Entyvio

CLINICAL PHARMACOLOGY

Mechanism Of Action

Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 integrin and blocks the interaction of α4β7 integrin with mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and inhibits the migration of memory T-lymphocytes across the endothelium into inflamed gastrointestinal parenchymal tissue. Vedolizumab does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 (VCAM-1).

The α4β7 integrin is expressed on the surface of a discrete subset of memory T-lymphocytes that preferentially migrate into the gastrointestinal tract. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T-lymphocytes to gut lymph tissue. The interaction of the α4β7 integrin with MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of ulcerative colitis and Crohn's disease.

Pharmacodynamics

In clinical trials with ENTYVIO at doses ranging from 0.2 to 10 mg/kg (which includes doses outside of the recommended dose), saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut-immune surveillance was observed.

In clinical trials with ENTYVIO at doses ranging from 0.2 to 10 mg/kg and 180 to 750 mg (which include doses outside of the recommended dose) in healthy subjects and in patients with ulcerative colitis or Crohn's disease, vedolizumab did not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T-lymphocytes, total memory helper T-lymphocytes, monocytes or natural killer cells.

A reduction in gastrointestinal inflammation was observed in rectal biopsy specimens from Phase 2 ulcerative colitis patients exposed to ENTYVIO for four or six weeks compared to placebo control as assessed by histopathology.

In a study of 14 healthy subjects, ENTYVIO did not affect the CD4+ lymphocyte cell counts, CD8+ lymphocyte cell counts, or the CD4+:CD8+ ratios in the CSF [see Pharmacokinetics].

Pharmacokinetics

Similar pharmacokinetics were observed in ulcerative colitis and Crohn's disease patients administered 300 mg ENTYVIO as a 30 minute intravenous infusion on Weeks 0 and 2, followed by 300 mg ENTYVIO every eight weeks starting from Week 6 (Table 2).

Table 2: Mean ± SD Vedolizumab Concentrations in Patients* with Ulcerative Colitis and Crohn's Disease

Patient Population Weeks 0 to 6 Weeks 6 to 52 ENTYVIO Every 8 Weeks
Trough Serum Concentration at Week 6 (mcg/mL) Trough Serum Concentration at Week 46†(mcg/mL)
Ulcerative Colitis 26.3 ± 12.9 (N=210) 11.2 ± 7.2 (N=77)
Crohn’s Disease 27.4 ± 19.2 (N=198) 13.0 ± 9.1 (N=72)
*Data from patients in UC Trials I and II and CD Trials I and III with pharmacokinetic data available; data from patients with anti-vedolizumab antibody were excluded.
†Steady-state trough serum concentration.

The presence of persistent anti-vedolizumab antibody was observed to substantially reduce serum concentrations of vedolizumab, either to undetectable or negligible levels at Weeks 6 and 52 (n=8).

Vedolizumab clearance depends on both linear and nonlinear pathways; the nonlinear clearance decreases with increasing concentrations. Population pharmacokinetic analyses indicated that the linear clearance was approximately 0.157 L/day, the serum half-life was approximately 25 days at 300 mg dosage, and the distribution volume was approximately 5 L.

Vedolizumab was not detected in the cerebrospinal fluid (CSF) of 14 healthy subjects at five weeks after a single intravenous administration of 450 mg ENTYVIO (1.5 times the recommended dosage).

Special Populations

Population pharmacokinetic analysis showed that the severity of disease state, body weight, prior treatment with TNF blocker therapy, age (18 to 78 years), serum albumin, coadministered immunomodulators (including azathioprine, 6-mercaptopurine, methotrexate), and co-administered aminosalicylates did not have a clinically meaningful effect on the pharmacokinetics of ENTYVIO.

Pharmacokinetics of vedolizumab in patients with renal or hepatic insufficiency have not been studied.

Clinical Studies

Clinical Studies In Ulcerative Colitis

The safety and efficacy of ENTYVIO were evaluated in two randomized, double-blind, placebo-controlled trials (UC Trials I and II) in adult patients with moderately to severely active ulcerative colitis (UC) defined as Mayo score of six to 12 with endoscopy subscore of two or three. The Mayo score ranges from zero to 12 and has four subscales that are each scored from zero (normal) to three (most severe): stool frequency, rectal bleeding, findings on endoscopy, and physician global assessment. An endoscopy subscore of two is defined by marked erythema, lack of vascular pattern, friability, and erosions; an endoscopy subscore of three is defined by spontaneous bleeding and ulceration.

Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine or 6mercaptopurine) and/or an inadequate response, loss of response, or intolerance to a TNF blocker. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of UC) or had an inadequate response or intolerance to corticosteroids.

Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.

UC Trial I

In UC Trial I, 374 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤ 30 mg/day or equivalent), and immunomodulators (azathioprine or 6-mercaptopurine) were permitted through Week 6.

At baseline, patients received corticosteroids (54%), immunomodulators (azathioprine or 6mercaptopurine) (30%), and/or aminosalicylates (74%). Thirty-nine percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Eighteen percent of patients had an inadequate response, inability to taper or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline Mayo score was nine in the ENTYVIO group and eight in the placebo group.

In UC Trial I, a greater percentage of patients treated with ENTYVIO compared to patients treated with placebo achieved clinical response at Week 6 (defined in Table 3). A greater percentage of patients treated with ENTYVIO compared to patients treated with placebo also achieved clinical remission at Week 6 (defined in Table 3). In addition, a greater percentage of patients treated with ENTYVIO had improvement of endoscopic appearance of the mucosa at Week 6 (defined in Table 3).

Table 3. Proportion of Patients Meeting Efficacy Endpoints at Week 6 (UC Trial I)

Endpoint Placebo N=149 ENTYVIO N=225 p-value Treatment Difference and 95% CI
Clinical response* at Week 6 26% 47% < 0.001 22% (12%, 32%)
Clinical remission† at Week 6 5% 17% 0.001 12% (5%, 18%)
Improvement of endoscopic appearance of the mucosa‡ at Week 6 25% 41% 0.001 16% (6%, 26%)
*Clinical response: reduction in complete Mayo score of ≥ 3 points and ≥ 30% from baseline with an accompanying decrease in rectal bleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point.
†Clinical remission: complete Mayo score of ≤ 2 points and no individual subscore > 1 point.
‡Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability).

UC Trial II

In order to be randomized to treatment in UC Trial II, patients had to have received ENTYVIO and be in clinical response at Week 6. Patients could have come from either UC Trial I or from a group who received ENTYVIO open-label.

In UC Trial II, 373 patients were randomized in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: ENTYVIO 300 mg every eight weeks, ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine or 6-mercaptopurine) were permitted outside the US but were not permitted beyond Week 6 in the US.

At Week 6, patients were receiving corticosteroids (61%), immunomodulators (azathioprine or 6-mercaptopurine) (32%) and aminosalicylates (75%). Thirty-two percent of patients had an inadequate response, loss of response or intolerance to a TNF blocker therapy. At Week 6, the median Mayo score was eight in the ENTYVIO every eight week group, the ENTYVIO every four week group, and the placebo group. Patients who had achieved clinical response at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.

In UC Trial II, a greater percentage of patients in groups treated with ENTYVIO as compared to placebo achieved clinical remission at Week 52, and maintained clinical response (clinical response at both Weeks 6 and 52) (Table 4). In addition, a greater percentage of patients in groups treated with ENTYVIO as compared to placebo were in clinical remission at both Weeks 6 and 52, and had improvement of endoscopic appearance of the mucosa at Week 52 (Table 4). In the subgroup of patients who achieved clinical response at Week 6 and were receiving corticosteroid medication at baseline, a greater proportion of patients in groups treated with ENTYVIO as compared to placebo discontinued corticosteroids and were in clinical remission at Week 52 (Table 4).

The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see DOSAGE AND ADMINISTRATION].

Table 4: Proportion of Patients Meeting Efficacy Endpoints at Week 52* (UC Trial II)

Endpoint Placebo†
N=126
ENTYVIO Every 8 Weeks
N=122
p-value Treatment Difference and 95% CI
Clinical remission at Week 52 16% 42% < 0.001 26% (15%, 37%)
Clinical response at both Weeks 6 and 52 24% 57% < 0.001 33% (21%, 45%)
Improvement of endoscopic appearance of the mucosa‡ at Week 52 20% 52% < 0.001 32% (20%, 44%)
Clinical remission at both Weeks 6 and 52 9% 21% 0.008 12% (3%, 21%)
Corticosteroid-free clinical remission§ 14%§ 31%§ 0.012 18% (4%, 31%)
*Patients must have achieved clinical response at Week 6 to continue into UC Trial II. This group includes patients that were not in clinical remission at Week 6.
†The placebo group includes those patients who received ENTYVIO at Week 0 and Week 2 and were randomized to receive placebo from Week 6 through Week 52.
‡Improvement of endoscopic appearance of the mucosa: Mayo endoscopy subscore of 0 (normal or inactive disease) or 1 (erythema, decreased vascular pattern, mild friability) at Week 52.
§Corticosteroid-free clinical remission: Assessed in the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (n=72 for placebo and n=70 for ENTYVIO every eight weeks). Corticosteroid-free clinical remission was defined as the proportion of patients in this subgroup that discontinued corticosteroids by Week 52 and were in clinical remission at Week 52.

Clinical Studies In Crohn's Disease

The safety and efficacy of ENTYVIO were evaluated in three randomized, double-blind, placebo-controlled clinical trials (CD Trials I, II, and III) in adult patients with moderately to severely active Crohn's disease (CD) (Crohn's Disease Activity Index [CDAI] score of 220 to 450).1

Enrolled patients in the United States (US) had over the previous five-year period an inadequate response or intolerance to immunomodulator therapy (i.e., azathioprine, 6mercaptopurine, or methotrexate) and/or an inadequate response, loss of response, or intolerance to one or more TNF blockers. Outside the US, prior treatment with corticosteroids was sufficient for entry if over the previous five-year period the patients were corticosteroid dependent (i.e., unable to successfully taper corticosteroids without a return of the symptoms of CD) or had an inadequate response or intolerance to corticosteroids.

Patients that had received natalizumab ever in the past, and patients that had received a TNF blocker in the past 30 to 60 days were excluded from enrollment. Concomitant use of natalizumab or a TNF blocker was not allowed.

CD Trial I

In CD Trial I, 368 patients were randomized in a double-blind fashion (3:2) to receive ENTYVIO 300 mg or placebo by intravenous infusion at Week 0 and Week 2. Efficacy assessments were at Week 6. Concomitant stable dosages of aminosalicylates, corticosteroids (prednisone dosage ≤ 30 mg/day or equivalent), and immunomodulators (azathioprine, 6mercaptopurine or methotrexate) were permitted through Week 6.

At baseline, patients were receiving corticosteroids (49%), immunomodulators (azathioprine, 6mercaptopurine, or methotrexate) (35%), and/or aminosalicylates (46%). Forty-eight percent of the patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. Seventeen percent of patients had inadequate response, inability to taper, or intolerance to prior corticosteroid treatment only (i.e., had not received prior immunomodulators or TNF blockers). The median baseline CDAI score was 324 in the ENTYVIO group and 319 in the placebo group.

In CD Trial I, a statistically significantly higher percentage of patients treated with ENTYVIO achieved clinical remission (defined as CDAI ≤ 150) as compared to placebo at Week 6 (Table 5). The difference in the percentage of patients who demonstrated clinical response (defined as a ≥ 100-point decrease in CDAI score from baseline), was however, not statistically significant at Week 6.

CD Trial II

Compared to CD Trial I, CD Trial II enrolled a higher number of patients who had over the previous five-year period had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76%); this was the primary analysis population. In CD Trial II, 416 patients were randomized in a double-blind fashion (1:1) to receive either ENTYVIO 300 mg or placebo at Weeks 0, 2 and 6. Efficacy assessments were at Weeks 6 and 10. Concomitant aminosalicylates, corticosteroids, and immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted through Week 10.

At baseline, patients were receiving corticosteroids (54%), immunomodulators (azathioprine, 6mercaptopurine, or methotrexate) (34%), and aminosalicylates (31%). The median baseline CDAI score was 317 in the ENTYVIO group and 301 in the placebo group.

For the primary endpoint (clinical remission at Week 6), treatment with ENTYVIO did not result in statistically significant improvement over placebo (Table 5). Secondary endpoints including assessments at Week 10 were not tested because the primary endpoint was not statistically significant.

Table 5: Proportion of Patients in Clinical Remission at Week 6 (CD Trials I and II)

  Placebo ENTYVIO p-value Treatment Difference and 95% CI
CD Trial I: Clinical Remission* at Week 6 7% (10/148) 15% (32/220) 0.041* 8% (1%, 14%)
CD Trial II†: Clinical Remission* at Week 6 12% (19/157) 15% (24/158) NS§ 3% (-5%, 11%)
*Clinical Remission: CDAI ≤ 150
†The primary analysis population for CD Trial II was patients that had an inadequate response, loss of response, or intolerance to one or more TNF blockers (76% of the overall population)
‡Adjusted p-value for multiple comparisons of two primary endpoints
§NS: Not significant (Secondary endpoints including assessments at Week 10 were not tested because the CD Trial II primary endpoint was not statistically significant)

CD Trial III

In order to be randomized to treatment in CD Trial III, patients had to have received ENTYVIO and be in clinical response (defined as a ≥ 70-point decrease in CDAI score from baseline) at Week 6. Patients could have come from either CD Trial I or from a group who received ENTYVIO open-label.

In CD Trial III, 461 patients were randomized in a double-blind fashion (1:1:1) to one of the following regimens beginning at Week 6: ENTYVIO 300 mg every eight weeks, ENTYVIO 300 mg every four weeks or placebo every four weeks. Efficacy assessments were at Week 52. Concomitant aminosalicylates and corticosteroids were permitted through Week 52. Concomitant immunomodulators (azathioprine, 6-mercaptopurine, or methotrexate) were permitted outside the US but were not permitted beyond Week 6 in the US.

At Week 6, patients were receiving corticosteroids (59%), immunomodulators (azathioprine, 6mercaptopurine, or methotrexate) (31%), and aminosalicylates (41%). Fifty-one percent of patients had an inadequate response, loss of response, or intolerance to a TNF blocker therapy. At Week 6, the median CDAI score was 322 in the ENTYVIO every eight week group, 316 in the ENTYVIO every four week group, and 315 in the placebo group. Patients who had achieved clinical response ( ≥ 70 decrease in CDAI score from baseline) at Week 6 and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen at Week 6.

In CD Trial III a greater percentage of patients in groups treated with ENTYVIO as compared to placebo were in clinical remission (defined as CDAI score ≤ 150) at Week 52. A greater percentage of patients in groups treated with ENTYVIO as compared to placebo had a clinical response (defined as ≥ 100 decrease in CDAI score from baseline) at Week 52 (Table 6). In the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response at Week 6 (defined as ≥ 70 decrease in CDAI score from baseline), a greater proportion of patients in groups treated with ENTYVIO as compared to placebo discontinued corticosteroids by Week 52 and were in clinical remission at Week 52 (Table 6).

The ENTYVIO every four week dosing regimen did not demonstrate additional clinical benefit over the every eight dosing week regimen. The every four week dosing regimen is not the recommended dosing regimen [see DOSAGE AND ADMINISTRATION].

Table 6: Proportion of Patients Meeting Efficacy Endpoints at Week 52* (CD Trial III)

  Placebo†
N=153
ENTYVIO Every 8 Weeks
N=154
p-value Treatment Difference and 95% CI
Clinical remission‡ at Week 52 22% 39% 0.001 17% (7%, 28%)
Clinical response§ at Week 52 30% 44% 0.013 13% (3%, 24%)
Corticosteroid-free clinical remission# 16%# 32%# 0.015 16% (3%, 29%)
*This group includes patients that were not in clinical remission at Week 6. Patients must have achieved clinical response (defined as ≥ 70 decrease in CDAI from baseline) at Week 6 to continue into CD Trial III.
†The placebo group includes those patients who received ENTYVIO at Week 0 and Week 2, and were randomized to receive placebo from Week 6 through Week 52
‡Clinical remission: CDAI ≤ 150
§Clinical response: ≥ 100 decrease in CDAI from baseline
#Corticosteroid-free clinical remission: Assessed in the subgroup of patients who were receiving corticosteroids at baseline and who were in clinical response (defined as ≥ 70 decrease in CDAI from baseline) at Week 6 (n=82 for placebo and n=82 for ENTYVIO every eight weeks). Corticosteroid-free clinical remission was defined as the proportion of patients in this subgroup that discontinued corticosteroids by Week 52 and were in clinical remission at Week 52.

REFERENCES

1. Best WR, Becktel JM, Singleton JW, Kern F: Development of a Crohn's Disease Activity Index, National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 439444

Last reviewed on RxList: 5/30/2014
This monograph has been modified to include the generic and brand name in many instances.

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