Microbiome-based therapies, which aim to modify the bacterial ecosystem that colonizes the human body, have been a hot area of research for the last decade, and promising early-stage therapies have reached the clinical phase of development in many indications. Some companies are leveraging the microbiome as either a drug discovery platform or a target for treatment; microbiome-derived or microbiome-targeting small molecule therapies will not be considered here, as they are unlikely to face the regulatory scrutiny expected for products delivering live bacteria. Notably, no therapy delivering live bacteria has yet been approved by the FDA, and no standardized regulatory framework is in place, although draft guidance is available and the FDA has signaled willingness to enter into discussion with industry.

The rapid advancement of live microbiome therapies into later-phase clinical trials motivated the FDA to host a public workshop, held September 17, 2018, to discuss the issues around the clinical, manufacturing, and regulatory considerations, and possibly to further refine their guidance for developers. Practicing clinicians, physicians focused on research, industry experts, and patient advocates all participated in the discussion, including presentations from the FDA’s own experts on current guidance for marketers.

Based on discussion during the workshop, the regulatory framework for LBPs (live bacterial products) approved as drugs is likely to use the already familiar IND process, with the FDA requiring any therapy making disease claims to secure this status before moving into clinical trials. During the workshop, representatives from the agency emphasized that they remain open to public input and are looking to find a path forward for LBPs. Additionally, the role of OTC probiotics was discussed, with clinical panelists reporting that many patients already take such therapies based on their own research and experience, while other clinicians seemed frustrated with the lack of oversight and ability to secure funding to perform rigorous studies on these OTC products. Some public advocates and a few clinicians argue that LBPs, especially those derived from stool samples, should be regulated under the same framework as a tissue transplant. The FDA considers that since they contain non-human cells, they are not eligible for these regulations, but enforcement discretion is in place for FMTs (fecal matter transplants), allowing clinicians to incorporate this technique into regular practice.

Clinical trials for LBP faced their first test in Phase I safety trials, and several including Rebiotix/Ferring Pharmaceutical’s RBX2660, Seres’ SER-106, and 4D Pharma’s Blautix, have established a positive profile; gastroenterologists interviewed as part of DRG’s ongoing primary research largely perceive that LBPs are safe, saying “if safety was a concern, the FDA would not have allowed us to do FMTs in clinical practice, and they wouldn't have allowed two banks to be giving out fecal transplant products.” Interviewed physicians in other specialties who are less familiar with FMT have more reservations, especially those working with pediatric, geriatric, or immunosuppressed populations who are at higher risk of infection; some physicians recommend maintaining such patients on current treatments not containing live bacteria. However, with the availability of heavily screened donor stool from banks like OpenBiome, the risk from FMT is acceptable to most gastroenterologists and some other clinicians, and further screening and controls involved in LBPs seeking regulatory approval may increase physician comfort with such therapies. To date, several LBPs have already advanced into Phase II or even III clinical trials, with the most advanced candidates, RBX-2660 from Rebiotix (recently purchased by and now a fully owned subsidiary of Ferring) and SER-106 from Seres Therapeutics having surpassed the safety hurdles.

Clinical trial design for Phase II and III efficacy studies will be critical in proving these therapies’ utility. A majority of emerging microbiome-based therapies are in development for markets with multiple therapies already available, and while interviewed physicians are confident that they will secure regulatory approval, if they demonstrate efficacy on well-accepted end points, additional metrics may be required. One consequential difficulty is the ability to measure persistence of the inoculated bacteria from the LBPs; at the FDA’s workshop, Vendanta Biosciences described the development of new high-sensitivity assays capable of separating the introduced LBP separately from a previously colonized population and from bacteria acquired from other sources during the treatment period. Expert research panelists also discussed the insufficiency of stool sampling, pointing out that mucosal adherence is important for benefits derived from LBPs, and bacteria that have successfully adhered will not pass through the gut and be available in stool samples. However, others emphasize that any sampling is better than no sampling, even if it results are imperfect. As one gastroenterologist interviewed by DRG states, “I think the FDA is going to insist on achieving the normal benchmarks for efficacy but in addition, you're going to need to show microbial profile alteration and retention of the strains. That certainly is not part of the typical clinical trial.”

Manufacturing hurdles may be a concern for LBPs and are likely to be strain specific; as another of DRG’s interviewed gastroenterologists says, “For a new therapy, you're not going to know what the requirements of this organism are ahead of time, if it's going to be culturable, or even needs to be alive. My sense is that it's going to have to be easily culturable, identifiable, and protected from outside plasmids to be produced consistently.” Additionally, the FDA’s nonbinding guidance specifies numerous requirements for an IND application, including details from the manufacturing process requiring extensive decontamination between process runs and extensive validation of the final product. Developers such as Seres Therapeutics, Vendanta Biosciences, and Rebiotix all seem prepared to meet these requirements, with Seres Therapeutics specifically highlighting their capability to culture anaerobic organisms, and clinicians emphasizing that the relevant capsule technology to deliver LBPs is already available. However, some physicians expect that LBPs will require cold chain transport and storage, which is already in place for other therapies, but may also drive up the costs for this emerging class of drugs.

In the United States, if clinical and manufacturing obstacles are addressed, regulatory approval is likely to follow. Many of the LBP therapies in development are targeting one disease initially, but are either in earlier-phase clinical trials for other diseases or have the potential to expand to related indications. For example, RBX2660, anticipated to be the first LBP to secure regulatory approval, is expected to launch for recurrent C. difficile but is currently undergoing clinical trials for pediatric UC and CD patients. A therapy that is early to market and expands its label over time has the potential to do quite well and will likely beat competitors who wait to launch until multiple indications are included on the label; an earlier launch will help boost physician familiarity, and if it achieves some use, can reassure clinicians that it is safe over the long term.

Overall, the outlook for LBPs in the U.S. market is quite good, with a strong pipeline of candidates. Although only draft guidance is currently available, the FDA’s has demonstrated a willingness to work with industry, clinicians, and other stakeholders to approve them, and relying on the already familiar IND approval process for clinical trials may ease the burden for new therapies entering clinical trials. DRG will continue to watch for initial approvals and will update our market forecasts accordingly.

A Special Topics report covering emerging microbiome therapies, drawing on DRG’s in-house expertise and interviews with expert physicians, has recently been made available, with a gastrointestinal focus, and including insights on allergic and non-GI inflammatory conditions. An additional series of blog posts covering other microbiome-related topics is planned.


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