Category Archives: C. difficile Treatment Clinical Studies

Research Provides New Data; C. difficile Changes In Testing and Management

 

 

 

 

 

 

Changes in Testing

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[14]: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[7]: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

Treatment Changes

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.

Microbiota Disruption

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[5]: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[7533]: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.

 

Source:  https://www.idse.net/Bacterial-Infections/Article/12-20/C-difficile-Old-Disease-New-Changes-In-Management/62162

Gut Microbes Raise the Bar In Treating C. difficile Infections

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.

 

 

 

 

 

Microbial Cocktails Raise Bar For C. diff. Treatments

To read the article in its entirety, please click on the  .pdf file link above or on the following resource link.  Thank you.

https://www.nature.com/articles/s41587-020-00765-8

 

Acurx Announces that All Patients Demonstrated Clinical and Sustained Cure in Ph2A Open-Label Trial of Ibezapolstat for the Treatment of a C. difficile Infection

 

 

 

 

– Ibezapolstat is the first of an entirely new class of antibiotics with a novel mechanism of action, a DNA polymerase IIIC inhibitor, to enter clinical efficacy trials

– 10 of 10 patients enrolled in the Ph2A trial met the study’s primary and secondary efficacy 

– No C. difficile was detected in any of the 65 fecal samples tested by Day 3 of treatment and thereafter

– Compelling evidence of efficacy allows early termination of Segment 2A and advancement to Segment 2B

C. difficile bacteria remain on CDC Urgent Threat list, highlighting the need for new CDI treatments

– Ibezapolstat is FDA QIDP and Fast Track Designated for priority review

Acurx Pharmaceuticals, LLC,  a privately held, clinical-stage biopharmaceutical company developing an entirely new class of antibiotics for difficult-to-treat bacterial infections, announced today (November 5, 2020) that all 10 patients (100%) with mild-to-moderate CDI enrolled in this Ph2A open-label clinical trial met the study’s primary and secondary efficacy endpoints following treatment with orally administered ibezapolstat given 450 mg twice daily for 10 days.  FDA has granted Qualified Infectious Disease Product (QIDP) designation and Fast-Track status to ibezapolstat for patients with CDI.

In this Phase 2 clinical trial, Segment 2A was designed to enroll up to 20 patients with a data review planned by a Trial Oversight Committee after 10 patients completed the trial. All 10 patients enrolled in the trial met the study’s primary and secondary efficacy endpoints of Clinical Cure at end of treatment and Sustained Clinical Cure of no recurrence of CDI at the 28-day follow-up visit.  Ibezapolstat was well-tolerated, with no serious adverse events (SAEs) reported in the trial. Based on these successful treatment results, and in consultation with the Company’s medical advisors, the Company has terminated enrollment in Segment 2A early and will advance to Segment 2B.   These results also represent the first-ever clinical validation of DNA polymerase IIIC as a therapeutically relevant antibacterial target.

Dr. Kevin Garey, Professor and Chair, University of Houston College of Pharmacy and the Principal Investigator for the microbiome aspects of the trial stated, “Data from my laboratory confirm that ibezapolstat eradicated C. difficile in all fecal samples tested by Day 3 of treatment in this patient population with mild or moderate CDI.  Our ongoing work will characterize the effects of ibezapolstat on the intestinal microbiome in these CDI patients.  A strength of this development program will be the ability to compare the microbiome results in CDI patients to our prior favorable effects relative to vancomycin previously demonstrated in the Phase 1 healthy volunteer trial.”

Stuart Johnson, MD, Professor of Medicine at Loyola University, a CDI expert and an Acurx Scientific Advisory Board (SAB) member, noted, “After reviewing Segment 2A , the SAB is encouraged by the promising results and fully support early termination and advancement to the Ph2B Segment with the next enrolled patient.  The SAB looks forward to successful results from Segment 2B that could pave the way for an important new antibiotic class for the treatment of CDI which remains an area of clear medical need.”

These data will be presented at the 8th Annual International C. diff.  Virtual Conference and Virtual Health Expo on November 14, 2020, https://cdiff2020.com which coincides with the US Centers for Disease Control and Prevention (CDC) declaration of November as Clostridioides difficile Awareness Month.

Robert J. DeLuccia, Co-Founder & Managing Partner of Acurx, stated, “We are very excited by these excellent results allowing early termination of our Phase 2A Segment at 10 patients. We are looking forward to starting our Phase 2B Segment early next year with expectation for completion by the end of next year”.   He further stated, “since ibezapolstat is the first DNA polymerase IIIC inhibitor to advance into clinical trials, this achieves the first human validation of our bacterial target and will enable further development of our pipeline of novel oral and I.V. antibiotics with the same bacterial target and mechanism of action.  Our new compounds are in pre-clinical development to treat other Gram-positive life-threatening infections in skin/skin structure, community-acquired pneumonia, bone & joint, and bacteremia. The spectrum of activity of Acurx’s DNA pol IIIC inhibitors includes pathogens resistant to currently available antibiotics and classified as priority pathogens by the WHO, CDC, and FDA, all of whom emphasize the need for new classes of antibiotics to prepare for the next global infectious disease pandemic, antimicrobial resistance.”

About the Phase 2 Clinical Trial.  In Segment 2A of this trial, 10 subjects with diarrhea caused by C. difficile were treated with ibezapolstat 450 mg orally for 10 days and evaluated for clinical cure. All cured subjects were followed for a sustained clinical cure at 28 ± 2 days. In Segment 2B, approximately 64 additional subjects with CDI will be enrolled and randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or vancomycin 125 mg orally every 6 hours for 10 days and will be followed for 28 ± 2 days for recurrence. The two treatments will be identical in appearance, dosing times, and the number of capsules administered to maintain the blind. Subjects in both segments will be evaluated for clinical and sustained clinical cure, safety, and tolerability. All subjects in both segments will have stool samples tested for microbiome profiles.  Additional information about the trial, including eligibility criteria, can be found at www.clinicaltrials.gov (Study identifier: NCT04247542).

About Clostridioides Difficile Infection (CDI).  Clostridioides (formerly Clostridium) difficile, also known as C. difficile or C. diff, is one of the most common causes of healthcare-associated infections in U.S. hospitals (Lessa, et al, 2015, New England Journal of Medicine).  Recent estimates suggest C. difficile approaches 500,000 infections annually in the United States and are associated with approximately 20,000 deaths. (Guh, 2020, New England Journal of Medicine).  Based on internal estimates including a recurrence rate of approximately 20%, we believe the annual incidence in the U.S. approaches 600,000.

About the C Diff Foundation:  The Company recognizes the month of November as                    C. Difficile Awareness Month as designated by the US Centers for Disease Control and Prevention (CDC) and supports the work of the C Diff Foundation in educating and advocating for the Prevention, Treatments, Clinical Trials, and Environmental Safety of Clostridioides difficile (C.difficile) Infections worldwide. https://cdifffoundation.org/.  The C Diff Foundation recently announced the release of the C diff and You app, available from the Apple Store (apple.com) and Google Store (play.google.com).  Developed with patients, family members, and caregivers in mind, the app provides information about C. difficile infection prevention, treatments, clinical trials, support, guidelines, environmental safety, and nutrition.

The U.S. Center for Diseases Control 2019 Update on Antimicrobial Resistance.  https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf  CDC reported that more than 2.8 million antibiotic-resistant infections occur in the U.S. each year and more than 35,000 people die as a result, nearly twice as many annual deaths as previously reported by CDC in 2013. These deaths are attributed to antimicrobial-resistant pathogens including Enterococcus (including vancomycin-resistant strains or VRE), Staphylococcus (including methicillin-resistant strains or MRSA), and Streptococcus (including antibiotic-resistant strains), which are the targets of the Company’s antibiotic pipeline currently in preclinical development and also eligible for QIDP and FDA-Fast-Track-Designation for priority review.

About ibezapolstat, FDA QIDP, and Fast Track Designation.  In June 2018, FDA granted Qualified Infectious Disease Product (QIDP) designation to ibezapolstat as an oral treatment for patients with CDI.  In addition, in January 2019, FDA granted Fast Track designation to ibezapolstat for the oral treatment for patients with CDI.

FDA’s QIDP Designation provides that ibezapolstat will be eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (the GAIN Act). These incentives include Priority Review and eligibility for Fast Track status, the latter of which Acurx has already applied for and been granted by the FDA.  Further, if ultimately approved by the FDA, ibezapolstat is eligible for an additional five-year extension of Hatch-Waxman marketing exclusivity.

FDA Fast Track Designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need. Ibezapolstat is a novel, first-in-class, orally administered antibacterial. It is the first of a new class of DNA polymerase IIIC inhibitors in clinical development by Acurx to treat bacterial infections.

About DNA polymerase IIIC (pol IIIC).  Working in scientific collaboration with WuXi AppTec, Acurx has identified additional potential therapeutic candidates to add to its pipeline of DNA pol IIIC inhibitors. Nonclinical research has established the mechanism of action of ibezapolstat as the selective inhibition of the enzyme DNA polpol IIIC, which is required for bacterial replication and pathogenesis. This enzyme is found only in certain Gram-positive bacteria, including C. difficile as well as the pathogens Enterococcus (including vancomycin-resistant strains or VRE), Staphylococcus (including methicillin-resistant strains or MRSA), and Streptococcus (including antibiotic-resistant strains). Accordingly, chemically related molecules with the same mechanism of action as ibezapolstat have the potential to treat a variety of serious systemic Gram-positive infectious diseases.

About Acurx Pharmaceuticals, LLC.  Acurx Pharmaceuticals is a privately-held clinical-stage biopharmaceutical company focused on developing new antibiotics for difficult-to-treat infections. Acurx’s approach is to develop antibiotic candidates that target the DNA polymerase IIIC enzyme and its R&D pipeline includes early-stage antibiotic candidates that target other Gram-positive bacteria, including Methicillin-Resistant Staphylococcus aureus (MRSA), Vancomycin-Resistant Enterococcus (VRE), and Penicillin-Resistant Streptococcus pneumoniae (PRSP).

For more information, please visit our website at www.acurxpharma.com.

Any statements in this press release about our future expectations, plans, and prospects, including statements regarding our strategy, future operations, prospects, plans and objectives, and other statements containing the words “believes,” “anticipates,” “plans,” “expects,” and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including whether ibezapolstat will benefit from the QIDP designation; whether ibezapolstat will advance through the clinical trial process on a timely basis; whether the results of the clinical trials of ibezapolstat will warrant the submission of applications for marketing approval, and if so, whether ibezapolstat will receive approval from the United States Food and Drug Administration or equivalent foreign regulatory agencies where approval is sought; whether, if ibezapolstat obtains approval, it will be successfully distributed and marketed; and other factors. In addition, the forward-looking statements included in this press release represent our views as of November 5, 2020.  We anticipate that subsequent events and developments will cause our views to change. However, while we may elect to update these forward-looking statements at some point in the future, we specifically disclaim any obligation to do so.

Investor Contact:
Acurx Pharmaceuticals, LLC
David P. Luci, Co-Founder & Managing Partner
917-533-1469; davidluci@acurxpharma.com

SOURCE Acurx Pharmaceuticals, LLC

Acurx Pharmaceuticals Phase 2 Clinical Trial of ibezapolstat Is In Progress

Acurx Pharmaceuticals, LLC (“Acurx” or the “Company”), a privately held, clinical stage biopharmaceutical company developing new antibiotics for difficult-to-treat bacterial infections, announced on July 27th, 2020 that a Phase 2 clinical trial of the Company’s lead antibiotic product candidate is in progress. In this trial, orally-administered ibezapolstat given 450 mg twice daily for 10 days will be evaluated for the treatment of patients with CDI. FDA has granted Qualified Infectious Disease Product (QIDP) designation and Fast-Track status to ibezapolstat for patients with CDI.

Up to 6 study centers in the U.S. will participate in the first segment (Segment 2A) of the trial. Additional information about the trial, including eligibility criteria, can be found at www.clinicaltrials.gov (Study identifier: NCT04247542). This Phase 2, multicenter, open-label single-arm segment (Segment 2A) will be followed by a double-blind, randomized, active-controlled segment (Segment 2B), and is designed to evaluate both clinical cure and sustained clinical cure, safety, and pharmacokinetics. All patients in both segments will have stool samples tested for ibezapolstat concentrations and microbiome effects. Pharmacokinetic testing for systemic exposure will be performed on blood samples in Segment 2A. All of the first 6 patients enrolled in the trial have met the study’s primary endpoint, Clinical Cure at end of treatment. All patients who have reached the 30-day follow-up milestone, no recurrence of CDI, have achieved Sustained Clinical Cure, the study’s secondary endpoint. Ibezapolstat has been well-tolerated in all patients to date. After the first 10 patients have completed treatment, the study’s Trial Oversight Committee will assess the ibezapolstat safety profile in relationship to treatment outcomes and will advise the company on any recommended trial modifications which could include early termination of Phase 2A and acceleration of the double-blind Segment 2B.

Robert J. DeLuccia, Co-Founder & Managing Partner of Acurx, stated “With today’s heightened awareness of antimicrobial resistance, even more so in the current Covid-19 environment, and the need for new classes of antibiotics to fight this global crisis, we are very excited to advance ibezapolstat to this stage of clinical development.” He further stated, “This is a significant value-creating development milestone for our Company. We believe this now clinically validated target of inhibition of bacterial DNA pol IIIC will pave the way forward for our pipeline of new oral/I.V. antibiotics in pre-clinical development to treat other Gram-positive life-threatening infections in skin/skin structure, community acquired pneumonia, bone & joint and bacteremia. This will include pathogens resistant to currently available antibiotics, and classified as priority pathogens by the WHO, CDC and FDA, all of whom emphasize the need for new classes of antibiotics to prepare for the next global infectious disease threat.”

Additionally, the U.S. Center for Diseases Control recently issued its 2019 update on antimicrobial resistance https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf and reaffirmed that CDI remains an URGENT threat causing at least 12,800 deaths in 2017, highlighting the need for new antibiotics, particularly those with a novel mechanism of action. It further reported that more than 2.8 million antibiotic-resistant infections occur in the U.S. each year and more than 35,000 people die as a result, nearly twice as many annual deaths than previously reported by CDC in 2013. These deaths are attributed to antimicrobial-resistant pathogens including Enterococcus (including vancomycin-resistant strains or VRE), Staphylococcus (including methicillin-resistant strains or MRSA), and Streptococcus (including antibiotic-resistant strains), which are the targets of Company’s second antibiotic candidate currently in preclinical development.

About the Phase 2 Clinical Trial.  In Segment 2A of this trial, up to 20 subjects with diarrhea caused by C. difficile will be treated with ibezapolstat 450 mg orally for 10 days and evaluated for clinical cure. All cured subjects will be followed for sustained clinical cure at 28 ± 2 days. In Segment 2B, approximately 64 additional subjects with CDI will be enrolled and randomized in a 1:1 ratio to either ibezapolstat 450 mg every 12 hours or vancomycin 125 mg orally every 6 hours for 10 days and followed for 28 ± 2 days for recurrence. The two treatments will be identical in appearance, dosing times, and number of capsules administered to maintain the blind. Subjects in both segments will be evaluated for clinical and sustained clinical cure, safety, and tolerability. All subjects in both segments will have stool samples tested for microbiome profiles.
Additional information about the trial, including eligibility criteria can be found at: www.clinicaltrials.gov (Study identifier: NCT04247542).

About ibezapolstat, FDA QIDP and Fast Track Designation.  In June 2018, FDA granted Qualified Infectious Disease Product (QIDP) designation to ibezapolstat as an oral treatment for patients with CDI. In addition, in January 2019, FDA granted Fast Track designation to ibezapolstat for the oral treatment for patients with CDI. 

FDA Fast Track Designation is a process designed to facilitate the development and expedite the regulatory pathway of new drugs to treat serious or life-threatening conditions and that fill a high unmet medical need. Ibezapolstat is a novel, first-in-class, orally administered antibacterial. It is the first of a novel class of DNA polymerase IIIC inhibitors under development by Acurx to treat bacterial infections. Acurx acquired ibezapolstat from GLSynthesis, Inc. in February 2018.

FDA’s QIDP Designation provides that ibezapolstat will be eligible to benefit from certain incentives for the development of new antibiotics provided under the Generating Antibiotic Incentives Now Act (the GAIN Act). These incentives include Priority Review and eligibility for Fast Track status, the latter of which Acurx has already applied for and been granted by FDA. Further, if ultimately approved by the FDA, ibezapolstat is eligible for an additional five-year extension of Hatch-Waxman marketing exclusivity. Ibezapolstat is being developed as a targeted, narrow spectrum oral antibiotic for the treatment of patients with CDI. Acurx is planning to advance ibezapolstat into a Phase 2 clinical trial in first quarter 2020. The CDC (Centers for Disease Control & Prevention) has designated Clostridium difficile bacteria as an urgent threat highlighting the need for new antibiotics to treat CDI.

Major Article: SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

SER-109, an Investigational Microbiome Drug to Reduce
Recurrence After Clostridioides difficile Infection: Lessons
Learned From a Phase 2 Trial.

Barbara H. McGovern,1,a,  Christopher B. Ford,1,a , Matthew R. Henn,1,a , Darrell S. Pardi 2
Sahil Khanna,2  Elizabeth L. Hohmann,3  Edward J. O’Brien,1
Christopher A. Desjardins,1, Patricia Bernardo,1, Jennifer R. Wortman,1, Mary-Jane Lombardo,1
Kevin D. Litcofsky,1, Jonathan A. Winkler,1, Christopher W. J. McChalicher,1, Sunny S. Li,1,
Amelia D. Tomlinson,1,Madhumitha Nandakumar,1 David N. Cook1,
Roger J. Pomerantz,1, John G. Auninš,1, and Michele Trucksis1,

1 Seres Therapeutics, Cambridge, Massachusetts, USA, 2 Mayo Clinic, Gastroenterology Division, Rochester, Minnesota, USA, and 3 Massachusetts General Hospital, Infectious Diseases Division, Boston, Massachusetts, USA

Background. Recurrent Clostridioides 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, phase (P) 1 study in subjects with multiple rCDIs.

Methods. In a P2 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 enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo
(44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years
(45.2% vs 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 nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed
an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 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 P3 trial. Clinical Trials Registration. NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw=2&rank=4.

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