Tysabri (natalizumab)

Tysabri is a humanized monoclonal antibody that belongs to a class of potential therapeutics known as alpha-4 integrin inhibitors. Tysabri binds to the cell surface receptors known as alpha-4-beta-1 (VLA-4) and alpha-4-beta-7. The receptors for the a4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. It is designed to block immune cell adhesion to blood vessel walls; it thus blocks subsequent migration of lymphocytes into tissue.

Tysabri is specifically indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-a.

Tysabri is supplied as a 300 mg vial designed for intravenous infusion. This concentrated solution that must be diluted prior to intravenous infusion. The recommended initial dose of the drug is a 300 mg intravenous infusion over one hour every four weeks. Tysabri should not be used with concomitant immunosuppressants or concomitant inhibitors of TNF-a. If the patient with Crohn’s disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue treatment.

FDA Approval
FDA approval of Tysabri for Crohn's disease was based on the results of three clinical trials. These randomized, double-blind, placebo-controlled trials enrolled a total of 1,414 adult patients with moderately to severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] =220 and =450). Concomitant stable doses of aminosalicylates, corticosteroids, and/or immunosuppressants were permitted. Induction of clinical response (defined as a greater than or equal to 70-point decrease in CDAI from baseline) was evaluated in two studies.

Study CD1
In this study, 896 subjects were randomized 4:1 to receive three monthly infusions of either 300 mg Tysabri or placebo. Clinical results were assessed at Week 10, and subjects with incomplete information were considered as not having a clinical response. At Week 10, 56% of the 717 subjects receiving Tysabri were responders compared to 49% of the 179 subjects receiving placebo (treatment effect: 7%; 95% confidence interval (CI): [-1%, 16%]; p=0.067. In a post hoc analysis of a subset of 653 subjects with elevated C-reactive protein (CRP), indicative of active inflammation, 57% of Tysabri patients were in response compared to 45% of those receiving placebo (treatment effect: 12%; 95% CI: [3%, 22%]; nominal p=0.01).

Study CD2
This trial enrolled 509 subjects with elevated serum C-reactive Protein (CRP). Clinical response and clinical remission (defined as CDAI score <150) were required to be met at both Weeks 8 and 12, rather than at a single time-point; patients with incomplete information were considered as not having a response. The study also assessed the proportion of patients who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. At weeks 8 and 12 the clinical response in the Tysabri arm was 56% and 60% versus 40% and 44% in the placebo arm, respectively. At weeks 8 and 12 the clinical remission in the Tysabri arm was 32% and 37% versus 21% and 25%in the placebo arm, respectively. For patients in Study CD2 with an inadequate response to prior treatment with inhibitors of TNF-a, clinical response at both Weeks 8 and 12 was seen in 38% of those randomized to Tysabri, and clinical remission at both Weeks 8 and 12 was seen in 17%.

Study CD3
This trial was designed to evaluate Tysabri maintenance therapy. Three hundred and thirty one subjects from Study CD1 that had had a clinical response to Tysabri at both Weeks 10 and 12 were re-randomized 1:1 to treatment with continuing monthly infusions of either 300 mg Tysabri or placebo. Maintenance of response was assessed by the proportion of patients who did not lose clinical response at any study visit for an additional 6 and 12 months of treatment. The study also assessed the proportion of patients who did not lose clinical remission at any study visit within the subset of those who were in remission at study entry. Clinical response through month 9 and month 15 in the Tysabri arm was 61% and 54% versus 29% and 20% for the placebo arm, respectively. Clinical remission through month 9 and month 15 was 45% and 40% for the Tysabri arm versus 26% and 15% for the placebo arm, respectively. For patients in study CD3 with an inadequate response to prior treatment with inhibitors of TNF-a, maintenance of clinical response through month 9 was seen in 52% of those randomized to Tysabri, and maintenance of clinical remission through month 9 was seen in 30%.

Adverse events associated with the use of Tysabri may include, but are not limited to, the following:

• Headache
• Upper respiratory tract infection
• Nausea
• Influenza
• Back pain
• Fatigue
• Arthralgia
• Rash
• Pharyngolaryngeal pain

In addition, Tysabri increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Patients who have significantly compromised immune system function should not ordinarily be treated with Tysabri. Because of the risk of PML, Tysabri is available only through a special restricted distribution program called the TOUCH Prescribing Program. Under this program only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program are able to prescribe, distribute, or infuse the product.

Tysabri is a humanized monoclonal antibody that belongs to a class of potential therapeutics known as alpha-4 integrin inhibitors. Tysabri binds to the cell surface receptors known as alpha-4-beta-1 (VLA-4) and alpha-4-beta-7. The receptors for the a4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) present on vascular endothelial cells of the gastrointestinal tract. The interaction of the a4ß7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer’s patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD.

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Macdonald JK, McDonald JW Natalizumab for induction of remission in Crohn's disease. Cochrane database of systematic reviews 2006 Jul 19;3:CD006097

Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P; International Efficacy of Natalizumab as Active Crohn's Therapy (ENACT-1) Trial Group; Evaluation of Natalizumab as Continuous Therapy (ENACT-2) Trial Group Natalizumab induction and maintenance therapy for Crohn's disease. The New England Journal of Medicine 2005 Nov 3;353(18):1912-25

Gordon FH, Lai CW, Hamilton MI, Allison MC, Srivastava ED, Fouweather MG, Donoghue S, Greenlees C, Subhani J, Amlot PL, Pounder RE A randomized placebo-controlled trial of a humanized monoclonal antibody to alpha4 integrin in active Crohn's disease. Gastroenterology2001 Aug;121(2):268-74

For additional information regarding Tysabri or Crohn's disease, please visit the Tysabri web page.