A microbiome therapeutic is closer than ever to market authorization in the US. What does it mean for the industry?

Ferring's RBX2660 received a positive FDA advisory committee vote on September 22nd, making it the most advanced microbiome-based therapy to date

Ferring Pharmaceuticals, Inc. has edged ahead in the race to bring the first microbiome-based drug to market in the United States, with its product REBYOTA receiving the thumbs up from the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) in a meeting on September 22nd. REBYOTA, dubbed a “standardized, stabilized” version of fecal microbiota transplantation (FMT), targets recurrent Clostridioides difficile infection (CDI) in adults following antibiotic treatment.

Ferring’s clinical stage biotechnology company Rebiotix submitted a biologics license application (BLA) for REBYOTA late last year. With the BLA still under review by the FDA at present, the VRBPAC held a meeting to discuss the evidence for both safety and efficacy of the drug candidate. During the eight-and-a-half-hour live-streamed meeting, the 17 committee members reviewed the clinical development program for RBX2660, which included data from six studies conducted in US and Canada: three Phase 2 studies, two Phase 3 studies, and one retrospective study. In total, 978 subjects were exposed to one or more doses of REBYOTA across the studies.

FDA advisory committee members expressed opinions that, in the strictest sense, the FDA criteria for efficacy had not been met; however, taking into consideration patients’ unmet need and the complexities of clinical studies for this indication, the evidence could be considered adequate in this specific context.

After the discussion, 13 / 17 committee members voted that available data were adequate to support the product’s efficacy; 12 / 17 voted that data were adequate to support safety. REBYOTA thus became the first microbiome-based drug candidate to reach the milestone of FDA VRBPAC approval, putting it in a favorable position for market authorization in the future. Some uncertainty still surrounds the FDA’s final decision on the Rebiotix BLA, however, since it is not bound by the advisory committee’s approval.

A spokesperson for Ferring says bringing the candidate this far was the result of a “cross-functional company-wide effort” and that the company will continue to work with the FDA throughout its review of the BLA.

Competitor Finch Therapeutics Group, which has an oral candidate (CP101) currently in Phase 3 development for prevention of recurrent CDI, sees the committee’s vote as a positive sign for the field overall, and particularly for patients with recurrent CDI.

[We see this as] an important milestone and believe the field is positioned for the first potential FDA approval of a microbiome therapy,” says a spokesperson for Finch. “With recent advances in the field, hope is on the horizon for patients who suffer from recurring episodes of C. difficile and are in need of additional treatment options.

A positive sign for investment

Georges Rawadi, Chief Biotech Studio Development at the investment firm eureKARE, which specializes in synthetic biology, including the microbiome, says investors have tended to see new microbiome therapeutics as risky.

“Clinical development of biotherapies, which include microbiome-based therapies, is not easy and still suffers from a high attrition rate,” he says. “Even the very hot space of CAR-T is facing now multiple failures because of either lack of efficacy or significant levels of toxicity.”

But while Rawadi says the success rate of a biotherapy transitioning from Phase 3 to BLA submission is only about 57%, a biotherapy transitioning from BLA submission to approval has a much higher success rate—about 90%. Thus, the odds appear to be in REBYOTA’s favor as it approaches market authorization.

If REBYOTA is approved and demonstrates the expected commercial success, Rawadi says it will open the door to future BLAs in the microbiome field—with companies learning from the experiences of the ones that came before.

“There is clearly a new business model for investing in this type of product, which will certainly benefit from incremental improvement and learning from real-life situations,” he says.

Rawadi adds that the BLA dossier of Seres Therapeutics, another leading competitor, will also be watched very closely by investors and pharmaceutical companies, because given the company’s ups and downs, its success will be key to increasing confidence in the industry.

A different European regulatory framework

Magali Cordaillat-Simmons, Scientific and Regulatory Affairs Director at the Pharmabiotic Research Institute, which focuses on the regulation of microbiome-based medicinal products in Europe, sees the FDA committee’s vote as an important milestone in the field. She says the advancement brings optimism at a time in the industry when several high-profile microbiome-focused companies have faced financial difficulties or ended drug development programs.

For Cordaillat-Simmons, the timeline for this advancement is a welcome surprise. She says,

“As Europeans, it certainly feels that the clarification of the regulatory framework as early as 2012 in the US and the involvement of the Center for Biologics Evaluation and Research (CBER) in following microbiome science was key in the US taking the lead in the microbiome field. We can only regret that ten years later, the EU is still struggling with clarifying the regulatory fate of microbiome-based medicinal products, and that the recent EMA Horizon Scanning Report on FMT is an example of the poor understanding of products derived from Human microbiomes, and particularly of the timeline with which they will reach European patients.”

She adds that the report sets five to ten years as the predicted timeline for such marketing authorizations in Europe.

“The regulators at the FDA have acquired a better understanding on the microbiome, thanks to pioneers such as Rebiotix / Ferring and others,” she says.

Safety challenges

Overall in the VRBPAC meeting, it was clear the committee found the data on REBYOTA safety less convincing than the data on efficacy.

Safety is a perpetual sticking point for therapies derived from donor fecal samples, says Emma Allen-Vercoe, a microbiologist who is Professor and Canada Research Chair at University of Guelph, and the co-founding CSO of a company advancing microbiome therapeutic products that are defined, complex consortia of gut bacterial species. She says that even when fecal-derived products are screened to ensure the absence of the ‘usual suspects’—known pathogens, virulence determinants, and antimicrobial resistance markers—safety is not guaranteed.

“It’s not possible to screen for unknowns, and there is also always the risk of passing on stool components that could have pathogenic consequences because they are present below the level of detection for whatever screening tests are deployed,”

she says. Nevertheless, she acknowledges the unmet need of patients with recurrent CDI after successive rounds of antibiotic treatment and says REBYOTA is moving in the right direction toward safety compared to the at-home FMT that some patients undertake out of desperation.

Alexander Khoruts, MD, a gastroenterologist and professor at University of Minnesota who has championed FMT for therapeutic use in recent decades, says maintaining safety will be a particular challenge for Ferring as it scales up production of REBYOTA.

He says,

“Unlike other drugs, this one critically depends on human donors. Managing a stool donor program is not like managing chemicals. It is critical that these individuals can be trusted.”

In a letter to the FDA prior to the VRBPAC meeting, Khoruts expressed concern about the company’s recruitment of stool donors, saying the financial incentives likely compromise the safety of the input material since donors might be less forthcoming about their medical history and infectious disease risk factors. He argues the donor program management practices should be reviewed by biomedical ethicists to ensure REBYOTA remains a safe product as the company scales up manufacturing.

Because of safety concerns, Allen-Vercoe believes fecal-derived drug therapies such as REBYOTA are a “stop-gap” in the evolution of therapies that target restoration of the gut microbiome. “I think the endgame therapies will be represented by specific, personalized microbiota-modulating products, including purified microbial ecosystems tailored to particular patients, and/or drugs which modify microbiomes in predictable and therapeutic ways. But we’re quite a way off from these, still.”

Kristina Campbell

Microbiome Science Writer

The Microbiome Times