MULTIPLE SCLEROSIS
Natalizumab
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).
Related Topics
Privacy Policy, Terms and Conditions, DMCA Policy and Compliant
Copyright © 2018-2026 BrainKart.com; All Rights Reserved. Developed by Therithal info, Chennai.