When Roger Pomerantz, the CEO of Cambridge, MA-based Seres Health said last week that he’s preparing to take his company public off of a promising, early study, it wasn’t just the natural next step for a biotech startup. It also marked a key transition point for an entire field of scientific research. After a lot of hype, therapeutics targeting the human microbiome—a catch-all term for the trillions of little bacteria that populate our bodies—just might be finally becoming more than cool lab experiments.
Indeed, should Seres follow through by filing papers with the Securities and Exchange Commission, and pitching itself to public investors, it will become the first company with a microbiome treatment to do so. The company is already blazing new paths in this emerging field: it’s planning a large clinical study later this year that could serve as a pivotal study, the last required before FDA approval. It’s also planning to apply for a “breakthrough” designation from the FDA, which would speed up development and regulatory review of its product, SER-109.
“I think they’re going to have a lot of attention,” says Miguel Barbosa, the head of Janssen Research & Development’s immunology research and scientific partnering strategy, of Seres as it moves forward.
Barbosa and Janssen have good reason to be interested. Janssen is a division of the big New Brunswick, NJ, healthcare conglomerate Johnson & Johnson (NYSE: JNJ) which, while not involved with Seres, has perhaps been perhaps the most aggressive pharmaceutical investor in microbiome therapeutics. J&J’s VC arm has made early bets on Cambridge-based Vedanta BioSciences, which is developing a microbiome treatment for inflammatory bowel disease, and San Bruno, CA-based Second Genome, which is exploring the role of microbes in other autoimmune diseases like ulcerative colitis. (Pfizer, too, began collaborating with Second Genome in May.) Those investments, and other academic collaborations with the Icahn School of Medicine at Mount Sinai and a few others, are all part of a broader effort by J&J to find clues to biological triggers underlying IBD.
Still, the field of microbiome therapeutics faces skepticism and logistical hurdles. And J&J is actually one of the few large pharmaceutical companies to put real dollars behind the research. The reason is that microbiome drugs represent a whole new class of potential medicines, so there are a number of unanswered questions: Will such drugs actually work? Can researchers gauge the effectiveness with biomarkers in clinical trials? Can products that essentially are live microorganisms culled from stool samples and packed into a pill be manufactured at scale? And can those bacteria be protected with intellectual property?
Even with the supposed potential of microbiome therapies, only a handful of startups are pursuing therapies: aside from Seres, Vedanta, and Second Genome, there’s Broomfield, CO-based MicroBiome Therapeutics, Paris-based Enterome Biosciences, which is developing a microbiome diagnostic, and Chapel Hill, NC-based Symberix. (Recently-launched Synlogic borrows from both synthetic biology and microbiome research.) Only Seres and MicroBiome have completed a Phase 1 study as of yet. In Seres’ study, its drug candidate SER-109, a pill made from a mix of bacterial spores, was reported to effectively cure 29 of 30 patients suffering from recurring infection of the potentially deadly bacterium Clostridium difficile, or C. diff.
All of which explains why Barbosa and others are keeping a close eye on Seres. Its progress, or lack thereof, both scientifically and in attracting investors or partners, may set the tone for the promise, and future investment dollars, that flow into the field. With microbiome drug development at a key crossroads, I spoke with Barbosa about potential—and the challenges—of developing and commercializing microbiome therapy, and what it’ll likely take to get these drugs to the finish line, among other things. Here are edited excerpts from our conversation:
Xconomy: Microbiome research hasn’t really been adopted across Big Pharma as of yet. Why is Janssen pushing hard, and what is it looking for?
Miguel Barbosa: This is a rapidly emerging and expanding field of research. Our interest here is twofold: one has to do with insights into how [IBD] is triggered—we’re very interested in looking at what components of the microbiome may be playing a key role. It’s also suggested in studies, both in the respiratory field as well as the gastrointestinal field, that at that very early stage, probably within that very first 18 months of life after birth when the newborn is beginning to be populated by these microbes, that the immune system is being educated to respond to some things and to tolerate other things. We’re interested in exploring the role of that early life immune education, [which] could provide insights as to what makes certain individuals more susceptible to autoimmune diseases, and other individuals less susceptible to those diseases.
X: What are the potential advantages of microbiome-based therapies?
MB: There is a real symbiotic relationship [between the microbes and human body] that maintains the right equilibrium [in the body]. If we can reset that equilibrium [after disease throws it out of whack] and bring individuals to that healthy state, there’s possibly less risk of overshooting and causing some of the adverse effects that all drug approaches have. In many cases with drugs, we take a normal human protein and inhibit it in some way, and we may go beyond the threshold, where that inhibition itself is causing some of the adverse effects. I think modulating the microbiome properly could overcome that issue, and basically reset our healthy state without going too far.
X: Given that potential, why hasn’t there been more early-stage investment in the field from VC’s and pharmaceutical companies?
MB: It’s an emerging area. It’s an area that, while the potential is almost overwhelming, is new enough where there is no precedence. Validating the use of a live biotherapeutic as a pharmaceutical product hasn’t been done before. So from an investment perspective for a startup, it’s likely that people are waiting for the first one to cross the line before the money then becomes available. There’s probably been that “wait and see” [approach]. Although, I’d say that since we’ve made our first couple of investments in biotechs, as well as several academic collaborations, we’ve noticed a new interest in the field over the last year and a half to two years. Several venture groups are beginning to support their own microbiome projects, as highlighted with the [$10 million Series B] investment announced in Seres [in June] and several other biotechs that were able to raise Series A funding. That investment is beginning to open up. I would expect much more as the data start coming out from this first generation of organizations—if it is positive, of course.
X: Where is microbiome research at right now, and what’s the next step?
MB: Certainly over the last several years if you just look at the number of publications, the field is making a lot of progress. But most of the evidence thus far is [finding that certain bacteria are associated with health or illness rather than proving that changing the microbiome will improve health]. I think the key transition point for us as pharmaceutical organizations interested in developing novel therapies is to take it from that associative data into conducting the proper studies to show cause-effect relationships that then enable insights into mechanisms [of action]. In different areas of the field, that transition is happening. We’re seeing that early data beginning to be generated in the broader field of gastrointestinal health. In metabolic diseases, there have been studies done that show that the way food is metabolized and how the [microbes] in the gut play a role in that has some real impact in how we metabolize food, obtain calories, metabolize fat and so on. These are the two front-running fields where the cause-effect relationships are now being established. [And] in the respiratory arena, studies are showing a correlation between early age exposure to environmental factors related to the microbiome, and the potential to develop allergic diseases and more severe incidence of asthma.
X: What are some of the biggest hurdles the early innovators in this field have to overcome?
MB: Individual organizations, [like Vedanta and Seres], are probing one fundamental question: can a live biotherapeutic actually have a therapeutic effect that would match what we’d expect from a pharmaceutical product to actually treat severe diseases? And that has to do both with the mechanism underlying the effect, and understanding it. [Then there’s] the ability to scale up and produce such products—which is a higher level of complexity and stringency than the standard probiotics that are made as part of the food industry.
X: And some of the other challenges unique to the field?
MB: We’re not going to be able to apply the old mentality where we take a very complex system, and reduce everything to one simple protein. A significant amount of the benefit [from these drugs] will be from [achieving] the appropriate equilibrium of multiple strains [of bacteria] in the microbiome. So the challenge is going to be, what tools can we apply to manage that equilibrium? We’re very eager to help and to participate ourselves in developing that insight, and at the same time we’re beginning to invest in some of these tools that we can apply to precisely modulate the equilibrium that one would want to achieve in a healthy microbiome. Of course the other challenge has to do with engaging with the regulatory agencies, and discussing the most effective path forward for this class of products. That is going to be a new path that is going to have to be defined, and the first generation of products are going to have to do that.
X: What would be different about it?
MB: Some [study goals] would be the same—signs and symptoms based on the disease, and also providing some local benefit to tissue protection, or repair of the tissue, that may have been destroyed during the disease process. But the discussion is likely to be more active on gauging the mechanism by which that effect is being accomplished. Right now you deliver the drug to the patient, you measure the pharmacokinetics of the drug, you measure some biomarker readout, and you align that with the clinical signs and symptoms assigned to that drug, which are agreed to by the clinical community and regulatory agencies. The mechanism itself is going to be more complex here. How do you deliver live microbes? How do you reset the microbiome in the right equilibrium? What do those biomarkers look like? And how do you quantify those, and correlate them to the clinical benefit itself? That’s why if you look at the potential in the field, and where the investments are, those are all areas of significant investment from an intellectual perspective by key laboratories, as well as from a financial perspective on where the technology needs to be developed and where the successful technology would have that significant benefit.
X: So that means you’ll be watching Seres as it moves forward.
MB: I think they’re going to have a lot of attention. They are right there at the front, and [C. diff infection] is an indication that allows very specific readouts, specific effects, so I think they are positioned to really educate the broader field about this approach.
X: Seres is starting with C. diff, a type of bacterial diarrhea, rather than an autoimmune disease like IBD. What’s the difference, from a development perspective?
MB: I think [Seres] chose well. The mechanism [underlying C. diff] is known—it is associated with one specific bacteria. So it may be a simpler project to tackle with a clear readout. IBD is a more complex disease, so the ability to match the mechanism with a clinical benefit in a quantifiable approach is going to be more complex, and will require more investment and more time. It’s going to take a more precise and deeper clinical experiment relying on biomarkers, and ensuring the readouts match the therapeutic approach being taken.