Fortunately, genomics, genetics, and the development of better animal models are revealing new common pathways and molecular mechanisms that underly many chronic inflammatory conditions.
Discoveries like Biogen Idec’s are giving researchers a wealth of new targets in addition to the cytokine TNF-a, the basis of blockbuster, first-generation anti-inflammatory drugs like Remicade and Enbrel, and COX-2, the target of Vioxx and Celebrex. Most large pharmas and many biotechs have active programs in inflammation.
New targets in the inflammation pathway include inhibitors to chemokine receptors, p38 MAP kinase, multiple cytokines including IL-1b and IL-6, nuclear hormone receptor modulators, leukotriene A4 hydrolase, and cathepsin S.
Last month, deCODE Genetics (www.decode.com) began enrolling patients in a Phase I trial for DG-051, its inhibitor of leukotriene A4 hydrolase, a pro-inflammatory protein made by a gene in the leukotriene pathway, which the company has shown to be linked to heart attack risk.
Inflammation is one of two areas of focus for Millennium Pharmaceuticals (www.millennium.com). With five drugs in development, two of which are partnered with Sanofi-Aventis (www.sanofi-aventis.com), the company recently made a strategic decision to focus its new discovery efforts on oncology, while continuing to develop its anti-inflammatory drugs.
Millennium’s compounds target three inflammatory pathways: chemokine-induced extravasation (exit of white blood cells from blood vessels) and migration to injured tissue; the activation and co-stimulation of T lymphocytes; and immune cell activation by NF-kB, a transcription factor that turns on numerous genes whose products mediate many steps of the inflammatory cascade.
Its most advanced compound, MLN-0002, is a humanized monoclonal antibody to the alpha4beta7 integrin, an adhesion molecule that is found on activated T cells that migrate to the gut. “This drug is a selective anti-adhesion molecule that carries with it a reduced chance of infection because it is selective to the gut,” notes Nancy Simonian, M.D., senior vp of clinical, medical, and regulatory affairs at Millennium.
The antibody has successfully completed Phase IIb trials in ulcerative colitis. In a Phase IIb trial with 180 patients, both doses produced clinical remission in patients, the primary endpoint; a Phase IIb trial did not accomplish the same goal in Crohn’s disease, although it did meet the secondary endpoint, but Millennium believes the problem was one of dosing.
The company is currently in the process of developing a commercially viable cell line for pivotal trials, she says. Millennium hopes to conduct preclinical and early-stage trials with the drug early in 2007 and to progress into trials soon afterward.
MLN-1202, Millennium’s second compound, an antibody to the CCR-2 chemokine receptor that is expressed on activated T cells and monocytes, is in a Phase IIa trial in multiple sclerosis. Results are expected in the second half of 2007, which will show whether the drug can reduce gadolinium-enhanced brain lesions.
Results with the drug in a Phase IIa trial in atherosclerosis were reported earlier this year. Over 100 patients at risk for cardiovascular disease were monitored for a reduction in levels of C-reactive protein. Levels of this surrogate marker for cardiovascular inflammation and risk dropped in the trial; the next trial will measure cardiovascular plaque regression, a more direct measure of heart attack risk, says Dr. Simonian.
A proof-of-concept Phase I trial in rheumatoid arthritis is under way with MLN-3897, an oral small molecule drug targeting the CCR-1 chemokine, which is expressed on activated T cells and monocytes. The company expects results in the second half of this year. This drug blocks a number of important inflammatory molecules, including macrophage-inflammatory protein-1a and RANTES, and is being developed in collaboration with Sanofi-Aventis.
Its second oral small molecule drug, MLN-0415, also in development with Sanofi-Aventis, targets the IKKb pathway, which is upstream to NFkB, a signaling molecule that is a central mediator of the inflammatory process. MLN-0415 entered the clinic last month. Since IKK is central to the inflammatory process, it could be challenging to find a therapeutic window of efficacy, but preclinical studies indicate that efficacy is possible without full inhibition.