Scrip: industry news and insights
By Kevin Grogan 05 Aug 2021
Just approved In US for chronic kidney disease in patients with type 2 diabetes, Kerendia is going to be an...
Buzz is growing over the potential of research on the microbiome to yield new therapeutics. Scrip asked pharma, academics and venture capitalists how long it might take to see results, what breakthroughs are needed and which therapeutic areas might benefit first. Vote to tell us what you think.
Research is exploding is around the microbiome, the trillions of microbes living in and on the human body, as a means to address a range of diseases. Academics are conducting early research, VCs are backing microbiome-focused start-ups and even big pharma is waking up to the potential for new therapeutics based on manipulating the microbiome.
But the reality is there is a lot to be sorted out when it comes to understanding how the microbiome works, how changes in microbiome impact disease and how therapeutics can be developed that target the microbiome – and how those can be made into commercially viable, patent-protected drugs.
Scrip asked a range of industry experts, from academics to venture capitalists to start-up executives and big pharma researchers, what they think about the status of microbiome drug development and the biggest challenges facing the field of research. The result is that while most people Scrip talked to think the microbiome presents enormous opportunity, the challenges remain daunting.
It’s happening! The increased focus on the microbiome over the past decade is already starting to result in multiple products that are under clinical development today, and could result in products on the market in the not too distant future. Several companies are undertaking clinical trials, including some in Phase II and III, to evaluate products that use a microbiome-based approach to tackle [gastrointestinal (GI)] infections with Clostridium difficile.
If one looks beyond purely therapeutics, we find DayTwo offering a personalized nutrition solution based on your gut microbiome aiming at improved glucose control. In addition, MicroBiome Therapeutics LLC completed their study aimed at diabetic dysbiosis and has stated that it’s targeting to be available in 2017. Behind these pioneers, we see a strong ecosystem of entrepreneurs pursuing a wide range of product types and unmet needs, holding a promise for many more solutions to follow.
"The microbiome field is ripe for innovative collaboration models that go beyond traditional in-licensing and investments." – Janssen's Gevers
That said, in terms of the potential to deliver products to patients, it is still a young field, and there is still much to learn about how we can harness the microbiome to inform new types of health solutions. We believe the microbiome field is ripe for innovative collaboration models that go beyond traditional in-licensing and investments. We need members of the community to work together and bring their specific expertise, be it in early-stage research, R&D, analytics or manufacturing. A robust community of microbiome innovators working together is going to be critical to effectively translate promising microbiome science into solutions that ultimately address the root cause of disease and promote health.
The human (gut) microbiome has a range of potential therapeutic applications. Live biotherapeutics, also colloquially referred to as “bugs as drugs”, as well as bacterial metabolites that mediate relevant host-microbiome interactions are among the most advanced therapies in development and may well be among the first approved microbiome therapeutics. However, in addition to the fundamental questions of efficacy and safety, a number of challenges related to manufacturing, IP, and designing a clinical and regulatory path remain to be resolved.
A different approach is to identify host or bacterial targets that mediate host-microbiome interactions and use established therapeutic modalities (e.g., small molecules) to drug them, making drug design more straightforward but requiring deeper understanding of the underlying cellular and molecular mechanisms. In addition, the microbiome can also serve as a biomarker for disease progression and drug response to inform precision medicine approaches to treating disease.
One of the biggest questions in translating human microbiome research into therapeutics is whether the observed dysbiosis causes disease or is a symptom thereof. It is one of the main reasons why the vast majority of advanced therapies in development are going after either C. difficile infection or inflammatory bowel disease (IBD): the former is a dysbiosis of the gut microbiome, and the latter is a disease of the gut with some evidence for causation. That said, intriguing associations have been shown in a wide range of diseases, including obesity, rheumatoid arthritis, (immuno-)oncology and neurological diseases like Parkinson’s, and further research into the underlying mechanisms will help improve our understanding of the role of the microbiome in these diseases.
The microbiome has rapidly emerged as one of the most interesting areas of science and therapeutic development. The good news about the microbiome is we have already seen results and know that the microbiome should be important to treat disease. This comes from the work over the past several years using microbiome transplants – better known as fecal transplants.
The challenge, however, is because of their heterogeneity and the fact that they have been shown to transmit everything from viruses to obesity to food allergies, they are not the substrate to become drugs. Companies like Seres Therapeutics Inc. and Evelo Biosciences have been leading in the charge to make microbiome therapeutics into drugs, and are lining up for important data to emerge in the next couple of years. Their focus on manufacturing issues is essential to making viable microbiome drugs – a challenge that has stymied many. Data will be emerging on infectious disease (particularly Clostridium difficile infection), ulcerative colitis, cancer and systemic immune diseases.
There are already people alive now who would be dead had they not received microbiome transplants for C. difficile. So microbiome therapies are the present, not the future. But the question is how general these therapies will be. Will they work for many diseases, as antibiotics have transformed our relationship to infections, or will they be limited to a few specific diseases? Think of the difference between snake oil as a general cure-all versus captopril isolated from snake venom as the first commercial ACE inhibitor. Will they only work for specific people, as antidepressants and anticancer agents do? And how can we separate the hype from the reality?
At UC San Diego's Center for Microbiome Innovation, we bring together clinicians, computer scientists, pharmacologists, ecologists and many other disciplines to address these hard problems. We are taking a two-pronged approach: (1) short-term targets with high promise such as using microbiomes to stratify patients for treatment, or using FDA-approved drugs to hit targets in the microbiome, and (2) developing the next generation of microbiome tools, including better technical readouts of who is in a microbiome and what they are doing, integration with immunology, physiology, nutrition and neuroscience on the host side, and an unprecedented database of microbiome and metabolome samples through American Gut, the Earth Microbiome Project, and our various government-, company-, and philanthropically-funded projects.
Most importantly, we are building a superb cohort of students and postdocs trained in this uniquely interdisciplinary view of microbiome science and poised to tackle the most challenging microbiome problems on scales from our bodies to our planet.
The microbiome is for certain both hype and happening. It will take more time to determine just what is hype and what is for real, but all indications suggest that it is more happening than hype. Remarkably, the reach of the microbiome in terms of human health clearly extends well beyond the gut.
The therapeutic benefits of microbiome-based “drugs” will come in two phases, the first based wave will be represented by improved probiotics that are GRAS [Generally Recognized As Safe] and therefore do not need FDA approval. Similarly, prebiotics are likely to have major impact in the near term so long as companies can find ways to protect inventions and make such supplements profitable. The next big push in probiotics will require advances in encapsulation technology to improve the delivery of live bacteria to their site of action.
I think the microbiome is going to be a key component of how we treat diseases in the future. I personally don’t believe it has been hyped at all. It’s the reason I left big pharma and came to lead a company that operates from the microbiome. I believe that it is a very important area.
Of course, the detail is the one that we have to work out, particularly as we develop drugs. I’m in the camp [that] there is absolutely no debate about the importance of the microbiome in human health. The question is how do you harness it to make medicines. There are many companies at the moment that are trying to understand that complexity. There are different approaches that are being used, and some of them will work, some of them will work in 10 years, some of them we hope with more focus, will work in less than 10 years.
"I personally don’t believe it has been hyped at all. It’s the reason I left big pharma and came to lead a company that operates from the microbiome." – Synlogic's Gutiérrez-Ramos
The areas that could be first, one is inflammatory diseases, another one is metabolic diseases and the third one is rare genetic disorders. These are the three. The connection between the human gut and the brain is one that is being more and more documented, but to develop drugs for the brain is complex by itself, so I don’t include them right away. Applications to cancer, adjuvant therapies might develop, but you have to be very aggressive.
One thing that is very close to our heart and why we are focusing so much [attention] is manufacturing, as you get into complex mixtures of bacteria. This is one area we have to watch for. The second thing is dose response and pharmacology. For this new class of drugs, drugs that operate from the microbiome, to be understood, to be used by physicians, to be adopted by pharma, basic pharmacology and dose responses that we are used to have to be brought to the field. This is another area where we are investing a lot of time and effort to really characterize the potency of our synthetic biotics.
It’s definitely happening. Scientists studying the gut have demonstrated that disturbance to the gut microbiome is a potential cause of disease. The research effort also appears to be showing a translational effect around the body; in other tissues, there is not only a link between an organ’s own microbiome, but also the gut microbiome and disease. The problem facing us now is how to harness the vast amount of research data into the creation of new therapies.
"The problem facing us now is how to harness the vast amount of research data into the creation of new therapies." – SkinBioTherapeutics' O'Neill
The best example currently is the use of fecal transplantation to help severe antibiotic-associated diarrhea. This has proved remarkably successful. Other therapies are starting to emerge but there is some way to go. This is partly because the microbiome is vast in terms of types of bacteria. Whilst offering a lot of promise, it will take some time to ascertain which aspects of the microbiome will be most useful and how best to harness it. Our approach at SBTX has been top use a bacterium that is already well characterized and see if it can offer similar benefits when applied to skin.
The microbiome is very real. These bacterial cells and viral and other microbial organisms are increasingly recognized for their role in normal human physiology and in disease states (dysbiosis) such as obesity, diabetes and metabolic disease. Advances in our understanding of the microbiome portend to new potential therapies for diseases characterized as autoimmune in nature as well. However, much of this experimental research is early and expected to take many years to yield clinical applications.
RedHill Biopharma takes a slightly different approach to the microbiome. Clinicians believe that bacteria play a significant role in human disease and that, in most cases, the appropriate treatment involves eradication of pathogenic bacterial infection. In rare instances, this may involve replacement of pathogenic organisms. RedHill is developing two therapeutic agents in the microbiome space, both currently in Phase III of development. Much like streptococcal infection causes pharyngitis and potentially rheumatic heart disease, and H. pylori causes peptic ulcer disease and gastric cancer, gut pathogens are putative causes of other disease that have been considered autoimmune in nature.
At Pfizer, we are tremendously excited about the promise of the human microbiome in treating disease. Given the many outstanding questions, our efforts are focused on applying our core capabilities to microbiome profiling for precision medicine, as well as to understanding the mechanisms of host-microbiome interactions to identify targets for conventional drug development. We also see the immediate potential in IBD and auto-immune diseases, but at the same time we are exploring potential applications in metabolic diseases, immuno-oncology and neurology.
The exploration of the microbiome as a therapeutic focus, like any new area, has followed the Gartner hype cycle [a way of looking at the maturity and adoption of technologies]. Over the past few years, we’ve seen enormous interest in the field, and some rather incredible claims – the peak of the cycle. But making microbiome-directed drugs will be much harder, as clinical development and therapeutic intervention in or with the microbiome is challenging.
That said, I do think we’ll see therapies developed in conditions like C. diff. in the coming years. Broader chronic diseases, like obesity, have been plagued by spurious microbiome correlations and low signal-to-noise noise, and will likely require more time for the science to mature.
In a previous article Scrip asked readers and Twitter followers to vote on whether pricing practices for rare disease products would come under more pressure and face greater scrutiny during in the next five years. The results above are from 46 respondents to that poll.
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