Microbiome Drug Development: An Investigation Into Challenges And Innovative Pipeline Approaches
Executive Summary
The discovery and deep investigation of the microbiome has been one of the most cutting-edge advances in biomedical research of recent times, but as the science moves forward new hurdles are emerging for microbiome therapies.
-
Research is now very much focused upon investigating how exactly the microbiome's interactions within the body contribute to health and disease.
-
As a deeper understanding of these interactions is gained, the floodgates have opened for drug development companies to investigate the potential of microbiome therapies for the treatment of disease.
-
So what? With the microbiome being a new area of research, it brings new challenges. Specifically, development of technology to allow for effective delivery of these new therapeutics to the microbiome is an obstacle R&D teams must face.
Every human being hosts between 10 trillion and 100 trillion symbiotic micro-organisms, including bacteria, viruses and archaea. The collective genomes of these micro-organisms form what is known as the human microbiome. As research reveals more about the microbiome, the pharmaceutical industry can better understand how it may interact with different types of drug in the body, which in turn may affect the way the sector goes about developing drugs in the future.
The Microbiome In Health And Disease
In medicine, microorganisms have traditionally been considered in two categories: pathogens that cause disease; or commensal organisms that reside within the gastrointestinal tract of host individuals with no effect. However, within the last decade, an abundance of research has demonstrated that these organisms do interact with the host’s physiological functions in multiple ways which may determine an individual’s health or disease state.
The human microbiome is the aggregate of the genomes of all microbes that reside on or within the body. The microbiota population can become imbalanced because of dysbiosis, when there are more ‘bad’ pathogenic bacteria present than ‘good’ bacteria. Evidence suggests that the microbiome contributes to an individual’s metabolic functions, provides protection against pathogens, interacts with immune system development, and can affect behavior through the gut-brain axis.
The gut microbiome has been a major focus of microbiome research. As noted in a 2013 paper in Clinical Chemistry, beneficial microbiota colonies within the gut help with the break-down of indigestible dietary fibers, and metabolize food to supply essential vitamins, nutrients and amino acids. Gut microbiota influences the way in which calories are extracted and stored from food, and in turn, our diet choices impact on the consortia of microbes that reside in the gut. Thus, the microbiome has the ability to influence metabolic disease states such as obesity and diabetes, as the microbiota consortia in obese and diabetic people differs to those observed in healthy individuals. Gut microbiota also act as an ally to the innate immune system and play an important role in regulating immune response. Dysbiosis of the gut microbiome is associated with autoimmune and inflammatory disorders, such as Crohn’s disease and ulcerative colitis (UC), as it can lead to misdirected autoimmune responses. But, microbiome research is not solely focused upon the gut. The authors of a 2012 Nature review highlighted that microbiota also inhabited and had an impact upon a vast number of other human tissues, including the skin, oral cavity, esophagus, oropharynx, vagina, uterus, and ovaries. Due to their presence all over the body, imbalances in the microbiota could cause a range of illnesses, offering immense potential for microbiome therapeutics.
Within the area of microbiome therapeutic development, the aim is to leverage the microbiome and its interactivity with an individual’s physiological processes to produce a therapeutic effect. Due to the vast amount of targets and physiological mechanisms associated with the microbiome, there is an abundance of drug mechanisms that can be classified as microbiome therapeutics. As summarized in the Mimmee et al. 2016 review in the journal Advanced Drug Delivery, microbiome therapeutics can be categorized as additive, subtractive, or modulatory.
Additive therapies are those in which a natural or engineered beneficial bacteria strains are introduced into a diseased individual to promote growth of a healthy bacterial consortia. An example of a natural additive therapy is fecal transplantation, which is the process of introducing fecal matter from a healthy donor into a diseased individual. The aim of this being to introduce healthy gut bacteria consortia to remedy the dysbiosis of the microbiome causing ill health in the recipient. Beneficial microbiota strains are being engineered for transplantation to achieve the same effect, but avoid some of the challenges of fecal transplantation (discussed in depth below). Subtractive therapies aim to eliminate unhealthy microorganisms that play a role in disease pathogenesis. Routinely, antibiotics have been used to rid the body of pathogenic bacteria, but antibiotic resistance is becoming one of the largest threats to global health. Antibiotics are not targeted to bad bacteria and they also kill good bacteria, which results in microbiome dysbiosis. The goal of subtractive microbiome therapies is to be targeted while preserving the microbiome consortia. Modulatory therapy involves administration of non-living agents, such as small molecule drugs or prebiotics, which positively influence changes in the composition of microbiota consortia that make up the microbiome.
The Novel Therapeutic Development Landscape
Informa Pharma Intelligence’s Pharmaprojects database has tracked trends in drug development each year from 1980 until present. These data reveal a boom in the development of novel microbiome modulator candidates over the past seven years (see exhibit 1). Industrial interest began in 2011, with two microbiome modulators in active development at that time. As of July 2018, the number of these drugs in development stands at 76. The sudden spark in industrial interest is recent, as seen by the 162% increase in the number of microbiome modulators being developed over the past two years.
The development of microbiome modulators is primarily at the early stages, with most candidates in preclinical development and fewer reaching clinical trials. The number of preclinical candidates has more than doubled in the past two years. Moreover, the number of candidates in the clinic has also increased, and there are currently more drugs at Phase III status than there ever has been before (see Exhibit 2). At this point in time, there are no drugs approved for use as human therapeutics, and therefore, the market is wide open in this space.
A total of forty-eight companies are involved in microbiome research. Exhibit 3 shows that Seres Therapeutics Inc. is the leader in microbiome R&D, with 10 candidates in active development. This landscape is dominated by small to mid-size pharma companies, with only four big pharma companies (Allergan PLC, Johnson & Johnson, Takeda Pharmaceutical Co. Ltd., and Bristol-Myers Squibb Co.) included in the top 20 microbiome developers.
Microbiome modulator drugs are being investigated in a broad range of therapeutic areas. Exhibit 4 presents the percentages of drugs in development for diseases for each therapeutic area (TA). Presently, the largest focus area of drug development is for gastrointestinal (GI) disorders. Infectious disease is another big area of development, with a major focus on therapeutics for Clostridium difficile (C.difficile) gut infections. Other TAs under development include metabolic disorders, dermatology, oncology, and neurological disorders.
Microbiome therapeutics have great potential in treating an abundance of diseases, and pharmaceutical companies have obviously recognized this, considering the wide range of therapeutic areas in the current development landscape. This is a new area of development, and traditionally, drugs have been developed to target an individual’s native physiological systems, rather than the microbial consortium interacting with these systems. As demonstrated in Exhibit 5, the clear majority of microbiome therapeutics are being formulated to be delivered orally. This is reflective of the fact that the most common therapeutic areas being investigated are localized to the gut or aim to treat metabolic disorders affected by digestion, such as obesity or diabetes.
It is important to assess the approaches to formulating and designing the delivery technology for additive, subtractive and modulatory microbiome therapeutics to treat disease. Moreover, considering increasing evidence that the microbiome plays a huge role in our metabolism and our health states, we must consider how drugs that interact with the microbiome have physiological side effects and whether bioavailability is affected by microbe metabolism. In Vivo has investigated the main challenges in developing orally delivered drugs for GI disorders, and highlighted innovative drugs in the pipeline targeting the microbiome.
Subtractive Therapies: Eliminating Pathogenic Bacteria While Preserving The Microbiome
The misuse of antibiotics has led to the growth of antibiotic resistance, which is described by the World Health Organization as one of the biggest threats to global health and development today. The standard antibiotics we use today, kill off the beneficial bacteria residing in our bodies as well as the pathogenic target, which leads to dysbiosis of the microbiome. This creates an environment in which pathogenic drug-resistant bacteria can thrive as competition by other bacterial consortia is depleted. Moreover, an abundance of literature suggests that there is an association between the infant exposure to antibiotics and the development of inflammatory bowel disorders (IBD) such as Crohn’s disease, due to dysbiosis and subsequent inflammation and autoimmune responses. Therefore, it is vital that preservation of the microbiome is considered when developing new targeted antibiotic drugs for infectious disease.
C. difficile is a common environmental bacterium, which most often resides in the bowel of both children and adults without causing any issues. However, in some cases it can act as an opportunistic pathogen and cause illness, ranging from mild diarrhea to more serious conditions such as pseudomembranous colitis, sepsis, and even death. C. difficile infection is commonly seen after broad-spectrum antibiotics have been taken for an unrelated issue, as the antibiotics remove both the protective resident bacteria as well as the pathogen targets, which allows for opportunistic infection and can cause so called antibiotic-associated diarrhea. Ironically, administration of alternative antibiotics is the standard treatment for C. difficile infection. But, various reviews available describe how the incidence of C. difficile is increasing due to the widespread use of antibiotics, and emergence of antibiotic resistant strains. Development of targeted subtractive therapies is therefore of utmost importance to stop the growth and spread of C. difficile superbugs.
Ridinilazole (SMT19969) is a great example of a novel subtractive antibiotic therapy, with targeted delivery to pathogenic bacteria in the gut. It is a narrow-spectrum, non-absorbable iminosugar antibiotic under development for the treatment of C. difficile infection by Summit Pharmaceuticals International Corp. The exact mechanism of action of this drug is unclear, but a study published in the Journal of Antimicrobial Chemotherapy in 2016 demonstrates that when ridinilazole is administered orally, it specifically targets C. difficile and significantly hinders the bacteria’s ability to produce toxin A and B, which cause symptomatic inflammation of the gut. Preclinical study results show that this drug has minimal impact on the gut microbiome, and Phase I and II clinical studies have demonstrated that it is well tolerated by patients, and superior to vancomycin in reducing recurrent disease. Currently it is in Phase II, but Phase III trials are planned to be initiated within the first quarter of 2019.
Delivering Additive Microbial Therapies To The Microbiome Safely At Effective Doses
As understanding about the protective ability of the microbiome has increased, development efforts have been driven towards identifying ways in which we can change the composition of the microbiome for therapeutic effect. Fecal microbiota transplantation (FMT) is a procedure which involves delivering a solution composed of the feces from a healthy donor into a diseased individual. Due to the nature of this procedure, it can be viewed as very undesirable by patients and there are worries about the transfer of pathogenic or ‘bad’ bacteria from donors. Complications associated with the delivery of FMT is another concern.
According to Citeline’s Trialtrove, as of August 2018, 93 trials investigating FMT treatment for a range of disorders have been completed. Half of these trials investigated the safety and efficacy of its use for the treatment of C. difficile infection. Due to the majority of evidence reporting efficacy for C. difficile, most experience of using FMT in medical practice is for patients with this indication. Other indications investigated in multiple trials include inflammatory bowel disorders (ulcerative colitis and Crohn’s disease) and irritable bowel syndrome. According to limited long-term, follow up-studies, FMT is relatively free of severe side effects, but short term gastrointestinal symptoms have been reported such as; nausea, vomiting, diarrhea, and abdominal cramps. There have also been reports of transfer of norovirus and E.coli infection from donor to recipient. FMT must be delivered directly to the GI tract while a patient is sedated, most often through the anus in an endoscopic procedure, or via nasoduodenal tube in some cases. Complications associated with delivery procedures include bowel perforation, bleeding and risk of infection, fecal regurgitation, upper gastrointestinal tract bleeding, peritonitis, and enteritis.
Moreover, as this is relatively new procedure to be used in clinics, there is a lack of knowledge on the potential long-term effects of FMT. Infectious disease transfer, such as HIV, hepatitis A, B and C, and syphilis, is a worry. Furthermore, transfer of bad bacteria which may play a role in contributing to non-communicable disease risk, such as cancers, inflammatory bowel disorders, and metabolic conditions must be seriously considered. Therefore, donors must be thoroughly screened before procedure to ensure safety. The process of identifying donors and screening them for safety is therefore laborious in the lead up to the procedure.
Although, the use of FMT for C. difficile treatment has increasingly been accepted by clinicians and patients as a natural therapy, there are many research groups looking into creating innovative synthetic versions of this additive therapy to avoid the potential risks discussed. For example, Seres Therapeutics are developing ‘Ecobiotic’ drugs for a range of indications. The company has built a proprietary library of thousands of microbial strains derived from human donors. Their research involves identifying the key microbial strains that are lacking or in abundance in microbiome dysbiosis states, to characterize the microbiota that need to be re-introduced into an unhealthy person in multiple disease states to achieve therapeutic effect. The ‘Ecobiotics’ are assembled combinations of specially selected key microbiota from their proprietary library that demonstrate beneficial properties. They are purified to improve their safety and eliminate risk of contamination. These drugs are being developed with both the natural biologically sourced microbiota, as well synthetically fermented bacterial species cultured in vitro. As they are compacted into a capsule form, they can be easily swallowed by patients, and no invasive procedures are necessary.
Developing Targeted Drugs To Positively Influence Microbiome Composition
While additive and subtractive therapies aim to directly alter the microbiome by introducing or eliminating certain bacteria, modulatory therapy involves indirectly influencing the composition of the microbiome to create an environment that promotes beneficial bacteria growth. Most commonly, probiotics and prebiotics used in conjunction to promote healthy bacteria growth in the gut. Probiotics are mixtures of live bacteria and yeasts with health benefits, which are added into various dairy products and fermented foods (e.g. yoghurt, kefir, kombucha, kimchi, sauerkraut etc.) or taken as supplements. Prebiotics are non-digestible dietary fibers which stimulate the growth and activities of beneficial gut microbiota. The most commonly consumed prebiotics include galacto-oligosaccharides and fructo-oligosaccharides, which are present in a variety of foods, including asparagus, leeks and onions. Many people struggle to consume enough probiotics and prebiotics through diet alone.
There is plenty of evidence suggesting that the metabolism of marketed drugs already available to patients is influenced by the microbiome
Probiotic and prebiotic supplements are widely available over the counter to help people to increase their uptake, but due to the fact they have never been tested in clinical trials, there is no way to assess the quality or efficacy of many brands. So, many important factors are not fully understood including; the exact dose of probiotic or prebiotics required to promote a healthy microbiome, how well they target the gut, and the shelf life of these supplements. Therefore, there may be an inadequate concentration of the biologically active substances in traditional probiotics and prebiotic supplements currently available. Moreover, despite a safe history of use, introducing a mix of live probiotics to the body may have negative effects in immuno-compromised or genetically vulnerable people. Every individual has a unique microbiome, which also differs depending on disease state, therefore these supplements may not necessarily be beneficial for everyone. Developing drugs which beneficially alter the microbiome composition, may have multiple advantages over the traditional supplements including; accurate delivery to targets in the gut, precision dosing, improved safety profile, and longer shelf-life. Moreover, there is the potential for them to be tailored for specific diseases.
Ritter Pharmaceuticals Inc.’s RP-G28, is an innovative example of a targeted prebiotic drug which is currently in Phase III clinical development for lactose intolerance. It is a novel galacto-oligosaccharide, formulated in a gel capsule, and it works to stimulate colonic bacterial adaptation which alters the population of anaerobic and microaerophilic bacteria. This increases intraluminal beta-galactosidase activity, which enhances digestion and reduces the production of fermentation product which has been demonstrated to significantly improve lactose digestion in lactose intolerant patients. Clinical trials have demonstrated that this drug improved overall tolerance to dairy products and reduced abdominal pain in patients.
Another interesting example is Xeno Biosciences’ XEN-101, which is not technically a prebiotic, but works to create a beneficial environment to promote a healthy microbiome. It is an orally delivered small molecule microbiome modulator specifically targeted to treat obesity by delivering oxygen to the lower GI tract, to mimic the beneficial microbiome composition change observed when a patient undergoes gastric bypass surgery. Anatomical changes caused by gastric bypass allows more swallowed air to pass to the gut, which leads to increased growth of aerobic bacteria which help with metabolism of food and increased weight loss in obese patients. This pill aims to create this environment in the gut, without need for surgery.
Considering The Impact Of Microbial Metabolism On Pharmacokinetics
It is vital that the microbiome is considered when developing oral drugs, not just because it is an important target for cutting-edge drug development, but also because research suggests that it may influence the way our body metabolizes drugs. When developing drugs and delivery systems for them it is important to consider how the drug will be metabolized in the body, to ensure that a safe and effective dose is absorbed into the blood stream. There is plenty of evidence suggesting that metabolism of marketed drugs already available to patients is influenced by the microbiome. A review published in 2016 in the Yale Journal of Biology and Medicine, provides multiple examples of where the microbiome influences the activation or inactivation, toxicity, bioavailability and uptake of drugs which have been widely used for many years including the following:
-
Lovastatin is directly activated in the gut by the microbiota
-
Uptake and bioavailability of simvastatin is influenced by the microbiota or by co-administration with probiotics
-
Microbial beta-glucuronidase activity in the gut elevates the toxicity of irinocetan
-
Paracetamol detoxification in the liver is inhibited by the gut microbial metabolite p-Cresol
-
Digoxin is inactivated in the gut by the enzymatic activity of particular strains of Eggerthella lenta which resides in the gut
The above examples provide just a snapshot of the many drugs that are impacted by the microbiota, and with emerging research in this area the more we will understand about the exact mechanisms that allow the microbiota to influence drug pharmacokinetics. The microbiome differs massively from person-to-person, so pharmacokinetics may potentially vary depending on the individual. Modern drugs with improved delivery systems, such as sustained-release or enteric coatings, tend to reside in the gut for longer, so they have prolonged exposure to the gut microbiota. Therefore, in the development of new drugs and delivery systems, an increased focus on the impact of the microbiome during preclinical and early clinical studies may be of great importance to ensure efficacy and tolerability of drugs is improved.
In Summary
As a result of groundbreaking advances in microbiome research, industrial interest in this area has boomed. In the current drug development landscape, most therapies under investigation are orally delivered and targeted to the gut microbiome for treating gastrointestinal disorders. These therapies can generally be categorized as additive, subtractive or modulatory. There are a wide range of challenges in targeting the gut microbiome through each of these approaches and there are many disadvantages to established therapies such as antibiotics, fecal microbiota transplantation, and prebiotic or probiotic supplements. There are many examples of ground-breaking novel drugs that overcome the challenges discussed including; subtractive targeted antibiotics, engineered additive ‘Ecobiotics’, and modulatory pharmacotherapy. Moreover, it is vitally important that the gut microbiome is considered in the development of new drugs and delivery technologies due to its ability to influence pharmacokinetics.