General Information

Tysabri (natalizumab) is a recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells. In development, Tysabri was originally slated to be named Antegren, but FDA regulators forced a change due to name confusion with existing products such as Integrilin and Edecrin.

Tysabri is indicated for the treatment of patients with relapsing forms of multiple sclerosis to reduce the frequency of clinical exacerbations. This indication is based on results achieved after approximately one year of treatment in ongoing controlled trials of two years in duration. The safety and efficacy of Tysabri beyond one year are unknown.

Mechanism of Action

MS is an auto-immune disease that damages and prevents the creation of the tissues that protect nerves, called myelin. This creates lesions, or scar tissue known as sclerosis. Lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier. Leukocyte migration involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The drug works by blocking the integrin molecule and preventing immune cells from migrating through blood vessels in the brain to areas of inflammation; however, the specific mechanism by which Tysabri exerts its effects in multiple sclerosis have not been fully defined.

Preclinical results from animal models of autoimmune encephalitis of multiple sclerosis demonstrated a reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown.

Side Effects

Adverse events associated with the use of Tysabri for MS may include (but are not limited to) the following:

• infections
• hypersensitivity reactions
• depression
• cholelithiasis (gallstones)
• urticaria (hives)
• irregular menstruation

Adverse events associated with the use of Tysabri for CD 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.

Dosing/Administration

The recommended dose of Tysabri is 300 mg IV infusion every four weeks.

On February 28, 2005, Biogen Idec and Elan announced a voluntary suspension of the marketing of Tysabri.

On June 5, 2006 Biogen Idec and Elan announced the approval of a supplemental Biologics License Agreement (sBLA) by the FDA for the reintroduction of Tysabri as a monotherapy treatment for relapsing forms of multiple sclerosis. This approval for reintroduction was based on the review of TYSABRI trial data, a revised labeling with enhanced safety warnings and a risk management plan (TOUCH Prescribing Program) designed to inform of the potential risk of progressive multifocal leukoencephalopathy (PML).

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.

Clinical Trial Results

FDA approval of Tysabri for the treatment of MS was based on two randomized, double-blind, placebo-controlled trials with over 2,000 subjects. Subjects were enrolled if they had experienced at least one relapse during the prior year and had a score of between 0 - 5.0 on the Kurtzke Expanded Disability Status Scale (EDSS). In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.
Study 1
All 942 subjects enrolled in this study had not received any interferon-beta or glatiramer acetate for at least the previous six months. In fact, roughly 94 percent had never been treated with these agents. The median age was 37, with a median disease duration of five years. Subjects were randomized to receive TYSABRI (300mg IV infusion) or placebo every four weeks for up to 28 months. Results showed that subjects who received TYSABRI had a relapse rate (annualized) of .25 compared with .74 for subjects taking placebo. 76 percent of subjects taking TYSABRI had remained relapse free compared with 53 percent of subjects taking placebo.
Study 2
All 1,171 subjects enrolled in this study had experienced one or more relapses while on treatment with Interferon beta-1a (30 mcg intramuscularly) once weekly during the year prior to study entry. The median age was 39, with a median disease duration of seven years. Subjects were randomized to receive TYSABRI (300mg IV infusion) or placebo every four weeks for up to 28 months. Subjects continued taking Interferon beta-1a at their normal dosing once weekly. Results showed that subjects who received TYSABRI had a relapse rate (annualized) of .36 compared with .78 for subjects taking placebo. Data demonstrated that 67 percent of subjects taking TYSABRI had remained relapse free compared with 46 percent of subjects taking placebo.

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-to-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 percent of the 717 subjects receiving Tysabri were responders compared to 49 percent of the 179 subjects receiving placebo (treatment effect: 7 percent; 95 percent confidence interval (CI): [-1 percent, 16 percent]; 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 percent of Tysabri patients were in response compared to 45 percent of those receiving placebo (treatment effect: 12 percent; 95 percent CI: [3 percent, 22 percent]; 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 percent and 60 percent versus 40 percent and 44 percent in the placebo arm, respectively. At weeks 8 and 12 the clinical remission in the Tysabri arm was 32 percent and 37 percent versus 21 percent and 25 percent 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 percent of those randomized to Tysabri, and clinical remission at both weeks 8 and 12 was seen in 17 percent.

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-to-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 six 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 percent and 54 percent versus 29 percent and 20 percent for the placebo arm, respectively. Clinical remission through month 9 and month 15 was 45 percent and 40 percent for the Tysabri arm versus 26 percent and 15 percent 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 percent of those randomized to Tysabri, and maintenance of clinical remission through month 9 was seen in 30 percent.