Continuing Education Activity

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. However, 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. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of natalizumab so that providers can direct patient therapy to optimal outcomes for MS patients.

Objectives:

• Identify the approved indications for natalizumab.
• Summarize the therapeutic mechanism of action of natalizumab.
• Review the recommended monitoring for potential adverse effects of natalizumab.
• Outline the importance of collaboration and communication among interprofessional team members to improve outcomes and treatment efficacy for patients who might benefit from therapy with natalizumab.

Indications

Natalizumab is an FDA-approved monoclonal antibody approved for the treatment of multiple sclerosis and Crohn's disease(CD).[1] 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.[2] 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 TOUCH Prescribing Program database. A facility is granted permission by the United States Federal Drug Administration to administer natalizumab and ensure that extensive monitoring data and follow-up regarding the patient's experience with natalizumab are collected.[3]

Natalizumab has been 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.[2] 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.[2] A controlled trial of natalizumab compared the average number of new lesions in 6 months between 3 groups: a placebo group, those on 3 mg/kg of natalizumab, and those on 6 mg/kg 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.[4]

Natalizumab is indicated to induce and maintain clinical response and remission in adult patients with moderately to severely active CD with positive evidence for inflammation. These patients must have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α.

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.[5] 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 the alpha4-beta1 integrin receptor that lines the blood-brain barrier, blocking leukocytes from entering the central nervous system (CNS) of the patient.[6] Several studies have shown a significant reduction in the number of lesions in multiple sclerosis patients taking natalizumab.[7]

Administration

Adult Dosing

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 treating physician's discretion. The infusion takes 1 hour, and the patient is then monitored closely by staff for one more hour 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.[8][9] In patients with CD, natalizumab should not be used concomitantly with immunosuppressants or inhibitors of TNF-α.

Specific Patient Population

Patients with Hepatic/Renal Impairment

Pharmacokinetic parameters of natalizumab in patients with hepatic or renal impairment have not been studied.

Pediatric Considerations

Clinical studies of natalizumab did not include pediatric patients under 18 years to determine whether they are safe and effective in treating patients with multiple sclerosis or Crohn's disease. Hence it is not indicated for use in these patients.

Geriatric Considerations

Safety and effectiveness in patients with multiple sclerosis or Crohn's disease have not been established as clinical trials had insufficient patients from this age group.

Pregnancy Considerations

There are inadequate data on the risk of major congenital disabilities, miscarriage, or other adverse maternal outcomes associated with the administration of natalizumab in pregnant women. In post-marketing surveillance, adverse fetal outcomes of neonatal thrombocytopenia, sometimes associated with anemia, have been reported. Monitor complete blood count in neonates with maternal exposure to natalizumab in utero.

Lactation/Breastfeeding Considerations 

Natalizumab is excreted in human breast milk. However, there is no data on the adverse effects of this exposure on maternal milk production and effects on the breastfed infant. Therefore, the developmental and health benefits of breastfeeding should be considered, along with the mother's clinical requirement for natalizumab and potential adverse effects on the breastfed infant from natalizumab and the underlying maternal condition.[10]

Adverse Effects

In the various studies and trials performed using natalizumab, patients' most common self-reported effect 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 low blood pressure. Most hypersensitivity issues will manifest within 2 hours of infusion.[11]

Given that natalizumab is an immune-modulating drug, its risk of association with other unusual and serious infections exists but is not definitive.[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 their 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.[12][13]

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 in 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.[14]

Natalizumab can increase the risk of developing encephalitis and meningitis caused by varicella-zoster viruses and herpes simplex. Serious, life-threatening, and rarely fatal cases have been reported in the post-marketing studies in patients with MS. The diagnosis was confirmed by laboratory PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with natalizumab before onset ranged from a few months to several years.

There is also an increased risk of acute retinal necrosis (ARN) caused by herpesviruses has been observed in patients being administered natalizumab. ARN can also occur in patients with herpes meningitis or encephalitis. Serious cases of ARN may lead to the blindness of one or both eyes in some patients. Therefore, following a confirmed diagnosis of ARN, consider discontinuation of natalizumab. The treatment reported in ARN cases included anti-viral medicines and sometimes surgery.

Contraindications

• Allergy to natalizumab
• History of progressive multi leukoencephalopathy

Box Warning

• When used with other immune-modulating drugs, the risk of progressive multi leukoencephalopathy (PML) and an opportunistic infection caused by the (John Cunningham) JC virus increases. There is a boxed warning for this reason, and prescribers should carefully consider the risks versus benefits of using natalizumab for each patient. Immune modulating drugs, including corticosteroids, should be discontinued if possible before using natalizumab.[15] PML risk increases as the number of repeated infusions increase to greater than two years. Checking for anti-JC antibodies can help but is not definitive for the risk stratification of acquiring PML. Those who tested 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.[2] 
• It is contraindicated for immunosuppressed individuals. This includes individuals with human immunodeficiency virus, AIDS, leukemia, lymphoma, or those who have had organ transplants.

Monitoring

Liver function tests, including bilirubin, should be monitored as signs of liver toxicity and jaundice can appear as early as six days. Natalizumab should be immediately discontinued to prevent further damage.[14]

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 new-onset, the underlying infectious process should prompt the physician for further workup.

Monitor patients for signs and symptoms of meningitis/encephalitis. If herpes encephalitis or meningitis occurs, natalizumab should be stopped, and appropriate treatment for herpes encephalitis or meningitis needs to be administered.

Patients presenting with eye symptoms, including redness, decreased visual acuity, or eye pain, should be referred for retinal screening for ARN.

Toxicity

Natalizumab safety at doses of more than 300 mg has not been adequately evaluated. It is recommended to call the local poison control center to get up-to-date information for treating the overdose with natalizumab.

Enhancing Healthcare Team Outcomes

While the risk of acquiring progressive multi-leukoencephalopathy with treatment can be daunting, one can take measures to best decrease the probability, given the current evidence at hand. 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 their 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.[12][13]

• Checking for anti-JC antibodies can help but is not definitive for the risk stratification of acquiring PML. Those tested 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.[2] 

• Immune modulating drugs, including corticosteroids, should be discontinued if possible before using natalizumab.[15]

• 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 clinicians to have a thorough discussion regarding the risks and benefits of treatment with their patients. Nursing needs to monitor patients after administration and comply with TOUCH program guidelines. Also, infusion centers and pharmacies must be certified to infuse or dispense natalizumab. The pharmacist needs to perform the medication reconciliation and notify the prescriber of any concerns. Open communication and collaboration among interprofessional team members can improve safety outcomes and treatment efficacy for patients treated with natalizumab. [Level 5]