Will the Launch of Commercial Microbiome-Based Therapies for Clostridium difficile infections Usher a New Era of Therapeutics?

In recent years, microbiome has become a common buzzword among scholars, medical experts, and biotechnology and pharmaceutical companies as a potential key to treating a variety of diseases. The importance of the microbiome in human and animal health has been known for a long time, but only relatively recently has its association with disease started to be actively explored. As evidence of a possible link between the microbiome and clinical manifestations such as obesity and immune disorders grew, so did the interest in the field. Indeed, our market analysis identifies a myriad of companies spanning both the biotech and pharmaceutical sectors, focusing on the microbiome as a therapeutic tool. However, the idea of using the microbiome as a therapy is not new, as fecal transplants for infections caused by Clostridium difficile (CDI) have been in place for several decades; there are even accounts of fecal transplants for the treatment of diarrhea during the 4th Century in China. Because of the well-understood pathophysiology of CDI and its link to the microbiota, this disease became an obvious target to explore the commercial development of microbiome-based therapies.

Clostridium difficile is an opportunistic pathogen, which typically does not cause disease in healthy individuals. However, when certain conditions are met, specifically a disturbance of the healthy microbiota that leads to a decrease in the phylogenetic diversity, the pathogen finds the appropriate conditions to colonize and multiply in the colon, and eventually produce disease. The current standard of care for CDIs is antibiotic therapy, mostly with vancomycin and metronidazole, and to a smaller extent fidaxomicin (Merck’s Dificid/Astellas’ Dificlir). While those agents are effective at eliminating C. difficile, because of their relatively broad spectrum activity, they also cause collateral damage to the host’s microbiota; the microbiome’s diversity remains reduced, and the predisposing factors that allowed C. difficile to find a niche for colonization and consequent development of disease continue in place. As a result, approximately 30% of patients who suffer a primary CDI episode, also experience a recurrence, which can be due to infection with the original strain (relapse) or a new strain (reinfection). With each subsequent antibiotic treatment course and recurrent episode, the likelihood of a new recurrence also increases, and patients enter in a never-ending cycle of recurrences. Recognizing the importance of restoring a healthy and diverse flora, physicians have started to turn to fecal microbiota transplants (FMTs) for patients who experience multiple recurrences, or who fail to respond to standard antibiotic therapy.

FMTs entail of the delivery of fecal material collected from healthy donors, which can be family members or people who share the same household, or from stool banks. Those samples are screened for pathogens and experience a minor degree of processing before being delivered to the patient, although there is no selection of specific bacterial species or laboratorial growth. The processed fecal material can be delivered through an upper route (capsules, gastroduodenal intubation) or lower route (colonoscopy), depending on the patients’ condition/preference, and on the capacity of the healthcare facility to perform it. While there are advantages and disadvantages to either delivery route, all forms of FMTs are equally efficacious in reducing the rate of recurrences in patients who experience multiple recurrences, leading to significantly higher cure rates in these patients than those achieved with antibiotic only therapy (50-90% vs. 30%, respectively).

Even though FMTs have demonstrated high efficacy in the reduction of recurrences, their uptake remains limited. Physicians interviewed by DRG note having concerns over the safety of the current procedures. While the short-term side effects are well characterized (and are limited and transitory), the long-term impact of manipulating the microbiome is not well understood, leading to concerns that the use of FMTs may be associated with future unexpected manifestations of the disease. Additionally, although the fecal samples are screened for common pathogens, there are concerns over and an inherent risk of transmitting unknown pathogens; interviewed physicians cite similarities with the transmission of hepatitis C (HCV) through blood transfusions, where ignorance about this pathogen led to millions HCV cases worldwide. And let’s not forget the patients; while many are desperate enough to undergo FMTs, the prospect of receiving someone else’s fecal material can be difficult for some. Finally, the current regulatory environment surrounding the procedure is very restrictive, likely a reflection of the concerns and unknowns that surround the therapy. The FDA considers FMTs an investigational new drug (IND), but because of the high unmet need and pressure from the medical community and patients, the FDA issued guidance allowing the use of this procedure outside of clinical trials. However, there are still limitations, specifying patient eligibility for FMT, which according to the guidance, should be only those with multiple recurrences or who fail to respond to standard therapy.

Despite the clinical and regulatory challenges that FMTs face, there is an obvious and high unmet need for therapies that effectively prevent recurrences. Several companies are developing so-called second-generation FMTs, which are commercially prepared FMTs; currently, two agents are undergoing Phase III trials:

  • RBX2660: Rebiotix is developing RBX2660 as a ready-to-use enema bag, which delivers a bacterial suspension prepared from fecal material obtained from donors. The agent initiated PUNCH CD 3, a Phase III trial in 2017, supported by the results obtained in three Phase II trials (PUNCH CD, PUNCH CD 2, PUNCH Open Label). In those trials, RBX2660 showed an overall efficacy in the prevention of recurrence ranging from 79-89%, after 1-2 administrations. Upon analysis of the microbiome of patients from PUNCH CD 2, there was evidence that patients who responded to RBX2660 showed a larger shift in the baseline microbiome composition than in those who did not respond, suggesting the engraftment of microbial populations present in the FMT.
  • SER-109: SER-109 is a capsule for oral delivery containing bacterial spores isolated from fecal material obtained from donors. The development of SER-109 by Seres Therapeutics is not without setbacks. After demonstrating an 87% clinical cure rate without recurrence in the ECOSPOR Phase I trial, it failed to significantly differentiate from placebo in the ECOSPOR II Phase II study (44% of patients experienced recurrence in the SER-109 arm in contrast to 53% in the placebo arm). Nonetheless, after analysis of the data obtained in the trial, Seres Therapeutics attributed the failure to the misdiagnosis of patients with CDI and recurrence, and to a suboptimal dosage of the agent. As a result, Seres Therapeutics decided to move forward with a new Phase II trial, adopting a more rigorous diagnostic and improved dosing strategy, and upon discussion with the FDA, the trial was upgraded to a Phase III trial. Analysis of microbiome samples collected during the ECOSPOR study, the company observed differences in composition among patients who responded to SER-109, and those who did not.

The primary completion of PUNCH CD 3 and ECOSPOR III studies are expected for Q3 2018 and Q1 2019, respectively. Assuming RBX2660 and SER-109 demonstrate positive results in their respective trials, it is likely that by the end of 2019 the two first ever commercially developed microbiome-based therapies will be approved by the FDA. Approval by the FDA will bring benefits: having FMTs commercially available and in ready-to-use formulations can make this procedure more convenient and accessible to physicians, especially those who do not have access to stool banks, and also more appealing to patients. It is also fair to assume that because these agents will be the object of scrutiny by the FDA, they will follow much more stringent and standardized screening and safety protocols, which may further alleviate the safety concerns of some physicians.

However, if the FDA’s current stance on the use of FMTs does not change, the eligible population to receive these agents will be limited (both agents have received orphan drug designation for recurrent CDI by the FDA). In order to justify their development, it is likely that Seres Therapeutics and Rebiotix will price these agents at a premium. While this pricing strategy is common in other indications, this approach may curb uptake in this market, where most of the available antibiotics are generic and cheap, and “homemade” FMTs or those obtained from stool banks have a relatively low cost. Therefore, how will manufactured second-generation FMTs compete in this price-sensitive market, despite proven efficacy? Would the FDA be willing to expand the patient populations that are eligible to receive these therapies? And how will the FDA approval of these agents impact the use of first-generation FMTs? And looking ahead, how will the evolving regulatory landscape affect the development of third-generation FMTs, which consist of bacterial combinations rationally designed and laboratory-grown, which bypass the need for donors? Seres Therapeutics and Vedanta Biosciences are developing agents already undergoing Phase I trials, with the potential to reach the market within the next decade or less. While Vedanta’s agent is being developed for recurrent CDI, Seres’ agent is being developed for primary cases of CDI, a target population that under the current guidance, should not have access to FMTs.

While currently there are plenty of unanswered questions and very few certainties, it is clear that there is a high unmet need for therapies that effectively reduce CDI recurrence rates, which will bring health benefits for patients, and economic savings for health systems. It is also obvious that the FDA is willing to bet on the development of FMTs as commercially available agents. Regardless of the outcome, microbiome-based therapies will undoubtedly pave the way for all other microbiome-based therapies targeting other indications, ushering a new class of therapies and therapeutic approach to the clinic and opening new possibilities for patients suffering from diseases that can benefit from modulating the microbiome.

Nuno Antunes is a Senior analyst on Infectious, Niche, & Rare Disease team at DRG, currently covering the hospital antibiotic markets, including Gram-Negative Infection and Clostridium difficile Infection markets. Nuno is the lead author of the recently published comprehensive market assessment study on Clostridium difficile infections, which includes forecasted sales estimates for Rebiotix’s RBX2660 and Seres Therapeutics’ SER-109. Follow Nuno on Twitter @NunoAntunesDRG.

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