A new study published online in the journal ClinicalInfectious Diseases looked at the use of a non-frozen capsule of microbiome restoration therapy for treating patients with recurrent C. difficile infection.
“Patients with C. difficile are typically managed with antibiotics or fecal transplantation for recurrent C. difficile,” says the study’s author, Sahil Khanna, M.B.B.S., a gastroenterologist at Mayo Clinic. Dr. Khanna says fecal transplantation has been demonstrated to have high success rates by restoring the gut microbiome of patients. However, he says there are several challenges with fecal transplantation including standardization of the product, keeping it frozen, and mitigating the risk of infectious disease transmission during the procedure.
To help reduce the risks, Dr. Khanna and his team studied a transplantation method using a non-frozen capsule instead of whole stool transplantation. An initial dose-finding, the investigator-initiated study looked at the efficacy of different doses of fecal matter and the safety of performing microbiome restoration therapy using an oral product, RBX7455 developed by Rebiotix, Inc. The team found no concerns related to safety.
“Our study has several implications,” says Dr. Khanna. “We think that products like capsules may be able to replace fecal transplantation that is currently done via a colonoscopy. We also think that products that are non-frozen may allow for repeat dosing and for patient-administered self-treatment at home. The good news is that we are moving closer to having safe and effective products to restore the gut microbiome for patients with recurrent C. difficile.”
Dr. Khanna says that larger clinical trials and blinded, placebo-controlled trials are the next step in moving this potential treatment from research into practice.
•Multi-omics reveals markers of CDI in pediatric IBD patients
•Identification of metabolites reveals distinctive features for IBD and CDI
•Isocaproyltaurine is made by C. difficile and associates with active IBD
•Identifies biomarkers potentially useful for distinguishing disease processes
Children with inflammatory bowel diseases (IBD) are particularly vulnerable to infection with Clostridioides difficile (CDI). IBD and IBD + CDI have overlapping symptoms but respond to distinctive treatments, highlighting the need for diagnostic biomarkers. Here, we studied pediatric patients with IBD and IBD + CDI, comparing longitudinal data on the gut microbiome, metabolome, and other measures. The microbiome is dysbiotic and heterogeneous in both disease states, but the metabolome reveals disease-specific patterns. The IBD group shows increased concentrations of markers of inflammation and tissue damage compared with healthy controls, and metabolic changes associate with susceptibility to CDI. In IBD + CDI, we detect both metabolites associated with inflammation/tissue damage and fermentation products produced by C. difficile. The most discriminating metabolite found is isocaproyltaurine, a covalent conjugate of a distinctive C. difficile fermentation product (isocaproate) and an amino acid associated with tissue damage (taurine), which may be useful as a joint marker of the two disease processes.
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SER-109 is an oral, first-in-field microbiome therapeutic candidate that has been granted Orphan Drug and Breakthrough Therapy designations by the U.S. Food and Drug Administration (FDA), and is being investigated for use in preventing recurrent Clostridiumdifficile infection (CDI).
“We are pleased to have achieved this critically important corporate milestone. SER-109 has the potential to be the first FDA-approved therapy for C. difficile infection to treat the underlying cause of this disease, and the first approved microbiome drug for any human condition. We believe SER-109 could fundamentally transform the treatment of patients with recurrent C. difficile infection, a life-altering infectious disease, and we eagerly look forward to topline clinical results in the middle of this year. With compelling Phase 3 ECOSPOR III clinical data, we plan to engage in discussions with the FDA regarding a filing for product approval,” said Eric Shaff, President and Chief Executive Officer of Seres. “We are also working to advance our other promising clinical development candidates in light of the COVID-19 pandemic. This remains an evolving situation and we are carefully reviewing our development plans to determine how to rapidly advance our pipeline toward high-quality data readouts.”
SER-109 Study Updates
The SER-109 Phase 3 ECOSPOR III study (ClinicalTrials.gov identifier: NCT03183128) is a multicenter, randomized, placebo-controlled study which has enrolled 181 patients with multiply recurrent CDI to date. ECOSPOR III had been designed to enroll 188 patients. The Company has decided to halt enrollment as a result of the COVID-19 pandemic. Seres believes that ECOSPOR III remains well-powered to evaluate the efficacy of SER-109. The ECOSPOR III study’s primary endpoint is the reduction of CDIrecurrence at up to eight weeks following SER-109 administration, and the Company expects to report study results in mid-2020 as had been planned.
Seres is grateful to the patients, principal investigators and clinical research teams who participated in ECOSPOR III, many of whom are now involved in the fight against COVID-19.
The SER-109 Phase 3 ECOSPOR III study includes use of an objective Clostridiumdifficile cytotoxin assay to ensure that all patients entering the study have active CDI, as well as to confirm CDI recurrences during the study (i.e., the ECOSPOR III primary endpoint).
Seres plans to initiate a SER-109 Expanded Access Program at selected clinical sites participating in the ongoing Phase 3 ECOSPOR III study, and the Company may also initiate the program at additional clinical sites for eligible patients to have access to SER-109.
Prior completed clinical studies have demonstrated SER-109 bacterial engraftment into the gastrointestinal microbiome, and that engraftment is associated with reduced recurrence of CDI. In all prior clinical studies, SER-109 was associated with a favorable safety profile.
The FDA has issued several safety alerts related to Fecal Microbiota Transplantation (FMT) and the risk of pathogen transmission including warnings related to Multi-Drug Resistant Organisms and SARS-CoV-2, the virus linked to COVID-19 (June 12, 2019Alert; March 12, 2020Alert; and March 23, 2020Alert). Unapproved FMT is widely used under an FDA Enforcement Discretion policy for the treatment of recurrent CDI that is not responsive to standard therapies.
In contrast to FMT, SER-109 is comprised of a highly purified consortia of spore-based commensal bacteria and is manufactured under Good Manufacturing Practices (GMP) conditions using stringent standards to ensure product quality and consistency. Seres utilizes a unique manufacturing process which has been demonstrated to inactivate numerous potential pathogens, including species of non-spore bacteria, such as Escherichia coli, and viruses. The Company’s manufacturing process inactivates many emerging potential pathogens where diagnostic assays may not yet be available, such as SARS-CoV-2. Seres has issued a position statement highlighting the criticality of including pathogen inactivation processes in the manufacture of microbiome therapeutics. Recent discussions with the FDA have indicated agency support regarding the fundamental differentiation between FMT and Seres’ product candidates.
COVID-19 Impact and Other Clinical Program Updates
Seres continues to monitor the impact of the COVID-19 pandemic on Company operations and ongoing clinical development activity, including the SER-287 Phase 2b study in ulcerative colitis, the SER-401 Phase 1b study in metastatic melanoma, and SER-301, a rationally designed, fermented development candidate for ulcerative colitis. Mitigation activities to minimize COVID-19-related operation disruptions are ongoing; however, given the severity and evolving nature of the situation, the timing of SER-287 Phase 2b and SER-401 Phase 1b clinical readouts is uncertain. Seres does not anticipate disruptions to the availability of its drug product candidates for ongoing studies.
The SER-287 Phase 2b study is currently approximately 60% enrolled based on the 201-patient target study size. SER-287 development activity has been adversely impacted by multiple clinical sites halting non-essential procedures, including endoscopies, which may make it difficult to achieve the original enrollment target in H2 2020 as planned. Seres is evaluating enrollment mitigation strategies and possible trial design modifications with the goal of obtaining a high-quality, clinically meaningful dataset within a timeframe consistent with Seres’ prior guidance for its cash runway extending into the second quarter of 2021. Furthermore, the Company is encouraged by the FDA’s indications of flexibility in light of the COVID-19 pandemic, and plans to engage the FDA in discussions regarding any potential trial modifications.
Seres continues to execute on activities to advance SER-301 clinical development and the planned initiation of patient dosing in Australia and New Zealand later this year.
Recurrent C. difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, open-label Phase (Ph)1 study in subjects with multiply rCDI.
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In a Ph2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment and bile acid changes were assessed.
89 subjects were enrolled; 67% were female; 80.9% diagnosed by PCR. rCDI rates were lower in the SER-109 arm than placebo (44.1% versus 53.3%, respectively) but did not meet statistical significance. In a pre-planned analysis, rates were reduced among subjects ≥65 years (45.2% versus 80%, respectively; RR:1.77, 95% CI:1.11-2.81) while the <65 group showed no benefit. Early engraftment of SER-109 was associated with non-recurrence (p <0.05) and increased secondary bile acid concentrations (p<0.0001). Whole metagenomic sequencing from this study and our prior Ph1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that Ph2 dosing was suboptimal. Adverse events were generally mild-to-moderate in severity.
Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current Ph3 trial.
The global public health community is responding to a rapidly evolving pandemic of respiratory disease caused by a novel coronavirus that was first detected in China.
The virus has been named “SARS-CoV-2” and the disease it causes has been named “COVID-19.”
The Food and Drug Administration (FDA) is informing health care providers and patients of the potential risk of transmission of SARS-CoV-2 virus by the use of fecal microbiota for transplantation (FMT) and that FDA has determined that additional safety protections are needed.
Summary of the Issue
Several recent studies have documented the presence of SARS-CoV-2 ribonucleic acid (RNA) and/or SARS-CoV-2 virus in stool of infected individuals.1,2,3 This information suggests that SARS-CoV-2 may be transmitted by FMT, although the risk of such transmission is unknown.4 At this time, testing nasopharyngeal specimens from stool donors for SARS-CoV-2 may not be widely available. Furthermore, there is limited information on the availability and sensitivity of direct testing of stool for SARS-CoV-2.
Additional Protections for the Use of FMT
At this time, FDA is advising that clinical use of FMT has the potential to transmit SARS-CoV-2, whether used as part of a study under an Investigational New Drug Application (IND) on file with the FDA or under FDA’s enforcement discretion policy. To address the risk, stool used for FMT should have been donated before December 1, 2019. Due to the potential for serious adverse events to occur, FDA has determined that the following protections are needed for any use of FMT that is found to be necessary for clincal care if it involves stool donated after December 1, 2019:
Donor screening with questions directed at identifying donors who may be currently or recently infected with SARS-CoV-2;
Testing donors and/or donor stool for SARS-CoV-2, as feasible;
Development of criteria for exclusion of donors and donor stool based on screening and testing; and
Informed consent that includes information about the potential for transmission of SARS-CoV-2 via FMT, including FMT prepared from stool from donors who are asymptomatic for COVID-19.
FDA is in the process of notifying IND holders of the potential risk of transmission of SARS-CoV-2 via FMT and of FDA’s determination that additional safety protections that are needed.
FDA is communicating this information with this statement to all other stakeholders to ensure that everyone is fully informed.
As the scientific community learns more about SARS-CoV-2 and COVID-19, FDA will provide further information as warranted.
Information for Health Care Providers and Patients on Enforcement Discretion
In July 2013, FDA issued a guidance document stating that it intends to exercise enforcement discretion under limited conditions regarding the IND requirements for the use of FMT products to treat C. difficile infection in patients that have not responded to standard therapies. The guidance states that FDA intends to exercise enforcement discretion provided that the treating physician obtains adequate consent for the use of FMT from the patient or his or her legally authorized representative. The consent should include, at a minimum, a statement that the use of FMT to treat C. difficile is investigational and a discussion of its potential risks.
Reporting Adverse Events
FDA encourages all health care providers and patients to report any suspected adverse events or side effects related to the administration of FMT products to the FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch.