, 435, 491, 547, and 637). AEs were classified using the Medical Dictionary for Regulatory Activities. Blood samples for C-reactive protein (CRP) evaluation, clinical chemistry, hematology, and urinalyses were collected throughout the study period (days 1, 43, 155, 267, 379, 491, and 637). Vital signs, physical findings, and electrocardiograms were also routinely monitored.

Because of the safety concerns associated with the less-selective integrin antagonists natalizumab and efalizumab, a dedicated risk minimization program for PML was implemented during this study to address this theoretical risk. All patients were closely monitored for signs and symptoms of PML through directed questionnaires that assessed recent changes in vision, speech, gait, sensation, comprehension, coordination, and personality, with any positive responses prompting objective testing by the principal investigator. Cases of new neurological symptoms were promptly evaluated by a neurologist and an independent adjudication committee of academic experts using a prespecified diagnostic algorithm that included stepwise contrast-enhanced brain magnetic resonance imaging and, if indicated, lumbar puncture with polymerase chain reaction analysis of cerebrospinal fluid for John Cunningham (JC) virus DNA. If patients entered the algorithm, study drug was withheld until PML could be definitively excluded. Also, for all patients, longitudinally acquired plasma specimens were tested for JC virus DNA using a commercially available quantitative polymerase chain reaction assay (ViraCor Laboratories, Lee's Summit, MO).

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Statistical Analyses

For PK and PD evaluations, descriptive statistics were analyzed by time point and dose group. Safety and exploratory efficacy outcomes analyses were also descriptive and were conducted on an observed-case basis. Given that the dose regimen was modified early in the course of the study, safety analyses were based on the lowest dose received, which was considered the most conservative approach (i.e., adverse events experienced by patients who began the study on 6 mg/kg, but who were then switched to 2 mg/kg, were attributed to the 2 mg/kg dose). For efficacy analyses, data were analyzed by indication and previous treatment experience, and clinical pharmacology analyses were performed by the actual dose received.

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Patient Disposition

A total of 72 patients (53 UC and 19 CD patients) were enrolled, all of whom received at least one dose of study drug and had at least one postdose efficacy assessment (Fig. 1). Of the 53 UC patients, 38 were rollover patients from the earlier phase 2 dose-ranging study and 15 were treatment naive. All 19 CD patients were treatment naive. Per the protocol amendment, the dose of vedolizumab was reduced for 15 patients. For these patients, the mean time from first dose to dose reduction was 64 days. Fifty-two patients (72%) either completed the study or completed the dose regimen per protocol. Patients who withdrew before day 637 to enroll in a vedolizumab phase 3 open-label safety extension study were also considered study completers. A total of 20 patients (28%) prematurely discontinued therapy (Fig. 1).

Figure 1
Figure 1
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Baseline Characteristics and Concomitant Therapy

The baseline characteristics of the patients are presented in Table 1. Of the 72 study participants, 68 (94%) received at least 1 concomitant medication, including 33 (89%) patients in the 2 mg/kg dose group and all 35 (100%) patients in the 6 mg/kg dose group. Commonly prescribed concomitant medications included intestinal anti-inflammatory agents, i.e., 5-aminosalicylates and topical steroids (69%), corticosteroids (46%), immunosuppressive agents (11%), and antimetabolites (10%) (Table 1).

Table 1
Table 1
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Clinical Pharmacology
Pharmacokinetics and Pharmacodynamics

Mean pre-infusion serum vedolizumab concentrations were dose proportional and remained steady and detectable throughout the study. As expected, there was a decrease in serum vedolizumab concentrations from day 43 to day 99 because of the dosing interval changing from 4 weeks (induction regimen) to 8 weeks (maintenance regimen). At later time points during the maintenance regimen, mean serum drug concentrations were dose proportional and remained constant for both the 2 mg/kg (approximately 7 µg/mL) and 6 mg/kg (approximately 25 µg/mL) dose groups.

PD evaluations were based on the percentage of MAdCAM-1+ binding by lymphocytes expressing high levels of α4β7 integrin [CD4+CD45RO High]. For patients whose dose assignment remained unchanged during the study, and also for patients who underwent dose modifications, target saturation, as evidenced by near complete inhibition of MAdCAM-1+ binding, was observed at all dose levels throughout the dosing interval.

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Efficacy Evaluation
Clinical Response and Remission

Overall, 38 UC patients (88%) achieved clinical remission by day 491, and 21 UC patients (49%) achieved a clinical response (Fig. 2A). The paradoxically higher remission rate in UC patients was because of the wide range in baseline disease activity (baseline PMS 0-8). Patients in the lower part of this range could meet the predefined criteria for remission more easily than they could the criteria for response. A post hoc subanalysis of UC patients with more active disease, defined as a baseline PMS score ≥4 (n = 13), revealed that 10 patients (77%) reached clinical remission by day 491 and 12 patients (92%) attained clinical response (Fig. 2B). For patients with active CD, all of whom had active CD at baseline (CDAI range: 220–450), a total of 4 patients (40%) achieved clinical remission and 7 patients (70%) demonstrated a clinical response (Fig. 2C) by day 491. At that time, 6 patients (60%) were noted to have achieved an enhanced clinical response (defined as a CDAI decrement of at least 100 points from baseline) (data not shown), which is considered another clinically important benchmark in CD trials.16

Figure 2
Figure 2
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Changes From Baseline in Disease Activity Indices

For UC patients, the mean PMS at enrollment was higher for treatment-naive patients (5.4) than for rollover patients (2.3); the latter had participated in the previous dose-ranging study. By day 43, disease activity had substantively decreased in both treatment-naive and rollover groups and continued to decline over time. By day 155, the mean PMS for treatment-naive (1.7) and rollover patients (1.4) approximated one another with scores for both groups leveling off thereafter. For CD patients, the mean CDAI score decreased from 295 at baseline to 238 at day 43. The mean CDAI score continued to exhibit a downward trend through day 155 and remained consistently below baseline through day 491.

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C-Reactive Protein

CRP was assessed through day 491 for the CD patients. Mean CRP decreased through day 155 and then leveled off (Fig. 3A). The proportion of Crohn's patients with abnormal CRP (≥2.87 mg/L) at baseline whose CRP normalized during the study increased gradually through day 491 and peaked at 50%; the interpretability of this analysis was limited by a sample size that decreased over time.

Figure 3
Figure 3
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Corticosteroid Sparing

At baseline, 19 patients were receiving oral corticosteroids, primarily prednisone. After the day 43 visit, patients on corticosteroids who had achieved a clinical response or had a Mayo score ≤2 or CDAI score ≤180 began a corticosteroid tapering regimen. A post hoc analysis revealed that 12 of these patients (63%) were able to discontinue corticosteroids completely while on study and remained corticosteroid free at their last assessment. An additional 3 patients were able to decrease their dose by more than 50%. Overall, 15 patients (79%) were able to substantially reduce or discontinue corticosteroid use.

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Inflammatory Bowel Disease Questionnaire

The UC rollover patients had the highest mean IBDQ score at baseline and showed the smallest improvement by day 43, consistent with a previous treatment effect (Fig. 3B). For treatment-naive UC patients, mean IBDQ scores consistently increased over the study period. CD patients had the lowest mean IBDQ score at baseline, probably reflecting the fact that all the CD patients had at least moderately to severely active disease at baseline. The mean IBDQ score for CD patients seemed to level off around day 155 but remained lower than that for UC patients (both treatment-naive and rollover) throughout the duration of the study. At baseline, 55% of the UC rollover group, 20% of the UC treatment-naive group, and 5% of the CD group had a “normal” IBDQ (defined as >170 points); on day 491, the proportion of patients in these same 3 groups with normal IBDQ scores were 78%, 100%, and 60%, respectively.

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Safety Evaluation
Extent of Exposure

For all patients, the mean exposure to vedolizumab was 549 (±191) days. For treatment-naive UC patients, the mean exposure to vedolizumab was 440 (±223) days, and for UC rollover patients, mean exposure was 636 (±97) days. For CD patients, the mean exposure to vedolizumab was 460 (±228) days. The mean combined vedolizumab exposure for UC rollover patients when including their exposure in the previous dose-ranging study was 859 (±141.48) days, or almost 2½ years.

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Treatment Emergent Adverse Events

AEs and severe AEs were reported more frequently among CD patients as compared with UC patients (Table 2). Most AEs were considered by the investigator to be mild to moderate in intensity. The most common (>3% of total patients) AEs are presented in Table 3. No deaths occurred on study. Ten patients (14%) reported a serious AE. The highest serious AE rates were observed in the CD group and in the patients who were assigned 6 mg/kg. Of the 10 serious AEs reported, 5 were deemed by the investigator to be related to drug treatment: furuncle, Salmonella sepsis (see below), blurred vision, spontaneous abortion, and infusion-related reaction. All but the furuncle resulted in the affected patient's discontinuation from the study. No systemic opportunistic infections were reported during the study. No patient reported signs or symptoms of PML on focused questionnaires designed to assist in early identification of possible PML cases.

Table 2
Table 2
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Table 3
Table 3
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Salmonella sepsis occurred in a 52-year-old female CD patient 51 days after receiving her eleventh dose of 6 mg/kg of vedolizumab. The patient was hospitalized with emesis, diarrhea, fever, and weakness; blood cultures later grew Salmonella enterica. After responding to intravenous antibiotics, she was prescribed a 10-day course of oral ciprofloxacin, which she discontinued after 6 days due to side effects. The patient then experienced recurrent symptoms, was readmitted to hospital, and was treated with 2 g of ceftriaxone intravenously for 5 days. Repeat blood cultures were negative. Several stool cultures grew S. enterica over the ensuing 3 months; however, the patient was asymptomatic. The patient was discontinued from the study.

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Other Safety Results—Immunogenicity

All 72 patients were evaluated for HAHA; 3 patients (4%) were positive at baseline. One of these patients had developed HAHA during the course of another study using an earlier version of vedolizumab and experienced an infusion-related reaction on receiving the first dose of vedolizumab in the current investigation (see Treatment Emergent Adverse Events); the patient was discontinued from the study. This patient was retrospectively noted to have had a baseline HAHA titer of 1:625 before her participation in this study. The other 2 patients were treatment naive and were only transiently HAHA positive, i.e., HAHA was not detected in these patients at subsequent time points.

One patient had detectable JC virus DNA in the serum at a single time point on day 155 of the study; however, the patient had negative JC virus test results at all other time points. There were no clinically significant changes in white blood cell subsets (absolute lymphocytes, monocytes, eosinophils, and basophils) nor were there any significant liver function abnormalities.

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Earlier, short-term studies of vedolizumab indicated promise for induction of response and remission in active UC and CD.8,9 This phase 2 study with vedolizumab was an 18-month open-label safety extension to a previous dose-ranging study and also enrolled treatment-naive UC and CD patients. Key objectives were to evaluate the long-term PK, PD, immunogenicity, efficacy, and safety of vedolizumab. The vedolizumab doses used in this study, which were lowered to 2 mg/kg and 6 mg/kg as a result of the protocol amendment, were higher than those used in earlier studies8,9 to support an extended maintenance dosing interval and to minimize immunogenicity.

As previously reported, vedolizumab demonstrated approximately dose proportional PK and maximally saturated α4β7 receptors over the dose range explored throughout the treatment period.10 It remains possible that α4β7 saturation on peripheral blood lymphocytes might be necessary but not sufficient for achieving optimal efficacy. This study was not powered for rigorous evaluation of the PK/PD/efficacy relationship.

The development of immunogenicity (HAHA) represents an important limitation to the sustained use of monoclonal antibody therapeutics. An earlier version of vedolizumab used in phase 2 proof-of-concept studies was associated with HAHA development (titer >1:125) in 24% of the UC patients and 23% of the CD patients, despite brief exposure.8,9 Based on data from the previous dose-ranging study10 and the current study, the combination of improved manufacturing process, higher doses, and more frequent dosing during induction may have all contributed to the lower observed HAHA rate in this study (4%).

Efficacy data from this open-label safety extension study were exploratory. Although the mean disease activity scores improved over time, the absence of a placebo arm, the possibility of regression to the mean, and the lack of endoscopic assessments limit the interpretation of the data. Despite these limitations, our results lend support to the hypothesis that α4β7 receptor blockade by vedolizumab results in sustained clinical benefit in both UC and CD, as evidenced by clinically meaningful rates of sustained clinical response and remission, decreased serum CRP, and improved IBDQ scores. Reducing corticosteroid dependency is an important and desirable feature of biologic therapy for inflammatory bowel disease. A substantial proportion of patients receiving vedolizumab in conjunction with oral corticosteroids were able to discontinue corticosteroid therapy. The overall findings of this study are therefore consistent with a sustained benefit of vedolizumab therapy on multiple disease parameters in all 3 treatment groups.

Vedolizumab was well tolerated in both UC and CD patients. Overall, 72% of the patients completed the study, many of whom elected to continue vedolizumab treatment by subsequently enrolling in a phase 3 safety extension study. The low rate of discontinuation (28%) over an 18-month period may also be partly attributable to the fact that this study included patients who had already demonstrated tolerance of the drug in an earlier study. The most frequent AEs were conditions associated with the underlying disease or common outpatient medical illnesses. Adverse event rates were higher in the 6 mg/kg group compared to the 2 mg/kg group. Two factors are likely to have contributed to this finding. First, UC rollover patients whose disease activity was under much better control at baseline were assigned the 2 mg/kg dose. Conversely, treatment-naive UC and CD patients, who were flaring at study entry, received the 6 mg/kg dose. Second, CD patients had a higher relative threshold for inclusion than did UC patients (CDAI 220 for CD versus PMS 2 for UC). Both these factors suggest that patients who were assigned to the 6 mg/kg dose were sicker than patients assigned to 2 mg/kg and that this may account for the higher AE rates in the former group, as opposed to a dose–toxicity relationship. Overall rates of immunogenicity were low and only one serious infusion-related reaction was reported. This occurred in a patient who had been sensitized to an earlier version of vedolizumab in a previous study. The most significant adverse event reported involved a patient with CD who developed Salmonella sepsis after 18 months of vedolizumab exposure. Given that the mechanism of action of vedolizumab involves modulation of gut immunity, it is possible that exposure to the investigational agent could have contributed to the occurrence of this event. However, it is noteworthy that the patient made an uneventful recovery on antibiotic therapy in the presence of a therapeutic concentration of vedolizumab.

The use of natalizumab, a humanized antibody to the α4 integrins, has been associated with an increased risk of PML, a rare but serious opportunistic central nervous system infection caused by reactivation of the latent and ubiquitous JC virus.6 In multiple sclerosis patients treated with natalizumab, the estimated risk of developing PML is approximately 2/1,000 overall and approximately 3/1,000 in those who have had at least 12 months of therapy.17 More recent data show a risk of approximately 11 of 1000 (i.e., >1/100 or >1%) in natalizumab-treated patients who have had more than 24 months of exposure to natalizumab, have had previous immunosuppressant use (e.g., azathioprine, 6-mercaptopurine, methotrexate), and have evidence of previous exposure to JC virus.17–19

In this study, which included approximately 21 to 30 months of continuous vedolizumab exposure in the majority of subjects, no systemic opportunistic infections, including PML, were reported. Although the patient numbers evaluated in this study were limited, we estimate that the exposure derived from much larger ongoing vedolizumab Phase 3 studies, in the absence of any PML events, should be sufficient to demonstrate meaningful differences in the risk of PML from natalizumab. Based on the rule of 3, only 300 patients with 24 months of vedolizumab exposure, JC virus seropositivity and previous immunosuppressant use, would be required to exclude the >1% PML rate observed with natalizumab with 95% confidence.20

A sizable body of scientific literature dating back to 1993 substantiates the gut selectivity of the α4β7/MAdCAM pathway.21,22 Given that vedolizumab exclusively binds to the α4β7 integrin (in contrast to natalizumab, which binds to all α4 integrins, thereby inhibiting both α4β7/MAdCAM and α4β1/vascular cell adhesion molecule interactions],17,23 the pharmacologic effects of vedolizumab should largely be restricted to the gastrointestinal tract.24 Theoretically, the pharmacologic and physiologic specificity should translate to a lower risk of generalized immune suppression and systemic opportunistic infection with vedolizumab. Functional studies have been performed in humans and animals to explore the effects of vedolizumab on systemic immunity. Most notably, in a primate model, cellular immunity in the central nervous system was preserved following vedolizumab exposure but not natalizumab exposure.25 In other experiments, vedolizumab did not impair T cell–dependent antibody responses, did not affect CD4+ or CD8+ cell counts or the CD4:CD8 ratio in human cerebrospinal fluid, or result in increased CD34+ lymphocytes (postulated to represent a reservoir of neurotropic JC virus) in the circulation.24,26,27 These results support the hypothesis that vedolizumab therapy should not increase the risk of PML.

In conclusion, this study is the longest study of vedolizumab to be reported to date, and furthers our scientific understanding of the clinical pharmacology, efficacy, and safety of this investigational therapy for UC and CD. Vedolizumab resulted in durable clinical benefit in both CD and UC and was well tolerated with prolonged use. A low incidence of serious infections was observed. It will be important to confirm these findings based on the results of large-scale pivotal studies that are nearing completion.

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Guarantor of the article: Brian G. Feagan, MD.

Author Contributions: A. Parikh, MD, PhD: planning, conducting, analyzing, interpreting, writing portions of the manuscript, revising the manuscript critically. I. Fox, MD: planning, conducting, analyzing, interpreting, writing portions of the manuscript, revising the manuscript critically. T. Leach, MD: trial oversight, data analysis/interpretation, revising the manuscript critically. J. Xu, PhD: statistical analysis, revising the manuscript critically. C. Scholz, PharmD: clinical pharmacology, writing portions of the manuscript, revising the manuscript critically. M. Patella, MSM: planning and managing clinical operations, revising the manuscript critically. B. G. Feagan, MD: planning, analyzing, interpreting, writing portions of the manuscript, and revising the manuscript critically.

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MLN0002; MLN02; LDP-02; Crohn's disease; ulcerative colitis; NCT00619489

© Crohn's & Colitis Foundation of America, Inc.


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