Biotech Tracker News - Publication Confirms Impact of Antegren on Brain Lesions in Multiple Sclerosis Patients
January 02, 2003 Wednesday’s issue of The New England Journal of Medicine features data from a 213-patient, randomized, double-blind, placebo-controlled, multiple sclerosis trial demonstrating that recipients of Biogen (NASDAQ: BGEN) and Élan’s (NYSE: ELN) Antegren (natalizumab) developed fewer new enhancing, inflammatory lesions on gadolinium-enhanced magnetic resonance imaging (MRI) and significantly fewer relapses than their counterparts receiving placebo. The follow-up period was only six months, but these results rigorously confirm earlier data presentations. The data support continued, ongoing, larger-scale, 2-year, phase III investigations of Antegren alone and in combination with Biogen’s Avonex.  Biogen’s approved drug for multiple sclerosis, Avonex, has recently been losing market share to Serono’s (NYSE: SRA) Rebif after the FDA ruled that Serono could market Rebif in the U.S. in spite of Avonex’s orphan drug protection. For Biogen, continued evidence of Antegren’s utility could eventually mitigate the effects of Avonex’s market share erosion. Antegren, which Biogen expects to reach the market in 2005, may be proven useful in combination with Avonex.  The impact of Antegren on brain lesions is a fine beginning, but phase III investigation needs to demonstrate a considerably greater impact on functional status, either on standard measures of functional status and disability reduction per se, or on standard measures of quality of life and health-related quality of life. We continue to be cautiously optimistic about Antegren’s potential. The fact that Antegren works by a novel mechanism is in its favor. Even if it generates a minimally significant clinical endpoint impact as monotherapy, it may prove effective when used in combination with existing recombinant interferons or small molecule formulations.  The International Natalizumab Multiple Sclerosis Trial Group studied patients with relapsing–remitting or relapsing secondary progressive multiple sclerosis. They were randomized to receive intravenous Antegren 3 mg per kilogram (68 study subjects), 6 mg per kilogram (74 study subjects), or placebo (71 patients) every 28 days for 6 months. The primary endpoint was the number of new brain lesions on monthly gadolinium-enhanced MRI during the six-month treatment period. Antegren treatment effect advantages were observed for:  reduction in mean number of new lesions pre patient on MRI 9.6 for placebo recipients  0.7 for Antegren 3 mg/kg (p<0.001)  1.1 for Antegren 6 mg/kg (p<0.001)  patients relapsing during treatment and follow-up 27 placebo recipients  13 Antegren 3 mg/kg recipients (p=0.02)  14 Antegren 6 mg/kg recipients (p=0.02)  self-reported well-being based upon a well-accepted, standardized tool  slight worsening for placebo recipients (mean decrease of 1.38 mm on a 100-mm visual-analogue scale)  clinically significant improvement for Antegren recipients (mean increases of 9.49 mm and 6.21 mm for 3 and 6 mg/kg recipients, respectively).  An accompanying editorial suggests that phase III trial appraisal should focus on the drug’s longer-term safety and efficacy preservation profiles, and should determine whether Antegren can actually reverse the multiple sclerosis-associated nerve insulation damage. Most important will be appraisal of the drug’s impact on patients’ performance status.  Multiple sclerosis is, in part, characterized by inflammatory brain lesions arising from autoimmune responses that involve activated inflammatory cells such as lymphocytes and monocytes. These cells express glycoprotein a4-integrin on their surface. a4-integrin helps circulating inflammatory cells adhere to blood vessels in a manner that facilitates their extravasation into tissue where they can wreak havoc. Antegren is a monoclonal antibody that binds to a4-integrin, preventing it from binding to its ligand and blocking its biological effects. Biogen and Élan hope that this mechanism of action can spare enough brain cells in multiple sclerosis to be clinically useful.  Biogen and Élan are also developing Antegren for Crohn disease, in which a4-integrin mediated inflammation is also implicated. Thus far, Crohn disease data have been less promising than multiple sclerosis data. After six weeks after study initiation in one Crohn disease trial, placebo recipients fared as well as Antegren recipients on a test that measures the severity of gut inflammation. However, Antegren recipients did better than placebo recipients on other important endpoints such as self-reported symptom decline for symptoms such as cramps and severe diarrhea. Ongoing phase III trials may reconcile these issues.
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