New Molecular Targets Reviving Anti-Inflammatory Therapeutics

Photo: Roger Riley NEW UNDERSTANDING: Kelvin Cooper predicts an upswing in interest because of new developments like comprehending the cytokine signaling pathway. Biochemical message-routing molecules are being discovered regularly, giving researchers new targets for developing more efficacious therapeutics to treat inflammatory disease. According to industry observers, these therapies constitute a multibillion-dollar market for treating disorders such as asthma, lupus, multiple sclerosis, osteoarthritis, psoriasis, and rheumatoid arthritis-many of which have been recognized as inflammatory diseases only in the last several years. Some observers also believe that as companies refine approaches to identify targets, more job opportunities for life scientists will emerge. "In the past five years, many companies were cutting back on anti-inflammatory research," comments Kelvin Cooper, director of medicinal chemistry at Pfizer Corp.'s central research facility in Groton, Conn. "Now, new discoveries are breaking. For example, we're finally comprehending the cytokine signaling pathway. This will increase the number of molecules that we can target with new therapeutics. I think this will translate into an upsurge in interest." EARLY DAYS: Fred Vinick and colleagues use combinatorial chemistry to look for a large number of compounds to screen. Many established companies have some type of inflammatory research program. George B. Zavoico, a scientific consultant for the biotech and pharmaceutical industries based in Green Farms, Conn., profiled more than 200 companies conducting research and development in inflammation in his book, Anti-Inflammatory Therapeutics: Development of New Therapeutic Approaches and Worldwide Market Opportunities (Southborough, Mass., Drug & Market Development Reports, International Business Communications Inc., 1997). "While there are interesting scientific developments in the field, it isn't spawning new companies," observes Steven G. Burrill, CEO of Burrill & Co., a private merchant bank located in San Francisco. "But that doesn't mean there isn't interest in existing companies." Burrill says some companies are reshuffling their resources to put more of an emphasis on anti-inflammatories than they did in the past. This change in focus may translate into job opportunities for those who have educational backgrounds in chemistry and life sciences. "I think there's employment for people trained in chemistry-specifically synthetic organic chemistry-at all levels, from B.S. to Ph.D.," says George Carter, vice president of immunologic disease research at Abbott Laboratories Inc. in North Chicago, Ill. "There are also opportunities for people in the biological sciences at all levels, as well, from identifying targets and developing biochemical assays to understanding cell biology, molecular biology, and genomics." OLD STANDBYS: Anti-inflammatories like aspirin have been around for a long time, says George Zavoico. Inflammatory diseases afflict every major organ system. Inflammation has evolved as a defense mechanism that gets rid of or prevents the spread of substances foreign to the human body. But many times, the function of mo- lecular components in this normally efficient system can go awry. A common example is the many forms of arthritis, with its familiar swelling and inflammation of the joints. For years, people suffering from arthritis and other related inflammatory diseases have relied on general, nonspecific painkillers for relief. "The same older drug types like corticosteroids and the salicylates like aspirin will remain on the market and will probably not be replaced for a long time," says Zavoico. "They're very cheap, and that's important in today's cost-saving environment." OPPORTUNITY: George Carter notes that there’s employment possibilities for biologists and chemists at all levels. He calls the 1960s to early 1980s a period of incredible research activity in immunology and thereby inflammation. During that time it became evident that some of the mechanisms that govern implant rejection were also operative in inflammatory diseases. "So people started using cyclosporine on an experimental basis to treat diseases like arthritis, and they found efficacy." He predicts that the use of such anti-implant-rejection drugs as cyclosporine to fight inflammatory diseases will be approved in the United States shortly. "But these drugs are also fraught with problems," he remarks. "They're immunosuppressive, so people [who] take cyclosporine, for example, are prone to an increased chance of malignancies and infection." This is where biotechnology-at both small and large firms-comes in, observers explain. "What biotechnology has done is to identify new molecular targets, which include cytokines and adhesion molecules, in particular, and others like nitric oxide," says Zavoico. The overall strategy is to block the effects of these molecules within a transduction pathway in the inflammation response to decrease or eliminate the symptoms of a certain disease. The key is to find some molecule specific to a particular inflammatory response. Both small biotechs and large pharmaceutical conglomerates are active in anti-inflammatory research and development. Pfizer, for example, has a broad range of anti-inflammatory programs that focus on many targets, including the cytokines interleukin-1(IL-1) and tumor necrosis factor-a (TNF-a) that cause unwanted tissue destruction. "Our goal is to prevent and reverse this damage," states Cooper. These cytokines release enzymes such as the matrix metalloproteinases, which also cause problems. He says that another "ripe area" of research is in seeking substances that will block receptor tyrosine kinases in the signaling pathways of the inflammatory response. "This is another way of ultimately blocking TNF-a and IL-1." A third strategy is to develop inhibitors of the matrix metalloproteinases. These break down collagen in cartilage, a classic symptom and source of pain in arthritis. "Most of this work is at the preclinical stage because these are fairly new approaches to blocking disease progression," reports Cooper. The large number of tissue types and biochemicals associated with the inflammatory response requires a combination of approaches, thus explaining, at least in part, the widespread participation and interest in this field. "We're a rational drug-design company," says FOR MORE INFORMATION Abbott Laboratories Inc. http://www.abbott.com Ariad Pharmaceuticals Inc. http://www.ariad.com BioCryst Pharmaceuticals Inc. http://www.biocryst.com Genzyme Corp. http://www.genzyme.com Pfizer Inc. http://www.pfizer.com T Cell Sciences Inc. http://www.tcell.com 'RATIONAL' APPROACH: BioCryst is making inhibitors against targets that cause inflammation, reports J. Claude Bennett. J. Claude Bennett, president and chief operating officer at BioCryst Pharmaceuticals Inc., a biotech firm in Birmingham, Ala. "We take the approach that once we have a target enzyme in the inflammatory response, we use X-ray crystallography to identify its active site. Then we develop small molecules that are specific inhibitors of those active sites." BioCryst is making inhibitors against such targets as purine nucleoside phosphorylase, which blocks DNA synthesis of T cells, the orchestrators of inflammation. "We have seven clinical trials for this target, with two in Phase III for cutaneous T-cell lymphoma and psoriasis," reports Bennett. On the other hand, says Fred Vinick, vice president of drug discovery at Genzyme Corp. in Cambridge, Mass., "It's still very early for us. We're looking at potential applications for surgical and tissue repair." Genzyme uses combinatorial chemistry to look for a large number of compounds to screen. "For example, we have a collaboration with Leukocyte Inc. in Cambridge to look for leads against their existing chemokine-receptor targets based on our understanding of inflammation. Internally, we've looked at tyrosine kinases associated with T-cell and B-cell function, and we're also interested in compounds that block the action of TNF-a." Michael Gilman, chief scientific officer at Ariad Pharmaceuticals Inc. in Cambridge, Mass., notes that in addition to his company's more traditional method of drug design, the firm is contemplating approaches based on gene therapy. In collaboration with Genovo Inc., a biotech firm located in Sharon Hill, Pa., Ariad plans to produce proteins that are part of the inflammatory response, such as cytokines and cytokine antagonists. "In this joint venture we're developing systems that could allow expression of the cytokines with great precision," explains Gilman. Using adenovirus and adeno-associated-virus vectors, the researchers are designing technologies that will enable clinicians to activate or deactivate the genes that encode for some molecules in the inflammatory response. The hope is that this will allow for greater control over therapies than is now possible. Cytokines remain a popular target for many companies. Others are interested in two other molecules important in the inflammatory response-the enzymes cyclooxygenase-2 (COX-2) and 5-lipooxygenase (5-LOX). "These enzymes metabolize a fatty acid called arachidonic acid," explains Abbott's Carter. "This lipid is found in cell membranes, and when cells are triggered by inflammatory or allergic reactions, they will release this substrate, and it can be converted via COX-2 to prostaglandins or by 5-LOX to leukotrienes." Leukotrienes are a family of substances involved in asthma. These metabolites can cause bronchoconstriction and attract inflammatory cells into the airways, which can lead to damage and swelling. Abbott has developed a drug that inhibits 5-LOX and thereby reduces the amount of the constrictor and proinflammatory substances. In addition to asthma, Carter notes, Abbott is focusing on molecular targets for rheumatoid arthritis, osteoarthritis, inflammatory skin diseases such as psoriasis and dermatitis, and inflammatory bowel diseases. "For example, in our COX-2 inhibitor project, we're targeting diseases where nonsteroidal drugs like aspirin work." Abbott aims to make drugs that will better target the inflammatory response so as to reduce side effects such as ulceration. ENIGMA: Matching the right molecular target to the correct disease is the real challenge, contends Thomas Beck. Thomas R. Beck, chairman and CEO of CytoMed Inc. in Cambridge, Mass., relates that his company is also targeting 5-LOX. COX-2 inhibitors work well for inflammation problems in the bones and joints, he says, while 5-LOX inhibitors work well for problems in such surface tissues as the gut, lung, and skin. CytoMed has a 5-LOX inhibitor product for skin problems in Phase II trials and another for asthma that will start Phase I trials in the fall, he reports. The complement system of enzymes is a new target for drug development, say many observers. A handful of companies-including CytoMed; BioCryst; Alexion Pharmaceuticals Inc. of New Haven, Conn.; and T Cell Sciences Inc. of Needham, Mass.-are at the forefront of this approach. The system consists of several blood proteins that go into action during acute inflammation, participating in a cascade of biochemical reactions that end up taking two directions. Photo: Joe Iadanza THERAPEUTIC TAKEOFF: Una Ryan calls complement-related pathways "launch pads" for getting at key molecular targets. Una Ryan, T Cell's CEO and president, calls complement-related pathways "launch pads" for getting at targets in many associated pathways. "We feel that inhibiting complement is really getting to the narrow neck of where the inflammatory response starts. Whereas if you go after cytokines and growth factors and other inflammatory mediators downstream, you've gotten to the point where the signals have fanned out and there's huge amplification of troublesome molecules. Then it's very difficult to intervene." T Cell Sciences has a drug called sCR1 in Phase II trials for use in adult respiratory distress syndrome and has just completed enrollment on a lung-transplantation Phase I/II trial, reports Ryan. CytoMed also targets the complement system. "Its role is to protect our bodies from abnormal substances like germs," says Beck. In the pathway, peptides produced downstream induce inflammation and cause problems like punching holes in cells. For example, with lupus, antibodies that are mistakenly produced activate the complement system. CytoMed is now developing a genetically altered cell surface protein that is a natural inhibitor of the entire complement system. "There are clearly many pathways that elicit an inflammatory response," concludes Beck. "The conundrum is figuring out which to target for which disease."

New Molecular Targets Reviving Anti-Inflammatory Therapeutics

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