TYSABRI (Page 5 of 7)

12 CLINICAL PHARMACOLOGY

12.1 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 α4-mediated 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 MAdCAM-1 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 α4ß7-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.

12.2 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 (5.7) ].

12.3 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 (6.2) ].

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 (6.2) ].

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

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No clastogenic or mutagenic effects of natalizumab were observed in the Ames test or in vitro chromosomal aberration assay in human lymphocytes. Natalizumab showed no effects in in vitro assays of α4-integrin positive human tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude mice with two α4-integrin positive human tumor lines (leukemia, melanoma) demonstrated no increase in tumor growth rates or metastasis resulting from natalizumab treatment.

In male guinea pigs administered natalizumab (0, 3, 10, or 30 mg/kg) by intravenous (IV) infusion on alternate days from 28 days prior to and continuing throughout mating (to untreated females), no effects on fertility were observed. The highest dose tested is 6 times the recommended human dose (RHD) (300 mg) on a body weight (mg/kg) basis.

In a separate study in female guinea pigs (mated with untreated males), natalizumab (0, 3, 10, or 30 mg/kg), administered by IV infusion on alternate days from gestation day (GD) 30 of the first pregnancy through GD 30 of the second pregnancy, resulted in a decrease in pregnancy rate and number of implantations at 30 mg/kg. (Fertility parameters were assessed for the second pregnancy.) The no-effect dose for effects on female fertility (10 mg/kg) is 2 times the RHD on a body weight basis.

14 CLINICAL STUDIES

14.1 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

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.

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
Median0.0 5.0
Percentage of patients with*:
0 lesions57% 15%
1 lesion17% 10%
2 lesions8% 8%
3 or more lesions 18% 68%
Gd-enhancing lesions
Median0.0 0.0
Percentage of patients with:
0 lesions97% 72%
1 lesion2% 12%
2 or more lesions 1% 16%
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

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.

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
Median0.0 3.0
Percentage of patients with*:
0 lesions67% 30%
1 lesion13% 9%
2 lesions7% 10%
3 or more lesions 14% 50%
Gd-enhancing lesions
Median0.0 0.0
Percentage of patients with*:
0 lesions96% 75%
1 lesion2% 12%
2 or more lesions 1% 14%

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

Figure 1
(click image for full-size original)

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