One-year data from the Phase III SENTINEL trial, presented at the 57th Annual Meeting - American Academy of Neurology ( AAN ), demonstrated that when Natalizumab ( Tysabri ) was added to Interferon beta-1a ( Avonex ) in patients with relapsing forms of multiple sclerosis ( MS ), the annualized clinical relapse rate was reduced by 54 percent over the effect of Avonex alone (p<0.001).

In addition, these data, demonstrated that the addition of Tysabri to Avonex resulted in significantly fewer new or newly enlarging T2 hyperintense lesions and gadolinium-enhancing lesions than Avonex alone, and that the proportion of Tysabri/Avonex patients who remained relapse-free was significantly higher than in the Avonex group.

On February 28, 2005, Biogen Idec and Elan Corporation, announced that they voluntarily suspended Tysabri from the U.S. market and all ongoing clinical trials.
This decision was based on reports of progressive multifocal leukoencephalopathy ( PML ), a rare and frequently fatal, demyelinating disease of the central nervous system.
Biogen Idec and Elan's comprehensive safety evaluation concerning Tysabri and any possible link to PML is ongoing.
The results of this safety evaluation will be discussed with regulatory agencies to determine possible re-initiation of dosing in clinical trials and future commercial availability.

“ SENTINEL is a large, clinical trial that for the first time evaluated the efficacy of add-on therapy for MS patients who continued to experience disease activity despite Interferon therapy, " said Richard Rudick, lead investigator of the SENTINEL trial and director of the Mellen Center for MS Treatment and Research at Cleveland Clinic Foundation. " We look forward to learning more from the ongoing evaluation of Tysabri. "

SENTINEL is a two-year, randomized, multi-center, placebo-controlled, double-blind study of 1,171 Avonex-treated patients in 123 clinical trial sites worldwide.
Avonex-treated patients who continued to experience disease activity were randomized to add Tysabri (n=589) or placebo (n=582) to their standard regimen.

The primary endpoint at one-year was the reduction in the rate of clinical relapses. The addition of Tysabri to Avonex resulted in a 54 percent reduction in the rate of clinical relapses over the effect of Avonex alone ( p<0.001 ). The annualized relapse rate was 0.36 for patients receiving Tysabri when added to Avonex versus 0.78 with Avonex plus placebo.

Analysis of annualized relapse rate by pre-specified subgroups of disease severity, including baseline Expanded Disability Status Scale ( EDSS ) ( measured on a scale 0-10 ) or relapse history, supported the primary endpoint finding.
In patients with an EDSS greater than or equal to 4.0, Tysabri reduced the relapse rate by 51 percent, while in patients with an EDSS less than 4.0, it reduced the relapse rate by 53 percent.
Additionally, in patients with more than two relapses in the year prior to study entry, Tysabri reduced the annualized relapse rate by 55 percent, while in patients with one relapse, Tysabri reduced the annualized relapse rate by 53 percent.

SENTINEL also met all secondary endpoints, including MRI measures.
In the group treated with Tysabri plus Avonex, 67 percent of patients developed no new or newly enlarging T2-hyperintense lesions compared to 40 percent in the Avonex plus placebo group ( p<0.001 ).
On the one-year MRI scan, 96 percent of Tysabri plus Avonex-treated patients had no gadolinium-enhancing lesions compared to 76 percent of Avonex plus placebo-treated patients ( p<0.001 ).
The proportion of patients who remained relapse-free was 67 percent in the Tysabri plus Avonex-treated group compared to 46 percent in the Avonex plus placebo-treated group ( p<0.001 ).

The adverse event profile in SENTINEL and AFFIRM were similar at one year.
Common adverse events included headache, fatigue, urinary tract infection, depression, lower respiratory tract infection, joint pain and abdominal discomfort.
The rate of infection was approximately one per patient-year in both Tysabri-treated patients and placebo-treated patients.
Serious infections occurred in 1.3 percent of placebo treated patients and 2.1 percent of Tysabri-treated patients. Tysabri has been associated with hypersensitivity reactions, including serious systemic reactions, which occurred at an incidence of less than 1 percent of patients.

The two PML cases reported in multiple sclerosis were in patients treated with more than two years of Avonex plus Tysabri.

All biologics have the potential to induce antibody formation.
Analysis of the one-year results indicated a low level of immunogenicity associated with Tysabri.
Patients were tested for antibodies every 12 weeks in the AFFIRM and SENTINEL trials.
Antibodies were detected in approximately 10 percent of patients at least once during treatment, with 6 percent of patients remaining persistently positive.
Persistently positive antibodies were associated with a substantial decrease in efficacy and an increase in certain infusion-related adverse events.
Almost all patients who tested positive for antibodies did so within the first 12 weeks of treatment.

Source: Biogen Idec, 2005


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