We are pleased to share “C. diff. Spores and More ” with you because, as advocates of C. diff., we know the importance of this cutting-edge new weekly radio show and what it means for our Foundation’s community worldwide.
July 20, 2021: Prevent CDI: Boost Immunity, Restore Microbiome, Replace the Bug
Neil Clark, Chief Executive Officer, Destiny Pharma, PLC
Mr. Clark qualified as an accountant with PwC in Cambridge, UK and worked for over ten years on a variety of national and international assignments in audit, corporate finance and consultancy. In 1997, Mr Clark joined CeNeS Pharmaceuticals plc, a venture capital backed private UK biotech company. Following the successful flotation of CeNeS in 1999, he was appointed CFO. In 2005, he became CEO and led the company through to its sale in 2008. He then joined Ergomed in January 2009 and was CFO during its IPO in July 2014. Mr. Clark joined Destiny Pharma as CEO in early 2017. Mr. Clark is a Fellow of the Institute of Chartered Accountants in England and Wales and has a BSc in Bioscience from the University of Nottingham.
Dale Gerding, MD, FACP, FIDSA, FSHEA
Dr. Dale Gerding is Research Physician at the Edward Hines Jr. VA Hospital and Professor of Medicine (Retired) at Loyola University Chicago Stritch School of Medicine. He is an infectious diseases specialist and hospital epidemiologist, past president of the Society for Healthcare Epidemiology of America. He is a fellow of the Infectious Diseases Society of America, is a Master of the American College of Physicians and the 2013 recipient of the William Middleton Award, the highest research award given by the Department of Veterans Affairs. He is board certified in Internal Medicine and Infectious Diseases. His major research interest is in the epidemiology, prevention and treatment of Clostridioides difficile infection and he is the discoverer of non-toxigenic C. difficile strain M3. (NTCD-M3)
Neil Clark, Chief Executive Officer, Destiny Pharma PLC and Dale Gerding, MD, FACP, FIDSA, FSHEA, with our Guest Host: Kevin Hersh, shared a robust discussion which touched upon important topics focused on the what, why, and how to Prevent a C. diff. infection: Boost Immunity, Restore Microbiome, Replace the Bug. Our guests exchanged a dialogue about the science to answer the many questions about a C. difficile infection, prevention, treatments, what is recurrent C. diff., and the immune system, and how the microbiome plays a part in everything. Click on the link provided above to access the archived episode and expand your basic CDI knowledge today.
SAVE THE DATES to listen in to the leading topic expert presentations
shared on January 15, 2021, at the Patient, Family, Caregiver Symposium:
Beginning Tuesday, March 9 from 1:00 p.m. – 2:00 p.m. EST following through on
March 16, March 23, and March 30.
A Symposium specifically developed for Patients Diagnosed With a C. diff. Infection, Being Treated For a Clostridioides diffiicile infection, Recovering From a Clostridioides difficile Infection and Recurrences with Family Members and Caregivers.
The Patient & Family C. diff. Symposium was a gathering of healthcare professionals, keynote speakers, health advocates, practitioners, educators, thought leaders, and patients who are transforming the patient experience and changing the way people experience C. diff. infections worldwide.
Unlike other conferences on this topic, patients will share their C. diff. infection journeys, providing a real-world perspective on patient experience. Our attendees will learn more from this virtual-online symposium and gain knowledge on important topics that will better aid their care and recovery through tools and strategies delivered by keynote speakers.
The Symposium followed the C Diff Foundation Mission statement – Educating and Advocating for the prevention, treatments, clinical trials, diagnostics, and environmental safety of Clostridioides difficile (C. diff.) infections worldwide.
Keynote speakers presented up-to-date data to expand on the existing knowledge and provide important information focused on, yet not limited to, a Clostridioides difficile infection (also known as C. diff., C. difficile, CDAD, CDI) ……
Clinical trials and studies
Introduction to Microbiome Research and Studies
Fecal Microbiota Restoration and Transplants
We hope you enjoy the broadcasts!
Program Chair: Paul Feuerstadt, MD, FACG
Barbara McGovern, MD “Treatment of recurrent C. difficile infection with SER-109, an investigational microbiome drug.”
Paul Feuerstadt, MD ” C. diff. Overview – What is a C. diff. Infection?”
MGB Biopharma, a biopharmaceutical company developing MGB-BP-3, a novel antibacterial, for the treatment of Clostridioides difficile (CDI), today announces the successful completion of its End-of-Phase 2 (EOP2) meeting with the US Food and Drug Administration (FDA), an important milestone for the company and its lead product.
The EOP2 Meeting is a formal step at which companies seek confirmation that their product is considered safe to proceed to broader clinical studies and to explore any additional studies that may be required before entering into Phase 3.
At the meeting, the US FDA confirmed that the design and the endpoints of our two prospective Phase 3 studies were appropriate. The Phase 3 studies, which are expected to recruit approximately 900 patients, will include the superiority of MGB-BP-3 against vancomycin in the critical measure of sustained clinical response as one of their endpoints.
Dr Miroslav Ravic, CEO of MGB Biopharma, said, “The successful completion of the End-of-Phase 2 meeting with the FDA marks the culmination of solid scientific and clinical endeavor by the Company. The positive Phase 2 data showed that MGB-BP-3 provides high rates of Sustained Cure from CDI, a devastating disease. We are very pleased with the guidance received from the FDA on key elements of the Phase 3 program that will support the submission of a New Drug Application (NDA).
“The global pandemic caused by COVID-19 has highlighted the importance of being adequately prepared for infectious diseases. CDI’s ongoing high mortality reminds us that this is a disease with a significant unmet medical need for which new treatments are urgently required. MGB-BP-3, with its unique mode of action, is perfectly positioned to meet the need and provide confidence to patients and clinicians that more effective treatments are just round the corner.”
Professor Thomas Louie, clinical professor at the Cumming School of Medicine at the University of Alberta, Calgary (Canada) and Principal Investigator said, “I am most pleased to have contributed to the success of the Phase 2 clinical study of MGB-BP-3. There is a real need for new agents to address CDI and it is gratifying to see this agent progressing onto its next phase of the study. CDI represents a major burden to the Canadian and US healthcare systems. A novel antibiotic that is able to kill this deadly pathogen before it is able to sporulate offers hope to patients and their families who suffer the pain and misery caused by this disease.”
MGB Biopharma is considering strategic options for the business and has engaged JMP Securities as its exclusive financial advisor.
MGB-BP-3 is a novel antibiotic that belongs to the Minor Groove Binder group, discovered at the University of Strathclyde, with a unique rapid bactericidal activity against Clostridioides difficile (CDI), a feature shared by no other treatment available. A recently completed Phase 2 clinical study in 33 CDI patients using three sequential ascending doses of MGB-BP-3 showed a high initial average cure of 94% in all dosages, a high average sustained cure of 95% in the 2 lower dosages, and preservation of the gut microbiota with the lower dosages. There were correspondingly low recurrence rates of less than 5% for the first two doses. MGB-BP-3 was shown to be safe and well-tolerated with no serious adverse events in either of Phase 1 or 2 clinical studies.
CDI is a serious and life-threatening infection of the large intestine and is the most frequent cause of diarrhea in hospitals and care homes. In the US alone, there are almost half a million cases every year associated with around 30,000 deaths; three people die of uncontrolled CDI each hour. CDI has been recognized as an urgent threat pathogen by the Centers for Disease Control and Prevention (CDC) in the US and is a common consequence of antibiotic treatment in hospitalized patients.
About MGB Biopharma
MGB Biopharma is a clinical-stage company developing a novel class of anti-infectives. Its lead candidate, MGB-BP-3, is an antibacterial that is active against a broad range of important multi-resistant and susceptible Gram-positive pathogens. The Company is developing an oral formulation of MGB-BP-3 for the treatment of Clostridioides difficile Infection (CDI).
In addition to its C. difficile programme, MGB Biopharma has a pipeline of early preclinical compounds against Gram-positive, Gram-negative, anti-fungal, anti-viral and anti-parasitic pathogens.
MGB Biopharma acquired rights to the proprietary minor groove binder (MGB) platform, developed at the University of Strathclyde, Glasgow, with exclusive worldwide licensing rights for all anti-infective fields. This platform provides an opportunity to develop various compounds with a completely new mode of action that are distinct from the antimicrobial drugs used in clinical practice today. As a result, many MGB-based drugs could have the potential to offer significant advantages over existing anti-infectives.
The Company, founded in 2010 and headquartered in Glasgow, Scotland, is backed by Scottish investors including Archangel Investors Limited, Barwell, TRICAPITAL, Syndicate Room, and the Scottish Investment Bank, Scottish Enterprise. The company also received significant support for its clinical programme from Innovate UK.
For example, new data published in The New England Journal of Medicine underscore the shortcomings of advances in testing technology, suggested Sahil Khanna, MBBS, an associate professor of medicine at Mayo Clinic College of Medicine and Science, in Rochester, Minn. (2020;382:1320-1330).
At first glance, the study, which used data from 10 sites nationwide to derive a national estimate of the incidence of CDI, reported a relatively unchanged rate of the disease over a six-year period: 476,400 cases in 2011 and 462,100 cases in 2017. However, Dr. Khanna noted that after adjusting for the increasing use of nucleic acid amplification testing (NAAT), the researchers concluded that the incidence of CDI had actually decreased by 24% during the study period, including a 36% drop in healthcare-acquired CDI cases.
The study highlights a problem with NAAT, according to Khanna.
“NAAT is approximately 95% sensitive in detecting the C. difficile gene, but it cannot determine if the gene is active and toxin-producing, so it has the potential for overdiagnosis and for producing clinical false positives,” he explained. “Because of this, it’s important that we interpret NAAT results in the context of patient symptoms.”
Clinicians must be selective when deciding which patients should be tested, he said, only using it in patients who have acute diarrhea with no obvious alternative explanation, and who have the risk factors for CDI. These include older age, longer hospitalization, immunosuppression, use of antibiotics, gastric acid-suppressing agents, gastrointestinal surgery, manipulation of the gastrointestinal tract, and tube feeding.
“Patients not experiencing an active infection can be colonized with C. difficile, in which case there is a risk of a clinical false positives and unnecessary treatment,” Khanna emphasized.
An alternative testing approach now recommended by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) is the use of a multistep algorithm including glutamate dehydrogenase (GDH) to identify pathogenic bacteria and enzyme immunoassay (EIA) to detect C. difficile toxin (Clin Infect Dis 2018;66:e1-e48). NAAT should be reserved for instances in which results from GDH and EIA are inconclusive, the guidelines recommend.
“Unfortunately, NAAT remains the most commonly used test method,” Khanna said, adding that laboratories are increasingly adopting a two-step protocol of GDH and EIA.
Recurrent CDI mostly occurs in people:65 and older who take antibiotics and receive medical care
staying in hospitals and nursing homes for a long time with weakened immune systems
The treatment landscape for CDI also has changed over the past few years, noted Kim Ly, PharmD, a clinical pharmacy specialist in critical care and infectious diseases at Sunrise Hospital and Medical Center, in Las Vegas. Bezlotoxumab (Zinplava, Merck), a monoclonal antibody, is now approved for combination treatment of toxin B–producing CDI, along with an established antibiotic. Additionally, metronidazole, while still approved for the treatment of CDI, is no longer recommended by IDSA/SHEA as a first-line agent for primary CDI in adults.
“For severe initial episodes of CDI, oral vancomycin and fidaxomicin [Dificid, Merck] are now the preferred agents, and metronidazole is only recommended for nonsevere initial episodes when patients are unable to be treated with oral vancomycin or fidaxomicin,” Kim explained.
For a first recurrence of CDI, the IDSA/SHEA guidelines recommend administering oral vancomycin as a tapered and pulsed regimen or fidaxomicin, rather than a standard 10-day course of vancomycin. For subsequent recurrences, clinicians can use the same regimen, with the addition of a standard course of oral vancomycin followed by rifaximin or fecal microbiota transplantation (FMT).
Metronidazole comes into play again in the management of fulminant CDI, Ly noted.
“The IDSA/SHEA guidelines recommend treating this with oral or rectal vancomycin 500 mg four times daily along with intravenous metronidazole,” she explained.
Given that antibiotic-induced microbiota disruption “is far and away the number one precipitant for getting recurrent CDI,” selecting the CDI treatment with the least impact on the microbiota is important, said former IDSA president Cynthia Sears, MD, a professor in the Department of Medicine, Division of Infectious Diseases, at the Johns Hopkins University School of Medicine, in Baltimore.
“Vancomycin is the most commonly used therapy for CDI and its recurrences, but it decreases intestinal diversity and so impedes the recovery of the normal microbiota after CDI, setting the stage for CDI recurrence,” Sears said. “We have learned that vancomycin hits the colon with full force when taken orally because it is not absorbed, and it has off-target effects on lots of anaerobic bacteria that are essential to intestinal resistance of CDI.”
Fidaxomicin has less of an effect on the microbiota and has been shown to sometimes decrease the risk for CDI recurrence when compared with vancomycin (N Engl J Med 2011;364:422-431), but it can be expensive, she said.
Fecal Microbiota Transplantation
FMT is a less expensive, highly effective treatment that has received increasingly widespread attention, specifically for the management of recurrent CDI. Despite the enthusiasm surrounding the treatment, Sears expressed significant reservations about employing it.
“While there’s no question that FMT benefits patients with recurrent CDI, I feel we don’t yet have a quality-controlled product that we know is safe as well as being effective,” she said.
Sears pointed to two recent FDA safety alerts that warned of the harm that FMT can cause. The first, from 2019, reported that stool from a single donor had not been thoroughly screened before FMT and contained extended-spectrum ss-lactamase–producing Escherichia coli. The specimen had been used in separate FMTs for two immunocompromised patients, leading to infection with the pathogen and death in one case.
In another FDA safety alert from earlier this year, the organization said a stool bank specimen that had undergone comprehensive screening nevertheless contained enteropathogenic E. coli and Shiga toxin-producing E. coli. Transfer of the stool for the treatment of recurrent CDI resulted in one nonfatal infection and one death.
“Stool banks try very hard to be sure their specimens are free of disease-causing microbes, but if you have very low-level colonization, molecular diagnostics can miss this,” Sears said. More recently, she noted, the FDA has also raised concerns about the possibility of transferring SARS-CoV-2 through FMT, given that the virus can be present in the stool of infected individuals.
What would a safer and equally effective microbiota-based treatment look like? According to Sears, while microbial diversity seems to be protective against recurrent CDI, there are suggestions that the administration of specific strains may be able to treat CDI and can be produced under the same strict quality control manufacturing processes as other FDA-approved drugs. One study published in 2015 using human and mouse samples found that colonization with Clostridium scindens, a strain of Firmicutes, increased resistance to CDI (Nature 2015;517:205-208). Many microbiota-based therapeutics are in the research pipeline as well.
“I am optimistic that we will see something emerge that’s safer and still as effective as FMT for patients, whether it’s an orally or rectally administered product,” Sears said.
Seres’s success with an industrially made bacterial mix in phase 3 trials against Clostridium difficile infection promises an alternative to fecal microbial transplantation in clinical practice.
The August announcement of positive data from Seres Therapeutics’ phase 3 trial to prevent recurrent Clostridium difficile infections renewed hopes that purified, defined mixtures of bacteria can treat such infections as effectively as — and presumably more safely than — fecal microbial transplantation (FMT). Several other companies have now also shown favorable late-stage trial data in ‘C. diff.’ using customized stool-derived cocktails. Along with Seres, they are teeing up clinical studies of these compounds in a variety of diseases.
……..Two other companies, Rebiotix, and Vedanta Biosciences are pursuing microbe-based drugs to stop C. diff infection recurrences, and both are in late-stage development. Rebiotix is running a pivotal phase 3 study of its commercially prepared FMT in enema form. Vedanta Biosciences is expecting a readout of its phase 2 trial of VE303, which, unlike the other three drug candidates, is a defined consortium of eight types of cultured, clonal commensal bacteria strains.