Natalizumab: AN 100226, anti-4alpha integrin monoclonal antibody

Natalizumab [AN 100226, anti-alpha4 integrin monoclonal antibody, Antegren] is a humanised monoclonal antibody that blocks alpha4beta1 integrin-mediated leukocyte migration. Natalizumab is in phase III trials for the treatment of multiple sclerosis in North America and the UK, and for the treatment of Crohn's disease also in the UK. It may have potential in the treatment of other immune-related inflammatory disease. Elan Corporation intends to examine the potential of natalizumab in rheumatoid arthritis and ulcerative colitis. 4beta1 integrin on circulating leukocytes binds to vascular cell adhesion molecule-1, which is expressed at high levels in the blood vessels in the CNS during exacerbations of multiple sclerosis. This allows leukocytes expressing alpha4beta1 integrin (very late antigen-4) to move from the peripheral blood into the CNS. Inflammatory proteins and other factors released from lymphocytes in the brain lead to the progression of symptoms. A limitation of natalizumab is that it must be injected and cannot be administered orally. Scientists have transformed the large anti-alpha4 monoclonal antibody into much smaller, drug-like molecules suitable for oral administration. Protein Design Labs has granted a worldwide nonexclusive licence under its antibody humanisation patents to Elan Pharmaceuticals for natalizumab. Biogen Inc. has entered into an agreement with Elan for a worldwide exclusive collaboration to develop, manufacture and commercialise natalizumab for multiple sclerosis and Crohn's disease and rheumatoid arthritis. Development of natalizumab is also being funded, in part, by Axogen (acquired by Elan in 1999). In November 2003, Biogen and IDEC Pharmaceuticals merged to form Biogen Idec. Elan repurchased royalty rights on a package of products, including natalizumab, from Autoimmune Disease Research Company. Elan and Genzyme Transgenics Corporation signed an agreement to produce natalizumab in GTC's genetically engineered goats, which will express the compound in their milk. Genzyme Transgenics Corporation changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. Following discussions with the US FDA, Elan completed enrolment in a second phase III trial, involving approximately 420 patients with Crohn's disease. This Evaluation of Natalizumab as Continuous Therapy-2 (ENACT-2) trial evaluated the effect of natalizumab on duration of response and remission in patients with Crohn's disease. In January 2004, Elan Corporation and Biogen Idec announced that the phase III, ENACT-2 maintenance trial of natalizumab in Crohn's disease met the primary endpoint of maintenance of response. Elan and Biogen Idec will discuss these data with regulatory authorities in both the US and Europe and determine the appropriate path forward for natalizumab in Crohn's disease. An NDA for Antegren in Crohn's disease was expected to be filed at the end of 2003; however, due to failing to meet the primary endpoint in the induction trial, Elan is unable to predict when and if a regulatory filing will be made. Earlier, on 23 January 2001, the Wall Street Journal reported that the Biogen CEO expects Antegren to become a blockbuster drug, with sales of at least $US1 billion. He also predicted that Antegren could be on the market as early as 2003 for the indication of Crohn's disease and in 2004 for multiple sclerosis. The Journal stated that Biogen is under pressure to develop new drugs since its flagship product Avonex will be losing its US Orphan Drug Act protection in 2003. Antegren has a different mechanism to that of Avonex and could be used either alone or as a combination therapy.