Natalizumab

(rINN)
Synonyms: Natalizumabum. Immunoglobulin G 4 (human-mouse monoclonal AN100226 4-chain antihuman integrin 4), disulfide with human-mouse monoclonal AN100226 light chain, dimer.
Cyrillic synonym: Натализумаб.

💊 Chemical information

CAS — 189261-10-7.
ATC — L04AA23.
ATC Vet — QL04AA23.

💊 Adverse Effects and Precautions

Natalizumab commonly causes infusion-related reactions including headache, dizziness, fatigue, urticaria, pruritus, rash, fever, rigors, nausea, hypotension, flushing, dyspnoea, and chest pain. Serious hypersensitivity reactions such as anaphylaxis can also occur. These reactions are usually associated with antibodies to natalizumab. The presence of these antibodies results in reduced serum concentrations and efficacy of natalizumab. The risk of infection is increased and there have been a few cases of progressive multifocal leukoencephalopathy (PML) reported; all patients should be monitored and if signs or symptoms of PML appear treatment should be withheld pending investigation. Clinically significant hepatotoxicity has also been reported with natalizumab and treatment should be stopped if there is evidence of jaundice or other significant liver injury. Natalizumab is contra-indicated in patients who have previously had PML. It is also contra-indicated in patients with, or at risk for, opportunistic infections, and in those with malignancies.

Antibody formation.

The incidence and clinical effects of antibody formation to natalizumab therapy in patients with relapsing multiple sclerosis were studied in the AFFIRM and SENTINEL studies.1 Of 625 patients treated with natalizumab in the AFFIRM study 20 (3%) were transiently positive for antibodies to natalizumab and 37 (6%) were persistently positive. Equivalent figures for 585 natalizumab-treated patients in the SENTINEL study were 32 (5%) and 38 (6%) respectively. Overall the presence of antibodies was generally correlated with reduced serum concentrations of natalizumab and a poorer treatment response, efficacy being restored in those patients who became antibody-negative during therapy. Antibody-positive patients also had a higher incidence of infusion-related adverse effects, including hypersensitivity reactions (17 of the 37 persistently positive patients in the AFFIRM study). It is recommended that patients with suboptimal response to natalizumab or persistent infusion-related adverse effects should be considered for antibody testing. UK licensed product information warns that therapy should not be restarted in patients who remain positive for antibodies 6 weeks after interrupting an initial short exposure to natalizumab.
1. Calabresi PA, et al. The incidence and significance of anti-natalizumab antibodies: results from AFFIRM and SENTINEL. Neurology 2007; 69: 1391–1403.

Hypersensitivity.

A review1 of the data for patients who had hypersensitivity reactions in the AFFIRM study2, which included 627 patients in the natalizumab treatment group, found that there was a low incidence (<1%) of serious reactions described as anaphylactoid or anaphylactic. All patients with hypersensitivity reactions responded promptly to discontinuation of the infusion and standard pharmacotherapy as necessary (adrenaline, oxygen, and antihistamines with or without corticosteroids); all recovered fully about 1 to 2 hours after the end of the infusion. UK licensed product information warns that patients should be counselled on the importance of uninterrupted dosing, particularly in the early months of treatment; the risk for hypersensitivity reactions is greatest with early infusions and in patients who, after an initial short exposure to natalizumab, are re-exposed after a treatment-free period of 3 or more months.
1. Phillips JT, et al. Infusion-related hypersensitivity reactions during natalizumab treatment. Neurology 2006; 67: 1717–18. Correction. ibid. 2007; 68: 473
2. Polman CH, et al. AFFIRM investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910.

Infections.

Three cases of progressive multifocal leukoencephalopathy (an opportunistic infection of the brain caused by JC virus, a human polyomavirus) have been described in patients given natalizumab.1-3 One patient1 died after receiving natalizumab with azathioprine for Crohn’s disease. The other patients2,3were given natalizumab with interferon beta for multiple sclerosis; one of these2 also died. After these reports, the use of natalizumab has been restricted (see Uses and Administration, below). A subsequent retrospective evaluation4 of more than 3000 patients who had received natalizumab found no further cases. However, 2 further cases have subsequently been reported5 in patients taking natalizumab as monotherapy for 14 months and 17 months; one of the patients had previously taken immunosuppressants.
1. Van Assche G, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005; 353: 362–8
2. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005; 353: 369–74
3. Langer-Gould A, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005; 353: 375–81
4. Yousry TA, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006; 354: 924–33
5. FDA. Alert for healthcare professionals: natalizumab injection for intravenous use (marketed as Tysabri) (issued 25/08/08). Available at: http://www.fda.gov/cder/drug/InfoSheets/HCP/ natalizumab2008HCP.htm (accessed 26/08/08)

Melanoma.

Long-standing naevi in two women developed into melanoma shortly after starting natalizumab treatment for multiple sclerosis.1
1. Mullen JT, et al. Melanoma complicating treatment with natalizumab for multiple sclerosis. N Engl J Med 2008; 358: 647–8.

💊 Interactions

Use with antineoplastics, immunosuppressants, or immunomodulators may further increase the risk of opportunistic infections including progressive multifocal leukoencephalopathy associated with natalizumab. Concurrent treatment with interferon beta or glatiramer acetate is contra-indicated.

💊 Uses and Administration

Natalizumab is a murine monoclonal antibody raised against human α4 integrin that is used as monotherapy to prevent relapses and delay progression of disability in patients with highly active relapsing-remitting multiple sclerosis. It is also used for inducing and maintaining response and remission in moderate to severe Crohn’s disease. However, because of an increased risk of progressive multifocal leukoencephalopathy (PML) its availability is restricted, and use is limited to patients who have had an inadequate response to, or are unable to tolerate, other therapies. A baseline magnetic resonance imaging scan must be done before natalizumab is started in order to differentiate newly developed lesions from pre-existing lesions. Patients should be evaluated for signs and symptoms of PML at 3 and 6 months after the first dose, then every 6 months thereafter. Natalizumab must be discontinued at the first sign of PML or other opportunistic infection developing; treatment may resume if this diagnosis is excluded, but should be permanently discontinued if confirmed. Patients who were previously taking interferon beta or glatiramer acetate may switch directly to natalizumab provided there are no treatment-related adverse effects such as neutropenia; blood counts must return to normal before starting natalizumab. Patients who have been receiving immunosuppressants such as azathioprine and cyclophosphamide must not start natalizumab until it has been confirmed that they are no longer immunocompromised. Likewise, the pharmacodynamic effects of natalizumab remain for about 12 weeks after stopping treatment, and therefore a wash-out period may be appropriate on stopping natalizumab before giving immunosuppressive drugs. Natalizumab 300 mg is given by intravenous infusion once every 4 weeks. The dose is diluted in 100 mL of sodium chloride 0.9% and given over about 1 hour. The patient should be observed during the infusion and for a further hour after it is complete; the infusion should be stopped if a hypersensitivity reaction occurs and treatment with natalizumab permanently discontinued. Treatment should also be discontinued if there is evidence of persistent raised antibodies to natalizumab since these reduce efficacy and increase the risk of hypersensitivity reactions. Continuation of therapy in multiple sclerosis patients who have shown no benefit after 6 months should be reconsidered. In the treatment of Crohn’s disease, natalizumab should be stopped if patients have not obtained therapeutic benefit after 12 weeks of induction ther apy or when patients are unable to discontinue chronic concomitant corticosteroid use within 6 months of starting natalizumab. Natalizumab has also been investigated for the treatment of ulcerative colitis.
1. Sweet BV. Natalizumab update. Am J Health-Syst Pharm 2007; 64: 705–16.

Inflammatory bowel disease.

The efficacy and safety of natalizumab in the treatment of Crohn’s disease have been reviewed, including proposed mechanisms for the role of α4 integrins in the immunopathogenesis of inflammatory bowel disease.1,2 A systematic review3 of controlled studies of the use of natalizumab in the treatment of Crohn’s disease concluded that it is effective for induction of clinical response and remission in some patients with moderately to severely active Crohn’s disease, particularly those with active inflammation or chronically active disease despite use of conventional treatment. However, this benefit must be weighed against the risks of developing progressive multifocal leukoencephalopathy. Natalizumab is also under investigation for ulcerative colitis.4
1. Keeley KA, et al. Natalizumab for the treatment of multiple sclerosis and Crohn’s disease. Ann Pharmacother 2005; 39: 1833–43
2. Lanzarotto F, et al. Novel treatment options for inflammatory bowel disease: targeting α 4 integrin. Drugs 2006; 66: 1179–89
3. MacDonald JK, McDonald JWD. Natalizumab for induction of remission in Crohn’s disease. Available in The Cochrane Database of Systematic Reviews; Issu
1. Chichester: John Wiley; 2007 (accessed 11/02/08)
4. Feagan BG, et al. Treatment of ulcerative colitis with a humanized antibody to the
α4β7 integrin. N Engl J Med 2005; 352: 2499–2507.

Multiple sclerosis.

The efficacy and safety of natalizumab in the treatment of multiple sclerosis have been reviewed, including proposed mechanisms for the role of α4 integrins in its immunopathogenesis.1-3 Randomised controlled studies4-7showed beneficial results in suppressing inflammatory lesions and reducing the frequency of relapse. Subsequent review8 of the data from the AFFIRM trial5 and the SENTINEL study6 demonstrated reduction of visual loss. In the SENTINEL study,6 natalizumab was given with interferon beta, a combination that may have contributed to the development of progressive multifocal leukoencephalopathy in 2 of the study patients, one of whom died (see Infections, above). As a consequence, natalizumab is currently licensed only as monotherapy.
1. Keeley KA, et al. Natalizumab for the treatment of multiple sclerosis and Crohn’s disease. Ann Pharmacother 2005; 39: 1833–43
2. Rice GPA, et al. Anti-α4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology 2005; 64: 1336–42
3. Ransohoff RM. Natalizumab for multiple sclerosis. N Engl J Med 2007; 356: 2622–9
4. Miller DH, et al. A controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2003; 348: 15–23
5. Polman CH, et al. AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899–910
6. Rudick RA, et al. SENTINEL investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med 2006; 354: 911–23
7. Miller DH, et al. AFFIRM Investigators. MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 2007; 68: 1390–1401
8. Balcer LJ, et al. AFFIRM and SENTINEL investigators. Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology 2007; 68: 1299–1304.

💊 Preparations

Proprietary Preparations

Austral.: Ty s ab r i; Cz.: Ty s ab r i ; Gr.: Ty sa br i; Port.: Ty sabr i; UK: Ty sa b ri; USA: Ty s ab r i.
Published May 08, 2019.