Introduction to Natalizumab

Natalizumab (brand name Tysabri) is a humanized monoclonal antibody against the cellular adhesion molecule α4-integrin. It was first approved by the FDA in 2004 for the treatment of relapsing forms of multiple sclerosis (MS). In 2008, it received approval for moderately to severely active Crohn's disease in adult patients who have had an inadequate response to, or are unable to tolerate, conventional therapies and TNF inhibitors.

Mechanism of Action

Natalizumab works by selectively binding to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of leukocytes, except neutrophils. This binding inhibits the α4-mediated adhesion of leukocytes to their counterreceptor(s).

Key points:

• Blocks the interaction between α4-integrin and vascular cell adhesion molecule-1 (VCAM-1)
• Prevents leukocyte transmigration across the blood-brain barrier (in MS) and into inflamed gastrointestinal tissue (in Crohn's disease)
• Reduces inflammation in the central nervous system and gastrointestinal tract
• Interrupts the inflammatory cascade in MS and Crohn's disease
• May suppress ongoing inflammatory reactions by inhibiting the binding of α4-expressing leukocytes to their ligands in the extracellular matrix and on endothelial cells

Indications

Natalizumab is FDA-approved for the following indications:

1. Relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults
2. Moderately to severely active Crohn's disease in adults with:
   • Inadequate response to, or inability to tolerate, conventional CD therapies and TNF inhibitors
   • Evidence of elevated C-reactive protein (CRP) or inflammation on colonoscopy

Off-label uses include:

• Pediatric multiple sclerosis
• Neuromyelitis optica spectrum disorders (NMOSD)

Dosage and Administration

Natalizumab is administered by intravenous infusion. The dosage is the same for both MS and Crohn's disease:

• 300 mg intravenous infusion over one hour, every 4 weeks

Important administration notes:

• Natalizumab should be administered by a healthcare professional in a setting equipped to manage infusion reactions and anaphylaxis
• Patients should be observed during the infusion and for 1 hour after the infusion is complete
• Dilute only with 0.9% Sodium Chloride Injection, USP
• Do not administer as an IV push or bolus injection
• Do not mix with other medications

Efficacy

Multiple Sclerosis:

• Reduces the annualized relapse rate by 68% compared to placebo
• Reduces the risk of sustained disability progression by 42-54% over 2 years
• Decreases the number of new or enlarging T2-hyperintense lesions by 83% over 2 years
• Reduces gadolinium-enhancing lesions by 92% over 2 years

Crohn's Disease:

• Induces clinical response in 56% of patients at week 4 (vs. 49% for placebo)
• Achieves clinical remission in 26% of patients at week 4 (vs. 16% for placebo)
• Maintains clinical remission in 26% of responders at week 36 (vs. 16% for placebo)
• Improves quality of life measures and reduces corticosteroid use

Side Effects

Common side effects (≥10% incidence) include:

• Headache (38%)
• Fatigue (27%)
• Arthralgia (19%)
• Urinary tract infection (18%)
• Lower respiratory tract infection (17%)
• Gastroenteritis (11%)
• Vaginitis (10%)
• Depression (10%)
• Pain in extremity (16%)
• Abdominal discomfort (11%)
• Diarrhea (13%)

Serious side effects:

• Progressive Multifocal Leukoencephalopathy (PML) - a rare but potentially fatal opportunistic infection caused by the JC virus
• Herpes encephalitis and meningitis
• Other opportunistic infections
• Hepatotoxicity
• Hypersensitivity reactions, including anaphylaxis
• Thrombocytopenia (including immune thrombocytopenia)

Precautions and Monitoring

• Screen for anti-JCV antibodies before starting therapy and periodically during treatment
• Monitor for signs and symptoms of PML (progressive multifocal leukoencephalopathy) during therapy and for at least 6 months after discontinuation
• Perform MRI scans as clinically appropriate to monitor for signs of PML
• Discontinue natalizumab at the first sign or symptom suggestive of PML
• Monitor liver function tests; discontinue if significant liver injury occurs
• Assess for hypersensitivity reactions during and after infusion
• Consider discontinuation if severe hypersensitivity or anaphylactic reactions occur
• Monitor for new or worsening neurological symptoms that may be suggestive of immune reconstitution inflammatory syndrome (IRIS) after discontinuation
• Pregnancy Category C: Use only if the potential benefit justifies the potential risk to the fetus
• Perform baseline and periodic complete blood counts, including platelet counts
• Natalizumab is available only through a restricted distribution program called the TOUCH® Prescribing Program due to the risk of PML