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Natalizumab
Natalizumab Fab fragment bound to the headpiece of an α4-integrin. From PDB 4IRZ​.
Monoclonal antibody
TypeWhole antibody
SourceHumanized (from mouse)
Targetalpha-4 integrin
Clinical data
Trade namesTysabri, others
Other namesAN100226M, Antegren
Biosimilarsnatalizumab-sztn,[1] Tyruko[1][2]
AHFS/Drugs.comMonograph
MedlinePlusa605006
License data
Pregnancy
category
Routes of
administration		Intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityn/a
Elimination half-life11 ± 4 days
Identifiers
CAS Number
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Molar mass149 kg/mol
 ☒NcheckY (what is this?)  (verify)

Natalizumab, sold under the brand name Tysabri among others, is a medication used to treat multiple sclerosis and Crohn's disease.[8] It is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin.[8] It is given by intravenous infusion.[8] The drug is believed to work by reducing the ability of inflammatory immune cells to attach to and pass through the cell layers lining the intestines and blood–brain barrier.[medical citation needed]

Natalizumab is a monoclonal antibody which targets a protein called α4β1 integrin on white blood cells involved in inflammation.[9] By attaching to integrin, natalizumab is thought to stop white blood cells from entering the brain and spinal cord tissue, thereby reducing inflammation and the resulting nerve damage.[9]

The most common side effects are urinary tract infection, nasopharyngitis (inflammation of the nose and throat), headache, dizziness, nausea, joint pain and tiredness.[9]

Natalizumab was approved for medical use in the United States in 2004. It was subsequently withdrawn from the market by its manufacturer after it was linked with three cases of the rare neurological condition progressive multifocal leukoencephalopathy (PML) when administered in combination with interferon beta-1a, another immunosuppressive drug often used in the treatment of multiple sclerosis. After a review of safety information and no further deaths, the drug was returned to the US market in 2006 under a special prescription program. As of June 2009, ten cases of PML were known. However, twenty-four cases of PML had been reported since its reintroduction by October 2009, showing a sharp rise in the number of fatalities and prompting a review of the chemical for human use by the European Medicines Agency.[10] By 2010, 31 cases of PML were attributed to natalizumab while by 2018 this had risen to 757 cases.[11][12] The US Food and Drug Administration (FDA) did not withdraw the drug from the market as benefits outweigh the risks.[13] In the European Union, it has been approved only for multiple sclerosis and only by itself as the initial cases of PML, and later the fatalities, were said by the manufacturers to be linked to the use of previous medicines by the person.[14]

Medical uses

[edit]

In the United states, natalizumab is indicated for the treatment of multiple sclerosis and Crohn's disease.[1][8] It is indicated to treat clinically isolated syndrome – a single, first occurrence of multiple sclerosis symptoms; relapsing-remitting disease – a type of multiple sclerosis that occurs when people have episodes of new neurological symptoms followed by periods of stability; and active secondary progressive disease – when, following a relapsing-remitting course, patients experience gradual disability worsening with continued relapses.[1][8][15]

Natalizumab offers a limited improvement in efficacy compared to other treatments for multiple sclerosis, but due to the lack of information about long-term use, as well as potentially fatal adverse events, reservations have been expressed over the use of the drug outside of comparative research with existing medications.[16][17][18] Natalizumab is used as a monotherapy.[19]

In the European Union, natalizumab is indicated as single disease modifying therapy in adults with highly active relapsing remitting multiple sclerosis for the following patient groups:

  • People with highly active disease activity despite a full and adequate course of treatment with at least one disease modifying therapy (DMT), or[9]
  • People with rapidly evolving severe relapsing remitting multiple sclerosis defined by two or more disabling relapses in one year, and with one or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.[9]

Adverse effects

[edit]

The US prescribing information for natalizumab contains a boxed warning about the increased risk of progressive multifocal leukoencephalopathy,[15] a viral infection of the brain that usually leads to death or severe disability.[9][15] Risk factors for the development of progressive multifocal leukoencephalopathy include the presence of anti-JCV antibodies (antibodies to the JC virus, a typically harmless virus carried by most humans), longer duration of therapy and prior use of immunosuppressants.[9][15]

It was first observed in seven patients who received natalizumab in late 2008;[20] three cases were noted in clinical trials in 2006[21] leading to the drug being temporarily pulled from the market; two cases were reported to the FDA in August 2008;[22] and two cases were announced in December 2008.[20] By January 2010, the FDA noted a total of 31 confirmed cases of PML,[11] with the chance of developing the infection increasing as the number of infusions received by a patient increased. Because of this association, the drug label and package insert accompanying the drug will be updated to include this information.[23] As of February 2012, there were 212 confirmed cases of PML among 99,571 patients treated with natalizumab (2.1 cases per 1000 patients). All 54 patients with PML for whom samples were available before the diagnosis were positive for anti–JC virus antibodies. When the risk of PML was evaluated according to three risk factors, it was lowest among the patients who had used natalizumab for the shortest periods, those who had used few if any immunosuppressant drugs to treat MS in the past, and lastly who were negative for anti–JC virus antibodies. The incidence of PML in the low risk group was estimated to be 0.09 cases, or less, per 1000 patients. Patients who had taken natalizumab for longer, from 25 to 48 months, who were positive for anti–JC virus antibodies, had taken immunosuppressants before the initiation of natalizumab therapy had the highest risk of developing PML. Their risk is fully 123 times higher than the low risk group. (incidence, 11.1 cases per 1000 patients [95% CI, 8.3 to 14.5]).[24] While none of them had taken the drug in combination with other disease-modifying treatments, previous use of MS treatments increases the risk of PML between 3 and 4-fold.[25] In 2016, EMA recommended all people taking natalizumab should undergo full MRI scans at least once a year due to concerns of progressive multifocal leukoencephalopathy (PML). In addition, more frequent MRI scans (e.g. every 3 to 6 months) should be performed using simplified protocols should be considered for those at higher risk of PML.[26]

Postmarketing surveillance in early 2008 revealed that 0.1% of people taking natalizumab experience clinically significant liver injury, leading to the FDA, EMEA and manufacturers recommending that the medication be discontinued in patients with jaundice or other evidence of significant liver damage.[27][28][29] This rate is comparable to other immune-suppressing drugs.[30] Evidence of hepatotoxicity in the form of elevated blood levels of bilirubin and liver enzymes can appear as soon as six days after an initial dose; reactions are unpredictable and may appear even if the patient does not react to previous treatment.[31] Such signs reoccur upon rechallenge in some patients, indicating that damage is not coincidental.[31] In the absence of any blockage these liver function tests are predictors of severe liver injury with possible sequelae of liver transplantation or death.[31]

Common adverse effects include fatigue and allergic reactions with a low risk of anaphylaxis,[32] headache, nausea, colds and exacerbation of Crohn's disease in a minority of patients with the condition.[medical citation needed] Adolescents with Crohn's disease experience headache, fever and exacerbation of Crohn's disease.[medical citation needed]

About 6% of the people in studies developed long-lasting antibodies against natalizumab, which reduced the medicine's effectiveness.[9]


Mechanism of action

[edit]
Structure of a generic antibody

Natalizumab is a humanized monoclonal antibody against alpha-4 (α4) integrin, the first drug developed in the class of selective adhesion molecule inhibitors. α4-integrin is required for white blood cells to move into organs, and natalizumab's mechanism of action is believed to be the prevention of immune cells from crossing blood vessel walls to reach affected organs.[33]

Multiple sclerosis

[edit]

The symptom-causing lesions of MS are believed to be caused when inflammatory cells such as T-lymphocytes pass through the blood–brain barrier through interaction with receptors on the endothelial cells. Natalizumab appears to reduce the transmission of immune cells into the central nervous system by interfering with the α4β7-integrin receptor molecules on the surfaces of cells. The effect appears to occur on endothelial cells expressing the VCAM-1 gene, and in parenchymal cells expressing the osteopontin gene. In animals used to model MS and test therapies, repeated administration of natalizumab reduced migration of leukocytes into the brain's parenchyma, and also reduced lesioning, though it is uncertain if this is clinically significant for humans.[8]

Individuals with MS dosed with natalizumab demonstrated increased CD34-expressing cells, with research suggesting a peak in expression after 72 hours.[34]

Crohn's disease

[edit]

The interaction of the α4β7 integrin and the addressin (also known as MADCAM1) endothelial cell receptor is believed to contribute to the chronic bowel inflammation that causes Crohn's disease. Addressin is primarily expressed in the endothelium of venules in the small intestine and are critical in guiding T-lymphocytes to lymphatic tissues in Peyer's patches. In CD patients, sites of active inflammation of the bowel in CD patients have increased expression of addressin, suggesting a connection between the inflammation and the receptor. Natalizumab may block interaction between the α4β7 integrin and addressin at sites of inflammation. Animal models have found higher levels of VCAM-1 expression in mice with irritable bowel syndrome and the VCAM-1 gene may also play a part in CD but its role is not yet clear.[8]

Interactions

[edit]

Natalizumab appears to interact with other immune-modulating drugs to increase the risk of progressive multifocal leukoencephalopathy (PML), an often-fatal opportunistic infection caused by the JC virus. In 2005, two people taking natalizumab in combination with interferon beta-1a developed PML. One died, and the other recovered with disabling sequelae.[35][36] A third fatal case initially attributed to an astrocytoma was reported in a patient being treated for Crohn's disease.[21] Though the patient was being treated with natalizumab in combination with azathioprine, corticosteroids and infliximab, indications of PML infection appeared only after natalizumab monotherapy was re-introduced.[21] No deaths from progressive multifocal leukoencephalopathy have been linked to natalizumab when it was not combined with other immune-modulating drugs[37] and other rates of opportunistic infections are not increased in patients taking natalizumab[38] possibly due to the drug's mechanism of action.[39] Other than a prior history of PML, there is no known method to identify patients at risk of developing PML.[40] Natalizumab's label indicates that it is contraindicated for immunosuppressed individuals or those with a history of PML.[8] Due to the uncertain risk of PML, natalizumab is only available through a restricted distribution program.[8] By January 2010, the United States Food and Drug Administration reported a total of 31 confirmed cases of PML associated with natalizumab.[11]

Though the small number of cases precludes conclusion on the ability of natalizumab alone to induce PML, its black box warning states that the drug has only been linked to PML when combined with other immune-modulating drugs and natalizumab is contraindicated for use with other immunomodulators.[8] Corticosteroids may produce immunosuppression, and the Tysabri prescribing information recommends that people taking corticosteroids for the treatment of Crohn's disease have their doses reduced before starting natalizumab treatment.[8] The risk of developing PML was later estimated to be 1 in 1,000 (0.1%) over 18 months[17][38][41] though the longer term risks of PML are unknown.[17]

History

[edit]

Biogen Idec announced the initiation of the first clinical trial of natalizumab as a potential cancer treatment as of September 2008.[42]

Society and culture

[edit]
[edit]

Natalizumab was originally approved for treatment of multiple sclerosis in 2004, through the FDA's accelerated Fast Track program, due to the drug's efficacy in one-year clinical trials. In February 2005, four months after its approval, natalizumab was withdrawn voluntarily by the manufacturer after two cases of progressive multifocal leukoencephalopathy. Groups representing individuals with MS lobbied to have the drug returned to the US market[43] and in June 2006, after recommendation by an advisory committee and a review of two years of safety and efficacy data, the FDA re-approved natalizumab for patients with all relapsing forms of MS (relapse-remitting, secondary-progressive, and progressive-relapsing) as a first-line or second-line therapy.[44][45] Patients taking natalizumab must enter into a registry for monitoring.[43] Natalizumab is the only drug after alosetron withdrawn for safety reasons that returned to the US market.[citation needed]

In April 2006, the Committee for Medicinal Products for Human Use recommended authorizing natalizumab to treat relapsing-remitting MS, and natalizumab was approved for medical use in the European Union in June 2006.[9][46]

Health Canada added natalizumab to Schedule F of the Food and Drug Regulations in April 2008, as a prescription drug requiring oversight from a physician.[47]

In 2007, the EMA rejected the application to market natalizumab for Crohn's disease due to concerns over its risk/benefit ratio.[48] In January 2008, the FDA approved it for the induction of remission and maintenance of remission for moderate to severe Crohn's disease.[49]

Biosimilars

[edit]

In July 2023, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Tyruko, intended for the treatment of multiple sclerosis.[50] The applicant for this medicinal product is Sandoz GmbH.[50][51] Tyruko was approved for medical use in the European Union in September 2023.[2]

In August 2023, the FDA approved Tyruko (natalizumab-sztn) and granted approval to Sandoz Inc.[15][52]

References

[edit]

Further reading

[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Natalizumab

View on Grokipedia
from Grokipedia

is a recombinant humanized IgG4κ monoclonal antibody that selectively binds to the α4-subunit of α4β1 and α4β7 expressed on leukocytes, thereby inhibiting their adhesion to vascular endothelium and subsequent transmigration into tissues such as the and . Approved by the U.S. in 2004 for the treatment of relapsing forms of (MS), it demonstrates high efficacy in reducing clinical relapses, MRI lesion activity, and disability progression in clinical trials, outperforming many other disease-modifying therapies through its potent blockade of immune cell trafficking. Marketed as Tysabri by , the drug is administered via intravenous infusion every four weeks and is also indicated for inducing and maintaining clinical response and remission in patients with moderately to severely active unresponsive to conventional therapies. Despite its therapeutic benefits, natalizumab carries a significant of (PML), a rare but often fatal of the caused by reactivation of the JC polyomavirus in immunocompromised individuals, with the drug's causally linked to impaired immune in the . This , estimated at approximately 1 in 1,000 after 18-24 months of treatment in JC virus-seropositive s and higher with longer durations or prior immunosuppressant exposure, prompted a temporary market withdrawal in following three confirmed PML cases, leading to reapproval in under a restricted distribution program (TOUCH) mandating monitoring, stratification via anti-JCV antibody testing, and MRI . Ongoing research emphasizes personalized to balance natalizumab's superior efficacy against this causal , with no evidence of systemic bias underreporting the PML incidence in peer-reviewed data.

Medical Indications

Multiple Sclerosis

Natalizumab is indicated as monotherapy for the treatment of relapsing forms of (MS) in adults, encompassing , relapsing-remitting MS (RRMS), and active secondary progressive MS (SPMS), to delay accumulation and reduce clinical frequency. Approval by the U.S. occurred in 2006 following suspension and reinstatement after initial 2004 authorization, based on demonstration of significant clinical benefits in reducing relapse rates and disability progression. In clinical practice, it is positioned for patients exhibiting highly active disease, particularly those with inadequate response to alternative disease-modifying therapies, due to its potent suppression of inflammatory activity. The drug's role emphasizes selection of patients with substantial relapse burden or radiographic evidence of ongoing inflammation, such as ≥2 in the preceding year despite treatment or multiple gadolinium-enhancing lesions on (MRI). This criteria-based approach aligns with empirical data from controlled studies showing natalizumab reduces annualized rates by 68% relative to and lowers the risk of sustained disability progression by 42% over two years in relapsing MS populations. For active SPMS, defined by ongoing or MRI lesion activity superimposed on gradual progression, natalizumab addresses residual relapsing components not fully controlled by other agents. Patient monitoring prior to and during therapy incorporates baseline assessment of MS activity via clinical history and MRI to confirm eligibility for this high-efficacy option, reserving it for cases where relapse frequency or lesion load indicates aggressive disease course. Such selection mitigates risks while leveraging natalizumab's capacity to stabilize neurological function in responsive subgroups, informed by observed reductions in both clinical and subclinical disease measures.

Inflammatory Bowel Disease

Natalizumab is approved by the U.S. for inducing and maintaining clinical response and remission in adult patients with moderately to severely active who have evidence of inflammation, such as elevated levels, and who have had an inadequate response to, or are unable to tolerate, conventional therapies and tumor necrosis factor-alpha (TNF-α) inhibitors. This approval, granted on January 14, 2008, targets patients with inflammation-driven disease refractory to standard immunomodulators like or and biologics such as or . The ENCORE trial demonstrated natalizumab's efficacy for induction in TNF-α-failure patients, with 300 mg intravenous doses at weeks 0, 4, and 8 yielding a sustained clinical response (≥70-point reduction in Activity Index [CDAI] score from baseline, maintained from week 8 to 12) in 48% of recipients versus 32% on (p < 0.001); remission (CDAI <150) occurred in 26% versus 16%. In the ENACT-2 maintenance trial, among induction responders, continued natalizumab every 4 weeks through week 56 sustained response in 61% versus 28% with (p < 0.001) and remission in 44% versus 26% (p = 0.005). Due to the risk of progressive multifocal leukoencephalopathy, natalizumab's use in Crohn's disease is restricted in guidelines to cases refractory to other biologics, with the American Gastroenterological Association no longer recommending it as a primary option amid safer alternatives like vedolizumab or ustekinumab. It remains positioned for moderate-to-severe luminal disease unresponsive to anti-TNF agents, emphasizing its role in select, high-need patients.

Pharmacology

Mechanism of Action

Natalizumab is a recombinant humanized monoclonal antibody of the IgG4κ isotype that selectively binds to the α4 subunit of the α4β1 (very late antigen-4, VLA-4) and α4β7 integrins expressed on the surface of leukocytes. This binding occurs at a site on the α4 β-propeller domain distinct from the ligand-binding groove, enabling non-competitive inhibition of integrin-ligand interactions. By antagonizing α4β1 integrin, natalizumab prevents its adhesion to vascular cell adhesion molecule-1 (VCAM-1) on activated endothelial cells, thereby inhibiting the capture, rolling, and firm adhesion of leukocytes during the multi-step process of extravasation. Similarly, blockade of α4β7 integrin disrupts binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), which is preferentially expressed on gut endothelium. These molecular interactions are essential for the tissue-specific homing of T- and B-lymphocytes, and their inhibition functionally restricts leukocyte trafficking without causing depletion of circulating immune cells, thus maintaining peripheral immune surveillance. In the context of central nervous system inflammation, such as in multiple sclerosis, this mechanism limits the entry of proinflammatory T- and B-cells across the blood-brain barrier by impairing their adhesion to VCAM-1-expressing endothelium. For inflammatory bowel disease, the blockade of α4β7-MAdCAM-1 interactions reduces lymphocyte migration into the gastrointestinal mucosa, attenuating localized gut inflammation. Overall, natalizumab's pharmacodynamic action is mediated through steric hindrance and allosteric modulation of integrin conformation, favoring a low-affinity state that precludes effective endothelial engagement.

Pharmacokinetics and Administration

Natalizumab is administered via intravenous infusion at a dose of 300 mg over approximately one hour, repeated every four weeks. This regimen applies to both multiple sclerosis and Crohn's disease indications, with no initial loading dose required. Premedication is not routinely recommended, though infusion-related reactions may necessitate supportive care such as antihistamines or corticosteroids in subsequent administrations. Pharmacokinetically, natalizumab demonstrates complete bioavailability due to intravenous delivery, with a steady-state achieved after approximately 16–24 weeks of every-four-week dosing, corresponding to mean trough serum concentrations of 23–29 μg/mL. The elimination half-life averages 11 ± 4 days, with clearance of 16 ± 5 mL/hour and a volume of distribution of 5.7 ± 1.9 L, reflecting primary confinement to plasma volume rather than extensive tissue distribution. As a recombinant monoclonal antibody, natalizumab undergoes minimal hepatic or renal metabolism and is primarily cleared through proteolysis via the reticuloendothelial system, resulting in no need for dose adjustments in patients with renal or hepatic impairment. In extended-interval dosing protocols, aimed at reducing cumulative exposure while preserving therapeutic levels, serum trough concentrations are monitored to guide interval adjustments, typically targeting levels above 2 μg/mL to maintain adequate α4-integrin saturation. For instance, six-week intervals may yield 60–70% lower trough levels compared to standard four-week dosing, necessitating individualized assessment via pharmacokinetic monitoring. Such strategies have been evaluated in prospective trials, confirming feasibility with therapeutic drug monitoring to optimize dosing frequency.

Clinical Efficacy

Pivotal Clinical Trials

The AFFIRM trial, a phase 3, randomized, double-blind, placebo-controlled study involving 942 patients with relapsing-remitting multiple sclerosis (RRMS), demonstrated that natalizumab monotherapy administered intravenously every 4 weeks for 2 years reduced the annualized relapse rate by 68% compared to placebo (rate ratio 0.32; 95% CI 0.28-0.37; p<0.001). It also lowered the cumulative probability of sustained disability progression confirmed at 12 weeks by 42% (hazard ratio 0.58; 95% CI 0.43-0.77; p=0.0006), with MRI endpoints showing a 92% reduction in new or enlarging T2 lesions (p<0.001) and an 89% decrease in gadolinium-enhancing lesions (p<0.001). The SENTINEL trial, another phase 3, randomized, double-blind study with 1,174 RRMS patients on interferon beta-1a, evaluated natalizumab as add-on therapy versus interferon alone over 2 years, yielding a 68% relative reduction in annualized relapse rate (rate ratio 0.32; 95% CI 0.28-0.37; p<0.001) and a 24% decrease in the risk of sustained disability progression at 12 weeks (hazard ratio 0.76; 95% CI 0.61-0.96; p=0.02). MRI measures supported these findings, with natalizumab plus interferon reducing new T2 lesions by 83% (p<0.001) and gadolinium-enhancing lesions by 92% (p<0.001) relative to interferon monotherapy. For Crohn's disease, the ENCORE trial, a phase 3, randomized, double-blind, placebo-controlled study in 511 patients with moderate-to-severe active disease, showed natalizumab induction (300 mg infusions at weeks 0, 4, and 8) achieved a significantly higher response rate at both weeks 8 and 12 (48% vs. 32%; p<0.001), with sustained remission through week 12 in 26% versus 16% (p=0.002). The ENACT-1 trial, an earlier phase 3 induction study in 905 patients, reported clinical response rates of 51% at week 4 for natalizumab versus 37% for placebo (p<0.001), though remission rates were not significantly superior after one infusion (8% vs. 4%; p=0.048, borderline in some analyses). The ASCEND trial, a phase 3, randomized, double-blind, placebo-controlled study in 889 patients with secondary progressive multiple sclerosis, failed to meet its primary endpoint of reducing confirmed disability progression over 2 years, as measured by a composite including timed 25-foot walk, 9-hole peg test, and cognitive battery (23% progression rate with natalizumab vs. 27% with placebo; hazard ratio 0.85; 95% CI 0.64-1.14; p=0.28).30069-3/abstract) However, it showed a nominally significant benefit in upper limb function (9-hole peg test progression: 20% vs. 25%; p=0.039).30069-3/abstract)

Real-World Outcomes and Long-Term Data

Real-world evidence from the Tysabri Observational Program (TOP) registry, encompassing over 6,000 multiple sclerosis patients treated for up to 10 years, shows natalizumab achieving an annualized relapse rate of 0.15, a 92.5% reduction from pre-treatment levels of 1.99. The cumulative probability of remaining relapse-free at 10 years was 45.8%, reflecting sustained suppression of relapses amid real-world factors such as variable adherence and comorbidities. Disability outcomes remained stable, with mean (EDSS) changes under 1.0 point from baseline, 27.8% experiencing confirmed worsening, and 33.1% showing confirmed improvement over the decade. Observational studies highlight predictors of durable response, including early treatment initiation, which correlates with superior long-term relapse control compared to delayed use after other therapies. In cohorts from registries like MSBase, natalizumab users demonstrated lower relapse rates and better disability trajectories than those on alternative disease-modifying therapies, underscoring its efficacy in heterogeneous populations beyond trial exclusions. Extended interval dosing (EID), typically every 6-8 weeks, preserves efficacy in real-world settings, with meta-analyses confirming comparable relapse rates and MRI lesion stability to standard monthly dosing, alongside reduced cumulative drug exposure. A 2025 comparative study reported no significant differences in clinical or radiological outcomes between EID and standard regimens over extended follow-up. Recent 2025 data from the TITAN study indicate natalizumab improves work productivity in relapsing-remitting multiple sclerosis, with significant reductions in work impairment via Work Productivity and Activity Impairment questionnaire scores at 6-12 months post-initiation, attributing gains to decreased relapses and fatigue. These pragmatic insights affirm natalizumab's role in maintaining low disease activity for long-term users, particularly when initiated promptly and optimized via EID.

Safety Profile

Progressive Multifocal Leukoencephalopathy Risk

Progressive multifocal leukoencephalopathy (PML) is the primary serious adverse event associated with natalizumab therapy, caused by reactivation of the John Cunningham (JC) virus in the central nervous system (CNS). As of 2023, a total of 246 confirmed PML cases have been reported globally among natalizumab-treated patients. The overall incidence rate stands at approximately 3.43 per 1,000 patients, with stability observed in global rates since mid-2016 despite increased patient exposure. Risk stratification for PML incorporates JC virus (JCV) seropositivity, anti-JCV antibody index, treatment duration, and prior immunosuppressant use. Patients seropositive for anti-JCV antibodies face elevated risk, further refined by antibody index levels; those with an index greater than 1.5 exhibit approximately 10 per 1,000 risk after 24 months of therapy.30282-X/abstract) Prolonged natalizumab exposure correlates with rising incidence, as viral reactivation accumulates with impaired CNS immune access over time. Prior immunosuppressant exposure independently heightens susceptibility, appearing in up to 33% of early inflammatory demyelinating PML cases compared to 5% in broader cohorts. Natalizumab promotes JCV reactivation by blocking α4-integrin-mediated leukocyte trafficking across the blood-brain barrier, thereby diminishing immune surveillance of latently infected oligodendrocytes and astrocytes in the CNS. This mechanism facilitates asymptomatic JCV DNA detection in cerebrospinal fluid and peripheral blood mononuclear cells, with higher viral loads in CD34+ hematopoietic precursors and monocytes among treated patients. PML outcomes remain grave, with mortality rates ranging from 20% to 25%, often occurring within months of diagnosis. Among survivors, severe neurological disability predominates, affecting 40% profoundly and 47% moderately, due to irreversible demyelination and gliosis.

Other Adverse Effects

Infusion-related reactions occur in approximately 24% of patients with multiple sclerosis treated with natalizumab, compared to 18% on placebo, manifesting as symptoms such as headache, nausea, dizziness, fatigue, chills, and urticaria, typically during or shortly after infusion. Hypersensitivity reactions, including rash, urticaria, and dyspnea, affect up to 4% of patients, with serious systemic reactions like anaphylaxis occurring in less than 1%. These reactions are more frequent in patients developing anti-natalizumab antibodies and often occur within two hours of infusion. Hepatic effects include post-marketing reports of clinically significant liver injury, characterized by elevated liver enzymes and features of autoimmunity, though trial incidences of enzyme elevations remain low and not distinctly quantified beyond rare spontaneous cases. Infections occur at a rate of about 1.5 per patient-year, with serious infections in roughly 3% of multiple sclerosis patients versus 2.6% on placebo; herpes infections, including progressive multifocal leukoencephalopathy-excluded cases of encephalitis or meningitis due to herpes simplex or varicella-zoster viruses, show slightly increased frequency and life-threatening potential in post-marketing surveillance. Anti-natalizumab antibodies develop in approximately 9-10% of patients, with persistent neutralizing antibodies in about 6%, correlating with reduced drug efficacy, higher infusion reaction rates, and hypersensitivity risk. Long-term follow-up data from observational programs indicate no significant signals for increased cardiovascular events or malignancies beyond background rates observed in trials.

Risk Stratification and Mitigation

Risk stratification for natalizumab-associated progressive multifocal leukoencephalopathy (PML) primarily relies on three factors: John Cunningham virus (JCV) antibody seropositivity, prior use of immunosuppressants, and cumulative treatment duration, with anti-JCV antibody index values further refining risk estimates in seropositive patients.30282-X/abstract) Quantitative anti-JCV antibody testing is recommended every 6 months to monitor seroconversion or index changes, enabling dynamic risk assessment. For JCV-seronegative patients, testing frequency aligns with this interval, while seropositive individuals with high index values (>1.5) or additional risk factors warrant heightened vigilance. Mitigation protocols emphasize proactive surveillance tailored to stratified risk levels. In JCV-seropositive patients, particularly those with prior immunosuppressant exposure or extended treatment (>24 months), (MRI) surveillance every 3-6 months using abbreviated protocols is advised to detect PML lesions early, facilitating intervention before clinical symptoms emerge. Extended interval dosing (EID), administered every 6-8 weeks instead of standard every-4-weeks, has been associated with substantially lower PML incidence—demonstrated in large registries as up to an reduction—while maintaining comparable clinical efficacy in prevention and stabilization. Upon suspicion of PML, confirmed via MRI and JCV PCR, immediate natalizumab discontinuation is critical to halt JC virus replication. Plasma exchange or immunoadsorption, typically 4-5 sessions, accelerates natalizumab clearance, restoring immune surveillance and potentially improving survival outcomes, though evidence on efficacy remains observational and tied to early detection. These interventions must balance against (IRIS), managed supportively with corticosteroids if severe. Ongoing risk-benefit evaluation, including switching to alternative therapies, is integral to long-term management.

Interactions and Contraindications

Drug Interactions

Natalizumab, as a targeting α4-integrin, exhibits primarily pharmacodynamic interactions with other immunosuppressive agents, which can amplify overall and elevate the risk of opportunistic infections such as (PML). Concomitant or prior use of immunosuppressants like , , , or mitoxantrone has been associated with a multiplicative increase in PML incidence, as these therapies further impair immune surveillance in mechanisms overlapping with natalizumab's blockade of leukocyte trafficking to inflamed tissues. No clinically significant pharmacokinetic interactions via enzymes have been identified, consistent with natalizumab's biologic nature and lack of hepatic metabolism typical of monoclonal antibodies. However, caution is advised with live attenuated vaccines, including measles-mumps-rubella (MMR) or varicella-zoster virus vaccines, due to natalizumab's interference with immune cell migration, which may diminish vaccine efficacy or precipitate disseminated infections from vaccine strains. Data on combinations with newer therapies, such as ocrelizumab (a CD20-depleting ), remain limited, with most evidence derived from switching strategies rather than concurrent administration; such overlaps could theoretically heighten infection risks through additive B- and T-cell dysregulation, though direct mechanistic studies are sparse. Clinical guidelines recommend avoiding unstudied concomitant use to prevent unforeseen immunosuppressive synergies.

Patient Selection Criteria

Natalizumab is indicated for adults with relapsing forms of (MS), particularly those exhibiting highly active disease characterized by frequent relapses or significant MRI lesion activity despite prior therapies. Selection prioritizes patients with breakthrough disease on first-line agents like interferons or , where its high efficacy in reducing relapses (by approximately 68% in pivotal trials) and disability progression justifies the PML risk. Guidelines recommend reserving it for relapsing-remitting MS (RRMS) subtypes unresponsive to oral disease-modifying therapies (DMTs) such as or , avoiding first-line use in JCV-seronegative patients with low-risk profiles where less intensive options suffice. Risk stratification centers on anti-JCV antibody status, prior immunosuppressive exposure, and treatment duration to estimate PML incidence, which rises from <0.1/1000 in JCV-negative patients to over 10/1000 in JCV-positive individuals with high antibody indices (>1.5) after 24 months. Initiation is favored in JCV-negative or low-index patients with aggressive RRMS, with mandatory enrollment in programs like TOUCH (U.S.) or similar protocols requiring and periodic JCV testing every 6 months. Extended interval dosing (every 6 weeks versus standard 4 weeks) may mitigate PML risk by 70-90% in eligible patients while preserving , serving as a strategy for prolonged use in intermediate-risk cases. Contraindications include prior PML diagnosis, to natalizumab, or active untreated infections, as these amplify neurological risks without countervailing benefits. lacks robust data but is approached cautiously (U.S. category D post-2015 updates due to potential fetal harm observed in animal models at high doses); human studies report no elevated or malformation rates, though third-trimester exposure may increase neonatal infections, prompting discontinuation 2-3 months preconception or switching to safer alternatives like interferons. Discontinuation is advised upon PML suspicion (e.g., new neurological symptoms with JCV positivity), (persistent relapses after 6-12 months), or thresholds exceeding 1/100 (e.g., JCV index >0.9 after 2 years with prior immunosuppressants). Switching to high-efficacy DMTs like ocrelizumab or rituximab minimizes rebound activity, with washout periods of 3-6 months to avoid carryover PML , guided by MRI surveillance and individualized relapse history. Plasma exchange accelerates natalizumab clearance if PML emerges, followed by immune reconstitution therapies.

Development and History

Preclinical and Early Development

Natalizumab's development originated from research into leukocyte adhesion mechanisms underlying inflammatory diseases. In 1992, researchers including Ted Yednock and Lawrence Steinman identified the α4 subunit as essential for lymphocyte homing to inflamed brain endothelium, using the Stamper-Woodruff assay in a rat model of experimental autoimmune encephalomyelitis (EAE), an animal analog of (MS). Antibodies targeting α4 prevented paralysis in approximately 75% of EAE-affected rats by blocking immune cell entry into the (CNS), reducing inflammation without broadly suppressing systemic immunity. This work, conducted in collaboration between and Athena Neurosciences (later acquired by Elan Corporation), established the rationale for inhibiting α4-mediated adhesion via very late antigen-4 (, α4β1) and α4β7 to endothelial vascular cell adhesion molecule-1 () and mucosal addressin cell adhesion molecule-1 (MadCAM-1). Preclinical studies further validated this approach in EAE models. In guinea pigs, natalizumab administered subcutaneously at 3 mg/kg on days 7 and 14 post-induction ameliorated active EAE symptoms when serum concentrations exceeded 1-5 μg/ml, demonstrating CNS protection through reversible blockade of leukocyte migration. The monoclonal antibody precursor inhibited α4 integrin-dependent adhesion to VCAM-1, MadCAM-1, fibronectin, and osteopontin in vitro, with binding affinity (Kd ≈ 0.3 nM) comparable across human and guinea pig lymphocytes. These findings extended to gut inflammation models, supporting potential applications in Crohn's disease by limiting T-cell infiltration into intestinal tissues. In the late , Elan and (initially via licensing) advanced a humanized version of the murine anti-α4 , originally termed Antegren, targeting both α4β1 and α4β7 while sparing neutrophils. Early human proof-of-concept emerged in phase 1/2 trials for MS starting in November 2000, where intravenous natalizumab (3 mg/kg every 28 days for six months) reduced gadolinium-enhancing lesions on MRI by over 90% and clinical relapses compared to in relapsing-remitting patients. Parallel investigations in from the early confirmed reduced gut inflammation in phase 2 studies, with response rates up to 63% in patients with elevated . These results affirmed natalizumab's potency in blocking pathogenic leukocyte trafficking across disease barriers.

Regulatory Approval and Market Withdrawal Events

Natalizumab, marketed as Tysabri, received initial U.S. (FDA) approval on November 17, 2004, for the treatment of relapsing forms of (MS) in adults, based on phase 3 trial data demonstrating significant reductions in rates and progression compared to . The approval followed the AFFIRM trial, which showed a 68% relative reduction in annualized rates, prompting accelerated review despite limited long-term safety data at the time. In Europe, the (EMA) granted conditional marketing authorization on June 27, 2006, shortly after U.S. reinstatement, restricting initial use to rapidly evolving severe MS due to emerging safety concerns. On February 28, 2005, Idec and Elan Corporation voluntarily suspended marketing and clinical use of natalizumab worldwide after post-approval identification of three (PML) cases: two in MS patients from the SENTINEL combination therapy trial and one in a trial patient. This action was causally linked to the drug's mechanism of blocking alpha-4 integrin-mediated leukocyte migration across the blood-brain barrier, which empirically increased susceptibility to JC virus reactivation in the , as confirmed by and PCR testing in affected patients. The suspension reflected a precautionary response to a cluster of rare but fatal events (PML incidence estimated at 1:1000 after one year of exposure in early data), prioritizing causal attribution over continued exposure amid incomplete risk quantification. Following a comprehensive , including independent expert analysis and additional trial data, the FDA reapproved natalizumab on June 5, 2006, for MS monotherapy, with a black box warning for PML and mandatory enrollment in the TOUCH (Tysabri Outreach: Unified Commitment to Health) Prescribing Program—a risk evaluation and mitigation strategy (REMS) requiring prescriber registration, patient , and MRI monitoring to detect early PML. This reinstatement was grounded in AFFIRM's (sustained two-year benefits) outweighing the low absolute PML (projected <1/1000 in monotherapy), particularly for patients failing other therapies, while mandating risk stratification to exclude high-risk cohorts like those with prior immunosuppressants. EMA alignment followed in 2006 with similar restrictions. Subsequent FDA expansion to moderate-to-severe occurred on January 14, 2008, after ENCORE trial data, but only for induction and maintenance in non-responders to conventional therapy, incorporating the same PML safeguards. No further full market withdrawals have occurred, as post-reinstatement PML rates stabilized at predictable levels (e.g., 3.99 per 1000 treated by ), validating the mitigation framework's causal in reducing incidence through patient selection and surveillance.

Post-Approval Surveillance and Updates

The TYGRIS (Tysabri Observational Program in Safety) 5-year global , involving over 6,000 patients with treated with natalizumab, reported 55 cases (0.9%) of serious opportunistic infections, including 44 confirmed PML cases, affirming the drug's established long-term safety profile under routine monitoring while highlighting the need for ongoing vigilance in high-risk subgroups. Similarly, the Tysabri Observational Program (TOP), a multicenter prospective study tracking real-world use, documented a PML incidence of 0.4% (3.73 cases per 1,000 patients), consistent with post-marketing estimates and underscoring effective through anti-JCV antibody testing and treatment duration limits in monitored populations. National registries, such as the Danish nationwide cohort with 13 years of follow-up and the Austrian Multiple Sclerosis Treatment Registry (AMSTR) spanning up to 14 years, have corroborated sustained efficacy with annualized relapse rates reduced by 72-91% and low PML rates in natalizumab-treated patients, informing adaptive strategies like personalized dosing adjustments. programs in regions like have further tracked usage patterns, revealing stable safety outcomes with rare post-infusion reactions and no unexpected signals beyond known risks. By 2024, global PML incidence stabilized at 3.43 per 1,000 patients overall, with evidence of a plateau after 5+ years of exposure in stratified cohorts, attributed to refined risk models incorporating JCV seropositivity, prior immunosuppressant use, and treatment duration. In Europe during the 2020s, extended interval dosing (EID, typically every 6 weeks versus standard 4 weeks) emerged as a standard risk-reduction practice, supported by prospective trials and real-world data showing preserved efficacy via maintained MRI lesion control and relapse suppression, alongside an 88-94% relative PML risk decrease in JCV-positive patients without heightened rebound activity. Recent analyses, including 2025 reports on EID-treated cases, confirm no PML onset shortly after switching to EID, though isolated incidents after prolonged use (1+ years) emphasize continuous MRI surveillance.

Regulatory Status and Market

Global Approvals and Restrictions

Natalizumab, marketed as Tysabri, received approval from the U.S. (FDA) on June 16, 2006, for monotherapy treatment of relapsing forms of (MS) in adults with an inadequate response to or inability to tolerate alternative therapies, following a voluntary market suspension in February 2005 due to three cases of (PML). The (EMA) granted marketing authorization on April 27, 2006, for the same indication in rapidly evolving severe relapsing-remitting MS. issued a Notice of Compliance on September 29, 2006, for monotherapy in relapsing-remitting MS patients with high disease activity despite treatment with interferon beta or after failing . Approvals extend to select countries, including via the , , and , where real-world use has been documented under PML risk management protocols. However, implementation remains restricted in some regions lacking robust infrastructure for mandatory PML surveillance, such as routine anti-John Cunningham virus (JCV) antibody testing, serial (MRI), and specialized neurological oversight, which elevates barriers in resource-limited settings. Regulatory approaches vary by jurisdiction to address PML risk: the FDA requires prescriber enrollment in the TOUCH Prescribing Program, including anti-JCV antibody status assessment every six months for negative patients to inform risk stratification, prior immunosuppressant use evaluation, and treatment duration monitoring. In contrast, the EMA's product information highlights extended interval dosing (average interval of about six weeks) for anti-JCV antibody-positive patients as associated with reduced PML risk relative to standard four-week intervals, based on observational pharmacovigilance data. These programs, akin to risk evaluation and mitigation strategies, confine use predominantly to labeled indications, rendering off-label applications negligible due to certification mandates and patient registries.

Biosimilars and Competition

In August 2023, the U.S. approved Tyruko (natalizumab-sztn), developed by and Polpharma Biologics, as the first to reference natalizumab (Tysabri) for relapsing forms of , based on analytical, nonclinical, and clinical data demonstrating no clinically meaningful differences in safety, purity, or potency. Approval relied on to other indications like , supported by a phase 3 trial (Antelope study) showing comparable efficacy in reducing relapses, safety profiles including , and in relapsing-remitting MS patients over 48 weeks. Tyruko launched first in on January 31, 2024, for highly active relapsing-remitting MS, while U.S. availability faced delays beyond initial 2024 expectations, with projections for market entry in late 2025 amid ongoing patent litigation and commercial preparations. The entry of Tyruko followed key patent expirations for natalizumab in the U.S. and , enabling competition without broad method-of-use protections blocking access. Early pricing positioned Tyruko at a 20-30% discount to Tysabri, with impact models forecasting U.S. savings of approximately $453,000 over three years through shifted utilization and reduced acquisition costs, assuming gradual . Initial uptake has been tempered by natalizumab's intravenous infusion requirement, which demands specialized clinic administration and persistent (PML) risk stratification via anti-JCV testing, mirroring originator protocols and limiting rapid substitution in established treatment pathways. No additional natalizumab biosimilars have gained approval as of October 2025, though pipeline candidates from other developers signal potential further erosion of reference product dominance, contingent on resolved disputes and demonstrated interchangeability in real-world for rare adverse events like PML. Projections indicate biosimilar shares could reach 10-40% within five years in select markets, driven by cost pressures but constrained by clinician familiarity with the originator's long-term data.

Economic and Access Considerations

Natalizumab treatment incurs substantial costs, with annual U.S. disease-modifying expenses ranging from approximately $57,000 to $92,000 per prior to biosimilar availability, excluding additional infusion and monitoring fees that can elevate first-year totals beyond $117,000. Cost-effectiveness evaluations indicate favorable incremental cost-effectiveness ratios (ICERs) for natalizumab in patients with active relapsing-remitting relative to untreated scenarios or lower-efficacy first-line therapies, with estimates as low as $2,300 per (QALY) gained versus interferon beta and up to $95,764 per QALY versus without switching. In low-resource settings, access remains limited by the drug's intravenous requirement every four weeks, which demands reliable healthcare for administration, observation, and coordination of laboratory and imaging resources often scarce in such environments. U.S.-based assistance programs, including Biogen's copay support, enable eligible commercially insured individuals to reduce out-of-pocket costs to $0 per prescription annually, though these do not extend broadly to global disparities. By 2025, entry is forecasted to yield payer savings of over $450,000 cumulatively over three years through lower acquisition costs and utilization shifts, potentially broadening access and equity; however, mandatory risk monitoring, including serial JC virus antibody testing, imposes recurring expenses that offset some gains.

Controversies and Debates

Risk-Benefit Analysis

Natalizumab exhibits a net positive risk-benefit profile in relapsing-remitting (RRMS) patients with high disease activity, where reductions in progression substantially outweigh the stratified risk of (PML). In the phase 3 AFFIRM trial, natalizumab reduced sustained progression over two years from 29% in the group to 17% in the treatment group, yielding an absolute risk reduction of 12% and a number needed to treat (NNT) of approximately 8 to avert one case of progression. This benefit stems from potent blockade of alpha-4 integrin-mediated leukocyte trafficking into the , which curbs inflammatory cascades driving rapid in severe RRMS, unlike less aggressive cases where baseline progression is slower. PML risk, linked to JC virus (JCV) reactivation, is quantifiable and mitigable through stratification by JCV , antibody index, prior immunosuppressant exposure, and treatment duration; JCV-seropositive patients without prior face a cumulative incidence of about 0.7 per 1,000 in the first 24 months, equating to a number needed to harm (NNH) exceeding 1,400, while higher-risk strata (e.g., prolonged with elevated JCV index) approach 2-11 per 1,000 cumulatively, for an NNH of 90-500 depending on cohort specifics. Extended-interval dosing further lowers PML odds by over 90% relative to standard intervals in JCV-positive patients, preserving while enhancing safety margins. Markov models project natalizumab's long-term utility, estimating 9.50 quality-adjusted life years (QALYs) over 20 years versus 8.70 untreated, a net gain of 0.80 QALYs even assuming PML at 1 per 1,000 patients; sensitivity analyses confirm benefits persist unless PML exceeds 7-8 per 1,000, with amplified gains in high-activity RRMS due to averted relapses and progression. Approaches advocating uniform caution, disregarding JCV/duration-based algorithms and vigilant MRI surveillance, undervalue this empirical trade-off, as data affirm net positives for severe cases where untreated outcomes entail swift, irreversible .

Comparisons to Alternative Therapies

Natalizumab demonstrates superior relapse suppression in relapsing-remitting (RRMS) compared to in indirect and observational comparisons, with meta-analyses reporting annualized relapse rates (ARR) approximately 0.28 for natalizumab versus 0.36 for fingolimod in long-term follow-up data from switching cohorts. This edge in ARR reduction ( 0.70, 95% CI 0.62–0.79) persists in network meta-analyses of second-line therapies, though natalizumab carries a distinctly higher of (PML) due to its blockade of leukocyte trafficking into the , a not substantially observed with fingolimod's modulation mechanism. Head-to-head observational data versus ocrelizumab, an anti-CD20 , show comparable effectiveness in suppressing s, new active s, and combined endpoints like no evidence of activity (NEDA) in RRMS patients, with both therapies reducing radiological activity by over 90% in short-term assessments. A 2025 comparative analysis of ublituximab, another anti-CD20 agent, indicates similar reductions in MRI counts and rates to natalizumab in RRMS, achieving low activity scores in nearly all patients by week 96, but without natalizumab's PML risk stemming from alpha-4 inhibition. In , natalizumab exhibits efficacy parity with —a gut-selective alpha-4 beta-7 —in inducing clinical remission (response rates ~50-60% at week 6) and response, as evidenced by pooled trial data showing no significant differences in remission induction or quality-of-life improvements between the agents, irrespective of prior anti-TNF exposure. Overall serious profiles for natalizumab exceed those of platform therapies like interferons in PML incidence but remain lower than historical chemotherapy options such as mitoxantrone, which carry higher rates of cardiotoxicity and secondary malignancies.

Ethical and Policy Implications

The administration of natalizumab necessitates robust processes due to its association with (PML), a rare but severe , emphasizing patient in weighing personalized risks against benefits for highly active relapsing-remitting (RRMS). Regulatory frameworks, such as the FDA-mandated warning, mandate disclosure of PML risks, including factors like JC virus seropositivity and treatment duration, yet data indicate this warning appropriately stratifies rather than prohibits use, as discontinuation rates remain low among informed patients who continue therapy beyond initial doses. Critiques of amplified public apprehension, often fueled by initial post-marketing PML cases and media coverage, highlight how disproportionate emphasis on events can undermine rational , despite showing PML incidence below thresholds that would justify outright withdrawal for suitable candidates. Policy responses, exemplified by the TOUCH prescribing program—a risk evaluation and mitigation strategy (REMS)—strike a pragmatic balance by requiring prescriber and enrollment, MRI monitoring, and anti-JC virus testing without imposing blanket bans, thereby preserving access for patients unresponsive to first-line therapies while addressing through structured surveillance. Extended interval dosing (EID), administered every six weeks rather than standard four-week intervals, emerges as a compromise supported by observational data from TOUCH registries, demonstrating reduced PML without evident loss of , thus enabling sustained treatment for long-term users while mitigating cumulative exposure concerns. This approach counters regulatory overreach tendencies by prioritizing data-driven adjustments over rigid protocols, though debates persist on program implementation flaws, such as potential underreporting in voluntary registries, underscoring the need for enhanced causal tracking of adverse events. Emerging biosimilars to natalizumab, approved in regions like the and under FDA review in the United States as of , hold potential to democratize access by eroding originator monopolies and lowering costs, thereby addressing equity disparities in high-risk therapy availability for underserved MS populations. Policy implications include incentivizing competition to expand treatment reach without compromising equivalence, as demonstrated in comparative trials confirming biosimilar and immunogenicity parity, yet require vigilant post-approval monitoring to ensure real-world parity amid manufacturer liability incentives. Long-term, such developments advocate for policies favoring patient-centered , where autonomy—bolstered by transparent risk stratification—prevails over paternalistic restrictions, provided empirical surveillance sustains benefit-risk favorability.

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