Taking a New Look at an Ancient Tradition

In March, Geron Corporation of Menlo Park, Calif., teamed up with Hong Kong University of Science and Technology's (HKUST) Biotechnology Research Corporation to find new drugs that would activate telomerase and, it is hoped, result in a treatment for age-related diseases. Scientists at the Hong Kong-based joint venture, called TA Therapeutics, systematically screened more than 50 Chinese medicines and identified several active compounds with strong telomerase-modulating activity. "The new joint venture will primarily focus on two compounds. We will carry out preclinical studies, which will hopefully lead to the filing of an investigational new-drug application in the United States. Then we can conduct clinical trials," says Wong Yung Hou, associate director of HKUST Biotechnology Research Institute. Traditional Chinese medicine (TCM) has incorporated the use of medicinal herbs for thousands of years. Pharmaceuticals have long been derived from plants, and TCM has 7,000-plus plants in its pharmacopoeia. Yet, only recently have there been efforts to link Chinese herbal medicine and western drug discovery. TCM presents some unique obstacles for drug researchers, but progress is being made. Promising drugs, or at least drug candidates, have been discovered for treating malaria, Alzheimer disease, and organ-transplant rejection. In the strictest sense, TCM also includes acupuncture, acupressure, and moxibustion, which is a treatment that involves the burning of mugwort (Artemisia vulgaris) near the skin. However, it is the plants that comprise TCM's materia medica that are of interest to drug developers. While there is plenty of anecdotal evidence that TCM works, what has proved elusive is the ability to extract the active ingredients from TCM for use in Western-style drugs. A DEEP PHILOSOPHICAL DIVIDE TRADITIONAL CHINESE MEDICINE IN USE Huperzia Serrata Herb ◆ Active Compound ● Use ■ Research Organization ▲ Status Artemisia annua ◆ Artemisinin ● Plasmodium falciparum malaria treament ■ Various ▲ In use Huperzia serrata ◆ Dimer derived from modified huperzine A ● Alzheimer disease treatment ■ Hong Kong University of Science and Technology (HKUST) Biotechnology Research Institute ▲ Preclinical Isaria sinclairii ◆ FTY720 ● Immunosuppression ■ Novartis ▲ Phase III for prevention of acute rejection in kidney transplant; completion due 2005. US and EU submissions expected early 2006; Phase II for MS, one-year data expected mid-2005; Phase III due to begin mid-2005. Tripterygium wilfordii Hook f ◆ Triptolide ● Immunosuppression ■ Chinese Academy of Sciences, Shanghai Institute of Materia Medica ▲ Preclinical The problems start at the beginning. Western medicine and TCM have two completely different underlying philosophies. TCM treats the patient rather than targeting the disease itself. It has a unique philosophical basis, with terminology that is a challenge to interpret in western scientific terms. A patient with a headache, for example, would typically visit a TCM practitioner, who would examine the patient holistically and make a diagnosis. The practitioner prescribes several herbs, which are boiled in water, and the liquid, known as a decotion, is consumed. The combination of herbs can change over the course of treatment and can differ from patient to patient depending on the individual's reaction to the treatment. "It is a very personal type of medicine that, like pharmacogenetics, recognizes the heterogeneity of individuals," says Walter K.K. Ho, professor and chair at the department of biochemistry and director of the Institute of Biotechnology at the Chinese University of Hong Kong. "A TCM doctor is aware of that throughout the process. It's not a one-goal situation; the doctor has to continually monitor the patient and modify the formula, while western medicine is done in a systematic manner based on the common denominator of everybody." Relative to the number of herbs and other natural materials in use, few of the active compounds in TCM have been identified. Indeed, views differ on the feasibility of isolating active ingredients. In TCM, it's all about the mix. For example, it's still a matter of debate whether individual herbs must be prepared together or can be prepared individually and then mixed. "There are those who believe that you have to study TCM medicines as a whole; otherwise you will lose some of the activity when you fractionate, and there are certainly examples of this," says Nancy Ip, head of the department of biochemistry at Hong Kong University of Science and Technology and director of the HKUST Biotechnology Research Institute. "Sometimes certain compounds have to be present together, but we believe that some are acting alone." These obstacles have largely deterred Big Pharma, with the exception of Novartis, from delving into the drug discovery potential of TCM. However, researchers in academia and smaller drug companies are actively searching for new drugs derived from TCM. FINDING SOME SUCCESS When searching for potential new drugs, the obvious place to start is with known Chinese remedies. "Since TCM has more than 2,000 years' history, if particular herbs did not work, if it was just hearsay, then they would have been lost in history. What is being handed on must have some function," says Ho. One successful example of drug discovery from Chinese herbs is the antimalarial drug, artemisinin. It is extracted from the herb Artemisia annua (sweet wormwood) and has been known in China for more than 2,000 years as a remedy for fever, including malaria-induced fever. In the 1970s the Chinese government researched artemisinin as an antimalarial drug. In the 1990s Novartis established a partnership with Cititec, a Beijing-based pharmaceutical company, to codevelop its artemisinin-based combination therapy. In 1994, Novartis was granted worldwide licensing for the marketing of Coartem (a combination of artemether and lumefantrine) outside China, and it garnered regulatory approval for the drug in 1998. Novartis sources artemether, an artemisinin derivative, from its Chinese partner Kunming Pharmaceuticals, and artemisinin from several Chinese suppliers, notably Chongqing Holley Holding. The drug is provided at cost to developing nations and is sold under the name Riamet elsewhere. The market size for Riamet is "minimal," according to Novartis. Other potential drugs derived from TCM are also emerging. Researchers at HKUST's Biotechnology Research Institute have used the herb Huperzia serrata as the basis for a potential treatment for Alzheimer disease. They have synthesized a series of novel dimers derived from huperzine A, a molecule found in the herb. Huperzine A is a reversible, potent, and selective acetylcholinesterase (AChE) inhibitor. The compound was discovered by Chinese researchers and has undergone clinical trials, but it has no patent protection. "The opportunity to develop it into a drug was lost 20 years ago because it was not patented at that time," explains HKUST's Wong. As a result huperzine A has not been used in the United States or other western countries. That could change if the research on the dimers continues to go well. "We are currently doing both acute and chronic toxicology studies to evaluate the safety of the dimers," explains Wong. "We are currently in discussion with biopharmaceutical companies to codevelop the dimeric compounds into viable drugs." The plant has the potential to tap into a huge market for Alzheimer disease treatment. According to the Alzheimer's Association, an estimated 4.5 million people have the disease in the United States alone, and that number could be as high as 16 million by 2050. Tripterygium wilfordii Hook f (TWHF) is another herb being studied. Zuo Jian-ping, an immunopharmacology professor at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM), says he thinks that TWHF could contain a treatment for autoimmune and inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus and dermatomyositis, or it could be used as an immunosuppressant after tissue or organ transplant. "Triptolide, which has been defined as the active component in TWHF, showed a strong immunosuppressive activity in vitro and in vivo. However, its high toxicity limited its clinical applications," Zuo says. "We have made great efforts on modifying triptolide to get new analogs with pharmacological evaluation and tried to find the more drug-likely compounds that retain the potent immunosuppressive activity of triptolide and reduce its toxicity." SIMM is the largest institute to try to bridge western and Chinese medicine, and is one of the leading organizations in drug discovery collaborations because of its extensive library of compounds derived from TCM. The Hong Kong University-Pasteur Research Center is working with SIMM to discover new drugs to treat HIV, hepatitis C, and dengue fever. "With HIV there is an increasing number of cases and increasing number of resistant strains," says Ralf Altmeyer, CEO and scientific director at the HKU-Pasteur Research Center. "We might see the whole AIDS pandemic starting over and all our drugs would be useless.""We are using HIV in specific assays that cover certain segments of the viral life cycle, predominantly focusing on the virus attachment and fusion stages, and will start screening the whole SIMM library in May," he explains. TCM AS A TREASURE TROVE NOVEL DIMER: Source: Biotechnology Research Institute, Hong Kong University of Science & Technology Above: Dimer derived from Huperzine A, a molecule that acts as a acetylcholinesterase inhibitor and is a possible Alzheimer disease treatment. (from J Am Chem Soc. 125(2):363–73, 2003.) Left: Researchers are studying the effects of TCM compounds in Alzheimer animal models. This radial-arm maze is used to test cognitive ability in rats. SIMM has been approached by pharmaceutical companies to sell its library, but to no avail. "This library is not for sale, it's a national treasure, says Zuo. "We can't compete with the big pharmaceutical companies of course, but our library now has over 100,000 compounds, of which about 70% are from TCM herbs and natural products. It's a unique resource." SIMM signed an agreement with Novartis to collaborate on natural product-based drug discovery. The agreement, initially for three years, was extended to run through 2007. Under the agreement SIMM will isolate 1,500 new compounds from TCM plants for screening. In return Novartis offers high-throughput screening, new drug discovery, and financial support. The active compound in the Novartis immunosuppressant drug FTY720, currently in Phase III trials for prevention of rejection in kidney transplantation and Phase II trials for treatment of multiple sclerosis, was derived from culture filtrates of the fungus Isaria sinclairii, a Chinese medicinal fungus. "GlaxoSmithKline also has a collaborative agreement with SIMM for a joint laboratory of combinatorial chemistry. It's not focused on TCM but the methodology can be used for TCM," adds Zuo, who is interested in using TCM to look for antiviral drugs and treatments for autoimmune conditions. "This is our destination. It's very challenging but we see TCM as a treasure trove," he says. Other institutes are also attracting western drug developers hoping to collaborate. The Italian pharmaceutical company Sygma-Tau is in partnership with Chongqing Holley, the nonprofit organization Medicines for Malaria Venture, and the University of Oxford to develop the artemisinin-based antimalarial drug, Artekin. Sygma-Tau is also in discussion with several Chinese institutes to set up a collaboration to use its experimental models to explore drug development from TCM. "Of course we are interested because a lot of commonly used drugs, for example in the cancer field, came from natural sources and our interest in this area is very high, particularly in oncology and also in diabetes," says Alessandro Noseda, head of the scientific office at Sygma-Tau. THE MOVE TO LEGITIMIZE TCM While western drug discovery is ongoing, other researchers are moving in a different direction. They want to legitimize TCM medicine in its own right, through clinical trials and peer-reviewed studies. So far, regulatory hurdles have kept TCM remedies strictly in the nutraceutical category. One problem with this approach is that it is not possible to patent natural products that have not been modified. Once drugs come under the umbrella of western-style pharmaceuticals, it then becomes possible to patent them. "To obtain patent protection you can argue that an extract has been substantially purified and that it does not exist in nature in such a substantially purified form," says Toby Mak, patent executive at Deacons, a law firm in Hong Kong. However, synthesizing a compound derived from TCM does not automatically confer patent protection, warns Mak. "If it has the same structure as occurs in nature it is not novel, unless you make some variation to one of the substituents. Obtaining a patent is very different from obtaining a valid patent." And it may be difficult to shepherd TCM treatments through clinical trials. In the early 1990s, pharmaceutical company Phytopharm in Cambridgeshire, UK, developed an eczema preparation, Zemaphyte, based on 10 Chinese medicinal herbs. The company did not proceed beyond submission of Phase III data because of a request by the UK licensing authority for a further long-term study. "We felt that it was not warranted given our limited cash resources and the other products we had then in development," says CEO Richard Dixey. "I think traditional medicines can be extremely impressive. Plants and animals are coevolved, and it is highly likely that we can find in medicinal plants substances that can do things in animals. The only thing you can do is look for anecdotal evidence of what works and then try to isolate the active ingredients," says Dixey. "We've done many years of research to try to find and understand the active ingredients of TCM but they are very hard to identify, partly because the mechanism is not well understood." Drug discovery via TCM materials requires a degree of lateral thinking and flexibility, as the path is not always straightforward. For example, Huperzia serrata has long been used in TCM to treat contusion, strain, swelling, and schizophrenia, but it may turn out to contain a treatment for a different neurological disease. Similarly researchers could not target TCM for telomerase activators because there is no such term in TCM. "We screened medicines that are used to enhance immune defenses and slow the aging process," explains Wong. "It is not always clear-cut because of the different philosophies used. There is an art to aligning traditional Chinese medicines with a therapeutic target."

Taking a New Look at an Ancient Tradition

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Jane Parry

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May 2005

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