Seeking therapeutic opportunities amid the complexity of the microbiome

The past decade has seen considerable excitement—and inevitably, hype—around the notion of exploiting the gut microbiome for therapeutic purposes. Numerous studies have now shown that the commensal microbial species that dwell in our gut communicate closely and constantly with their hosts, and that these exchanges can directly influence human health not just within the digestive tract, but throughout the body. However, the evidence suggests the honeymoon may now be over.

Some once-promising startups have gone under in the past year, including Flagship Pioneering spin-out Kaleido Biosciences, which folded in April, and 4D Pharma, which declared bankruptcy in late June. Other companies have continued to push forward despite setbacks. For example, both Vedanta Biosciences and Finch Therapeutics have announced sizable layoffs over the past few months; for Finch, these cutbacks followed the early termination of a years-long partnership with Takeda. Chris Howerton, a biotech analyst covering the microbiome sector for Jefferies, believes that many pharma companies are now thinking twice about making strong investments in this area. “I would say that enthusiasm is generally low in the space right now,” he said.

But the news isn’t all bad, and Vedanta CEO and co-founder Bernat Olle sees a lot of important progress. “It’s a ‘tale of two cities’—what the science has done, versus what the investment community has done,” said Olle. “And I think that depending on the modality, you’re starting to see more people getting into this stage of progressively building on knowledge so that the modalities become less and less risky.”

Indeed, 2022 could see the first regulatory approval of a microbiome-based therapy. In late September, an advisory committee of the US Food and Drug Administration (FDA) voted in favor of approving Ferring Pharmaceutical’s Rebyota, a fecal microbiome transplantation (FMT)-based treatment for recurrent infection with the gastrointestinal pathogen Clostridium difficile. And although investment activity has slowed down, some big deals are still going through. For example, Nestlé Health Science remains heavily engaged in this space, allocating $40 million to a collaboration with Enterome in July, following on from a deal with Seres Therapeutics a year earlier that could net the latter company up to $525 million (Table 1). And in March, Microbiotica closed out a round of Series B fundraising with $67 million in investment.

Homing in on a clearly defined target

As Olle notes, the magnitude of the field’s progress varies considerably depending on both the clinical indication and the microbiome-based modality being used to address that condition. The industry’s most advanced programs at present are those targeting C. difficile, a bacterium that can opportunistically infect the gut in the aftermath of heavy antibiotic use. Such infections initially cause gastrointestinal distress, but can eventually give rise to severe outcomes such as organ failure or sepsis. C. difficile has been shown to recur following initial treatment in one in six patients, and FMT—in which the full cohort of gut flora from a healthy donor is relayed to a sick recipient—has a well-established track record for preventing such recurrence. Ferring’s Rebyota is essentially a standardized, quality-controlled approach to FMT, and Finch is now in the midst of a pivotal trial for its own donor-derived FMT approach for recurrent C. difficile infection.

But the FMT approach is also something of a blunt instrument and potentially challenging to scale, and many companies are focused on homing in on specific subsets of gut microbes that are differentially represented in health versus disease. The identification and optimization of such rationally designed microbial consortia requires considerably more effort, and most clinical progress with this approach to date has occurred with the same indications that benefit from FMT.

Following the successful completion of a phase 3 trial in late May, Seres has now filed with the FDA for approval of its SER-109 microbial formulation as a treatment for recurrent C. difficile infection. This is also Vedanta’s flagship indication. Funding from the US Biomedical Advanced Research and Development Authority (BARDA) and the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) helped the company to move its VE303 formulation, which consists of a defined mix of eight hand-picked microbial species, up to and through a successful phase 2 trial. And in July 2021, Vedanta pulled in $68 million in Series D funding, which will support the launch of a phase 3 trial for VE303 in 2023.

Moving to tougher terrain

By comparison, progress in other indications is lagging, and Howerton questions the level of enthusiasm beyond the tried-and-true realm of C. difficile therapeutics. “Investors are saying ‘Show me the data,’ he said, “and it just hasn’t really panned out.” Some of the most aggressive research activity has been in the area of inflammatory bowel disease (IBD), a condition that is well known to be exacerbated—and may even be triggered—by perturbations in the gut microbial ecosystem. But microbiome companies are still waiting for a home run in this space. Following an unsuccessful phase 2 trial for ulcerative colitis, Seres suspended its plans for another phase 1b trial for the same indication, and it is currently unclear how the company plans to proceed. Takeda’s now-terminated partnership with Finch was also focused on drug development for IBD.

Several other IBD programs are picking up momentum, however. For example, Vedanta showed that its VE202 formulation could safely establish itself in the gut microbiome of healthy volunteers in a phase 1b study last year. The company’s Series D windfall from last summer included a $25 million investment from Pfizer, which is specifically interested in moving VE202 into efficacy trials (Table 2). “The program is ready to start phase 2,” said Olle. “And we saw some pharmacology in the healthy volunteers […] that suggests that the drug works by the mechanisms we intended it to, like the production of certain microbial metabolites that are known to be anti-inflammatory.” In addition, UK-based Microbiotica’s machine-learning-assisted platform for the rational design of microbial consortia has produced a candidate therapy for IBD that is now moving into phase 1 trials, powered by funding from the company’s recent Series B round as well as a years-old partnership with Genentech.

But for indications that entail microbial influence beyond the immediate confines of the gastrointestinal tract, the data are considerably thinner. “There’s less clinical experience with fecal transplantation [for these indications],” said Olle. Immuno-oncology is one indication that initially garnered considerable excitement, predicated on the notion that the interaction between a healthy microbiome and the host immune system might positively impact the way patients respond to checkpoint inhibitor drugs that stimulate anti-tumor immunity. For now, the field is still waiting on evidence of utility—in 2021, Vedanta announced that a phase 1 trial conducted in collaboration with Bristol Myers Squibb (BMS) had yielded disappointing results in terms of indicators of likely efficacy. The company is now looking into whether it might be possible to identify subgroups of patients who are more likely to benefit from this combination therapy.

Other trials are now underway in the immuno-oncology space that might shed further light on the utility of coupling checkpoint inhibitors with microbial therapeutics. For example, Korea-based Genome & Company is working with Pfizer and Merck on a pair of phase 2 trials to assess whether individual, hand-picked strains of gut microbes might enhance the performance of those two companies’ immunotherapeutics against certain solid tumors.

More generally, drug development based on defined species and strains poses a number of unique and daunting challenges. Even after a promising cohort of microbes has been identified, companies must figure out how to combine them at a ratio and dose that will effectively establish them in the recipient’s gut and produce the desired effect. Getting to this stage also requires the microbiology acumen to cultivate these organisms, which entails careful characterization in order to identify the right growth and preparation conditions. “You have to have different cell banks, different fermentation trains, different lyophilization conditions, and each bacteria likes different things,” said Olle.

Accordingly, many companies working in this area have made been making deals to establish the necessary specialized manufacturing capacity. For example, Seres has forged a collaboration with Bacthera, a Switzerland-based contract development and manufacturing organization (CDMO), to produce its SER-109 product, which is now nearing regulatory approval. In France, MaaT Pharma is working with another CDMO, Skyepharma, to establish what will be the country’s first dedicated microbiome-therapeutic manufacturing facility, and Genome & Company purchased American CDMO List Labs outright for $27 million in September 2021 to build out its production capabilities in the US.

Alternative approaches to microbiome therapeutics

But microbiome-derived drugs do not necessarily need to make use of the gut microbes themselves, and there is also enthusiasm around the idea of identifying microbe-derived small-molecule or biologic compounds that might be converted into treatments via more conventional drug development methods. Enterome is one of the pioneers for this approach to microbiome drug discovery, and the company has clinical trials now underway in collaboration with Takeda and BMS for Crohn’s disease and combination therapy with cancer immunotherapy, respectively. In September, the company reported efficacy data from its immunotherapy trials, with a five-fold improvement in response rate for glioblastoma patients who received their microbiome-derived EO2401 therapeutic in conjunction with checkpoint inhibitor therapy; they also described promising results from a second study, focused on adrenal tumors.

Second Genome is another leading company in the microbiome-derived biomolecule space. At the Digestive Disease Week meeting in May 2022, the company shared preclinical results from its lead compound for IBD, which was developed as part of an ongoing strategic collaboration with Gilead Sciences—a deal forged in 2020 that could ultimately be worth up to $1.5 billion if all program milestones are met.

As a further alternative, there are a handful of companies that are exploring approaches grounded in synthetic biology as a means for introducing new strains with specifically engineered functional properties into the gut microbiome. Howerton sees a lot of enthusiasm around Synlogic, a company that has been working closely with genetic-engineering specialists at Ginkgo Bioworks to produce modified strains of Escherichia coli that express enzymes that can remedy various metabolic disorders. The company’s lead program, which employs bacteria to break down the excessive quantities of the amino acid phenylalanine that arise in patients with the genetic disorder phenylketonuria, is slated to begin pivotal testing in the coming year on the strength of promising efficacy from its SynPheny-1 phase 2 trial. Synlogic also has a number of early clinical stage and preclinical programs in the works, including a year-old partnership with Roche for IBD that recently yielded its first milestone payment.

There are some potential limitations to this approach. Howerton noted that although the E. coli bacterium being used in this work is a well-known ‘chassis’ organism that is easy to engineer, it also produces cell-surface markers that can potentially induce inflammation. “That necessarily causes tolerability issues,” he said, although he also added that the company has put considerable effort into managing this issue and optimizing dosing strategies. And importantly, these microbes never establish formal residency in the gut—instead, they are dosed regularly like a probiotic, and get flushed out of the system after exerting their therapeutic effect.

Novome Biotechnologies is pursuing a different angle, with therapies that are delivered by engineered versions of native gut bacteria. “We basically have a suite of tools for programming the genus Bacteroides, which makes up about 50% of the microbes in the average human gut,” said Will DeLoache, Novome’s CSO and co-founder. “We can pick whatever strain we want within that genus.” Unlike Synlogic’s microbes, these bacteria will integrate themselves into the host microbiome, but with an important additional ‘control knob’—the cells are engineered to depend on an unusual, seaweed-derived polysaccharide for nutrition. As long as patients dose themselves with this molecule, the therapeutic microbes can flourish; without it, they will perish and wash out, providing a way to manage adverse effects and minimize the risk of engineered organisms entering the outside environment.

As of mid-September, Novome had raised $43.5 million in Series B funding to support an ongoing phase 2 trial for NOV-001, a treatment for enteric hyperoxaluria—a metabolic disorder that can lead to severe kidney damage or even organ failure. The company also has an ongoing collaboration with Genentech for the development of new IBD therapies, although this research program is still in the early discovery stage.

DeLoache acknowledges that the field has gone through tough times, but still sees exciting opportunities for growth and progress. “There’s been pullback on the market side, which has created headwinds,” he said. “But I would say we’re in a reasonably good place in terms of support for the modalities that I think have the most promise.” Olle expressed similar sentiments, emphasizing that microbiome research is still a nascent field grappling with a staggeringly complex biological system. “There are things that you can break into pieces to make progress, and that’s what we’ve tried to do,” he said. “But at the end of the day, nothing in the field is simple.”