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Natalizumab …
- Updated 03.01.2021
- Released 01.17.2003
- Expires For CME 03.01.2024
Natalizumab
Introduction
Historical note and terminology
Natalizumab, a humanized monoclonal antibody, is an alpha4 integrin antagonist that has been shown to reduce the development of brain lesions in experimental models as well as in patients with multiple sclerosis in clinical trials. Integrins are adhesion molecules that stabilize the interaction between cells and their environments by cell signaling. Early evidence for alpha4 integrin-mediated central nervous system disease was based on study of autoimmune encephalomyelitis, a T cell–mediated disease that resembles multiple sclerosis in animals (45). In 2004, the FDA approved natalizumab and it is marketed under the trade name of “Tysabri” (Biogen Idec and Elan). In 2005, it was temporarily withdrawn from the market because of a link with cases of progressive multifocal leukoencephalopathy, but it was restored to the market in 2006 as the benefit was shown to be greater than the risk of adverse effects.
Pharmacology
Natalizumab, a selective adhesion molecule inhibitor, blocks the ability of alpha4 beta1 integrin to bind to its receptor, the vascular cell adhesion molecule. This interaction is needed for the lymphocytes to enter the central nervous system, a process that is implicated in the pathogenesis of acute inflammatory lesions and the breakdown of blood-brain barrier in patients with multiple sclerosis. Binding of natalizumab to integrin inhibits the activation of T lymphocytes and prevents the development of new lesions of multiple sclerosis. The reduction in the formation of lesions in a clinical trial was 90%, and greater than 50% to 80% reduction was reported with beta interferons and a 30% reduction with glatiramer acetate. Reduction of angiogenetic activity may also contribute to antiinflammatory effect of natalizumab in patients with relapsing remitting multiple sclerosis (16).
Pharmacodynamics. Total lymphocyte counts are increased in patients treated with natalizumab, with increases in these counts that are compatible with the concept of action of natalizumab. Natalizumab treatment has also been shown to alter the surface integrin expression on monocytes, suggesting a role for them as mediators of natalizumab effects (07). Natalizumab mobilizes hematopoietic stem cells from the bone marrow, which is associated with clinical remission and increased proportion of circulating B and regulatory T cells (22). Therefore, hematopoietic stem and progenitor cell counts in the blood can be considered as early biomarkers of response to natalizumab. A clinical study has shown that natalizumab's effects on peripheral immune cells and pharmacodynamic biomarkers are reversible, with changes starting 8 weeks after the last natalizumab dose and with levels returning to those observed in untreated patients approximately16 weeks following the last dose (27).
Pharmacokinetics. Serum levels of natalizumab are proportional to the dose given. Serum natalizumab is detectable for several weeks after a single 1 or 3 mg/kg intravenous dose.
Pharmacogenetics. JCV-associated granule cell neuronopathy (GCN) in patients on natalizumab treatment is associated with mutations in the JCV VP1 gene (01).
Clinical trials
The AFFIRM trial, a 2-year, randomized, multicenter, placebo-controlled, phase 3 double-blind study of approximately 900 patients, was designed to determine whether natalizumab is effective in slowing the rate of disability in multiple sclerosis and reducing the rate of clinical relapses. Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis (28). SENTINEL, a 2-year, randomized, multicenter, placebo-controlled, phase 3 double-blind study of approximately 1200 patients, was designed to determine whether the treatment of multiple sclerosis with natalizumab in combination with interferon beta 1a is more effective than interferon beta 1a treatment alone in slowing the rate of disability in multiple sclerosis and in reducing the rate of clinical relapses. Natalizumab added to interferon beta 1a was significantly more effective than interferon beta 1a alone in patients with relapsing multiple sclerosis (32). MRI follow-up of patients from both trials showed that natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis (23).
Further analyses of AFFIRM and SENTINEL clinical trials data showed that natalizumab reduced the risk of disability progression by 64% and relapse rate by 81% in treatment-naive patients with highly active disease and by 58% and 76%, respectively, in patients with highly active multiple sclerosis, despite interferon beta-1a treatment (15).
A systematic review of controlled clinical trials in the Cochrane Database indicates reduction in relapses and disability at 2 years in relapsing remitting multiple sclerosis treated with natalizumab (30). Although the drug is well tolerated, there are significant safety concerns due to reports of progressive multifocal leukoencephalopathy in patients treated with natalizumab.
A prospective open-label 2-year study has shown that short-term natalizumab treatment improves cognitive performances and fatigue in patients with multiple sclerosis (17).
Safety of TYSABRI Re-dosing and Treatment (STRATA) was a prospective, observational, open-label, long-term study of natalizumab over 240 weeks in patients with relapsing-remitting multiple sclerosis who had been previously treated in controlled clinical trials (26). Results show that natalizumab stabilizes Expanded Disability Status Scale (EDSS) scores and decreases relapse rates, but is associated with an increased risk of progressive multifocal leukoencephalopathy.
STRIVE is a multicenter, observational, open-label, single-arm study of natalizumab in anti-JC virus seronegative patients with early relapsing-remitting multiple sclerosis (29). The results showed that natalizumab was effective during 2 years of treatment, and nearly 75% of the patients with early relapsing-remitting multiple sclerosis maintained no evidence of disease activity.
Indications
Natalizumab is approved for the treatment of relapsing-remitting or relapsing secondary progressive multiple sclerosis.
Off-label uses
• Stem cell mobilization in patients with hematologic malignancies (24). | |
• Crohn disease (02). | |
• Treatment of refractory epilepsy in patients with multiple sclerosis suggests that inhibition of leukocyte adhesion may represent a new potential therapeutic approach in epilepsy to complement antiepileptic drugs (36). |
Goals and duration of treatment
Goals and duration of treatment with natalizumab are not defined yet, although the aim of clinical studies is determination of long-term benefit. Retrospective review of patients followed up after clinical trials of natalizumab indicates improvement of ambulatory function in disabled subjects with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis, although the latter finding needs to be confirmed in a prospective study (05). A prospective, open-label study of multiple sclerosis patients treated with natalizumab showed that there was no evidence of disease activity at 2 years in 93% of the patients, which indicates stabilization of clinical and imaging biomarkers of disease activity during natalizumab treatment (37). Results of a nonrandomized study demonstrate improvement in information processing speed in multiple sclerosis patients with cognitive impairment following 12 months of natalizumab treatment, which is likely due to antiinflammatory properties of natalizumab (31).
The Tysabri Observational Programme, which started over 10 years ago, is an open-label, multinational, prospective observational study to evaluate the long-term safety and effectiveness of natalizumab in relapsing-remitting multiple sclerosis patients. A 10-year interim analysis further supports the robust real-world effectiveness and well-established safety profile of natalizumab (04).
Although natalizumab is used as a second-line therapy in patients who do not respond to first-line agents such as glatiramer acetate and interferon‑beta, there are nonresponders to it as well. In an attempt to find a biomarker of response to natalizumab, a subset of genes of CD4+ T cells that predict the response of relapsing‑remitting multiple sclerosis patients to natalizumab form the basis for personalized therapeutic approach to patients with multiple sclerosis (10).
Dosing
The recommended dose is 300 mg intravenously once a month.
Special considerations
Pregnancy and nursing. Natalizumab therapy in pregnant women should be used during pregnancy only if clearly needed. Before starting natalizumab treatment, women of childbearing age must be informed of the risk of recurrence of disease activity when the drug is discontinued even though pregnancy is considered as protective for women with multiple sclerosis (09). An analysis from the Tysabri® (natalizumab) pregnancy exposure registry showed that although the incidence of birth defects was higher than the population without drug exposure, the pattern did not suggest drug-induced malformations (11). The spontaneous abortion rate in this study was consistent with that of the general population.
Natalizumab can be considered as a therapeutic option in patients with highly active multiple sclerosis during pregnancy, and use in early pregnancy is safe. According to a retrospective chart review, complications following natalizumab administration during the second and third trimester of pregnancy occurred in 33% of newborns, but did not result in mortality or morbidity (39). Anemia and thrombocytopenia may occur in newborns exposed to natalizumab during the third trimester (14). Dose alterations during the third trimester, pre-delivery umbilical cord sampling, and intravenous immune globulin administration may reduce hematological effects on newborns.
Elderly patients. Clinical studies of natalizumab did not include adequate numbers of patients aged 65 years and older to determine whether they respond differently than younger patients.
Children. Safety and effectiveness of natalizumab in pediatric multiple sclerosis patients below the age of 18 years has not been studied. Natalizumab is not indicated for use in pediatric patients.
Interactions
No clinically significant interaction has been observed with interferon beta 1a or glatiramer acetate. No data are available on the effects of vaccination in patients receiving natalizumab.
Adverse effects
Adverse reactions reported in clinical trials were generally mild and included nonserious infections (such as urinary tract, lower respiratory tract, gastrointestinal system, and vaginal infections), headache, depression, joint pains, and menstrual disorders. Serious adverse reactions were rare. Anaphylactic reaction with urticaria and bronchospasm can be rapidly reversed with antihistamines and cortisone. Delayed allergic reactions to natalizumab are associated with formation of neutralizing antibodies. Postmarketing data show that natalizumab can cause severe liver damage. A case of myocardial infarction following injection of natalizumab has been reported (08).
Primary central nervous system lymphoma, which is usually a disease of the elderly with no increased prevalence in multiple sclerosis, has been reported in a patient treated with natalizumab (35). The association, however, is not clear.
In 2005, Biogen Idec, the manufacturer of natalizumab, reported 1 confirmed fatal case and 1 possible case of progressive multifocal leukoencephalopathy in patients receiving natalizumab for multiple sclerosis. The diagnosis of multifocal leukoencephalopathy was confirmed on postmortem examination of the brain (20). JC viral DNA was detected in cerebrospinal fluid and was confirmed at autopsy. In another case of death following natalizumab therapy for Crohn disease, JC virus DNA had appeared in the serum 3 months after the initiation of therapy and 2 months before the appearance of symptomatic multifocal leukoencephalopathy (40). From these observations, it appears that testing for the appearance of JC virus in plasma, along with a high degree of clinical suspicion, may enable early diagnosis of multifocal leukoencephalopathy and discontinuation of natalizumab therapy with the possibility of recovery. No new cases of multifocal leukoencephalopathy have been observed since the initial 3 cases. Risk of progressive multifocal leukoencephalopathy in patients treated with natalizumab was estimated to be 1 in 1000 patients based on more than 3000 patients treated in clinical trials (46). A revised application for approval of the product submitted to the FDA contains integrated safety assessment of patients treated in clinical trials and a revised label and risk management plan. In 2006, the Peripheral and Central Nervous System Drugs Advisory Committee of the Food and Drug Administration voted unanimously to recommend reintroduction of natalizumab as a monotherapy for patients with relapsing forms of multiple sclerosis who have had an inadequate response to, or are unable to tolerate, alternative treatments (25). The risk of developing progressive multifocal leukoencephalopathy in a pooled clinical trial cohort has been estimated to be 1 person for every 1000 patients treated for an average of 17.9 months (13). A risk-benefit analysis concluded that more than 7-fold increase in actual risk of progressive multifocal leukoencephalopathy was required to decrease natalizumab's health gain below that of interferon beta-1a (38). In 2012, the FDA approved a product label change for Tysabri® (natalizumab) that will help enable individual benefit-risk assessment for patients with multiple sclerosis. The new label identifies positive anti-JCV antibody status as a risk factor for developing progressive multifocal leukoencephalopathy whereas negative anti-JCV antibody status indicates that exposure to the JC virus has not been detected. Irrespective of treatment, approximately 55% of multiple sclerosis patients are anti-JCV positive. Stratify JCV Antibody ELISA Testing Service (Quest Diagnostics) enables neurologists to determine their multiple sclerosis patients' anti-JCV antibody status and is the first blood test to be approved by the FDA for the qualitative detection of antibodies to the JC virus. Quantification of T and B lymphocytes can be used to monitor natalizumab therapy safety because new lymphocyte production indicates the integrity of immune surveillance (47). An unusually low percentage of l-selectin-expressing CD4+ T cells in peripheral blood is a possible biomarker for risk of development of progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab (34).
Plasma exchange and immunoadsorption have been used to accelerate clearance of natalizumab successfully, with improvement of symptoms in patients who developed progressive multifocal leukoencephalopathy after natalizumab monotherapy (21; 42). Although rapid withdrawal of the drug and administration of plasma exchange has enabled survival in some of the patients with progressive multifocal leukoencephalopathy, a new problem, immune reconstitution inflammatory syndrome, has been reported after drug withdrawal (19). This complication requires treatment with corticosteroids.
In 2012, there were 212 confirmed cases of progressive multifocal leukoencephalopathy among 99,571 patients treated with natalizumab; the risk was associated with anti-JC virus antibodies, previous use of immunosuppressants, and increased duration of natalizumab treatment, alone or in combination (03). Currently, more than 110,000 multiple sclerosis patients worldwide have been treated with natalizumab, and the risk of developing progressive multifocal leukoencephalopathy is approximately 2.7 per 1000 cases. Planned dosage interruptions of natalizumab have been recommended for decreasing the cumulative risk of multifocal leukoencephalopathy, but it is associated with clinical flares and recurrence of radiographic lesions. Some of these flares can be clinically severe, with a high number of contrast-enhanced lesions, suggesting a possible rebound of disease activity (43). Postmortem study in a patient with multiple sclerosis who died following natalizumab-associated progressive multifocal leukoencephalopathy showed coexistence and lack of interplay between lesions of chronic multiple sclerosis and progressive multifocal leukoencephalopathy (44).
Progressive multifocal leukoencephalopathy associated with natalizumab has better prognosis than that due to other causes. Early diagnosis, localized disease on MRI, and aggressive management may improve outcomes (41).
Natalizumab withdrawal because of progressive multifocal leukoencephalopathy triggers an immune reconstitution syndrome that can lead to neurologic complications or even death. According to a retrospective study, either disease-modifying treatment or “no treatment” can abolish reactivation of disease activity after discontinuation of natalizumab (06). RESTORE, a randomized, partially placebo-controlled exploratory study, showed that in most patients, gadolinium-enhancing MRI lesions during natalizumab interruption did not exceed pre-natalizumab levels or levels seen in historical control patients (18).
Because of the effect of natalizumab treatment on JCV seroconversion, monitoring of patients' JCV serology as well as incorporation of additional risk factors into the progressive multifocal leukoencephalopathy risk stratification is recommended (33). However, regardless of JCV antibody status, the possibility of progressive multifocal leukoencephalopathy should be considered in a natalizumab-treated patient with any new MRI lesion or neurologic symptoms (12).
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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