New Plant-Derived Drugs from Traditional Chinese Medicine Discussed at UN Conference

HerbalEGram: Volume 12, Issue 7, July 2015 ILSC’s Conference Highlights Safety and Benefits of Natural Products

By Erika L. Kurt, LLB, BLC On June 1, 2015, the Institute for Life Sciences Collaboration (ILSC) hosted a conference — “Sustainable Development Healthcare Delivery: Nutraceuticals & Natural Products” — as part of the “United Nations at 70” non-governmental organization series. The event took place at the United Nations Church Center in New York City and highlighted natural product (particularly medicinal plant) breakthroughs and new resources. The conference series convenes leading experts to uncover the mechanisms of action of natural products, identify and promote recent progress and developments in healthcare, and improve global healthcare delivery through evidence-based approaches. This series advances ILSC’s mission to make meaningful and measurable improvements in the global healthcare landscape. Herbal Breakthroughs and Updates Several speakers presented updates in their efforts to take natural products and traditional Chinese medicine (TCM) into mainstream American medical therapy. This included significant progress in treating people with asthma, food allergies, non-alcoholic fatty liver disease (NAFLD), the gastrointestinal and inflammatory side effects of chemotherapy, and inflammatory bowel disease (IBD). Asthma and food allergies Xiu-Min Li, MD, the director of the Center for Integrative Medicine for Allergies and Wellness at Mount Sinai Hospital’s Icahn School of Medicine, shared two novel treatments her team is developing for asthma and food allergies using TCM. The first treatment addresses asthma, which results in the deaths of between 3,000-4,000 Americans annually and costs $56 billion in medical costs and indirect costs (e.g., missed work).1,2 Currently, the most effective treatments involve conventional pharmaceutical steroid drugs, which are not curative and not advised for long-term use due to undesirable side effects. Thus, there is a strong need to develop a better treatment for asthma. Dr. Li’s team has developed a safe and effective therapy for moderate-to-severe asthma. Anti-Asthma Simplified Herbal Medicine Intervention (ASHMI) is made from three herbs of the 14-herb formula MSSM-002. It consists of capsules of dried water extract of 63% ling zhi (reishi mushroom, Ganoderma lucidum) fruiting body, 28% gan cao (licorice, Glycyrrhiza glabra, G. uralensis) root, and 9% ku shen (Sophora flavescens) root. In mouse models and human clinical trials, ASHMI has been shown to have long-lasting therapeutic benefits, unlike other treatments, and to be effective as a stand-alone therapy for moderate-to-severe asthma. Its effects were comparable to the conventional pharmaceutical steroid drug prednisone in improving lung function and reducing levels of serum IgE (immunoglobulin E, an antibody involved in allergic diseases); but unlike prednisone, it did not exhibit adverse side effects.3 In a four-week clinical study on adults, ASHMI normalized Th1 immune functioning (i.e., the part of the immune system that protects against microbial and viral infections, which is often deficient in highly allergic patients) and moderated Th2 function, which is associated with allergies. It also reduced reliance on beta2-agonists, inhaled bronchodilator drugs that relax the muscles lining the airways, which are used during asthma attacks. Further, cortisol levels remained normal unlike with steroid use, which causes adrenal suppression. Phase I human clinical trials showed positive safety and tolerability. In children with asthma, with or without allergic rhinitis, a combination therapy of ASHMI and inhaled steroids was found to be safe and more effective than steroids alone. It is well established that asthma is a heritable condition, influenced by the environment and modified by in utero exposures and aging. Interestingly, the animal models also demonstrated that desensitizing an asthmatic mother with ASHMI may provide transgenerational benefits and reduce the risk for allergic asthma in offspring.2,4 Dr. Li’s team has also developed the first botanical Investigational New Drug (IND) for food allergies and the sole clinical trial of a therapy directed at multiple food allergies. Food Allergy Formula 2 (FAHF-2) is made from 46% reishi mushroom, 20% Chinese plum (Prunus mume), 6% gold thread (Coptis chinensis) root, 6% Asian ginseng (Panax ginseng) root, 6% ginger (Zingiber officinale) root/rhizome, 6% angelica (Angelica sinensis) root, 4% Amur cork tree (Phellodendron amurense), 4% true cinnamon (Cinnamomum verum) bark, and 2% prickly ash (Zanthozylum simulans) peel.5 In animal models, this formula completely blocked anaphylaxis in mice. Moreover, it provided persistent protection for 50 weeks after treatment versus a 2-4 week protection provided by conventional pharmaceutical drug therapy. In human studies, it was shown to be safe and have immunomodulatory effects on T cells and suppress basophil activation. However, due to the large dose requirement of this formula, nearly 50% of patients reported poor compliance. To ease compliance, the research team used butanol purification to concentrate the active compounds in an extract and create B-FAHF-2. This reduced the required effective daily dose by 80% to just six pills and was nine times more potent than FAHF-2 in suppressing IgE production by human B cells. The team discovered that berberine (BBR, a key isoquinolone alkaloid found in gold thread root) is a key compound in inhibition of IgE production by human B cells and would like to create a formula composed of specific bioactive components, enhance BBR bioavailability and absorption, and use nanotechnology to encapsulate BBR — all of which would reduce dosage requirements. Dr. Li has found that if she can connect the classical TCM formulas with pathology recognized by Western physicians, she may get a head start on finding cures. Before she had the idea to test Chinese herbs for food allergies, she had tested at least 10 different types of immunotherapy. Since the symptoms of food allergies overlap with those of parasites, Dr. Li made the leap to try an herbal formula for parasites. While each of the ingredients was tested individually, it was revealed that the whole package was more effective than any lesser combination and that it acted on multiple cells involved in the allergic response. While it is possible to follow these herbal treatments under the care of a professional or individually, both ASHMI and B-FAHF-2 have eight-to-10 more years ahead of them until they are approved as new drugs. Non-alcoholic fatty liver disease Peikwen Cheng, MBA, and Yung-Chi Cheng, PhD, founded the biotechnology company Yiviva along with Yale University and Shwu-Huey Liu, PhD, to develop evidence-based botanical products to address aging-associated diseases. One of the diseases that Yiviva is tackling is non-alcoholic fatty liver disease (NAFLD), which is common in metabolic syndrome and affects one in three people in the United States. It is the most common liver disease in the United States, Europe, and Asia and a gateway condition to serious chronic diseases. Currently, there are no approved pharmaceuticals for NAFLD. Yiviva has developed an herbal formulation, YIV001, the contents of which are being held as confidential, which significantly reduced fat and inflammation in liver in preclinical studies. In vitro and in vivo studies are currently underway. Being developed as a dietary supplement, YIV001 will likely get to market in one year instead of the 12 years on average that drug approval requires. Gastrointestinal and inflammatory side effects of chemotherapy In a separate effort, Dr. Yung-Chi Cheng tested an herbal mixture in use for more than 1,800 years as the basis for PHY906 to reduce the gastrointestinal side effects of chemotherapy (chemo) while enhancing the effects of the cancer treatment. The proprietary pill consists of four herbs — skullcap (Scutellaria baicalensis) root, Chinese licorice (Glycyrrhiza uralensis) root, Chinese peony (Paeonia lactiflora) root, and Chinese date tree (Ziziphus jujuba) fruit — based on an ancient recipe called Huang Qin Tang used to treat nausea, vomiting, and diarrhea. In a Phase I study funded by the US National Institutes of Health’s (NIH) National Cancer Institute (NCI), mice undergoing chemo that were given PHY906 lost less weight and experienced more anti-tumor activity than mice not given the formula. The herbal formula reduced toxicity of chemo by inhibiting inflammation and promoting creation of new intestinal cells. Of probably little surprise to those who are experts in the use of herbs and medicinal plants in therapy, the herbs in the formula were found to have a synergistic effect that diminished if any one herb was removed.6 Thanks to an NCI grant, PHY906 is currently in Phase II clinical trials at Yale University and the University of Pittsburgh for people undergoing irinotecan chemotherapy for colorectal cancer.* The study’s primary outcome measures the effect of PHY906 on irinotecan toxicity, with the goal of achieving a 30% reduction in the overall incidence of grade 2-4 toxicity.† Koraljka Gall Troselj, MD, PhD, senior research associate at Croatia’s Rudjer Boskovic Institute, spoke about the potential use of curcumin, a group of polyphenols derived from the turmeric (Curcuma longa) rhizome, for combined cancer therapy. Dr. Gall Troselj acknowledged that much recent research has documented that curcumin has many activities related to cytokines, has been shown to be a strong inhibitor of NF-kappaB activity (a mediator of inflammatory reactions), and often leads to cellular apoptotic response (normal, programmed cell death). It also exhibits antibacterial, antioxidant, and anti-arthritic properties, has hepato-, uro-, neuro-, and cardioprotective effects, and is thrombosuppressive. There is a strong link between inflammation and cancer, mediated by NF-kappaB, including human papilloma virus (HPV) and cervical cancer, smoking and lung cancer, and microbial infections. Signaling pathways activated by NF-kappaB commonly result in cellular proliferation. Further, the link extends into the area of cancer treatment with chemo-induced cellular damage and the consequential inflammatory reaction, which may lead to resistance to cytostatic agents. As shown in various cell line models, curcumin can, through its inhibitory effect on NF-kappaB, synergistically add to the antiproliferative action of the cytostatic agent. However, the effect strongly depends on timing. In the majority of in vitro studies, this effect takes place only if curcumin is administered several hours before the cytostatic agent. If given in the reverse order, the effect is antagonistic. In a review of current research, Dr. Gall Troselj has found that the animal studies are promising but highly variable. Inflammatory bowel disease Longgui Wang, MD, executive director of Natrogen Therapeutics International, took a TCM formula (Danggui Longhui Wan) that reduces symptoms of chronic myeloid leukemia and, discovering what he considers its primary active herbal component, qing dai (Indigo naturalis‡), used it to develop Natura-alpha. According to Dr. Wang, Natura-alpha is a derivative of indiribin, a compound found in qing dai. At high concentrations, Natura-alpha inhibits cyclin-dependent kinases (cdks). At low concentrations, Natura-alpha selectively blocks STAT3-Y705 (phosphorylation), thereby inhibiting pro-inflammatory cytokine expression and stimulating anti-inflammatory cytokine IL-10. Dr. Wang believes that Natura-alpha may have other applications, including inflammatory bowel disease (IBD). Currently, Natura-alpha is in Phase II trials for the treatment of ulcerative colitis (UC), which is the most common form of IBD. Natural Products Eric Patridge, PhD, founder of ChemStats, discussed the importance of natural products in developing new antibiotics. While Dr. Patridge was a research associate at Yale’s Natural Products Lab, he was part of a team that examined all 14,053 new molecular entities (NMEs) that were FDA-approved and not reformulated as of the end of 2013.7 This is important because, even as the problem of antimicrobial resistance expands, the cumulative number of FDA-approved antibiotic NMEs on the market has been decreasing. Only 62% of these NMEs are currently available as fewer antibiotics are being approved and more are exiting the market. Further, many pharmaceutical companies have abandoned this space, including Pfizer, Eli Lilly, Bristol-Myers Squibb, Johnson & Johnson, Bayer, and Abbvie, as antibiotics are not as lucrative as drugs for chronic conditions. Yet, as multiple reports confirm, “[t]he true cost of antimicrobial resistance would be $100 trillion and 300 million premature deaths if no action was taken between now and 2050.”8 Yet, as Dr. Patridge pointed out, natural products, and microbes in particular, may be the key to developing a new pipeline of antibiotics. Specifically, since 2000, 77% of FDA-approved antibiotics are natural products derived from microbes. In looking towards the ancient origins of bioactive natural products, it is interesting to note that some of the first antibiotics were derived from fermented soybean curd and early African Sudanese beer fermented with Streptomyces fungi. One innovative model in this arena is the Small World Initiative, a program to crowdsource new antibiotics from soil microbes that was formulated at Yale in 2012 and is now being managed by ILSC. New Guidelines and Information Pudupakkam K. Vedanthan, MD, president and founder of Global Chest Initiatives, covered his experience treating asthma and allergy patients and training doctors in the developing world for six months each year. Through this work, he often sees patients taking natural remedies and speaks of the need to educate both patients and providers. In particular, he cautions that just because something is natural and works on a specific condition does not mean that it can be safely used. He also highlighted a new source of information — the Traditional Knowledge Digital Library — containing 1,200 herbal formulations selected from the classical texts of Ayurveda, Unani, and Siddha traditional systems of medicine. This library, offered in five languages, was undertaken as a collaborative project between the Indian Council of Scientific & Industrial Research and the Department of Ayurveda, Yoga & Naturopathy, Unani, Siddha and Homeopathy (AYUSH). In addition, India’s National Center for Complementary and Alternative Medicine is funding three Centers of Excellence to explore TCM therapies. Gary Deng, MD, PhD, at Memorial Sloan Kettering Cancer Center discussed how, over the last 13 years, he has worked to incorporate natural products into a general approach to oncological care. After overcoming resistance from mainstream physicians, he worked towards disseminating evidence-based knowledge on natural products to doctors and patients. Since many cancer patients are interested in complementary and alternative medicine, Dr. Deng stresses the importance of providing accurate information. For example, popular natural products used by patients may inadvertently detox the chemo treatments, increase bleeding tendencies, or heighten estrogen effects. For these reasons, Dr. Deng has been generating a natural products database based on the pharmocokinetic and pharmacodynamic effect matched with prescribed treatments. As a result, he provides information to doctors and patients about what helps and what might be counterproductive. In addition, his team developed a website of educational materials to share knowledge on dietary supplements, the About Herbs app, and three clinical practice guidelines backed by the NIH Clinical Practice Guidelines Clearinghouse. Improvements Needed for TCM Several speakers tackled the challenges of bringing TCM into Western Medicine. In particular, they highlighted the issues of quality control (QC) and determining the mechanism of action. Dr. Yung-Chi Cheng stressed the importance of ensuring QC of product, including that the right high-quality species is used, there is no adulteration with other substances or contamination with heavy metals, and a standard procedure for harvesting and preserving herbs is employed. As covered extensively by the American Botanical Council in response to the New York Attorney General’s recent investigation, the use of the DNA barcoding method to test herbal dietary supplements, particularly botanical extracts, is extremely problematic.9 A novel approach is required to determine what to measure and how to measure it. To assess quality, Yiviva created its own patented QC platform, Phytomics, which integrates unique chemical and biological fingerprints. The fingerprint technology measures more than 100 parameters to ensure consistency even for complex botanical mixtures. A simplified analysis could occur once chemicals relevant to the pharmacological activity are determined. According to Peikwen Cheng, Phytomics has allowed Yiviva to achieve more than 90% consistency in its herbal preparations over a 10-year period. To develop novel solutions from TCM and gather evidence-based information, Yiviva developed its own proprietary database — STAR (Signal Transduction, Action and Response) Discovery Platform — and has screened over 250 herbal formulations across 30 signal transduction pathways. This has provided Yiviva’s team with greater insight into how different botanicals affect biological responses, including inflammation, immunomodulation, and hormones, and the team is using bioinformatics to mine this database. A challenge in determining the mechanism of action in TCM is that Western medicine tends to follow a single target-single chemical reductionist approach while TCM goes after a multiple target-multiple herbs polychemical and herbal interaction approach. Drs. Cheng and Li believe that multiple targets should be entertained more often in Western medicine as one herb can make another herb more effective and can affect the larger immune system. By looking at them one at a time, Dr. Li cautioned that we may be missing out. While there are limited financial incentives or regulatory requirements to study dietary supplements, Dr. Cheng stressed the importance of additional studies to determine proper dosages, schedules, and durations of treatment; ensure safety; and examine potential interactions with other treatments. Further, studies also are needed to determine the microbiota impact on herbs and vice versa, mechanism of actions of herb formula for each indication, and determination of active compounds. This will help traditional medicine advance from being experience-based and often vague to evidence-based and more information-rich medicine. To this end, Dr. Cheng chairs the Consortium for the Globalization of Chinese Medicine (CGCM) to bring government, academia, and industry together to advance the field of Chinese medicine. Regulatory Issues — Dietary Supplements vs. Drugs A panel on regulatory issues brought together the expertise of Target Health Inc.’s team. Target Health is a full service CRO (contract research organization) dedicated to all aspects of Drug and Device Development. Its President, Jules Mitchel, PhD, highlighted a new online database of country-specific clinical research regulatory information that the NIH’s National Institute of Allergy and Infectious Disease (NIAID) is developing to save time and effort in planning and implementing clinical research (ClinRegs). Glen Park, PharmD, Target Health’s senior director of clinical and regulatory affairs, defined the well-known differences between dietary supplements and drugs. A substance or preparation is a dietary supplement when it is intended to supplement the diet, taken orally (ingested), and labeled as a dietary supplement. A compound is a drug when it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease (specific claim). For a botanical to become a drug and gain marketing approval via the US Food and Drug Administration’s (FDA) Botanical Drug Approval process, all safety and efficacy requirements must be met on a pre-market approval basis. However, the initial human studies do not require animal toxicology studies if the botanical has extensive use as dietary supplement. Due to cost and time, only two botanical drugs have so far been approved by the FDA (e.g., Veregen® [sinecatechins], an extract of dried green tea [Camellia sinensis] leaves for the topical treatment of external genital and perianal warts, and Fulyzaq® [crofelemer], derived from red sap of the Croton lechleri tree bark to relieve symptoms of diarrhea in HIV/AIDS patients taking antiretroviral drugs). One of Target Health’s regulatory affairs experts, Mary Shatzoff, MS, then provided some examples to demonstrate how similar products may fall into different categories. For example, capsaicin, the active component in chili pepper, can be regulated as either a dietary supplement or an over-the-counter (OTC)/nonprescription or prescription drug. If the product is in an oral form, it can be regulated as a dietary supplement as long as there are no therapeutic claims. This is because any product that was on the market prior to 1994 can be marketed as a dietary supplement without the need to establish evidence of safety (grandfathered in by the Dietary Supplement Health and Education Act of 1994 [DSHEA]). However, if the capsaicin product is in topical form, it is regulated as an OTC drug at concentrations below 0.25% and as a prescription drug above 0.25%. The 8% topical concentration is approved only for the management of neuropathic pain associated with postherpetic neuralgia. Shatzoff also described how digestive enzymes are regulated based on the source of the compounds and the evidence of historical safety and label claims. Digestive enzymes of animal origin are considered drugs and regulated according to the Federal Register announcement10 in 2004 and the FDA Exocrine Pancreatic Insufficiency (EPI) Drug Product FDA Guidance.11 On the other hand, enzymes of bacterial, fungal, or plant origin are considered dietary supplements and regulated per DSHEA. * There may be future development or off label usage, given the strong Phase I clinical trial data for PHY906 and other indications and therapies, including PHY906+Xeloda and PHY906+Nexavar for Hepatocellular Carcinoma (HCC, liver cancer), as well as PHY906+Xeloda and PHY906+Gemzar for advanced pancreatic cancer (APC). † NCI has developed Common Terminology Criteria for Adverse Events, which are reported by grade on a scale of 1 to 5. (1=mild, 2=moderate, 3=severe but not life-threatening [hospitalization required], 4=life-threatening [urgent intervention required], 5=death related to adverse event) ‡ Qing dai (pharmaceutical name: Indigo naturalis) is a preparation of five botanicals: Baphicacanthus cusia, Polygonum tinctorium, Indigo tinctoria, Isatis indigotica, and Isatis tinctoria.12 Erika L. Kurt, LLB, BCL, is Managing Director of the Institute for Life Sciences Collaboration — a 501(c)(3) nonprofit organization focused on developing innovative solutions to pressing global health challenges.She also leads ILSC’s Small World Initiative. This is an innovative program to address a worldwide health threat — the increase in antimicrobial resistant pathogens — by crowdsourcing new antibiotics from soil microbes. Erika graduated Phi Beta Kappa from Vassar College with Highest Honors and earned two law degrees with Distinction from McGill University Faculty of Law. She can be reached aterikakurt@ilscollaboration.org or (347) 762-4818. References 1. Sicherer SH. Epidemiology of food allergy. J Allergy Clin Immunol. March 2011;127(3):594-602. 2. Ehrlich H. Food Allergies: Traditional Chinese Medicine, Western Science, and the Search for a Cure. New York, NY: Third Avenue Books; 2014. 3. Wen MC, Wei CH, Hu ZQ et al. Efficacy and tolerability of anti-asthma herbal medicine intervention in adult patients with moderate-severe allergic asthma. J Allergy Clin Immunol. 2005;116(3):517-524. 4. Lopez-Exposito I, Srivastava, KD, Birmingham N, Castillo A, Miller RL, Li XM. Maternal ASHMI-therapy prevents airway inflammation and modulates pulmonary innate immune responses in young offspring mice.Ann Allergy Asthma Immunol. January 2015;114(1):43-51. 5. Wang J, Sampson HA. Food anaphylaxis. Clin Exp Allergy. May 2007;37(5):651-660. 6. Wang SS. Chinese medicine goes under the microscope. Wall Street Journal. April 2, 2012. 7. Patridge EV, Gareiss PC, Kinch MS, and Hoyer DW. An analysis of original research contributions toward FDA-approved drugs. Drug Discovery Today. June 22, 2015. 8. Review on Antimicrobial Resistance. Securing New Drugs for Future Generations: The Pipeline of Antibiotics. May 2015. This mirrors recent statements from the President’s Council of Advisors on Science and Technology, the President’s Advisory Council on Combating Antibiotic-Resistant Bacteria, and the World Health Organization. 9. Smith T. The supplement saga: a review of the New York attorney general’s recent actions against herbal dietary supplements. HerbalGram. 2015;106:44-55. Available here. Accessed July 8, 2015. 10. US Department of Health and Human Services. Exocrine pancreatic insufficiency drug products. Federal Register. 2004;69(8):23410-23411. Available here. Accessed July 8, 2015. 11. US Department of Health and Human Services. Guidance for industry: exocrine pancreatic insufficiency drug products – submitting NDAs. April 2006. Available here. Accessed July 8, 2015. 12. Plitzko I, Mohn T, Sedlacek N, Hamburger M. Composition of Indigo naturalis. Planta Med. 2009;75(8):860-863. Available here. Accessed July 8, 2015.