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Oct 1, 2006 (Vol. 26, No. 17)

Inflammation Research Leads to Targets

Safer and More Effective Drugs Are the Focus

  • Late last month, GlaxoSmithKline (GSK; www.gsk.com) and ChemoCentryx (www.chemocentryx.com) signed a multitarget strategic alliance, potentially worth 1.5 billion, to discover, develop, and market novel medicines targeting four chemokine and chemoattractant receptors for the treatment of a variety of inflammatory disorders.

    ChemoCentryx will be responsible for the discovery and development of small molecule drug candidates against the four targets through proof of concept, at which point GSK will have the exclusive option to license each product for further development and commercialization.

    Also last month, scientists at Biogen Idec (www.biogenidec.com) and the University of Geneva in Switzerland reported that activating a newly discovered inflammation pathway, called Tweak, may play a crucial role in the rheumatoid arthritis (RA) disease process. They found that Tweak, which belongs to the tumor necrosis factor (TNF) family, plays a key role in normal immune and inflammatory responses.

    “Despite considerable progress, many RA patients do not adequately respond to current treatments, indicating that other pathways are involved in this complex disease,” explains Biogen Idec senior scientist of molecular discovery Timothy Zheng, Ph.D. “Our research suggests that Tweak contributes to RA through multiple mechanisms, and inhibiting this pathway may represent new opportunities for treatment.” The research was published in a recent issue of the Journal of Immunology.

    Acute inflammation, which may occur in response to an infection or injury, can be part of the healing process, but chronic inflammation, which may be caused by an autoimmune reaction, wreaks progressive damage to tissues and organs and contributes to a wide variety of diseases, including asthma; chronic obstructive pulmonary disease; coronary heart disease; autoimmune disorders such as RA, scleroderma, inflammatory bowel disease, psoriasis, and multiple sclerosis; diabetes; Alzheimer’s; and some malignancies including colon, liver, cervical, and bladder cancer. There is increasing evidence that chronic inflammation also plays a key role in obesity, hypertension, and stroke.

    If the number of diseases linked to chronic inflammation was not enough to spur robust research in this area, an August decision by a federal jury awarding a former user of Merck & Co’s (www.merck.com) Vioxx $51 million underscores the urgent need for effective and safe anti-inflammatory drugs.

  • Drug Development

    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.

  • Oral Drugs

    Celgene (www.celgene.com) is developing five oral drugs for a range of inflammatory diseases that inhibit the production of multiple proinflammatory mediators including interleukin-2 (IL-2), IL-12, interferon gamma, TNF-a, leukotrienes, and nitric oxide synthase. Its most advanced compound, CC-10004, in Phase II testing for psoriasis, inhibits three major inflammatory cytokines—IL-12, interferon gamma, and TNF-a—and elevates levels of IL-10, an anti-inflammatory cytokine.

    In earlier Phase I and II studies, CC-10004, a phosphodiesterase type-4 inhibitor, was safe and well-tolerated and significantly reduced symptoms in patients with severe plaque-type psoriasis. Revlimid is a small molecule, oral immunomodulator and Celgene’s lead in a new class of four novel immunomodulatory drugs, IMiDs, which are based on thalidomide.

  • p38

    Vertex Pharmaceuticals (www.vpharm.com) is developing two anti-inflammatory drugs—VX-702, a p38 MAP kinase inhibitor, and VX-765, a selective ICE (IL-B-converting enzyme) inhibitor. “We have had a longstanding anti-inflammation program, and in the early- and mid-1990s, as TNF-a antagonists demonstrated what they could do in RA, we redoubled our efforts to develop an orally active small molecule inhibitor of inflammatory cytokine production,” says John Alam, M.D., executive vp of the medicines division and CMO. p38 is involved in the production and regulation of four inflammatory cytokines: IL-6, IL-8, IL-1b, and TNF-a, he notes.

    Dr. Alam explains how Vertex zeroed in on p38. “We were looking for regulators of cytokine production; our underlying assumption was that with small molecule technology we would not be able to develop receptor inhibitors—the approaches did not exist,” says Dr. Alam.

    VX-702 is Vertex’ second-generation anti-p38 compound that does not cross the brain-blood barrier and as a monotherapy shows no liver toxicity. Not metabolized by the liver but rather excreted through the kidneys, it was tested in a recently completed Phase II study with 300 RA patients. The drug is bone-sparing and anti-inflammatory.

    “It has been a challenge to find a therapeutic window, but we did with the Phase II study,” Dr. Alam explains. Vertex will begin a six-month Phase IIb study in early 2007 in combination with methotrexate, Dr. Alam notes. There is some concern about safety, as p38 is involved with a number of crucial biological processes, and p38 knockout mice are embryonic-lethal—with the gene knocked out, mice die in embryonic stage. The company’s second anti-inflammatory compound, VX-765, is a selective oral inhibitor of IL-18 and IL-1b, which correlates to disease activity in psoriasis.

    Biogen Idec has Tysabri in development for Crohn’s disease, and Rituxan is now being tested in multiple sclerosis. Tysabri is approved for relapsing MS in the U.S., and was approved for relapsing-remitting MS in Europe in late June. It was returned to the U.S. market in June 2006 after having been withdrawn in February 2005 due to safety concerns.

    Tysabri is a selective adhesion molecule inhibitor (SAM) designed to prevent the movement of potentially damaging immune cells from the bloodstream across the blood-brain barrier into the brain and spinal cord. Tysabri inhibits this movement by adhering to the alpha 4-integrin, an adhesion protein on the surface of T cells that normally enables them to attach to and pass through the blood-brain barrier. Rituxan selectively depletes CD20+ B cells, it has been approved for RA and non-Hodgkin’s lymphoma, and it is being tested in lupus.

    The company is also developing four other compounds: an immunomodulator, BG-12/oral fumarate, has completed Phase III testing for psoriasis; lymphotoxin beta receptor, which plays critical roles in inflammation and lymphoid organogenesis through activation of NF-kB, is in Phase II for RA; fontolizumab (HuCAF) completed Phase II in Crohn’s disease; and a humanized anti-CD20 monoclonal antibody also completed a Phase II in RA.

  • Chronic Inflammation

    Atherogenics (www.atherogenics.com) is focusing exclusively on the impact of chronic inflammation in a range of diseases with its most advanced drug, AGI-1067, in late-Phase III trials in cardiovascular disease. Russell Medford, M.D., Ph.D., and R. Wayne Alexander, M.D., the company’s founders, were among the first to show that chronic inflammation underlies cardiovascular disease. They discovered a new class of drugs, v-Protectants, that block a class of redox signals generated within endothelial cells (ECs), the cells that line blood vessels of the cardiovascular system, which in turn activate pro-inflammatory genes.

    Specifically, one protein product of these genes, VCAM-1, an adhesion molecule that binds to VLA-4 on activated white blood cells, attracts white blood cells to ECs. Blocking the binding of activated white blood cells to ECs breaks the inflammatory cascade that causes plaque to accumulate and rupture, says Dr. Medford, CEO.

    V-protectants act as anti-oxidants and can block the specific type of inflammation caused by oxidants acting as signals. “Trials show that v-protectants provide a specific anti-inflammatory benefit without affecting normal immune function such as protection against infection,” Dr. Medford adds.

    Atherogenics’ lead compound, AGI-1067, is designed to treat the chronic inflammatory process in cardiac blood vessels that leads to heart attacks and strokes. It is in the final stage of a Phase III clinical trial, with over 6,000 patients enrolled in over 250 cardiac centers worldwide. In the blinded trial, patients who recently suffered a heart attack get standard-of-care (SOC), or SOC plus AGI-1067, to determine if AGI-1067 can reduce cardiac morbidity and mortality. Results are expected in early 2007.

    Earlier trials showed that the drug blocks VCAM-1 expression and has direct anti-atherosclerotic effects on coronary blood vessels consistent with reversing coronary artery disease progression. It also blocked restenosis in separate trials. AGI-1067 is partnered with AstraZeneca (www.astrazeneca.com) in a deal struck in December 2005 worth a potential $1 billion in milestones and royalties.

    Atherogenics’ second drug, AGI-1096, is another member of the v-Protectant class that is being developed to address transplant organ rejection. Usually in the third year after transplantation a patient suffers transplant arteritis, the accelerated inflammation of grafted blood vessels, which can cause graft failure.

    AtheroGenics began a Phase I clinical trial in February 2002; the results demonstrated that the drug was well-tolerated at all oral doses with no drug-related adverse events. Atherogenics entered into an R&D collaboration with Astellas(www.astellas.com) in January 2004 for organ transplant rejection. It is now conducting preclinical and early clinical development studies.

    Atherogenics is also evaluating a number of next-generation v-Protectants. The AGI-series is now in the research stage to treat asthma and arthritis. In addition, the company is developing its MEKK technology platform, which targets the MAP kinase activation pathway. “This enzyme mediates leukocyte activation in response to antigen binding, and blocks the white blood cell response to inflammation, in contrast to v-Protectants, that target the tissue,” explains Dr. Medford. These drugs could be tested in asthma and RA.

    Resverlogix (www.resverlogix.com) has earlier-stage NexVas compounds in development that, it says, also reduce vascular inflammation via an undisclosed mechanism of action by upregulating ApoA-1, a protein involved in the production of high density lipoprotein. “Preliminary findings demonstrate that NexVas compounds have inhibitory effects on a number of inflammation markers,” says president and CEO Don McCaffrey. The company planned to publish mechanism-of-action studies within the next few months and to file an IND for a NexVas compound by February 2007.



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