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Tysabri

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Tysabri

CLINICAL PHARMACOLOGY

Mechanism Of Action

Natalizumab binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the α4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-α4-integrin antibodies also block α4mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, natalizumab may further act to inhibit the interaction of α4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.

The specific mechanism(s) by which TYSABRI exerts its effects in multiple sclerosis and Crohn's disease have not been fully defined.

In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of α4β1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown.

In Crohn's disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab in CD may therefore be secondary to blockade of the molecular interaction of the α47-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear.

Pharmacodynamics

TYSABRI administration increases the number of circulating leukocytes (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space. TYSABRI does not affect the absolute count of circulating neutrophils [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

Multiple Sclerosis (MS) Patients

In patients with MS, following the repeat intravenous administration of a 300 mg dose of TYSABRI, the mean ± SD maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 11 ± 4 days, 5.7 ± 1.9 L, and 16 ± 5 mL/hour, respectively.

The effects of covariates such as body weight, age, gender, and presence of anti-natalizumab antibodies on natalizumab pharmacokinetics were investigated in a population pharmacokinetic study (n=2195). Natalizumab clearance increased with body weight in a less than proportional manner such that a 43% increase in body weight resulted in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold [see ADVERSE REACTIONS].

Crohn's Disease (CD) Patients

In patients with CD, following the repeat intravenous administration of a 300 mg dose of TYSABRI, the mean ± SD maximum observed serum concentration was 101 ± 34 mcg/mL. The mean ± SD average steady-state trough concentration was 10 ± 9 mcg/mL. The estimated time to steady-state was approximately 16 to 24 weeks after every four weeks of dosing. The mean ± SD half-life, volume of distribution, and clearance of natalizumab were 10 ± 7 days, 5.2 ± 2.8 L, and 22 ± 22 mL/hour, respectively.

The effects of total body weight, age, gender, race, selected hematology and serum chemistry measures, co-administered medications (infliximab, immunosuppressants, or steroids), and the presence of anti-natalizumab antibodies were investigated in a population pharmacokinetic analysis (n=1156). The presence of anti-natalizumab antibodies was observed to increase natalizumab clearance [see ADVERSE REACTIONS].

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

Animal Toxicology And/Or Pharmacology

In reproductive studies in monkeys and guinea pigs, there was no evidence of teratogenic effects at doses up to 30 mg/kg (7 times the human clinical dose based on a body weight comparison). In one study where female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at post-natal day 14 with respect to control (3 pups/litter for the group treated with 30 mg/kg natalizumab and 4.3 pups/litter for the control group). In one of five studies that exposed monkeys or guinea pigs during pregnancy, the number of abortions in treated (30 mg/kg) monkeys was 33% versus 17% in controls. No effects on abortion rates were noted in any other study. TYSABRI underwent trans-placental transfer and produced in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7-fold the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum natalizumab levels. A study in pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetus. These changes included mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. In offspring born to mothers treated with natalizumab at 7-fold the clinical dose, platelet counts were also reduced. This effect was reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and via breast milk had no natalizumabrelated changes in the lymphoid organs and had normal immune response to challenge with a T-cell dependent antigen.

Clinical Studies

Multiple Sclerosis

TYSABRI was evaluated in two randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0. Results for each study are shown in Table 5 and Table 6. Median time on study drug was 120 weeks in each study. In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study MS1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Median age was 37, with a median disease duration of 5 years. Patients were randomized in a 2:1 ratio to receive TYSABRI 300 mg intravenous infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions).

Study MS2 enrolled patients who had experienced one or more relapses while on treatment with AVONEX® (Interferon beta-1a) 30 mcg intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomized to receive TYSABRI 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28 months (30 infusions). All patients continued to receive AVONEX 30 mcg IM once weekly. The efficacy of TYSABRI alone was not compared with the efficacy of TYSABRI plus AVONEX.

The primary endpoint at 2 years was time to onset of sustained increase in disability, defined as an increase of at least 1 point on the EDSS from baseline EDSS ≥ 1.0 that was sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS=0 that was sustained for 12 weeks. Time to onset of sustained increase in disability was longer in TYSABRI-treated patients than in placebo-treated patients in Studies MS1 (Figure 1) and MS2. The proportion of patients with increased disability and the annualized relapse rate were also lower in TYSABRI-treated patients than in placebo-treated patients in Studies MS1 and MS2 (Table 5 and Table 6).

Table 5: Clinical and MRI Endpoints in Study MS1 (Monotherapy Study) at 2 Years

  TYSABRI
n=627
Placebo
n=315
CLINICAL ENDPOINTS
Percentage with sustained increase in disability 17% 29%
Relative Risk Reduction 42% (95% CI 23%, 57%)
Annualized relapse rate 0.22 0.67
  Relative reduction (percentage) 67%
Percentage of patients remaining relapse-free 67% 41%
MRI ENDPOINTS
New or newly enlarging T2-hyperintense lesions
  Median 0 5
  Percentage of patients with*:
    0 lesions 57% 15%
    1 lesion 17% 10%
    2 lesions 8% 8%
    3 or more lesions 18% 68%
Gd-enhancing lesions
  Median 0 0
  Percentage of patients with:
    0 lesions 97% 72%
    1 lesion 2% 12%
    2 or more lesions 1% 16%
All analyses were intent-to-treat. For each endpoint, p < 0.001. Determination of p-values: Increase in disability by Cox proportional hazards model adjusted for baseline EDSS and age; relapse rate by Poisson regression adjusting for baseline relapse rate, EDSS, presence of Gd-enhancing lesions, age; percentage relapse-free by logistic regression adjusting for baseline relapse rate; and lesion number by ordinal logistic regression adjusting for baseline lesion number.
Annualized relapse rate is calculated as the number of relapses for each subject divided by the number of years followed in the study for that subject. The value reported is the mean across all subjects.
*Values do not total 100% due to rounding.

Table 6: Clinical and MRI Endpoints in Study MS2 (Add-On Study) at 2 Years

  TYSABRI plus AVONEX
n=589
Placebo plus AVONEX
n=582
CLINICAL ENDPOINTS
Percentage with sustained increase in disability 23% 29%
Relative Risk Reduction 24% (95% CI 4%, 39%)
Annualized relapse rate 0.33 0.75
  Relative reduction (percentage) 56%
Percentage of patients remaining relapse-free 54% 32%
MRI ENDPOINTS
New or newly enlarging T2-hyperintense lesions
  Median 0 3
  Percentage of patients with*:
    0 lesions 67% 30%
    1 lesion 13% 9%
    2 lesions 7% 10%
    3 or more lesions 14% 50%
Gd-enhancing lesions
  Median 0 0
  Percentage of patients with*:
    0 lesions 96% 75%
    1 lesion 2% 12%
    2 or more lesions 1% 14%
All analyses were intent-to-treat. For disability accumulation p=0.024, for all other endpoints, p < 0.001. Determination of p-values: Increase in disability by Cox proportional hazards model adjusted for baseline EDSS; relapse rate by Poisson regression adjusting for baseline relapse rate, EDSS, presence of Gd-enhancing lesions, age; percentage relapse-free by logistic regression adjusting for baseline relapse rate; and lesion number by ordinal logistic regression adjusting for baseline lesion number.
Annualized relapse rate is calculated as the number of relapses for each subject divided by the number of years followed in the study for that subject. The value reported is the mean across all subjects.
*Values do not total 100% due to rounding.

Figure 1: Time to Increase in Disability Sustained for 12 Weeks in Study MS1

Time to Increase in Disability Sustained for 12 Weeks in Study MS1 - Illustration

Crohn's Disease

The safety and efficacy of TYSABRI were evaluated in three randomized, double-blind, placebo-controlled clinical trials in 1414 adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] ≥ 220 and ≤ 450) [see REFERENCES]. Concomitant inhibitors of TNF-α were not permitted. Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunosuppressants (e.g., 6-mercatopurine, azathioprine, or methotrexate) were permitted, and 89% of patients continued to receive at least one of these medications. Although permitted in the clinical trials, combination therapy with immunosuppressants is not recommended [see INDICATIONS AND USAGE]. Overall, approximately two-thirds of patients were not taking concomitant immunosuppressants, and approximately one-third of patients were taking neither concomitant immunosuppressants nor concomitant corticosteroids.

Induction of clinical response (defined as ≥ 70-point decrease in CDAI from baseline) was evaluated in two studies. In Study CD1, 896 patients were randomized 4:1 to receive three monthly infusions of either 300 mg TYSABRI or placebo. Clinical results were assessed at Week 10, and patients with incomplete information were considered as not having a clinical response. At Week 10, 56% of the 717 patients receiving TYSABRI were in response compared to 49% of the 179 patients receiving placebo (treatment effect: 7%; 95% confidence interval (CI): [-1%, 16%]; p=0.067). In a post hoc analysis of the subset of 653 patients with elevated baseline C-reactive protein (CRP), indicative of active inflammation, 57% of TYSABRI patients were in response compared to 45% of those receiving placebo (treatment effect: 12%; 95% CI: [3%, 22%]; nominal p=0.01).

In the second induction trial, Study CD2, only patients with elevated serum C-reactive Protein (CRP) were studied. A total of 509 patients were randomized 1:1 to receive three monthly infusions of either 300 mg TYSABRI or placebo. In Study CD2, in contrast to Study CD1, clinical response and clinical remission (defined as CDAI score < 150) were required to be met at both Weeks 8 and 12, rather than at a single time-point; patients with incomplete information were considered as not having a response (Table 7).

Table 7: Induction of Clinical Response and Remission in Study CD2

  TYSABRI n=259 Placebo n=250 Treatment Difference (95% CI)
Clinical Response at:
  Week 8 56% 40% 16%
(8%, 26%)
  Week 12 60% 44% 16%
(7%, 25%)
  Both Weeks 8 & 12* 48% 32% 16%
(7%, 24%)
Clinical Remission at:
  Week 8 32% 21% 11%
(3%, 19%)
  Week 12 37% 25% 12%
(4%, 21%)
  Both Weeks 8 & 12* 26% 16% 10%
(3%, 18%)
*p < 0.005
Response is defined as a ≥ 70-point reduction in CDAI score from baseline.
Remission is defined as CDAI < 150.

In studies CD1 and CD2, for subgroups defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower clinical response and lower clinical remission in both the treatment and placebo groups. For patients in Study CD2 with an inadequate response to prior treatment with inhibitors of TNF-α, clinical response at both Weeks 8 and 12 was seen in 38% of those randomized to TYSABRI, and clinical remission at both Weeks 8 and 12 was seen in 17%.

Maintenance therapy was evaluated in Study CD3. In this study, 331 patients from Study CD1 that had had a clinical response to TYSABRI at both Weeks 10 and 12 were re-randomized 1:1 to treatment with continuing monthly infusions of either 300 mg TYSABRI or placebo.

Maintenance of response was assessed by the proportion of patients who did not lose clinical response at any study visit for an additional 6 and 12 months of treatment (i.e., Month 9 and Month 15 after initial treatment with TYSABRI). The study also assessed the proportion of patients who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. Requiring maintenance of response or remission at each visit, as opposed to just at Month 9 or Month 15, may result in lower proportions meeting endpoint criteria, and may make a comparison of these results with those of other products used to treat Crohn's disease misleading (Table 8).

Table 8: Maintenance of Clinical Response and Remission in Study CD3

  TYSABRI
n=164
Placebo
n=167
Treatment Difference (95% CI)
Clinical Response through:
  Month 9* 61% 29% 32% (21%, 43%)
  Month 15 54% 20% 34% (23%, 44%)
Clinical Remission through:
  n=128† n=118†
  Month 9* 45% 26% 19% (6%, 31%)
  Month 15 40% 15% 25% (13%, 36%)
*p < 0.005
†Number of patients included for analysis of “through” Month 9 and Month 15 includes only those in remission upon entry into Study CD3.
Response is defined as CDAI < 220 and a ≥ 70-point reduction in CDAI score compared to Baseline from Study CD1.
Remission is defined as CDAI < 150.

For subgroups in study CD3 defined by prior use of, or by inadequate response to prior therapies (i.e., corticosteroids, immunosuppressants, and inhibitors of TNF-α), the treatment effect was generally similar to that seen in the whole study population. In the subgroup of patients that were taking neither concomitant immunosuppressants nor concomitant corticosteroids, the treatment effect was generally similar to that seen in the whole study population. Patients with inadequate response to inhibitors of TNF-α appeared to have lower maintenance of clinical response and lower maintenance of clinical remission in both the treatment and placebo groups. For patients in study CD3 with an inadequate response to prior treatment with inhibitors of TNFα, maintenance of clinical response through Month 9 was seen in 52% of those randomized to TYSABRI, and maintenance of clinical remission through Month 9 was seen in 30%.

Given the requirement to discontinue chronic steroids it is important to note that in the subgroup of patients (n=65) who were receiving corticosteroid medication at baseline, responded to TYSABRI in Study CD1, and were re-randomized to TYSABRI in Study CD3, approximately two-thirds were able to discontinue steroids within 10 weeks of initiating a steroid taper.

REFERENCES

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): 439-444.

Last reviewed on RxList: 12/30/2013
This monograph has been modified to include the generic and brand name in many instances.

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