Natalizumab is a recombinant humanized IgG4k mono-clonal antibody, is the first in a new class of selective adhesion molecule inhibitors and is used for the treatment of patients with relapsing forms of multiple sclerosis (MS) (package insert for Tysabri, 2006).
MS is a chronic inflammatory disease character-ized by focal areas of nerve fiber and myelin destruction (lesions) within the central nervous system. The majority of individuals with MS develop a relapsing-remitting form of the disease (RRMS) (Weinshenker et al., 1989), which consists of episodic bouts of neurological deterioration, separated by periods of relative stability (Lublin and Reingold, 1996). Approximately 90% of untreated patients with RRMS develop a more progressive form of the disease (secondary progressive MS) (Weinshenker et al., 1989). There is no cure for MS; current therapies for RRMS modify the course of the disease by reducing the number of clinical relapses and slowing disability progression. Prior to the approval of natalizumab, available first-line therapies for patients with RRMS consisted of interferon-b (IFNβ) (Betaseron ), intra-muscular (IM) IFNβ1a (Avonex ), and SC IFNβ1a (Rebif ) and glatiramer acetate (Copaxone ). These therapies reduce relapse rate by approximately 30% and slow disability progression by 12% to 37% (IFNβ Multiple Sclerosis Study Group, 1993; Jacobs et al., 1996; Johnson et al., 1995; PRISMS Study Group, 1998).
Natalizumab binds to the a4 subunit of a4b1 (also known as very late antigen (VLA)-4) and a4b7 integrins, preventing its ability to interact with vascular-cell adhesion molecule-1 (VCAM-1; theendothelial receptor of a4b1 integrin), mucosal ad-dressin-cell adhesion molecule-1 (MadCAM-1; the endothelial receptor of a4b7 integrin), fibronectin, osteopontin, and other extracellular matrix proteins. Natalizumab has also been studied for the potential treatment of CD (Sandborn et al., 2005) and rheuma-toid arthritis. It is believed that natalizumab exerts its beneficial effects in MS by: (1) inhibiting the migration of immune cells into the central nervous system and (2) inhibiting interactions between b4-integrin and its ligands, thereby possibly reducing immune cell activation and promoting apoptosis of lymphocytes (Rudick and Sandrock, 2004; Tchilian et al., 1997).
Following repeat IV administration of the appro-ved dose of natalizumab (300 mg IV every 4 weeks) to patients with MS, the observed mean maximum serum concentration was 110 – 52 g/mL, the mean average steady-state trough concentrations over the dosing period ranged from 23 to 29 g/mL, and the observed time to steady-state was approximately 24 weeks after every 4 weeks of dosing. The mean half-life was 11 – 4 days, with a volume of distribution of 5.7 – 1.9 L, and a clearance of 16 – 5 mL/hour. Age and gender did not influence natalizumab pharmacokinetics (package insert for Tysabri 2006). Natalizumab increases the number of circulating leukocytes (lymphocytes, monocytes, basophils, and eosinophils, but not neutrophils) due to inhibition of transmigration out of the vascular space (package insert for Tysabri, 2006). Administration of natalizu-mab with IFNβ1a did not significantly alter the pharmacokinetic or pharmacodynamic profiles of natalizumab (Rudick and Sandrock, 2004; Vollmer et al., 2004).
The efficacy and safety of natalizumab were studied in two randomized, double-blind, placebo-controlled trials in patients with relapsing multiple sclerosis. The first study, the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, evaluated natalizumab monother-apy. In AFFIRM, 942 patients were randomly assigned in a 2:1 ratio to receive natalizumab 300 mg (n¼ 627) or placebo (n¼ 315) administered as an IV infusion once every 4 weeks for up to 116 weeks (Polman et al., 2006). Compared with placebo, treatment with nata-lizumab significantly reduced the cumulative prob-ability of sustained disability progression by 42% (HR 0.58, 95% CI 0.43, 0.77), the annualized rate of clinical relapse by 68% (0.23 vs. 0.73), and the risk of relapse by 59% (HR 0.41; 95% CI 0.34, 0.51) over 2 years (package insert for Tysabri, 2006; Polman et al., 2006). In addition, natalizumab reduced inflammatory activ-ity and the accumulation of new lesions in the brain as shown by magnetic resonance imaging scans; the mean number of new or enlarging T2-hyperintense lesions was reduced by 83% and the mean number ofgadolinium-enhancing lesions by 92% in natalizu-mab-treated patients compared with placebo. The second study, the Safety and Efficacy of Natalizumab In Combination with Avonex (IFNβ1a) in Patientswith Relapsing-Remitting MS study (SENTINEL), evaluated natalizumab in combination with IM IFNβ1a (Avonex ). In SENTINEL, 1,171 patients, who had experienced ‡ 1 relapse while receiving treatment with IFNβ1a 30 mg IM once weekly during the year prior to study entry, were randomly assigned to receive natalizumab 300 mg (n¼ 589) or placebo (n¼ 582) IV once every 4 weeks for up to 116 weeks; all patients continued treatment with IM IFNβ1a. Natalizumab significantly reduced the cumulative probability of sustained disability progression by 24% (HR 0.76, 95% CI: 0.61, 0.96), the annualized rate of clinical relapse by 55% (0.34 vs. 0.75), and the development of lesions over the effect produced by IFNβ1a alone (Rudick et al., 2006).
Natalizumab therapy was well tolerated in clinical trials. In the AFFIRM study, fatigue (27% natalizumab vs. 21% placebo) and allergic reaction (9% natalizumab vs. 4% placebo) were significantly (P< 0.05) more common in the natalizumab group than the placebo group (Polman et al. 2006). Serious adverse events occurred in 19% of patients in the natalizumab group and 24% in the placebo group (P¼ 0.06), with the most common being infection (3.2% vs. 2.6%), acute hypersensitivity reactions (1.1% vs. 0.3%), depression (1.0% for each group), and cholelithiasis (1.0% vs. 0.3%) (Polman et al., 2006). The incidence of infection was 79% in each treatment group; the rate of infection was 1.52 and 1.42 per patient-year in the natalizumab and placebo groups, respectively. Two deaths occurred in the natalizumab group (one due to malignant melanoma in a patient with a history of such and a new lesion at the time of the first natalizumab dose, and one due to alcohol intoxication).
Two cases of progressive multifocal leukoence-phalopathy (PML) were reported in patients with MS treated with natalizumab in combination with IFNβ1a (Kleinschmidt-DeMasters and Tyler, 2005). A subsequent retrospective review of the natalizumab safety data identified an additional fatal case of PML in a patient with CD who had received eight infusions of natalizumab and had been previously diagnosed with astrocytoma (Van Assche et al., 2005). PML, which primarily affects individuals with suppressed immune systems, is an opportunistic infection of the brain that usually leads to death or severe disability. Symptoms of this rare disorder include mental deterioration, vision loss, speech disturbances, ataxia, paralysis, and, ultimately, coma. An evaluation of 3116 patients who received natali-zumab in clinical trials of MS, CD, or rheumatoidarthritis found no new cases of PML (Yousry et al., 2006). Based on the results of this study (mean natalizumab exposure of 17.9 months), the estimated risk of PML associated with natalizumab is 1.0 in 1000 patients (95% CI 0.2, 2.8 per 1000) (Yousry et al., 2006).
Natalizumab is approved as monotherapy for the treatment of patients with relapsing forms of MS to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. Due to the increased risk of PML, natalizumab is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate MS therapies. Natalizumab is only available through a restricted distribution program (TOUCH Precribing Program (package insert for Tysabri, 2006). Under this program, only prescribers, pharmacies, and infusion centers enrolled in the program are able to prescribe, distribute, or infuse natalizumab. As part of TOUCH ), prescribers and patients are educated regarding the risk and symptoms of PML, and prescribers and infusion centers are instructed to withhold dosing immediately with any signs or symptoms suggestive of PML. As noted above, natalizumab is approved for use as monotherapy, as it is unknown whether the concomitant administra-tion of natalizumab with other immunomodulatory agents increases PML risk (package insert for Tysabri, 2006).