Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

Pharmacotherapeutic group: immunosuppressants, monoclonal antibodies, ATC code: L04AG05.

Mechanism of action
Vedolizumab is a gut-selective immunosuppressive biologic. It is a humanised monoclonal antibody that binds specifically to the α4β7 integrin, which is preferentially expressed on gut homing T helper lymphocytes. By binding to α4β7 on certain lymphocytes, vedolizumab inhibits adhesion of these cells to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but not to vascular cell adhesion molecule-1 (VCAM-1). MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to tissues within the gastrointestinal tract. Vedolizumab does not bind to, nor inhibit function of, the α4β1 and αEβ7 integrins.

The α4β7 integrin is expressed on a discrete subset of memory T helper lymphocytes which preferentially migrate into the gastrointestinal (GI) tract and cause inflammation that is characteristic of ulcerative colitis and Crohn’s disease, both of which are chronic inflammatory immunologically mediated conditions of the GI tract. Vedolizumab reduces gastrointestinal inflammation in UC and CD patients. Inhibiting the interaction of α4β7 with MAdCAM-1 with vedolizumab prevents transmigration of gut-homing memory T helper lymphocytes across the vascular endothelium into parenchymal tissue in nonhuman primates and induced a reversible 3-fold elevation of these cells in peripheral blood. The murine precursor of vedolizumab alleviated gastrointestinal inflammation in colitic cotton-top tamarins, a model of ulcerative colitis.

In healthy subjects, ulcerative colitis patients, or Crohn’s disease patients, vedolizumab does not elevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T lymphocytes, total memory T helper lymphocytes, monocytes or natural killer cells, in the peripheral blood with no leukocytosis observed.

Vedolizumab did not affect immune surveillance and inflammation of the central nervous system in Experimental Autoimmune Encephalomyelitis in non-human primates, a model of multiple sclerosis.
Vedolizumab did not affect immune responses to antigenic challenge in the dermis and muscle (see section 4.4). In contrast, vedolizumab inhibited an immune response to a gastrointestinal antigenic challenge in healthy human volunteers (see section 4.4).


Immunogenicity

Antibodies to vedolizumab may develop during vedolizumab treatment most of which are neutralising.
The formation of anti-vedolizumab antibodies is associated with increased clearance of vedolizumab and lower rates of clinical remission.

Pharmacodynamic effects

In clinical trials with intravenous vedolizumab at doses ranging from 0.2 to 10 mg/kg, > 95% saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut immune surveillance was observed in patients.

Vedolizumab did not affect CD4+ and CD8+ trafficking into the CNS as evidenced by the lack of change in the ratio of CD4+/CD8+ in cerebrospinal fluid pre- and post-vedolizumab administration in healthy human volunteers. These data are consistent with investigations in nonhuman primates which did not detect effects on immune surveillance of the CNS.

Clinical efficacy and safety

Ulcerative colitis - vedolizumab for intravenous administration
The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥ 2) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 6 and week 52 (GEMINI 1). Enrolled patients had failed at least 1 conventional therapy, including corticosteroids, immunomodulators, and/or the TNFα antagonist infliximab (including primary non-responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators were permitted.

For the evaluation of the week 6 endpoints, 374 patients were randomised in a double-blind fashion (3:2) to receive vedolizumab 300 mg or placebo at week 0 and week 2. Primary endpoint was the proportion of patients with clinical response (defined as 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) at week 6. Table 2 shows the results from the primary and secondary endpoints evaluated.

Table 2. Week 6 efficacy results of GEMINI 1
Placebo                        Vedolizumab
Endpoint                                            n = 149                        n = 225 Clinical response                                    26%                               47%* Clinical remission§                                   5%                               17%† Mucosal healing¶                                     25%                               41%‡ *p < 0.0001
† p ≤ 0.001
‡ p < 0.05
§
Clinical remission: Complete Mayo score of ≤ 2 points and no individual subscore > 1 point ¶
Mucosal healing: Mayo endoscopic subscore of ≤ 1 point

The beneficial effect of vedolizumab on clinical response, remission and mucosal healing was observed both in patients with no prior TNFα antagonist exposure as well as in those who had failed prior TNFα antagonist therapy.

In GEMINI 1, 2 cohorts of patients received vedolizumab at week 0 and week 2: cohort 1 patients were randomised to receive either vedolizumab 300 mg or placebo in a double-blind fashion, and cohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacy at week 52, 373 patients from cohort 1 and 2 who were treated with vedolizumab and had achieved clinical response at week 6 were randomised in a double-blind fashion (1:1:1) to 1 of the following regimens 
beginning at week 6: vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, or placebo every 4 weeks. Beginning at week 6, patients who had achieved clinical response and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen. Primary endpoint was the proportion of patients in clinical remission at week 52. Table 3 shows the results from the primary and secondary endpoints evaluated.

Table 3. Week 52 efficacy results of GEMINI 1
Vedolizumab IV        Vedolizumab IV
Placebo            every 8 weeks         every 4 weeks
Endpoint                                           n = 126*              n = 122               n = 125 Clinical remission                                    16%                  42%†                   45%† Durable clinical response¶                            24%                  57%†                   52%† Mucosal healing                                       20%                  52%†                   56%† Durable clinical remission#                           9%                   20%§                   24%‡ Corticosteroid-free clinical remission♠               14%                  31%§                   45%† *The placebo group includes those subjects who received vedolizumab at week 0 and week 2, and were randomised to receive placebo from week 6 through week 52.
† p < 0.0001
‡ p < 0.001
§ p < 0.05
¶
Durable clinical response: Clinical response at weeks 6 and 52
#
Durable clinical remission: Clinical remission at weeks 6 and 52
♠
Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinued corticosteroids beginning at week 6 and were in clinical remission at week 52. Patient numbers were n = 72 for placebo, n = 70 for vedolizumab every 8 weeks, and n = 73 for vedolizumab every 4 weeks 

Exploratory analyses provide additional data on key subpopulations studied. Approximately one-third of patients had failed prior TNFα antagonist therapy. Among these patients, 37% receiving vedolizumab every 8 weeks, 35% receiving vedolizumab every 4 weeks, and 5% receiving placebo achieved clinical remission at week 52. Improvements in durable clinical response (47%, 43%, 16%), mucosal healing (42%, 48%, 8%), durable clinical remission (21%, 13%, 3%) and corticosteroid-free clinical remission (23%, 32%, 4%) were seen in the prior TNFα antagonist failure population treated with vedolizumab every 8 weeks, vedolizumab every 4 weeks and placebo, respectively.

Patients who failed to demonstrate response at week 6 remained in the study and received vedolizumab every 4 weeks. Clinical response using partial Mayo scores was achieved at week 10 and week 14 by greater proportions of vedolizumab patients (32% and 39%, respectively) compared with placebo patients (15% and 21%, respectively).

Patients who lost response to vedolizumab when treated every 8 weeks were allowed to enter an open-label extension study and receive vedolizumab every 4 weeks. In these patients, clinical remission was achieved in 25% of patients at week 28 and week 52.

Patients who achieved a clinical response after receiving vedolizumab at week 0 and 2 and were then randomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-label extension study and receive vedolizumab every 4 weeks. In these patients, clinical remission was achieved in 45% of patients by 28 weeks and 36% of patients by 52 weeks.

In this open-label extension study, the benefits of vedolizumab treatment as assessed by partial Mayo score, clinical remission, and clinical response were shown for up to 196 weeks.



Health-related quality of life (HRQOL) was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ), a disease specific instrument, and SF-36 and EQ-5D, which are generic measures.
Exploratory analysis show clinically meaningful improvements were observed for vedolizumab groups, and the improvements were significantly greater as compared with the placebo group at week 6 and week 52 on EQ-5D and EQ-5D VAS scores, all subscales of IBDQ (bowel symptoms, systemic function, emotional function and social function), and all subscales of SF-36 including the Physical Component Summary (PCS) and Mental Component Summary (MCS).

Ulcerative colitis - vedolizumab for subcutaneous administration

The efficacy and safety of subcutaneous vedolizumab for the treatment of adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥ 2) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 52 (VISIBLE 1). In VISIBLE 1, enrolled patients (n = 383) had failed at least 1 conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators were permitted.

Patients who achieved clinical response to open-label treatment with intravenous vedolizumab at week 6 were eligible to be randomised For the evaluation of the week 52 endpoints, 216 (56.4%) patients were randomised and treated in a double-blind fashion (2:1:1) to 1 of the following regimens: subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo.

The baseline demographics were similar for patients in vedolizumab and placebo groups. The baseline Mayo score was between 9 to 12 (severe ulcerative colitis) in about 62% and 6 to 8 (moderate ulcerative colitis) in about 38% of the overall study population.

Primary study endpoint clinical remission was defined as a complete Mayo score of ≤ 2 points and no individual subscore > 1 point at 52 weeks in patients who had achieved a clinical response at week 6 of intravenous vedolizumab induction treatment. Clinical response was defined as a 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 ≤ 2 points and no individual subscore >1 point.

Table 4 shows the evaluated results from the primary and secondary endpoints.

Table 4. Week 52 efficacy results of VISIBLE I
Estimatec of
Vedolizumab
Vedolizumab                                treatment b                             IV
Placebo       SC 108 mg                                 difference
Endpointa                                                    300 mg                                   P-valuec n = 56      every 2 weeks                              (95% CI) every 8 weeks n = 106                              Vedolizumab SC n = 54 vs. Placebo
Clinical remissiond       14.3%            46.2%              42.6%           32.3 (19.7, 45.0)      p < 0.001 Mucosal healing    e
21.4%            56.6%              53.7%            35.7 (22.1, 49.3)     p < 0.001 Durable clinical
28.6%            64.2%              72.2%            36.1 (21.2, 50.9)     p < 0.001 responsef
Durable clinical                                                                                     p = 0.076 5.4%            15.1%              16.7%            9.7 (-6.6, 25.7) remissiong                                                                                             (NS) Corticosteroid-free                                                                                  p = 0.067 8.3%            28.9%              28.6%            20.6 (-4.5, 43.7) remissionh                                                                                             (NS) a
Endpoints are presented in the order that fixed-sequence testing was performed for control of Type 1 error at 5% b
The placebo group includes those subjects who received intravenous vedolizumab at week 0 and week 2, and were randomised to receive placebo from week 6 through week 52.


c
Estimate of treatment difference and the p-value for all endpoints is based on the Cochrane-Mantel-Haenszel method d
Clinical remission: Complete Mayo score of ≤ 2 points and no individual subscore > 1 point at week 52 e
Mucosal healing: Mayo endoscopic subscore of ≤ 1 point f
Durable clinical response: Clinical response at weeks 6 and 52 g
Durable clinical remission: Clinical remission at weeks 6 and 52 h
Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinued corticosteroids and were in clinical remission at week 52. Patient numbers using oral corticosteroids at baseline were n = 24 for placebo, n = 45 for subcutaneous vedolizumab and n = 21 for intravenous vedolizumab NS = non significant (2-tailed p-value > 0.05)

The primary and secondary endpoints were analysed in subgroups of patients who had failed prior TNFα antagonist therapy (37%; n = 80) and patients who were naïve to previous TNFα antagonist therapy (63%; n = 136). Results of study patients treated with placebo and subcutaneous vedolizumab in these subgroups are presented in Table 5.

Table 5. VISIBLE 1 Study results at week 52 analysed by response to prior previous TNFα antagonist therapy
Treatment once every 2 weeks
Placebo         Vedolizumab SC 108 mg
Failure prior TNFα antagonist therapy            n = 19          n = 39 Clinical remission                                       5.3%            33.3% Mucosal healing                                          5.3%            46.2% Durable clinical response                                15.8%           66.7% Durable clinical remission                                  0%              2.6% Corticosteroid free clinical remissiona                      8.3%            27.3% 

Naive TNFα antagonist therapy                                   n = 37          n = 67 Clinical remission                                       18.9%           53.7% Mucosal healing                                          29.7%           62.7% Durable clinical response                                35.1%           62.7% Durable clinical remission                               8.1%            22.4% Corticosteroid free clinical remissionb                      8.3%            30.4% a
Patients who had failed prior TNFα antagonist therapy and using oral corticosteroids at baseline were n = 12 for placebo and n = 22 for subcutaneous vedolizumab b
Patients who were naïve to prior TNFα antagonist therapy and using oral corticosteroids at baseline were n = 12 for placebo and n = 23 for subcutaneous vedolizumab

Health related quality of life (HRQOL) was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ), a disease specific instrument, and EuroQol-5 Dimension (EQ-5D, including EQ 5D VAS), which is a generic measure. Work productivity was assessed by work productivity and activity impairment questionnaire (WPAI-UC). Patients treated with subcutaneous vedolizumab maintained improvements in IBDQ, EQ-5D and WPAI-UC scores at week 52 to a greater extent than patients who received placebo.

Patients who completed VISIBLE 1 were eligible to enrol in an ongoing, open-label extension study to evaluate long-term safety and efficacy of subcutaneous vedolizumab treatment in patients with ulcerative colitis or Crohn’s disease.

Patients in VISIBLE 1 who did not achieve clinical response at week 6 received a third dose of vedolizumab 300 mg by intravenous infusion at week 6. Of patients who received a third dose of vedolizumab 300 mg by intravenous infusion at week 6, 79.7% (114/143) achieved a clinical response at week 14. Patients who achieved a clinical response at week 14 were eligible to enter the open-label extension study and receive subcutaneous vedolizumab 108 mg every 2 weeks. Clinical remission as 
assessed by the partial Mayo score (a standardised measure that includes 3 of the 4 scored subscales of the complete Mayo score: stool frequency, rectal bleeding, and physician global assessment) was achieved by 39.2% (40/102) of these patients at week 40 after transitioning to subcutaneous vedolizumab in the open-label extension study.

Patients randomised to intravenous vedolizumab treatment group in VISIBLE 1 received vedolizumab 300 mg intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter until week 52. At week 52, these patients entered the open-label extension study and received subcutaneous vedolizumab 108 mg every 2 weeks. Clinical remission as assessed by the partial Mayo score was maintained in 77% of patients at 24 weeks after transitioning to subcutaneous vedolizumab in the open-label extension study.

Crohn’s disease – vedolizumab for intravenous administration

The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450) were evaluated in 2 studies (GEMINI 2 and 3). Enrolled patients have failed at least 1 conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non-responders). Concomitant stable doses of oral corticosteroids, immunomodulators, and antibiotics were permitted.

The GEMINI 2 Study was a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 6 and week 52. Patients (n = 368) were randomised in a double-blind fashion (3:2) to receive 2 doses of vedolizumab 300 mg or placebo at week 0 and week 2. The 2 primary endpoints were the proportion of patients in clinical remission (defined as CDAI score ≤ 150 points) at week 6 and the proportion of patients with enhanced clinical response (defined as a ≥ 100-point decrease in CDAI score from baseline) at week 6 (see Table 6).

GEMINI 2 contained 2 cohorts of patients that received vedolizumab at weeks 0 and 2: cohort 1 patients were randomised to receive either vedolizumab 300 mg or placebo in a double-blind fashion, and cohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacy at week 52, 461 patients from cohorts 1 and 2, who were treated with vedolizumab and had achieved clinical response (defined as a ≥ 70-point decrease in CDAI score from baseline) at week 6, were randomised in a double-blind fashion (1:1:1) to 1 of the following regimens beginning at week 6: vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, or placebo every 4 weeks.
Patients showing clinical response at week 6 were required to begin corticosteroid tapering. Primary endpoint was the proportion of patients in clinical remission at week 52 (see Table 7).

The GEMINI 3 Study was a second randomised, double-blind, placebo-controlled study that evaluated efficacy at week 6 and week 10 in the subgroup of patients defined as having failed at least 1 conventional therapy and failed TNFα antagonist therapy (including primary non-responders) as well as the overall population, which also included patients who failed at least 1 conventional therapy and were naïve to TNFα antagonist therapy. Patients (n = 416), which included approximately 75% TNFα antagonist failures patients, were randomised in a double-blind fashion (1:1) to receive either vedolizumab 300 mg or placebo at weeks 0, 2, and 6. The primary endpoint was the proportion of patients in clinical remission at week 6 in the TNFα antagonist failure subpopulation. As noted in Table 6, although the primary endpoint was not met, exploratory analyses show that clinically meaningful results were observed.



Table 6. Efficacy results for GEMINI 2 and 3 studies at week 6 and week 10 Study                                         Placebo                Vedolizumab IV Endpoint
GEMINI 2 Study
Clinical remission, week 6
Overall                                             7% (n = 148)                 15%* (n = 220) TNFα Antagonist(s) Failure                        4% (n = 70)                  11% (n = 105) TNFα Antagonist(s) Naïve                          9% (n = 76)                  17% (n = 109) Enhanced clinical response, week 6
Overall                                             26% (n = 148)                31%† (n = 220) TNFα Antagonist(s) Failure                       23% (n = 70)                  24% (n = 105) TNFα Antagonist(s) Naïve                         30% (n = 76)                  42% (n = 109) Serum CRP change from baseline to week 6, median (mcg/mL)
Overall‡                                             -0.5 (n = 147)                -0.9 (n = 220) GEMINI 3 Study
Clinical remission, week 6
Overall‡                                         12% (n = 207)                 19% (n = 209) TNFα Antagonist(s) Failure         ¶
12% (n = 157)                 15%§ (n = 158)
TNFα Antagonist(s) Naïve                         12% (n = 50)                   31% (n = 51) Clinical remission, week 10
Overall                                          13% (n = 207)                 29% (n = 209) TNFα Antagonist(s) Failure         ¶,‡
12% (n = 157)                 27% (n = 158)
TNFα Antagonist(s) Naïve                         16% (n = 50)                   35% (n = 51) #,¶
Sustained clinical remission
Overall                                          8% (n = 207)                  15% (n = 209) TNFα Antagonist(s) Failure¶,‡                    8% (n = 157)                  12% (n = 158) TNFα Antagonist(s) Naïve                         8% (n = 50)                   26% (n = 51) Enhanced clinical response, week 6

Overall^                                        23% (n = 207)                 39% (n = 209) TNFα Antagonist(s) Failure            ‡
22% (n = 157)                 39% (n = 158)
TNFα Antagonist(s) Naïve^                       24% (n = 50)                   39% (n = 51) *p < 0.05
† not statistically significant
‡ secondary endpoint to be viewed as exploratory by pre-specified statistical testing procedure § not statistically significant, the other endpoints were therefore not tested statistically ¶ n = 157 for placebo and n = 158 for vedolizumab
#
Sustained clinical remission: clinical remission at weeks 6 and 10
^Exploratory Endpoint


Table 7. Efficacy results for GEMINI 2 at week 52
Vedolizumab IV                   Vedolizumab IV
Placebo     every 8 weeks                    every 4 weeks n = 153*        n = 154                         n = 154
Clinical remission                              22%            39%†                  36%‡ Enhanced clinical response                30%                 44%‡                   45%‡ Corticosteroid-free clinical              16%                 32%‡                   29%‡ remission§
Durable clinical remission¶               14%                 21%                    16% *The placebo group includes those subjects who received vedolizumab at week 0 and week 2, and were randomised to receive placebo from week 6 through week 52.
† p < 0.001
‡ p < 0.05
§
Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinued corticosteroids beginning at week 6 and were in clinical remission at week 52. Patient numbers were n = 82 for placebo, n = 82 for vedolizumab every 8 weeks, and n = 80 for vedolizumab every 4 weeks ¶
Durable clinical remission: Clinical remission at ≥ 80% of study visits including final visit (week 52) 
Exploratory analyses examined the effects of concomitant corticosteroids and immunomodulators on induction of remission with vedolizumab. Combination treatment, most notably with concomitant corticosteroids, appeared to be more effective in inducing remission in Crohn’s disease than vedolizumab alone or with concomitant immunomodulators, which showed a smaller difference from placebo in the rate of remission. Clinical remission rate in GEMINI 2 at week 6 was 10% (difference from placebo 2%, 95% CI: -6, 10) when administered without corticosteroids compared to 20% (difference from placebo 14%, 95% CI: -1, 29) when administered with concomitant corticosteroids.
In GEMINI 3 at week 6 and 10 the respective clinical remission rates were 18% (difference from placebo 3%, 95% CI: -7, 13) and 22% (difference from placebo 8%, 95% CI: -3, 19) when administered without corticosteroids compared to 20% (difference from placebo 11%, 95% CI: 2, 20) and 35% (difference from placebo 23%, 95% CI: 12, 33) respectively when administered with concomitant corticosteroids. These effects were seen whether or not immunomodulators were also concomitantly administered.

Exploratory analyses provide additional data on key subpopulations studied. In GEMINI 2, approximately half of patients had previously failed TNFα antagonist therapy. Among these patients, 28% receiving vedolizumab every 8 weeks, 27% receiving vedolizumab every 4 weeks, and 13% receiving placebo achieved clinical remission at week 52. Enhanced clinical response was achieved in 29%, 38%, 21%, respectively, and corticosteroid-free clinical remission was achieved in 24%, 16%,
0%, respectively.

Patients who failed to demonstrate response at week 6 in GEMINI 2 were retained in the study and received vedolizumab every 4 weeks. Enhanced clinical response was observed at week 10 and week 14 for greater proportions of vedolizumab patients 16% and 22%, respectively, compared with placebo patients 7% and 12%, respectively. There was no clinically meaningful difference in clinical remission between treatment groups at these time points. Analyses of week 52 clinical remission in patients who were non-responders at week 6 but achieved response at week 10 or week 14 indicate that non-responder CD patients may benefit from a dose of vedolizumab at week 10.

Patients who lost response to vedolizumab when treated every 8 weeks in GEMINI 2 were allowed to enter an open-label extension study and received vedolizumab every 4 weeks. In these patients, clinical remission was achieved in 23% of patients at week 28 and 32% of patients at week 52.

Patients who achieved a clinical response after receiving vedolizumab at week 0 and 2 and were then randomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-label extension study and receive vedolizumab every 4 weeks. In these patients, clinical remission was achieved in 46% of patients by 28 weeks and 41% of patients by 52 weeks.



In this open-label extension study, clinical remission and clinical response were observed in patients for up to 196 weeks.

Exploratory analysis showed clinically meaningful improvements were observed for the vedolizumab every 4 weeks and every 8 weeks groups in GEMINI 2 and the improvements were significantly greater as compared with the placebo group from baseline to week 52 on EQ-5D and EQ-5D VAS scores, total IBDQ score, and IBDQ subscales of bowel symptoms and systemic function.

Crohn’s disease - vedolizumab for subcutaneous administration

The efficacy and safety of subcutaneous vedolizumab for the treatment of adult patients with moderately to severely active Crohn’s disease (CDAI score of 220 to 450) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 52 (VISIBLE 2). In VISIBLE 2, enrolled patients (n = 644) had inadequate response to, loss of response to, or intolerance to one conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non-responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators were permitted.

Patients who achieved clinical response to open-label treatment with intravenous vedolizumab at week 6 were eligible to be randomised. For the evaluation of the week 52 endpoints, 409 (64%) patients were randomised and treated in a double-blind fashion (2:1) to receive subcutaneous vedolizumab 108 mg (n = 275) or subcutaneous placebo (n = 134) every 2 weeks.

The baseline demographics were similar for patients in vedolizumab and placebo groups. The baseline CDAI was > 330 (severe Crohn’s disease) in about 41% and ≤ 330 (moderate Crohn’s disease) in about 59% of the overall study population.

Beginning at week 6, patients who had achieved clinical response (defined as a ≥ 70-point decrease in the CDAI score from baseline) and were receiving corticosteroids were required to begin a corticosteroid tapering regimen. Primary endpoint was the proportion of patients with clinical remission (CDAI score ≤ 150) at week 52. The secondary endpoints were the proportion of patients with enhanced clinical response ( ≥ 100 point decrease in CDAI score from baseline) at week 52, the proportion of patients with corticosteroid-free remission (patients using oral corticosteroids at baseline who had discontinued corticosteroids and were in clinical remission) at week 52, and the proportion of TNFα antagonist naïve patients who achieved clinical remission (CDAI score ≤ 150) at week 52.
Table 8 shows the evaluated results from the primary and secondary endpoints.



Table 8. Week 52 efficacy results of VISIBLE 2
Estimate‡ of
Vedolizumab treatment difference
Placebo†    SC 108 mg
Endpoint*                                                                (95% CI)                P-value‡ n = 134    every 2 weeks
Vedolizumab SC vs.
n = 275
Placebo
Clinical remission§                  34.3%      48.0%              13.7 (3.8, 23.7)          p = 0.008 p = 0.167
Enhanced clinical response#          44.8%      52.0%              7.3 (-3.0, 17.5) (NS)
Corticosteroid-free
18.2%      45.3%              27.1 (11.9, 42.3)         p = 0.002‡‡ remission**
Clinical remission in TNFα
42.9%      48.6%              4.3 (-11.6, 20.3)         p = 0.591‡‡ antagonist naïve patients††
*
Endpoints are presented in the order that fixed-sequence testing was performed for control of Type 1 error at 5%
†
The placebo group includes those subjects who received intravenous vedolizumab at week 0 and week 2, and were randomised to receive placebo from week 6 through week 52.
‡
Estimate of treatment difference and the p-value for all endpoints is based on the Cochrane-Mantel-Haenszel method
§
Clinical remission: CDAI score ≤ 150, at week 52
#
Enhanced clinical response: ≥ 100-point decrease in CDAI score from baseline (week 0), at week 52 **Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinued corticosteroids and were in clinical remission at week 52. Patient numbers using oral corticosteroids at baseline were n = 44 for placebo and n = 95 for subcutaneous vedolizumab.
†† Clinical remission (CDAI score ≤ 150, at week 52) in TNFα antagonist naïve patients (n = 63 placebo; n = 107 subcutaneous vedolizumab
‡‡ nominal p-value
NS = non significant (2-tailed p-value > 0.05)

The primary and secondary endpoints were analysed in subgroups of patients who were naïve to prior TNFα antagonist therapy (42%; n = 170), patients who had failed prior TNFα antagonist therapy (51%; n = 210), and patients who had exposure to prior TNFα antagonist therapy but did not experience treatment failure (7%; n = 29). Results of study patients treated with placebo and subcutaneous vedolizumab in these subgroups are presented in Tables 9 and 10.

Table 9. Week 52 efficacy results in TNFα antagonist naïve patients in VISIBLE 2 Vedolizumab SC 108 mg            Treatment difference
Placebo          every 2 weeks                   (95% CI)
Endpoint                              n = 63             n = 107             Vedolizumab SC vs. Placebo Clinical remission                    42.9%               48.6%                    4.3 (-11.6, 20.3) Enhanced clinical response                   47.6%                  54.2%                          4.4 (-11.6, 20.3) **
Corticosteroid-free remission                18.2%                  41.0%                          22.8 (-3.2, 46.8) **
Patients who were naïve to prior TNFα antagonist therapy and using oral corticosteroids at baseline were n = 22 for placebo and n = 39 for subcutaneous vedolizumab



Table 10. Week 52 efficacy results in patients who failed TNFα antagonist therapy in VISIBLE 2 Treatment difference
Vedolizumab SC 108 mg                (95% CI)
Placebo             every 2 weeks             Vedolizumab SC vs.
Endpoint                               n = 59                n = 151                      Placebo Clinical remission                     28.8%                 46.4%                    17.6 (3.8, 31.4) Enhanced clinical response                  45.8%                     49.0%                         3.2 (-11.8, 18.2) **
Corticosteroid-free remission               15.0%                     46.2%                          31.2 (5.2, 54.5) **
Patients who had failed prior TNFα antagonist therapy and using oral corticosteroids at baseline were n = 20 for placebo and n = 52 for subcutaneous vedolizumab


HRQOL was assessed by IBDQ, a disease specific instrument, and EQ-5D (including EQ-5D VAS), which is a generic measure. Work productivity was assessed by WPAI-CD. Patients treated with subcutaneous vedolizumab maintained improvements in IBDQ, EQ-5D and WPAI-CD scores at week 52 to a greater extent than patients who received placebo.
Patients who completed VISIBLE 2 were eligible to enrol in an ongoing, open-label extension study to evaluate long-term safety and efficacy of subcutaneous vedolizumab treatment in patients with ulcerative colitis or Crohn’s disease.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

The single and multiple dose pharmacokinetics of vedolizumab have been studied in healthy subjects and in patients with moderate to severely active ulcerative colitis or Crohn’s disease.

Absorption

In patients administered 300 mg intravenous vedolizumab as a 30 minute intravenous infusion on weeks 0 and 2, mean serum trough concentrations at week 6 were 27.9 mcg/mL (SD ± 15.51) in ulcerative colitis and 26.8 mcg/mL (SD ± 17.45) in Crohn’s disease. In studies with intravenous vedolizumab, starting at week 6, patients received 300 mg intravenous vedolizumab every 8 or 4 weeks. In patients with ulcerative colitis, mean steady-state serum trough concentrations were
11.2 mcg/mL (SD ± 7.24) and 38.3 mcg/mL (SD ± 24.43), respectively. In patients with Crohn's disease mean steady-state serum trough concentrations were 13.0 mcg/mL (SD ± 9.08) and 34.8 mcg/mL (SD ± 22.55), respectively.

In studies in patients with ulcerative colitis or Crohn’s disease receiving subcutaneous vedolizumab, starting at week 6, patients received 108 mg subcutaneous vedolizumab every 2 weeks. The mean steady state serum trough concentrations were 35.8 mcg/mL (SD ± 15.2) in patients with ulcerative colitis and 31.4 mcg/mL (SD ± 14.7) in patients with Crohn’s disease. The bioavailability of vedolizumab following single-dose subcutaneous administration of 108 mg relative to single-dose intravenous administration was approximately 75%. The median time to reach maximum serum concentration (tmax) was 7 days (range 3 to 14 days), and the mean maximum serum concentration (Cmax) was 15.4 mcg/mL (SD ± 3.2).



Distribution

Population pharmacokinetic analyses indicate that the distribution volume of vedolizumab is approximately 5 litres. The plasma protein binding of vedolizumab has not been evaluated.
Vedolizumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.

Vedolizumab does not pass the blood brain barrier after intravenous administration. Vedolizumab 450 mg administered intravenously was not detected in the cerebrospinal fluid of healthy subjects.

Elimination

Population pharmacokinetic analyses based on intravenous and subcutaneous data indicate that the clearance of vedolizumab is approximately 0.162 L/day (through linear elimination pathway) and the serum half-life is 26 days. The exact elimination route of vedolizumab is not known. Population pharmacokinetic analyses suggest that while low albumin, higher body weight and prior treatment with anti-TNF drugs may increase vedolizumab clearance, the magnitude of their effects is not considered to be clinically relevant.

Linearity

Vedolizumab exhibited linear pharmacokinetics at serum concentrations greater than 1 mcg/mL.
Special populations

Age does not impact the vedolizumab clearance in ulcerative colitis and Crohn’s disease patients based on the population pharmacokinetic analyses. No formal studies have been conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of vedolizumab.