Botanical Drug Development Overview

My name is Nilanjan Bose. I am the Chief Scientific Officer at Emory Pharma. I hold a PhD in analytical chemistry and Chemical Biology from Cornell University. And for the past 15 years I have been working in developing analytical and mass spectrum workflows for pharmaceutical discovery and development. Today I'm going to talk to you about botanical drugs, what they are and what you should be considering if you are developing a new botanical drug. So what are botanical drugs? The U.S. food and Drug Administration or FDA defines botanical drugs as products from plant materials, algae, macroscopic fungi and combination thereof. We'll also go into what botanical drugs are not and both of these are really important if you are developing drug modalities such as this. So natural products have been used as an inspiration or directly as pharmaceuticals from virtually the beginning of human civilization. I'm showing you just a few examples. These are very well known molecules such as vancomycin, which is used as an antimicrobial. Taxol, the famous oncology drug or paclitaxel comes from a plant source as well as artemisinin which is used to treat malaria. As a matter of fact, in 2015, the Chinese researcher Tu Yoyo was awarded the Nobel Prize in Physiology or Medicine for her work in discovering this natural product. So how is botanical or botanical drugs as a drug modality different from these natural products that have been there for many, many decades now? The formal definition, as I said, comes from the US FDA guidance for us and I'm giving you the specific guidance that talks about botanical drugs. It was released in 2016. It replaces USFDA's guidance from 2004 and makes substantial upgrades to the regulatory guideline around botanical drugs. But the most important thing that this does is it defines what botanical drug is not, which is what I'm going to tell you. As the name suggests, it's not coming from animal or animal parts. It needs to have a plant or fungal origin. But the fundamental difference between botanical drugs and all the other natural product based pharmaceuticals that are out there is the fact that botanical drugs are complex mixtures. All the other natural products, stuff that are out there are mostly being developed or have been developed as purified or simple single natural product. That is regulatory perspective, no different than how you would develop a rationally designed or synthesized small molecule pharmaceutical. And that is where botanical drugs has its most important benefits that you should consider. The fact that botanical drugs are complex mixtures mean that it can have multifactorial activity profile. This is something what I'm showing you here is a botanical drug that emery Pharma has been involved for many years now. We went through the conception of this drug to the current product that's in phase two clinical trial. And this single product comes from a plant in South America. But it has all these wonderful properties. A single product that works as an antimicrobial, works as an anti inflammatory, it works in wound healing and also works as a liquid bandage. As you can imagine, it's a topical product and it does it all further. The reason why FDA and other regulatory bodies even give out this guidance for developing botanical drug is that everybody is now recognizing the vast untapped potential that nature has for us. As we make more and more progress in synthetic and rationally designed drugs, we should also be considering all the natural products and the natural resources around us. Botanical drugs in essence have been used in Ayurvedic or Chinese traditional medicines for hundreds of years. And all of that we need to bring formally to the table and develop from a more scientific perspective, develop them as complete pharmaceuticals that can now go through a traditional drug discovery pipeline and can be approved by major regulatory bodies around the world. Third, exclusivity around botanical drugs is a huge point to consider if you are developing one. Because botanical drugs are complex mixtures. If you can introduce a specific extraction or perhaps an enrichment process to a naturally occurring plant material, it is extremely difficult to genericize and unlikely to be genericized using an abbreviated pathway, which means you can hold on to the exclusivity for much longer than traditional small molecule pharmaceuticals. And finally, the fact that botanical drugs have been used across the globe in various different cultures for hundreds of years. In most cases, there is a vast established safety profile which can also circumvent some of the most time consuming and expensive safety studies that come in a traditional pharmaceutical discovery and development pipeline. But botanical drugs do come with some challenges. There are challenges across the board and I am not going into all the regulatory or discovery based challenges. What I'm specifically pointing out are what you should consider if you are embarking on a new project around botanical drugs. The most important thing is that botanical drugs are complex mixtures and can contain innumerable thousands, even millions of compounds in a complex biological matrix, which means traditional pharmaceutical API or active pharmaceutical ingredient characterizing analytical tools and techniques may not be suitable. In our experience at Emory Pharma, what we have found is that if you can bring in tools and concepts from biologics, drug discovery pipeline, or even bioanalysis, such as high resolution mass spectrometry, tandem mass spectrometry, LC MSMS, or even 2D NMR or nuclear magnetic resonance spectroscopy, you can get a broad sense of the botanical product and can track specific components across batches of the product without explicitly identifying each individual component. The second is batch to batch variability. Now, the fact that botanical drugs come from a natural resource, you are going to be subject to natural variation in geographic or climatic conditions that you have very little oversight or control over. Which means that you would have to, from the get go, define sensitive and accurate biological assays in addition to analytical characterization to track your raw material from one batch to the other. In the FDA guidance it is not required until late in the project, but in our experience this is something you should consider from the get go. And finally, because botanical rugs are complex mixtures, they of course lack a distinct active ingredient which is the case with most small molecule pharmaceutical product, which means that it's very difficult to assign the mode of action and understand exactly the pathways it's targeting in a biological system. It is thus important that you identify at least a handful of active ingredients and understand if there are potential synergistic contributions of these active ingredients and both the analytical tools and techniques as well as the biological assays help in defining this. And finally, there are going to be challenges in formulations and testing formulations with botanical drugs because these are complex mixtures. We recommend that you work with experienced formulation scientists with broad experience in both small and large molecules, as well as use non traditional analytical techniques such as high resolution mass spectrometry and LC MSMs as well as NMR in certain cases to understand formulations, study stability as well as come up with stability indicating criteria of your final drug product. And thank you for listening. We at Emory Pharma have extensive experience with botanical drugs. Please reach out to us if you have any questions, concerns or would like to partner with us. Sam.