By Daniel Dupuis
BOTANICAL DRUGS OFFER THE BEST OF BOTH WORLDS
Almost all new drug development is on a quest to deliver maximum efficacy, while being not only safe, but well tolerated due to exhibiting few side effects. Anyone that has brought a prescription home from the pharmacy or listened to the warnings listed at the conclusion of any drug advertisement on television realizes that all conventional drugs have a long list of warnings about the dangers and side effects that are inherent to all medications.
Botanical drugs, however, offer the promise of comparable efficacy, but with little or no side effects, while exhibiting negligible safety risks. It is a sector that is no longer in its infancy and has become part of the research and development activity for most large pharmaceutical companies, as well as a number of smaller entities with a long history in this arena.
GROWTH WITHIN THE BOTANICAL DRUG MARKET
The botanical market in the United States has been stalled for a number of reasons in the United States, but recent regulatory changes and the growth of the immuno-therapy sector are attracting immense interest from all elements of the pharmaceutical and biotech industry.
The already exploding global market for botanicals and plant-derived drugs will grow from $29.4 billion in 2017 to around $39.6 billion by 2022 for an anticipated compound annual growth of just under 7%, however, the botanical sector alone has a projected growth rate of 49.5%. Much of this growth will be driven by the United States market, as botanicals have only recently gained a foothold in the United States over the last several years, while being a long-accepted component of health care in both Asia and Europe.
While the scientific world can sometimes ignore business projections, innovation is driven by capital investment and a confluence of factors has dictated that botanicals will be an area of concentration within the drug industry over the next decade.
WHAT IS A BOTANICAL DRUG?
Per the FDA, a botanical drug goes through many of the same rigors as a conventional drug.
Unlike a dietary supplement that can make no disease-based claims, a botanical drug product is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in humans.
- A botanical drug product consists of vegetable materials, which may include plant materials, algae, macroscopic fungi, or combinations thereof.
- A botanical drug product may be available as (but not limited to) a solution (e.g., tea), powder, tablet, capsule, elixir, topical, or injection.
- Botanical drug products often have unique features, for example, complex mixtures, lack of a distinct active ingredient, and substantial prior human use. Fermentation products and highly purified or chemically modified botanical substances are not considered botanical drug products.
There is nothing new about medications that are derived from plant-based sources. While Bayer introduced aspirin in 1899, it was synthesized from willow bark and its use was found in the writings of Hippocrates in 400 BC. A major component of Alexander Fleming accidentally inventing penicillin was the mold that grew on a plate of cheese that was on the top of a stack of dirty dishes that were left in the sink.
WHY NOW?
The main drivers of growth include increasing population, rising awareness towards botanical and plant-derived drugs and the increasing prevalence of chronic diseases. Most botanical drugs have a favorable side effect profile and present few safety risks, but many in the United States have questioned the efficacy claims of botanicals.
As botanical research has evolved, they have now been the subject of numerous clinical trials and have demonstrated efficacy that is comparable to traditional drugs.
The United States has lagged behind the rest of the world in the development of botanical therapies, mainly because of a lack of regulatory guidelines. The problems are largely due to the semantics employed by the FDA. For example, Germany has over 70 commonly prescribed therapies that are not recognized in the U.S. for no other reason than they fell into what was, until recently, a “gray” area within the FDA. While the majority of countries do not see a distinction between botanicals, plant derived or synthesized drugs, the United States did not even create a botanical category until 2004. The FDA, however, amended the botanical guidelines in 2016 in a manner that is much more favorable to their development.
ONCOLOGY IS THE MAIN AREA OF CONCENTRATION
While “Big Pharma” was slow to enter the botanical market, they are now actively involved (Sanofi alone has 12 different botanicals under development). While doing some in-house research, many large pharmaceutical companies augmented their development strategy by licensing formulations from smaller companies, or simply acquiring them, in addition to partnering with foreign-based entities that have documented success in this sector.
This confluence of foreign entities, academic research, large pharmaceutical companies and research and development from smaller companies that have pioneered this field has led to an explosion of submissions to the FDA.
As of 2016, more than 600 botanical applications were in various phases of development with the FDA.
There are a number of disease states that are currently targeted for treatment by botanicals, but oncology is a clear area of concentration, with cancer research being the sector that has the highest number of active FDA filings.
In fact, over one third of all applications are for cancer treatment, while no other disease state exceeds 10% (see table). This is not surprising as the immuno-oncology sector has been the most robust among all drug development initiatives over the last several years from both an active research and investment perspective. Consider that Keytruda, which can only be administered to populations that have a unique genetic expression, has been projected to be the third-best-selling prescription in the world within the next five years with global sales of over $12 billion.
The promise of immuno-oncology is comparable, or enhanced, efficacy, with significantly reduced side effects. Botanicals, however, have an inherent advantage to deliver on that promise due to their lack of toxicity.
The leap from “traditional” drugs to botanicals in the oncology sector is not as considerable as some might imagine. Two of the first, and most commonly prescribed medications for a variety of cancers, are paclitaxel and docetaxel. Paclitaxel (Taxol) was derived from an extract from the bark of the rare Pacific yew tree. Due to the scarcity and difficulty of formulating paclitaxel, scientists developed docetaxel (Taxotere), which is synthesized from the renewable and more readily available leaves of the European yew tree.
ONCOLOGY IS THE DISEASE STATE WITH THE HIGHEST NUMBER OF PENDING BOTANICAL APPLICATIONS
The following is a small sample of some of the companies in various stages of botanical drug development:
Omnitura Has Developed a Botanical Immuno-Oncology Drug
Omnitura is a company that was an early entrant into the botanical drug sector and is further along than many of the relatively new entrants into the field. They utilized a PDX model (implanting human tumors into mice with no immune system) to develop Aneustat, their lead drug candidate, which is a multifunctional, multitarget, systems biology platform that is their first submission to the FDA for prostate cancer.. It has been shown in studies to both kill, and inhibit the growth, of cancer cells as either a stand-along medication or as a companion to many current standard of care cancer medications. In addition to prostate cancer, Aneustat is currently in phase II development for a wide array of cancers, including, lung, breast, pancreatic, liver and colon.
The fact that Aneustat has been shown to be effective as a stand-alone therapy is a rare trait, even when compared to the many new medications being developed within the “traditional” drug sector. Many of the new immuno-therapy drugs are meant to enhance the efficacy or limit the side effects as a component of a combination therapy, but few have demonstrated effectiveness in killing cancer cells as a stand-alone medication.
Yiviva Publishes Clinical Trial for Cancer Drug
Yale biotech startup Yiviva was recently awarded an Innovation Award at the U.S. China Health Summit. Yiviva is developing therapeutics, inspired by botanical medicines, to treat chronic diseases and cancer.
Yiviva’s lead candidate cancer drug, PHY906, is based on an 1800-year old traditional
Chinese medicine formula.
In clinical studies targeting liver, colorectal and pancreatic cancer, PHY906 has been shown to increase the safety and efficacy for a broad spectrum of cancer treatments. In a Phase I/II hepatocellular carcinoma study at Yale, Stanford and City of Hope, data suggests that PHY906 may significantly reduce gastrointestinal side-effects and increase the survival rate for patients with Hepatitis B-associated liver cancer.
Axcella Targets Amino Acids For Multiple Disease States
Axcella is pioneering revolutionary new medicines with a focus on amino acid homeostasis. The company has discovered more than 2,000 diseases with amino acid imbalances and developed a systems pharmacology approach to restore health at the cellular level.
Axcella’s proprietary platform is clinically validated across several indication areas, with clinical-stage candidates in muscle, neurodegenerative and liver conditions.
Izun Pharmaceuticals Completes Phase II Trial
Izun Pharmaceuticals Corporation is a clinical-stage company focused on developing high efficacy products based on pharmaceutically active compounds derived from botanical sources. They have announced that the results from a recently completed double-blind, Phase II clinical study for oral mucositis, indicated promising positive outcomes for the investigational product IZN-6N4.
The study was conducted at 12 centers in the United States and Israel. The trial enrolled a total of 110 patients with head and neck cancer who were scheduled to receive standard regimens of concomitant chemoradiation. Not only did patients treated with IZN-6N4 have less mouth and throat pain and soreness than controls, but more importantly, they were also more able to maintain their weights throughout the course of radiotherapy. The data supports that the best efficacy of IZN-6N4 was related to its initiation of use at the start of chemoradiation.
Dantonic is Shown to Prevent Chronic Stable Angina
T89, a 3-herb composition drug that improves microcirculation in and increases energy supply to the heart, and reduces blood viscosity in patients with chronic stable angina (A) and has been shown to improve clinical outcomes in comparison to current anti-anginal drug (CAAD), such as β-blockers, Ca++ channel blockers or nitrates that only targets on coronary arteries.
CONCLUSION
As some of the 600 applications become approved the medical community may learn to embrace medications that are not only effective, but safe and easy to take without troubling side effects. While botanicals have a long history, their use, especially in the United States, is truly the most forward looking direction that new drug development can undertake and offers patients the promise of new therapies that can help cure disease and dramatically improve their quality of life.