CARB-X today announced an award of up to $1.26 million to Facile Therapeutics of Belmont, California, to develop a new oral drug for recurrent Clostridioides difficile infections.Facile Therapeutics of Belmont, California, to develop a new oral drug for recurrent Clostridioides difficile infections.
The money will help fund preclinical development of Ebselen, a small-molecule anti-toxin that inhibits a key biochemical function of C difficile toxins A and B, which attack the lining of the intestine. Previous studies showed Ebselen provided protection against severe intestinal damage in mice after they were exposed to virulent C difficile infections. The drug has also been tested in humans in clinical trials for stroke, and although it was not approved for that indication, it was shown to be safe.
“This is a terrific example of an attempt to repurpose a compound for use in the infectious-disease arena,” CARB-X chief of research and development Erin Duffy, PhD, said in a press release. “If successful and ultimately approved for use in patients, Facile’s project could represent tremendous progress in the prevention of recurrent C. difficile infections, and save many lives.”
C difficile infections are traditionally treated with antibiotics, which can cure the infection but also further disrupt the microbiome and clear a path for C difficile bacteria to spread, leading to recurrent infections. At least 20% of patients who get an initial C difficile infection have a recurrent infection.
Facile could receive an additional $17 million if the project achieves certain milestones.
Since its launch in 2016, CARB-X (the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator) has awarded more than $222 million to companies developing new treatments and diagnostics for drug-resistant pathogens.
May 18 CARB-X press release
MGB’s antibacterial avoids infection recurrence cycle in promising phase IIa study
In the trial, 250-mg MGB-BP-3 enteric-coated tablets given twice a day for 10 days cured acute infections and prevented recurrence at eight weeks. That is in contrast to standard of care vancomycin where there is initial cure but the infection recurs in 20% to 30% of cases.
The company points to the ability to prevent recurrent infections as a key differentiator that gives the compound potential to become a first-line treatment.
MGB-BP-3 achieves that effect by rapidly killing vegetative C. difficile in the 10 to 15 hours before it sporulates and lies dormant in the gut.
“We are absolutely delighted to get that effect and to get a very clean safety profile,” said Chris Wardhaugh, chief business officer. “We’ve confirmed we have a compound that is both safe and highly effective in the target of reducing recurrence. There is a surprisingly high mortality from C. diff infections; it’s because the bugs aren’t killed,” he told BioWorld.
Glasgow, U.K.-based MGB Biopharma said the trial demonstrates the 250-mg dose is able to strike the right balance between maximal killing effects, whilst having a minimal effect on the normal gut flora.
That prevents MGB-BP-3 from sparking the usual vicious circle, in which broad-spectrum antibiotic treatment destroys the microbiota, giving resting C. difficile spores an opening to germinate and form vegetative cells that cause a further bout of diarrhea. Each recurrence is associated with increased risk of further recurrence.
The impact on the microbiome is one of the secondary endpoints, but that analysis is not completed yet. “We are still very much going through the data. We only got the safety and efficacy results last week,” Wardhaugh said. “But we’ve shown in previous studies that [MGB-BP-3] kills bacteria so they don’t form spores. We’ve been able to demonstrate in previous studies it is very rapidly bactericidal and wipes out bacteria in the vegetative state.”
It also has been demonstrated MGB-BP-3 is effective against a hypervirulent strain of
C. difficile that is largely resistant to current therapy. That strain accounts for 20% of cases in Europe and 50% in North America.
The cure rate is impressive, but the numbers are small, with only 10 patients in each of three dose cohorts, of which 250 mg was the middle dose. The company has drawn up plans to move straight to phase III, with an interim analysis on the way.
The next step will be to hold a phase II meeting with the FDA, which Wardhaugh suspects will be delayed because of the COVID-19 pandemic. “So we can’t confirm the size of the phase III yet. We did have a post phase I meeting and looked at a number of options. That gave us comfort a single phase III demonstrating superiority over vancomycin, in particular in hypervirulent strains of C. difficile, would be enough for approval,” Wardhaugh said.
“Phase III is really beyond us, so we are looking for partners or investors to take it on. We have it planned out so we can complete clinical development and have started to talk to companies large and small.”
Eligible for incentives
MGB Biopharma has had a hand to mouth existence since it was spun out of Strathclyde University in Glasgow in 2010, to commercialize research of chemistry professor Colin Suckling into compounds that are selective binders of the minor groove of pathogen DNA.
The main backers are Archangel Investors, a syndicate of business angels, and the government-backed Scottish co-investment fund, but the company has not disclosed the value of any rounds of investment. The phase IIa trial, which took place in North America, was funded through a £2.78 million (US$3.4 million) U.K. government grant.
C. difficile infection is recognized as an urgent threat pathogen by the U.S. CDC and MGB-BP-3 has FDA qualified infectious disease product status. That could lead to fast track submission and five years of extra marketing exclusivity.
The product also will be eligible for the prescribing incentives being put in place under the DISARM (Developing an innovative strategy for antimicrobial resistant micro-organism) Act. MGB Biopharma has also talked up the chances of MGB-BP-3 being recommended as first-line treatment in the Infectious Diseases Society of America guidelines, if it makes it through to approval.
The phase IIa dataset has even more resting on it, in that MGB-BP-3 also is active against seven of 21 priority pathogens listed in the GAIN (Generating antibiotic incentives now) Act. Those include the gram-positive infections vancomycin-resistant Staphylococcus aureus and Enterococcus, and gram-negative Pseudomonas, Klebsiella and Escherichia coli.
MGB Biopharma has developed other formulations of MGB-BP-3, including liquid-filled capsules and a freeze-dried product which is designed to be reconstituted for intravenous administration.
Final formulation optimization and scale up of the intravenous formulation have been completed, as have preclinical proof-of-concept studies against Staphylococcus aureus, Streptococcus pyogenes and pneumoniae. There also is a topical formulation for treating MRSA-infected skin lesions in the works.
MGB Biopharma Ltd. is looking for new investors or a commercialization partner to take its lead program, MGB-BP-3, through to market, after reporting 100% initial and sustained cure of Clostridium difficile infections in a phase IIa dose-ranging study.
Clostridioides difficile in COVID-19 Patients, Detroit, Michigan, USA, March–April 2020
We describe 9 patients at a medical center in Detroit, Michigan, USA, with severe acute respiratory syndrome coronavirus 2 and Clostridioides difficile. Both infections can manifest as digestive symptoms and merit screening when assessing patients with diarrhea during the coronavirus disease pandemic. These co-infections also highlight the continued importance of antimicrobial stewardship.
Coronavirus disease (COVID-19), which is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), predominantly includes pulmonary symptoms; however, <10% of cases also include gastrointestinal events, including abdominal pain, diarrhea, and vomiting (1–4). During the COVID-19 pandemic, clinicians must be vigilant of co-infections in patients with COVID-19.
Several studies have collected data on concomitant antibiotic use in patients with COVID-19. A single-center study of 52 critically ill patients cited hospital-acquired infection in only 7 (13.5%) patients, yet 49 (94%) patients received antibiotic therapy (5). Another study, which analyzed 113 deceased patients from a cohort of 799 moderate-to-severely ill COVID-19 patients during January 13–February 12, 2020, reported that 105 (93%) deceased patients and 144 (89%) survivors had received empiric antibacterial therapy with either moxifloxacin, cefoperazone, or azithromycin (6). These antibiotics are strongly associated with C. difficile infection (CDI) (7). We report an observation of CDI as a co-occurrence or sequalae of overuse of antibiotics in COVID-19 patients.
We conducted a clinical surveillance review of CDI for all laboratory-confirmed COVID-19 patients treated at any of the hospitals belonging to Detroit Medical Center (Detroit, Michigan, USA). We screened patients by using TheraDoc software (https://www.theradoc.comExternal Link) during March 11–April 22, 2020. We abstracted data regarding baseline demographics, medical history, symptoms, laboratory values, microbiologic findings, concomitant antibiotic use, and treatment for CDI. We obtained institutional review board approval for this study.
We identified 9 cases of co-infection with SARS-CoV-2 and C. difficile. This cohort mainly included elderly patients who were predominantly female (Table). The rate of CDI at the center was 3.32/10,000 patient-days during January–February 2020 and increased to 3.6/10,000 patient-days during March–April 2020.
We noted prior CDI in 3 patients; these infections occurred 1–4 months before admission. All patients were confirmed to be positive for C. difficile by PCR and showed symptoms of diarrhea in addition to other characteristic signs and symptoms, such as abdominal pain, nausea, and vomiting. Two patients had diarrhea and were found to be positive for C. difficile at admission, whereas the remaining 7 had onset of diarrhea only after COVID-19 diagnosis; median duration from CDI diagnosis to COVID-19 diagnosis in these 7 patients was 6 days. This group of patients were severely ill, having high ATLAS scores (https://www.mdcalc.com/atlas-score-clostridium-difficile-infectionExternal Link) and multiple underlying conditions; hypertension (n = 8) and diabetes (n = 5) were the most frequent of these conditions.
Three patients received antibiotics in the month before admission; 8 received antibiotics at admission. One patient was initiated on antibiotics on day 15; this patient was also receiving antibiotics the month before admission. The most commonly administered antibiotics were cefepime (n = 5), ceftriaxone (n = 3), meropenem (n = 2), and azithromycin (n = 2). Specific CDI therapies were oral vancomycin (n = 6); vancomycin and intravenous metronidazole (n = 1); no treatment (n = 1); and a combination of oral vancomycin, intravenous metronidazole, rectal vancomycin, fidaxomicin, and fecal microbiota transplantation (n = 1). One patient who did not receive antibiotics was considered to be colonized with C. difficile. Four (44.4%) patients died during hospital admission, 1 (11.1%) was discharged to hospice, 1 (11.1%) is still hospitalized, and 3 (33.3%) were discharged to a long-term care facility.
CDI is a challenging disease, with a recurrence rate of 15%–20% and a mortality rate of 5% (8). When CDI is present as a co-infection with COVID-19, CDI therapy can be difficult to monitor if diarrhea persists because of COVID-19.
These cases highlight the importance of judicious use of antibiotics for potential secondary bacterial infection in patients with COVID-19. Antibiotics are known to have unintended consequences, such as C. difficile infection. All 9 patients received antibiotics; the median duration of antibiotic use before PCR-positive CDI was 5 days. All patients in our cohort were elderly, an age group at higher risk for complications from overuse of antibiotics, such as adverse events, antibiotic resistance, and concomitant infections like CDI (9). Secondary infections on top of CDI can increase the risk for death in patients with severe COVID-19; in this cohort, 4 patients died and 1 was discharged to hospice. To prevent CDI co-infections during the COVID-19 pandemic, integrated use of antimicrobial stewardship is needed to monitor appropriate antibiotic use.
Symptoms of CDI can complicate diagnosis of COVID-19 because both conditions can have similar manifestations; in a study of 206 COVID-19 patients, 19.4% had diarrhea as the first symptom onset (10). Of the 2 patients who had CDI diagnosed at admission, 1 patient solely had gastrointestinal symptoms, which possibly led to delayed diagnosis of COVID-19. Both COVID-19 and CDI should be considered when evaluating patients with diarrhea during the COVID-19 pandemic. Distinguishing between actual CDI versus colonization also is vital; 1 patient in our cohort was colonized. A limitation of this study is the small number of cases. However, in the face of the COVID-19 pandemic and the extensive use of antibiotics, clinicians should remain awaren of possible CDI and SARS-CoV-2 co-infection.
Dr. Sandhu is an infectious diseases–epidemiology fellow at Detroit Medical Center, Wayne State University School of Medicine. Her current research interest is in multidrug-resistant hospital-acquired infections.
G.T. is a consultant to Melinta, Crestone, Ferring, AirMmax, and Shionogi. Other authors in the manuscript have no relevant conflict of interest or financial disclosure. No funding was needed for this manuscript.
US Centers for Disease Control and Prevention. Interim clinical guidance for management of patients with confirmed coronavirus disease (COVID-19) [cited 2020 May 1]. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al.; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382:1708–20.
Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. Lancet. 2020;395:507–13.
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA. 2020;323:1061–9.
Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020;8:475–81.
Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, et al. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ. 2020;368:m1091.
Brown KA, Khanafer N, Daneman N, Fisman DN. Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother. 2013;57:2326–32.
Guh AY, Mu Y, Winston LG, Johnston H, Olson D, Farley MM, et al. Emerging Infections Program Clostridioides difficile Infection Working Group. Trends in US burden of Clostridium difficile infection and outcomes. N Engl J Med. 2020;382:1320–30.
Biedron C, Chopra T. Issues surrounding antibiotic use in older adults. Curr Transl Geriatr Exp Gerontol Rep. 2013;2:151–8.
Han C, Duan C, Zhang S, Spiegel B, Shi H, Wang W, et al. Digestive symptoms in COVID-19 patients with mild disease severity: clinical presentation, stool viral RNA testing, and outcomes. Am J Gastroenterol. 2020;1; Epub ahead of print.
In The News:
– Data from SER-109 Phase 3 study in recurrent C. difficile infection expected mid-2020 –
Seres Therapeutics, Inc. announced that it will host a virtual webcast symposium focused on SER-109 as a potential new therapeutic option for recurrent Clostridioides difficile infection (CDI) on Wednesday, May 27, 2020 from 8:30 to 9:30 a.m. ET.
During the event, Mark Wilcox, M.D., Professor of Medical Microbiology, University of Leeds, and Seres’ management will discuss the CDI patient burden, the ongoing SER-109 Phase 3 ECOSPOR III study and the potential for SER-109 to become the standard of care for recurrent CDI.
SER-109 is being evaluated in an ongoing Phase 3 study for the prevention of recurrence of CDI. SER-109 has obtained both Breakthrough Therapy Designation and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA).
Seres previously reported the completion of enrollment in the Phase 3 ECOSPOR III study (ClinicalTrials.gov identifier: NCT03183128), a multicenter, randomized 1:1, placebo-controlled study in patients with multiply recurrent CDI. ECOSPOR III has enrolled 182 patients. Seres expects to report SER-109 Phase 3 top-line results in mid-2020.
Based on prior discussions with the FDA, Seres believes that ECOSPOR III has the potential to be the single pivotal study supporting product registration; however, this will depend on the strength of the data, and additional safety data may be required. If approved, SER-109 has the potential to be the first FDA-approved therapy for CDI to treat the underlying cause of this disease, and the first approved microbiome drug for any human condition.
To join the live webcast, on May 27, 2020 at 8:30 a.m. ET, including presentation slides, please visit the “Investors & Media” section of the Seres website at www.serestherapeutics.com. To access the conference call, please dial 844-277-9450 (domestic) or 336-525-7139 (international) and reference the conference ID number 4884302. Webcast Link: https://edge.media-server.com/mmc/p/3qo4hxiv.
A webcast replay will be available on the Seres website beginning approximately two hours after the event and will be archived for approximately 21 days.
To view press release in its entirety please click on the following link: