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 (UN) Church Center in New York City and highlighted natural product (particularly medicinal plant) breakthroughs and new resources. The UN 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 incorporate 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), 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 that her team is developing for asthma and food allergies using TCM.

The first treatment addresses asthma, which results in the deaths of 3,000-4,000 Americans annually and $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 or advised for long-term use due to undesirable side effects. Thus, there is a strong need to develop better treatments for asthma.

Dr. Li’s team has created 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 extracts of 63% ling zhi (reishi mushroom; Ganoderma lucidum, Ganodermataceae) fruiting body, 28% gan cao (licorice; Glycyrrhiza glabra, G. uralensis, Fabaceae) root, and 9% ku shen (Sophora flavescens, Fabaceae) 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 immunoglobulin E (IgE; an antibody involved in allergenic diseases); but, unlike prednisone, it did not exhibit adverse side effects.³ In a four-week clinical study of 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 beta-2 agonists such as inhaled bronchodilator drugs that are used to relax the muscles lining the airways 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, animal models have shown 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 carried out the first 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, Rosaceae), 6% gold thread (Coptis chinensis, Ranunculaceae) root, 6% Asian ginseng (Panax ginseng, Araliaceae) root, 6% ginger (Zingiber officinale, Zingiberaceae) root/rhizome, 6% angelica (Angelica sinensis, Apiaceae) root, 4% Amur cork tree (Phellodendron amurense, Rutaceae), 4% true cinnamon (Cinnamomum verum, Lauraceae) bark, and 2% prickly ash (Zanthoxylum simulans, Rutaceae) peel.⁵

In animal models, FAHF-2 completely blocked anaphylaxis in mice. Moreover, it provided persistent protection for 50 weeks after treatment versus the 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, resulting in B-FAHF-2. The modified formula reduced the required 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. Dr. Li and colleagues discovered that berberine (BBR; a key isoquinolone alkaloid found in gold thread root) is a key compound that inhibits IgE production by human B cells; the team 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. Each of the ingredients was tested individually, but 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 8-10 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 — in conjunction with Yale University and Shwu-Huey Liu, PhD — founded the biotechnology company Yiviva 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 it is 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 confidential), that has been shown in preclinical studies to significantly reduce fat and inflammation in the liver. In vitro and in vivo studies are currently underway. Since it is 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 & Inflammatory Side Effects of Chemotherapy

In a separate effort, Dr. Yung-Chi Cheng tested an herbal mixture that has been used more than 1,800 years as the basis for PHY906 to reduce the gastrointestinal side effects of chemotherapy while enhancing the effects of cancer treatment. The proprietary pill consists of four herbs — Chinese skullcap (Scutellaria baicalensis, Lamiaceae) root, Chinese licorice root, Chinese peony (Paeonia lactiflora, Paeoniaceae) root, and Chinese date tree (Ziziphus jujuba, Rhamnaceae) fruit — based on an ancient recipe called Huang Qin Tang traditionally 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 chemotherapy that were given PHY906 lost less weight and experienced more anti-tumor activity than mice not given the formula. The herbal formula reduced chemotherapy toxicity 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 plants 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, Zingiberaceae) 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 chemotherapy-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 — using what he considers its primary active herbal component, qing dai (Indigo naturalis^‡) — developed a formula known as 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 phosphorylation, thereby inhibiting pro-inflammatory cytokine expression and stimulating the anti-inflammatory cytokine IL-10. Dr. Wang believes that Natura-alpha may have other applications, including for use in inflammatory bowel disease (IBD). Currently, Natura-alpha is in Phase II trials for the treatment of ulcerative colitis, which is the most common form of IBD.

Importance of 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

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 have been natural products derived from microbes. In looking toward 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 (www.smallworldinitiative.org), a crowdsourcing program that aims to develop 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. Through this work, he often sees patients taking natural remedies and speaks of the need to educate both patients and providers. In particular, he cautioned 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 (www.tkdl.res.in) — which contains 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 has worked to disseminate evidence-based knowledge on natural products to doctors and patients. Since many patients with cancer are interested in complementary and alternative medicine, Dr. Deng stressed the importance of providing accurate information. For example, popular natural products used by patients may inadvertently detox chemotherapy treatments, increase bleeding tendencies, or heighten estrogenic effects. For these reasons, Dr. Deng has been generating a natural products database based on pharmocokinetic and pharmacodynamic effects 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 materials⁹ 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 mechanisms of action.

Dr. Yung-Chi Cheng stressed the importance of ensuring product QC, 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 problematic.¹⁰ A novel approach is required to determine what to measure and how to measure it. To assess quality, Yiviva has 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 has also developed its own proprietary database — STAR (Signal Transduction, Action and Response) Discovery Platform — and 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 herb 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 researchers 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. Furthermore, studies are needed to determine the microbiota impact on herbs and vice versa, mechanisms of action of herbal formulas 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 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 (https://clinregs.niaid.nih.gov/index.php).

Glen Park, PharmD, Target Health’s senior director of clinical and regulatory affairs, defined the well-known differences between dietary supplements and drugs. 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, 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, Theaceae] leaves for the topical treatment of external genital and perianal warts, and Fulyzaq^® [crofelemer], derived from red sap of the Croton lechleri [Euphorbiaceae] tree bark to relieve symptoms of diarrhea in patients with HIV/AIDS taking antiretroviral drugs).

One of Target Health’s regulatory affairs experts, Mary Shatzoff, provided examples to demonstrate how similar products may fall into different categories. For example, capsaicin, the active component in chili pepper (Capsicum annuum, Solanaceae), can be regulated as a dietary supplement, an over-the-counter (OTC) drug, or a prescription drug. If the product is in oral form, it can be regulated as a dietary supplement as long as there are no therapeutic claims. 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 at concentrations 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 a Federal Register announcement¹¹ in 2004 and the FDA Exocrine Pancreatic Insufficiency Drug Product FDA Guidance.¹² On the other hand, enzymes of bacterial, fungal, or plant origin are considered dietary supplements and regulated per DSHEA.

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 at erikakurt@ilscollaboration.org.

* 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, as well as PHY906+Xeloda and PHY906+Gemzar for advanced pancreatic cancer.

^† 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 [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 (Acanthaceae), Polygonum tinctorium (Polygonaceae), Indigofera tinctoria (Fabaceae), Isatis indigotica (Brassicaceae), and I. tinctoria.¹³

References

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