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, CD and pouchitis 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.

Infusion related reactions after vedolizumab infusion are reported in subjects with anti-vedolizumab antibodies.

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
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 one 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 IV
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 TNF antagonist exposure as well as in those who had failed prior TNF 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 one 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 TNF 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).

Crohn’s disease

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 one 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 4).

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 one 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 5).

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 TNF 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 TNF antagonist therapy. Patients (n = 416), which included approximately 75% TNF 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 TNF antagonist failure subpopulation. As noted in Table 4, although the primary endpoint was not met, exploratory analyses show that clinically meaningful results were observed.


Table 4. Efficacy results for GEMINI 2 and 3 studies at week 6 and week 10 Study
Endpoint                                                 Placebo                            Vedolizumab IV 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 5. 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 remission§          16%                   32%‡                      29%‡ 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.

Pouchitis

The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with chronic pouchitis were demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy at week 14 and week 34 (EARNEST). Enrolled patients had undergone proctocolectomy and ileal pouch anal anastomosis (IPAA) for ulcerative colitis at least one year prior to randomisation and had developed active chronic pouchitis (defined as antibiotic-dependent (recurrent) or antibiotic- refractory), with a baseline modified Pouchitis Disease Activity Index (mPDAI) score ≥ 5 and endoscopic subscore ≥ 2. All patients received concomitant antibiotic treatment with ciprofloxacin 500 mg twice daily from the start of treatment through week 4. Patients received additional courses of antibiotics during the study as needed, including for pouchitis flares.

Patients (n=102) were randomised (1:1) to receive either intravenous vedolizumab 300 mg or intravenous placebo at 0, 2 and 6 weeks, and every 8 weeks thereafter, until week 30. The primary endpoint was clinical remission (defined as an mPDAI score < 5 and a reduction in total mPDAI score of ≥ 2 points from baseline) at week 14. Table 6 shows the results from the primary and secondary endpoints at week 14 and Table 7 shows the results from secondary endpoints at week 34.

Table 6. Efficacy results for EARNEST at week 14
Difference
Placebo         Vedolizumab IV          Vedolizumab-Placebo (95% CI)
Endpoint                            n = 51             n = 51                    [percentage points] Clinical remission*                  9.8%                31.4%†                     21.6 (4.9, 37.5) PDAI remission   ‡
9.8%                35.3%                      25.5 (8.0, 41.4)
Clinical response    §
33.3%                62.7%                      29.4 (8.0, 47.6)
*Clinical remission is defined as mPDAI score < 5 and a reduction in total mPDAI score of ≥ 2 points from baseline
† p < 0.05
‡
PDAI remission is defined as PDAI score < 7 and a reduction in PDAI score of ≥ 3 points from baseline §
Clinical response is defined as reduction of mPDAI score of ≥ 2 points from baseline 

Table 7. Efficacy results for EARNEST at week 34
Difference
Placebo          Vedolizumab IV         Vedolizumab-Placebo (95% CI)
Endpoint                            n = 51              n = 51                   [percentage points] Clinical remission*                 17.6%                 35.3%                     17.6 (0.3, 35.1) PDAI remission‡                     17.6%                 37.3%                     19.6 (1.9, 37.0) Clinical response§                  29.4%                 51.0%                     21.6 (1.9, 39.8) *Clinical remission is defined as mPDAI score < 5 and reduction in total mPDAI score of ≥ 2 points from baseline
‡
PDAI remission is defined as PDAI score < 7 and a reduction in PDAI score of ≥ 3 points from baseline §
Clinical response is defined as reduction of mPDAI score of ≥ 2 points from baseline 

Approximately two-thirds of patients had received prior (for UC or pouchitis) TNF α antagonist therapy (33 in vedolizumab and 31 in placebo treatment groups). Among these patients, 33.3% in the vedolizumab group achieved clinical remission at W14 compared with 9.7% in the placebo group.

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. The pharmacokinetics of vedolizumab has not been studied in patients with pouchitis but is expected to be similar to that in patients with moderate to severely active ulcerative colitis or Crohn’s disease.

In patients administered 300 mg 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.

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. Age is not expected to impact the vedolizumab clearance in patients with pouchitis. No formal studies have been conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of vedolizumab.