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 at erikakurt@ilscollaboration.org or (347)
762-4818.
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