Natalizumab

Article Author:
Arezou Babaesfahani
Article Editor:
Brianne Kuns
Updated:
10/9/2019 3:31:57 PM
PubMed Link:
Natalizumab

Indications

Natalizumab is an FDA-approved, monoclonal antibody approved for the treatment of multiple sclerosis and Crohn's disease. The drug was originally approved to treat multiple sclerosis in 2004, but after reported cases of death due to progressive multifocal leukoencephalopathy during treatment with natalizumab, the FDA removed the drug from the market. In 2006, the FDA reintroduced the drug when multiple protests by those with multiple sclerosis advocated for the use of natalizumab in conjunction with the establishment of an advisory committee that would monitor those on natalizumab. All patients receiving treatment with natalizumab are part of a database called the TOUCH Prescribing Program in which a facility is granted permission by the United States Federal Drug Administration to administer natalizumab and ensure the extensive monitoring data and follow up regarding the patient's experience with natalizumab is collected. [1][2][3][4]

Natalizumab has shown to slow down the progression of symptoms during a flare-up in individuals with multiple sclerosis and decrease the rate of relapse in those with relapsing-remitting multiple sclerosis. In a randomized, placebo-controlled study, 77% of patients were relapse-free at the end of 1 year compared to 56% of those on placebo. The 2-year relapse-free rate was 67% with natalizumab versus 41% with placebo.[1] When the MRI images of its participants receiving natalizumab versus placebo were compared, the results showed 83% reduction in the number of lesions detected by T2 weighted MRI and 83% fewer lesions on the gadolinium-enhanced MRI images of patients who received natalizumab over those who received placebo.[1] A controlled trial of natalizumab compared the average number of new lesions in a 6-month period between 3 groups: a placebo group, those on 3 mg/kg of natalizumab, and those on 6 mg/kg of natalizumab. The average number of new lesions per patient in the placebo group was 9.6 compared to 0.7 and 1.1 for those on natalizumab 3-mg and 6-mg therapy, respectively.[5]

Mechanism of Action

Natalizumab is a monoclonal antibody that binds to alpha-4 integrin receptors on endothelial cells lining blood vessels.  Integrins are a class of selective adhesion molecules composited of multiple subunits and as a class aid in the chemotaxis of leukocytes to sites of inflammation throughout the body.[6] Natalizumab decreases inflammation by adhering to the receptors that would bind these integrins during an inflammatory flare, and thereby directly blocks leukocytes from crossing the blood vessel and exerting pro-inflammatory responses.  In patients with multiple sclerosis, natalizumab blocks alpha4-beta1 integrin receptor that lines the blood-brain barrier, blocking leukocytes from entering the central nervous system (CNS) of the patient. Several studies have shown a significant reduction in the number of lesions in multiple sclerosis patients taking natalizumab.[1][7][8][9]

Administration

Natalizumab is administered via intravenous infusions every 28 days at a TOUCH Prescribing Program approved site. The recommended dose is 300 mg/15 mL (20 mg/mL); however, this dose can be modified at the discretion of the treating physician. The infusion itself takes 1 hour, and the patient is then monitored closely by staff an hour after for any significant side effects. Natalizumab should not be given as an intravenous bolus or push. The drug should be administered within 8 hours of preparation.[10][8]

Adverse Effects

  • When used in combination with other immune modulating drugs, the risk of progressive multi leukoencephalopathy (PML), an opportunistic infection caused by the JC virus increases.
  • Immune modulating drugs including corticosteroids should be discontinued if possible before using natalizumab.[11]
  • PML risk increases as the number of repeated infusions increase to greater than 2 years.
  • Checking for anti-JC antibodies can helpful but not definitive for the risk stratification of acquiring PML. Those who are negative for the antibody have a decreased risk, but it does not provide 100% immunity against acquiring PML. Therefore, periodic testing should be done for anti-JC antibodies while on natalizumab.[1] 
  • It is contraindicated for immunosuppressed individuals. This includes individuals with human immunodeficiency virus, AIDS, leukemia, lymphoma, or those who have had organ transplants.
  • In the various studies and trials performed using natalizumab, the most common self-reported effect from patients was fatigue. 
  • Additional self-reported effects included headache, nausea, and rhinorrhea.
  • There is a low risk of anaphylaxis.
  • Hypersensitivity issues manifested with rash, urticaria, bronchospasm, chest pain, flushing of the skin, and have low blood pressure been reported. Most hypersensitivity issues will manifest within 2 hours of infusion.[12]
  • Given natalizumab is an immune modulating drug, its risk of association with other unusual and serious infections exist but are not definitive at this point.[1]
  • Three risk factors have been associated with a decreased incidence of PML which include (1) that the patient was on Natalizumab for the shortest period, (2) the patient did not have a large list of immunosuppressant drug use in his or her history, and (3) those patients who were negative for virus antibodies. The incidence of PML in a low-risk group (as defined by those mentioned above) was 0.09 cases per 1000 patients, compared to the high-risk group’s 11.1 cases per 1000 patients. [13][14]
  • Increases in nucleated red cells were seen in some patients. The changes were not permanent and without clinical effect. The levels returned to baseline within 16 weeks. An increase of lymphocytes, monocytes, and eosinophils can be seen in a patient on Natalizumab therapy. No increase in the neutrophil count has been noted in patients on natalizumab therapy. The increase in lymphocytes is expected, as the alpha 4 integrin is located on these cells. By blocking their navigation across the blood-brain barrier, it is expected that they would remain at high levels in the serum.[1]
  • No significant negative psychiatric effects have been associated with disease-modifying drugs like natalizumab.
  • Reviews suggest that there may be either an indirect or direct benefit in helping to reduce psychiatric symptoms of depression.[15]

Contraindications

  • Allergy to natalizumab
  • History of progressive multi leukoencephalopathy.

Monitoring

  • Liver function tests including bilirubin should be monitored as signs of liver toxicity and jaundice can appear as early as 6 days. Natalizumab should be immediately discontinued to prevent further damage.[15]
  • Changes in a complete blood count (CBC) such as leukocytosis can be expected given the drug's mechanism of action. Additional signs and symptoms suggestive of a new-onset, underlying infectious process should prompt the physician for further workup.

Enhancing Healthcare Team Outcomes

While the risk of acquiring progressive multi leukoencephalopathy with treatment can be daunting, given the current evidence at hand, one can take measures to best decrease the probability. As mentioned before:

  • Three risk factors have been associated with a decreased incidence of PML which include (1) that the patient was on Natalizumab for the shortest period, (2) the patient did not have a large list of immunosuppressant drug use in his or her history, and (3) those patients who were negative for virus antibodies. The incidence of PML in a low-risk group (as defined by those mentioned above) was 0.09 cases per 1000 patients, compared to the high-risk group’s 11.1 cases per 1000 patients. [13][14]

  • Checking for anti-JC antibodies can helpful but not definitive for the risk stratification of acquiring PML. Those who are negative for the antibody have a decreased risk, but it does not provide 100% immunity against acquiring PML. Therefore, periodic testing should be done for anti-JC antibodies while a patient is on natalizumab.[1] 

  • Immune modulating drugs including corticosteroids should be discontinued if possible before using natalizumab.[11]
  • Patients deemed immunocompromised such as HIV, AIDS, leukemia, lymphoma, or organ transplant recipients are at increased risk of acquiring PML.  

The long-term effects of natalizumab have yet to be determined. It is the responsibility of the physician to have a thorough discussion regarding the risks and benefits of treatment with their patient.


References

[1] Kleinschmidt-DeMasters BK,Tyler KL, Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. The New England journal of medicine. 2005 Jul 28     [PubMed PMID: 15947079]
[2] Vargas DL,Tyor WR, Update on disease-modifying therapies for multiple sclerosis. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. 2017 Jun     [PubMed PMID: 28130412]
[3] Hutchinson M, Natalizumab: A new treatment for relapsing remitting multiple sclerosis. Therapeutics and clinical risk management. 2007 Jun     [PubMed PMID: 18360634]
[4] Havrdova E,Galetta S,Hutchinson M,Stefoski D,Bates D,Polman CH,O'Connor PW,Giovannoni G,Phillips JT,Lublin FD,Pace A,Kim R,Hyde R, Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. The Lancet. Neurology. 2009 Mar     [PubMed PMID: 19201654]
[5] Radue EW,Stuart WH,Calabresi PA,Confavreux C,Galetta SL,Rudick RA,Lublin FD,Weinstock-Guttman B,Wynn DR,Fisher E,Papadopoulou A,Lynn F,Panzara MA,Sandrock AW, Natalizumab plus interferon beta-1a reduces lesion formation in relapsing multiple sclerosis. Journal of the neurological sciences. 2010 May 15     [PubMed PMID: 20236661]
[6] Lu ZY,Chen WC,Li YH,Li L,Zhang H,Pang Y,Xiao ZF,Xiao HW,Xiao Y, TNF-α enhances vascular cell adhesion molecule-1 expression in human bone marrow mesenchymal stem cells via the NF-κB, ERK and JNK signaling pathways. Molecular medicine reports. 2016 Jul     [PubMed PMID: 27221006]
[7] Kanwar JR,Kanwar RK,Wang D,Krissansen GW, Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression. Immunology and cell biology. 2000 Dec     [PubMed PMID: 11114975]
[8] Rae-Grant A,Day GS,Marrie RA,Rabinstein A,Cree BAC,Gronseth GS,Haboubi M,Halper J,Hosey JP,Jones DE,Lisak R,Pelletier D,Potrebic S,Sitcov C,Sommers R,Stachowiak J,Getchius TSD,Merillat SA,Pringsheim T, Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018 Apr 24     [PubMed PMID: 29686116]
[9] Rice GP,Hartung HP,Calabresi PA, Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005 Apr 26     [PubMed PMID: 15851719]
[10] Gerardi C,Bertele' V,Rossi S,Garattini S,Banzi R, Preapproval and postapproval evidence on drugs for multiple sclerosis. Neurology. 2018 May 22     [PubMed PMID: 29695598]
[11] Yousry TA,Major EO,Ryschkewitsch C,Fahle G,Fischer S,Hou J,Curfman B,Miszkiel K,Mueller-Lenke N,Sanchez E,Barkhof F,Radue EW,Jäger HR,Clifford DB, Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. The New England journal of medicine. 2006 Mar 2     [PubMed PMID: 16510746]
[12] Stüve O,Hemmer B, The genetics of natalizumab hypersensitivity: One learns to itch where one can scratch. Neurology(R) neuroimmunology     [PubMed PMID: 25520959]
[13] Ho PR,Koendgen H,Campbell N,Haddock B,Richman S,Chang I, Risk of natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. The Lancet. Neurology. 2017 Nov     [PubMed PMID: 28969984]
[14] Bloomgren G,Richman S,Hotermans C,Subramanyam M,Goelz S,Natarajan A,Lee S,Plavina T,Scanlon JV,Sandrock A,Bozic C, Risk of natalizumab-associated progressive multifocal leukoencephalopathy. The New England journal of medicine. 2012 May 17     [PubMed PMID: 22591293]
[15] Gasim M,Bernstein CN,Graff LA,Patten SB,El-Gabalawy R,Sareen J,Bolton JM,Marriott JJ,Fisk JD,Marrie RA, Adverse psychiatric effects of disease-modifying therapies in multiple Sclerosis: A systematic review. Multiple sclerosis and related disorders. 2018 Sep 12     [PubMed PMID: 30248593]