In the last decade, the idea of tapping into the gut has attracted much interest from investors and the public, but recent years have showed that a lot more work needs to be done before such treatments enter the mainstream.  

This is largely due to the FDA’s rigorous approach to the safety of microbiome therapeutics, which has manifested in clinical holds, resulting in delays that have dimmed the enthusiasm in the space in recent times.

Finch Therapeutics’s Phase III PRISM4 trial for recurrent Clostridioides difficile infection (CDI) and plans for MaaT Pharma’s Phase III trial in steroid-resistant acute graft-versus-host disease were both put on hold. While the French MaaT Pharma has submitted further information to the FDA, its IND application for the US-based trial remains on hold. In January 2023, Finch announced plans to scrap the PRISM4 trial altogether.

The idea behind these treatments relies on altering the gut microbiome by designing therapeutics that contain bacteria derived from donated stool samples. In November 2022, Ferring Pharmaceuticals’s Rebyota became the first FDA-approved microbiome-based therapeutic to treat recurrent CDI. But the approval came through after an FDA Advisory Committee meeting.

Moreover, the Covid-19 pandemic put a spotlight on microbiome-based therapeutics due to the potential transmission risks in this class.

“This whole field has been set back a little bit by the pandemic. We lost three years,” says Dr. Susy Hota, infectious disease specialist at University Health Network, University of Toronto.

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Coupled with this, the harsh conditions of the biotech market affected some companies. On February 16, the microbiome therapeutics-focused biotech 4D Pharma was pulled from the London Stock Exchange after falling into administration in June 2022. When Finch decided to end the PRISM4 program, it announced plans to reduce its workforce by 95%. Back in April 2022, the microbiome-focused biotech Kaleido Therapeutics folded due to financial and regulatory setbacks.

Although there was a lot of hype surrounding the microbiome about five years ago, it is a question if this is still the case, says Hota. Also, microbiome therapies need to work in other indications for continued interest. “If recurrent CDI is the main indication, it is not an extremely attractive area to a lot of people,” says Hota.

Regulatory concerns remain

Overall, microbiome research has not advanced as much as expected, which is partly due to safety issues, says Hota. Though the pandemic disrupted research in general, it was particularly difficult to conduct research that relied on stool samples, adds Hota.

Such caveats centre around the risk of infection caused by different diseases such as Covid-19 and mpox. In March 2020, the FDA shared a safety alert on the use of faecal microbiota transplants (FMTs) due to Covid-19, which added questions identifying those infected with Covid-19 to donor screening protocols.

More than two years later, the FDA shared a similar alert that requested additional protections on the use of FMTs due to the mpox virus.

These safety concerns froze research, says Dr. Sarah McGill, associate professor of medicine at the University of North Carolina School of Medicine, Chapel Hill. “It will take some time for research to thaw,” she adds.

McGill says she does not know of a single confirmed case of Covid-19 transmission through FMTs. The best approach here would be to screen every sample, but that raises questions on the sustainability of such protocols, Hota notes.

Wild west of development

Currently, the sector is in its “wild west stage,” says Jack Gilbert, PhD, professor in paediatrics and the Scripps Institution of Oceanography, University of California San Diego. Although research here is about 20 years old, it remains new compared to other areas like genomics, says Gilbert.

To an extent, the use of FMT in CDI paved the way for microbiome therapies, says Dr. Neilanjan Nandi, associate professor of clinical medicine at the University of Pennsylvania, Philadelphia. While Rebyota was the first to be approved, more could be coming up soon, says Gilbert.

Rebyota is a faecal microbiota-based treatment for patients with recurrent CDI that is administered through an enema. In the Phase III PUNCH CD3 trial, Rebyota was superior to placebo in the reduction of CDI recurrence, with a 70.6% treatment success rate after eight weeks compared to 57.5% with placebo.

Seres Therapeutics’s SER-109 is under Priority Review and the FDA has set a PDUFA date of April 26, 2023, for its use as a treatment for recurrent CDI. Unlike Rebyota, SER-109 comes in capsule form and is taken over the course of three days.

Elsewhere, Vedanta Biosciences aims to bring its oral CDI treatment VE303 into a Phase III trial this year. Vedanta is a subsidiary of Puretech Health. Destiny Pharma’s CDI treatment NTCD-M3 is expected to enter a Phase III next year. Unlike Rebyota and SER-109, Vedanta’s treatment is based on clonal bacteria strains and does not use donated stool samples.

CDI should be seen as only the beginning, says Nandi, adding that inflammatory bowel disease (IBD) is also an interesting avenue.

However, the results here are quite mixed, say Hota and McGill. For instance, Seres’s Phase IIb study of SER-287 to treat ulcerative colitis did not meet its primary endpoint of clinical remission compared to placebo. Both SER-109 and SER-287 are made from a purified consortium of Firmicutes spores derived from stool samples. According to the company’s website, the biotech is undertaking research to decide on the future of the ulcerative colitis program, which also includes another candidate called SER-301.

Last year, Takeda Pharmaceutical ended its deal with Finch in August after a review of its pipeline. Previously, Takeda had licensed the two Finch treatments FIN-524 and FIN-525 for their development in IBD. Still, other companies are keen on exploring IBD further, such as the UK-based company Microbiotica. The start-up expects to start its Phase Ib in ulcerative colitis this year, and focuses on the development of orally administered live therapeutics that are derived from bacterial consortia.  

The potential use of microbiome therapeutics in cancer comes with its own set of questions. While humans normally encounter microorganisms in their day-to-day activities, their functioning immune systems can handle those, says Hota. But since the immunity of cancer patients is suppressed by treatments like chemotherapy, the risks here are much greater, she explains.

Microbiome therapeutics here could be used as adjunct treatments, rather than primary therapies, says Dr. Louis Korman, co-director of Chevy Chase Clinical Research, Chevy Chase, Maryland. A lot of immunotherapies cause side effects in the gastrointestinal tract, says Korman. With that in mind, therapeutics could be used to reduce toxicity, he explains.

Although enthusiasm for microbiome therapeutics is broadly quite high, it is slightly waning at expert meetings, says McGill. There is some confusion from the side of the investors due to the field’s broad nature, says Gilbert. This is further emphasised by the current state of the biotech market , he adds.

But this could change with the first approvals, notes McGill. In a way, the accessibility could increase enthusiasm and interest, she adds.

Update: This article has been updated with additional context on Maat Pharma's MaaT013 clinical program, which includes Phase III trials in US and Europe. Paragraph 3 and the table titled "Investigational microbiome therapies lag in other indications behind CDI" have been updated accordingly.