Tag Archives: Clostridioides difficile Research and Development

Children with inflammatory bowel diseases (IBD) are particularly vulnerable to infection with Clostridioides difficile (CDI)

Multi-omic Analysis of the Interaction between Clostridioides difficile Infection and Pediatric Inflammatory Bowel Disease

Highlights

  • 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

Summary

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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https://www.cell.com/cell-host-microbe/fulltext/S1931-3128(20)30423-6

Seres Therapeutics Announced on March 30th, 2020, That the Company Has Completed Enrollment of its SER-109 Phase 3 Clinical Study, ECOSPOR III

On March 30th, 2020

Seres Therapeutics, Inc., announced that the Company has completed enrollment of its SER-109 Phase 3 clinical study, ECOSPOR III.

www.serestherapeutics.com

 

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 Clostridium difficile 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 CDI recurrence 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 Clostridium difficile 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.

 

SOURCE:  http://ir.serestherapeutics.com/news-releases/news-release-details/seres-therapeutics-announces-completion-enrollment-ser-109-phase

Seres Therapeutics SER-109, Investigational Microbiome Drug to Reduce rCDI, What Was Learned From a Phase 2 Clinical Trial

Abstract

Background

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.

To read publication in its entirety please click on the following link to be redirected. Thank you.

https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa387/5817059?rss=1

Methods

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.

Results

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.

Conclusions

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 Food and Drug Administration (FDA) Informs Health Care Providers and Patients of the Potential Risk of Transmission of SARS-CoV-2 Virus and COVID-19 By the Use of Fecal Microbiota for Transplantation (FMT)

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.

Actions

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.

 


1 Xiao F, Tang M, Zheng X, Liu Y, Li X, Shan H, Evidence for gastrointestinal infection of SARS-CoV-2, Gastroenterology (2020), doi: https://doi.org/10.1053/j.gastro.2020.02.055External Link Disclaimer
2 Tang A, Tong Z-d, Wang H-l, Dai Y-x, Li K-f, Liu J-n, et al. Detection of novel coronavirus by RT-PCR in stool specimen from asymptomatic child, China. Emerg Infect Dis. (2020), https://doi.org/10.3201/eid2606.200301External Link Disclaimer from https://wwwnc.cdc.gov/eid/article/26/6/20-0301_article
3 Wang, W, Xu, Y, Gao, R, et al., Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA (2020), https://doi.org/10.1001/jama.2020.3786External Link Disclaimer
4 Gu J, Han B, Wang J, COVID-19: Gastrointestinal manifestations and potential fecal-oral transmission, Gastroenterology (2020), doi: https://doi.org/10.1053/j.gastro.2020.02.054

C Diff Foundation with Leading Gastroenterologist’s Oneto and Feuerstadt Announce November Clinic Dedicated for C.difficile

C Diff Foundation ( https://cdifffoundation.org/)  is a one hundred percent volunteer, world-renowned 501(c)(3) not-for-profit organization and has announced that the Foundation will offer a November clinic sponsored by the C Diff Foundation and dedicated to patients diagnosed and recovering from a C. difficile infection (CDI).

The November 19th C Diff Foundation Clinic will be hosted by Concorde Gastroenterology at their  233 Broadway Suite 840,  New York, NY 10279 office.
The clinic will hold office hours from 10:00 a.m. until  4:00 p.m. ET
With Doctor’s Caterina Oneto, MD and  Paul Feuerstadt, MD

Please call +1 212 889 5544 Ext 199
To schedule an appointment.

The August clinic received an overwhelming response from patients in various stages of recovery, including 15 individuals already scheduled with multiple spots planned for patients with recently diagnosed infection or those who have had multiple episodes and need further guidance and management.

Dr. Oneto said, “Through this clinic, we will provide access to high-level care to a number of new consults, as well as existing patients, who are recovering from the infection. It is my pleasure to partner with the C Diff Foundation and lend my expertise to the management and hopefully, eradication of this debilitating disease.”

“We are delighted with the immediate and overwhelming response from the patient community. It is a testament to the needs of those suffering from this infection. With this clinic, we hope to bring awareness, education and more importantly, cutting edge treatment to the general public,” stated Dr. Feuerstadt.

There are plans for additional clinic dates in 2020  in Florida, New York, Connecticut, Illinois, and Minnesota.

“The clinics demonstrate Doctor Oneto and Feuerstadt’s commitment over the years raising
C. diff. awareness while providing management of those suffering with
a C. diff. infection. Patients who might not otherwise be able to gain access to providers sub-specializing and caring for those with this infection will have this opportunity available.  Doctor’s Oneto and Feuerstadt’s dedication resonates within the C. diff. community and we are grateful for their participation and support.” stated Nancy Caralla, Founding President and Executive Director of the C Diff Foundation.

About C Diff Foundation

C Diff Foundation’s mission is dedicated to reaching out to communities from villages to cities, to medical practitioners, medical students, C. diff. survivors, caregivers, and the patients combating a C. difficile infection (CDI) while providing the general public important information on prevention, treatments available, clinical trials in progress, nutrition, diagnostics, and EPA registered products available for environmental safety worldwide.

About Caterina Oneto, MD

Dr. Caterina Oneto, MD is a Gastroenterologist in private practice in New York and is affiliated with NYU Langone. She completed her Fellowship in Gastroenterology at Montefiore Medical Center, Albert Einstein College of Medicine. Dr. Oneto is the Co-Director of Clinical trials at Concorde Medical Group. Her main focus is Irritable Bowel Disease (IBD),

About Paul Feuerstadt, MD

His areas of interest Clostridioides difficile infection (CDI) and ischemic diseases of the gut and in these areas he has presented his research extensively, authored and co-authored many manuscripts, textbook chapters, and online modules. Another passion of Dr. Feuerstadt is teaching, frequently giving lectures locally, regionally and nationally. He holds a clinical appointment as an Assistant Clinical Professor of Medicine at the Yale University School of Medicine and is a full-time attending physician at the Gastroenterology Center of Connecticut seeing patients with a broad spectrum of clinical gastroenterological diseases.

Dr. Feuerstadt attended the Weill Medical College of Cornell University in Manhattan for medical school and completed his residency in internal medicine at New York-Presbyterian Hospital/Weill Cornell. His clinical fellowship training was completed at Montefiore Medical Center in the Bronx, New York.

Clostridioides difficile infections (AKA C. diff., C.difficile, CDI) and Microbiome modification.
Dr Oneto is also Co-Director of the C.diff. Community Global Support program offered by the
C Diff Foundation.  Dr. Oneto appears regularly on Doctor Radio on Sirius Xm
and C. diff. Spores and More Radio (cdiffradio.com).

About C.difficile

It is the most common Healthcare-associated infection affecting an estimated 450,000 people annually in the United States alone with ~28,000 deaths from complications of this infection. This infection accounts for ~16% of all healthcare-associated infections.

In the USA: Nearly half a million Americans suffer from Clostridioides difficile (C. diff.) infections in a single year according to a study released on February 25, 2015, by the Centers for Disease Control and Prevention (CDC).

**Approximately 29,000 patients died within 30 days of the initial diagnosis of C. difficile. Of those, about 15,000 deaths were estimated to be directly attributable to C. difficile infections (CDI), making C. difficile a very important cause of infectious disease death in the United States alone. More than 80 percent of the deaths associated with C. difficile occurred among Americans aged 65 years or older. C. difficile causes an inflammation of the colon and deadly diarrhea.