Category Archives: C. diff. Research & Development

Rebiotix Features Three Posters Highlighting RBX2660 Clinical and Microbiome Data at ID Week™ 2017 in San Diego, October 4th – 8th

Positive Topline Data from Open-Label Phase 2 Trial of RBX2660 in Recurrent Clostridium
difficile to be Presented for First Time

 

 

 

Rebiotix Inc., a clinical-stage microbiome company focused
on harnessing the power of the human microbiome to treat challenging diseases, today announced that three posters highlighting RBX2660 clinical and microbiome data will be featured at ID Week™ 2017 in San Diego, Oct. 4th to the 8th.

The posters describe clinical findings that highlight the key changes to
the human microbiome profiles of patients who received RBX2660, Rebotix’s Phase 3 drug candidate.

For the first time, researchers will discuss findings from the open-label Phase 2 trial of RBX2660 for the prevention of recurrent Clostridium difficile (C. diff.) infection. Data indicated that RBX2660 was well tolerated and achieved the primary efficacy endpoint of preventing C. diff. recurrence; patients treated with RBX2660 exhibited a treatment success rate of 78.8% compared with a historical control of 51.8% (p<0.0001, N=242). These results demonstrate a 55% reduction in recurrence for those patients treated with RBX2660 compared to the historical controls reflecting standard-of-care antibiotics today.

RBX2660 is currently being evaluated in a multinational Phase 3 clinical trial for the prevention of recurrent C. diff.  Researchers will also be presenting two posters on the microbiome analyses of the Phase 2B  randomized, placebo-controlled, double-blind clinical trial of RBX2660. The analyses, utilizing leading  edge genomic sequencing technology to measure the patient’s microbiome, provide measurable  evidence of RBX2660’s rehabilitative effect on human microbiome profiles of patients who were successfully treated with Rebiotix’s microbiota drug technology.

“The clinical potential of RBX2660 has been highlighted in multiple trials, including our recently
completed open-label Phase 2 study, and the data being presented at ID Week enables us to more fully understand RBX2660’s ability to rehabilitate a dysbiotic intestinal microbiome,” commented Lee Jones, president and CEO of Rebiotix. “These findings are important in that not only can we observe the clinical 2 effect of RB X2660, such as in the open-label Phase 2 study, but by analyzing the microbiota of RBX2660-treated patients, we can see how the microbiome changes in response to RBX2660 treatment and how those changes correlate to treatment success and to the microbiomes of healthy individuals.”

The first poster (#1863; to be presented Friday, Oct. 6th), titled RBX2660 is Safe, Superior to Antibiotic- Treated Controls for Preventing Recurrent Clostridium difficile, and May Rehabilitate Patient Microbiomes:  Open Label Trial Results, reported data from an open-label Phase 2 study of RBX2660 that included 242 subjects. Data from the study indicated that RBX2660’s efficacy in preventing recurrent Clostridium difficile infection (rCDI) was higher (78.8%) than CDI-free rates in the Historical Control Group (51.8%, p<0.0001). The reduction in recurrence of C. diff between these two arms is approximately 55%. Moreover, the safety profile of RBX2660 was consistent with results from previous clinical trials, and microbiota analysis suggested that RBX2660 may rehabilitate patient microbiota as RBX2660-treated subjects’ microbiomes were significantly altered compared to baseline and more closely resembled the RBX2660 microbiome profile than at baseline (p<0.05 by Dirichlet multinomial Wald-type pairwise hypothesis test).

The second poster (#1267; to be presented Saturday, Oct, 7th), titled Successful Response to
Microbiota-Based Drug RBX2660 in Patients with Recurrent Clostridium Difficile Infection is Associated with More Pronounced Alterations in Microbiome Profile, involved an analysis of 58 patients whose stool samples were collected in the randomized Phase 2B clinical trial to determine the effect of RBX2660 on rCDI patient microbiomes. 16s RNA sequencing analyses of patients’ microbiomes indicated that RBX2660 treatment shifted the relative microbiome densities, with taxa-specific increase in Bacteroidia, Clostridia, and decrease in Gamma-proteobacteria abundance. Importantly, a larger shift from baseline microbiome was seen in responders to RBX2600 compared to non-responders, and RBX2660 treatment appears to increase microbiome diversity.

 

The third poster (#1870; to be presented Saturday, Oct. 7th), titled Microbiome Profile is Distinct in Patients with Successful Response to Microbiota-Based Drug RBX2660 Relative to Placebo Responders involved a sub-analysis of 57 patients who participated in the randomized Phase 2B clinical trial of RBX2660. 16s rRNA sequencing analysis was used to compare the microbiome changes from baseline of patients classified as responders to RBX2660 vs placebo. Investigators determined that RBX2660 treatment for rCDI is associated with greater changes in patient microbiomes than placebo treatment. Notably, at 7, 30 and 60 days, microbiomes from RBX2660-treated patients had high Kullback-Leibler divergence from baseline and significantly different means from baseline (p<0.001). Further, active responders trended toward higher Bacteroides and lower Gamma-proteobacteria and Bacilli after treatment, both of which are characteristic of a healthier microbiome. According to the 3 researchers, these changes are consistent with the hypothesis that RBX2660 can restore a healthier microbiome in rCDI patients.

Rebiotix, Inc. funded all three studies.

For More Information About Rebiotix Please

Click On the Following Link:

http://www.rebiotix.com

Ribaxamase Protects the Gut Microbiome and Reduces Risk For New Opportunistic C.diff. Infections According To Phase 2b Study

From IDWeek  2017- SanD iego, CA

 

Ribaxamase is associated with reduced risk for new, opportunistic Clostridium difficile infections (CDI) in hospital patients, according to findings from a multinational, double-blind, placebo-controlled Phase 2b study presented at IDWeek 2017.

 

 

“These data support that ribaxamase can maintain the balance of the gut microbiome and thereby prevent opportunistic infections like CDI during IV beta-lactam treatment,” said lead study author John Kokai-Kun, PhD, of Synthetic Biologics, Inc., Rockville, MD.

“Ribaxamase also protected the diversity of the gut microbiome and reduced the emergence of antibiotic resistance in ceftriaxone-treated patients,” he said.

CDI represent an “urgent threat” but there are no FDA-approved drugs or vaccines to prevent infections, Dr. Kokai-Kun noted.

“SYN-004 (ribaxamase) is a beta-lactamase designed to be orally administered with IV beta-lactam antibiotics and remain localized in the intestine to degrade antibiotics excreted into the intestine,” he said. “This is expected to protect the gut microbiome from disruption thus preventing deleterious effects including, CDI, colonization by opportunistic pathogens and emergence of antibiotic resistance in the gut microbiome.”

“Ribaxamase was well tolerated and not systemically absorbed in Phase 1 studies and efficiently degraded ceftriaxone excreted into the human intestine while not altering the plasma pharmacokinetics of ceftriaxone in Phase 2a studies,” he told the IDWeek audience.

The researchers conducted their study to assess if ribaxamase prevents new-onset CDI. They also assessed non-CDI antibiotic-associated diarrhea, colonization by opportunistic pathogens, gut microbiome alterations and acquired antibiotic resistance.

Data from 412 patients (man age 70 years) in the intention-to-treat population “enriched for higher risk for CDI” were hospitalized for ≥5 days of IV ceftriaxone for treatment lower respiratory tract infections,” Dr. Kokai-Kun said. Patients were randomly assigned 1:1 to receive oral ribaxamase 150mg four times daily or placebo during IV ceftriaxone treatment and for an additional 72 hours.

“Fecal samples were collected at pre-specified points for determination of colonization by opportunistic pathogens and to examine changes in the gut microbiome,” Dr Kokai-Kun said. Patients were monitored for 6 weeks for CDI, defined as diarrhea plus the presence of C. difficile toxin.

Study participants saw a 71% relative risk reduction in CDI (P=0.045) and a statistically significant 44% relative risk reduction in new colonization by vancomycin-resistant enterococci (P=0.0002). Moreover, the respiratory infection was cleared in ~99% of cases demonstrating that concomitant ribaxamase did not impact the cure rate of ceftriaxone.

For continuous infectious disease news coverage from the IDWeek 2017, check back to MPR’s IDWeek page for the latest updates.

Reference: 

Kokai-Kun J, Roberts T, Coughlin O, Whalen H, Le C, Da Costa C, Sliman J. SYN-004 (ribaxamase) prevents New Onset Clostridium difficile Infection by Protecting the Integrity Gut Microbiome in a Phase 2b Study. Poster presented at IDWeek; October 4–8, 2017; San Diego, CA. http://www.idweek.org/.

 

 

Surotomycin Failed To Show Benefit Over Vancomycin In a Pivotal Phase 3 Trial To Treat C. difficile Infections

A similar proportion of patients with Clostridium difficile infection showed clinical response at the end of treatment with surotomycin vs. vancomycin in a pivotal phase 3 trial.

However, surotomycin did not demonstrate superiority for key secondary endpoints including sustained clinical response and clinical response over time, and therefore failed to show benefit over vancomycin.

 

As published :  https://www.healio.com/gastroenterology/infection/news/online/%7B3531418d-42aa-4092-a9f2-55ba2ce6dcda%7D/surotomycin-meets-non-inferiority-endpoint-fails-to-show-benefit-over-vancomycin-in-c-difficile

This follows previously reported results of a parallel phase 3 trial in which surotomycin failed to meet non-inferiority criteria relative to vancomycin for primary and key secondary endpoints.

“Surotomycin has a narrow spectrum of activity, demonstrating low resistance rates and rapid activity against C. difficile with similar dose- and time-dependent pharmacodynamics to vancomycin in resolving CDI in a hamster model,” Sahil Khanna, MBBS, of the division of gastroenterology and hepatology at the Mayo Clinic in Rochester, Minn., told Healio Gastroenterology and Liver Disease.

In this second phase 3 trial, “surotomycin demonstrated non-inferiority to vancomycin for CDI clinical response at end of treatment. It was similar to vancomycin for sustained clinical cure.”

In this double-blind, international multicenter trial, Khanna and colleagues randomly assigned 285 patients with confirmed CDI to receive 250 mg oral surotomycin twice daily alternating with placebo twice daily, and 292 to receive 125 mg oral vancomycin four times daily for 10 days.

At the end of treatment, clinical response with surotomycin (83.4%) was non-inferior to vancomycin (82.1%), with a difference of 1.4% (95% CI, 4.9-7.6).

Through 30 to 40 days of follow-up, clinical response over time was not superior to surotomycin, nor was sustained clinical response (63.3% vs. 59%; difference, 4.3%; 95% CI, 3.6-12.2).

Both treatments were generally well tolerated, with typical treatment-emergent adverse events occurring in 52.4% of patients treated with surotomycin and 60.1% of those treated with vancomycin.

“Interestingly, in the hypervirulent strain of CDI, recurrence rate was lower for surotomycin vs. vancomycin,” Khanna said, though he and colleagues noted in the study manuscript that “this finding is nominal due to a lack of multiplicity control.”

Based on the results of these trials, the surotomycin development program has been discontinued, but “the non-inferiority of surotomycin to vancomycin observed in the current trial is in contrast with the parallel trial,” investigators wrote. – by Adam Leitenberger

Disclosures: This study was funded by Merck. Khanna reports he has served as an advisor to Summit Pharmaceuticals and serves as a consultant to Rebiotix and Assembly Biosciences. Please see the full study for a list of all other researchers’ relevant financial disclosures.

SOURECE:  https://www.healio.com/gastroenterology/infection/news/online/%7B3531418d-42aa-4092-a9f2-55ba2ce6dcda%7D/surotomycin-meets-non-inferiority-endpoint-fails-to-show-benefit-over-vancomycin-in-c-difficile

Researchers From Loyola Medicine Retrospectively Studied 100 Vancomycin Taper and Pulse Treatment Patients Treated For Recurrent C. difficile Infection

A tapered and pulsed regimen with vancomycin — with diligent follow-up — can achieve significant cure rates in recurrent Clostridium difficile (C. difficile) infected patients, according to a new study.

Researchers from Loyola Medicine retrospectively studied 100 vancomycin taper and pulse treatment patients treated for recurrent C. difficile infection between January 1, 2009 and December 31, 2014. Their clinic, the study authors wrote, has been a referral center for the infection for the past decade.

To read the article in its entirety please click on the following link:

http://www.mdmag.com/medical-news/pulsed-and-tapered-vancomycin-likely-route-to-recurrent-clostridium-difficile-cure

However, despite the guidelines for treatment of recurrent C. difficile infection being not too different than recurrent episodes – except for the use of vancomycin when the case is severe – there have not been many studies on this vancomycin taper and pulsed dosing. 

The researchers observed that after a referral, the confirmed recurrent C. difficile patients were treated with a vancomycin taper and pulse regimen: a taper of vancomycin to once-daily, followed by alternate day dosing; or once-daily followed by alternate day dosing; followed by every third day, for at least 2 weeks. After this regimen, all patients had 90-day follow-up documentation.

On average, the patients in the clinic were on their third C. difficile diarrhea episode. Half of the patients had also received a standard course of vancomycin, while another third had received some type of vancomycin taper regimen, the researchers said.

Despite the fact that many of these patients were a “treatment experienced” population, 75% of the patients who received a supervised vancomycin taper and pulsed regimen achieved a cure,  study author Stuart Johnson  MD, . He added that the results were further improved for patients who received the expended pulse phase: 81% achieved a cure.

“The findings were not unexpected to us, but I think that many clinicians will be surprised how well a deliberate, prolonged vancomycin taper and pulse regimen – with careful follow up – works,” Johnson said.

There were no significant differences among the patients in terms of gender, age, concomitant antibiotics, proton pump inhibitor use, histamine receptor-2 blocker use, or patients with a regimen greater than 10 weeks in length, the researchers continued.

The researchers added that their finding of improved cure rates with alternate-day dosing plus every third day dosing over strictly alternate-day dosing is consistent with the hypothesis that pulsed dosing can promote a cyclical decrease in spore burden, they wrote. This can also permit the resetting of normal microbiota in the gut.

Johnson concluded that the clinical implications of the study show most recurrent C. difficile patients do not need fecal microbiota transplant (FMT).

“FMT has received an enormous amount of press and this procedure is now widely available throughout the US,” Johnson said. “FMT is attractive because it addresses one of the primary mechanisms involved with recurrent C. difficile infection, a marked disruption of the resident bacteria that populate the intestine and provide an important host defense against C. difficile.

Although physicians screen donor feces for “known pathogens,” not all is known of the potential complications to come from FMT, Johnson said.

“In addition, it appears that efficacy with a carefully supervised vancomycin taper and pulse regimen compare to that achieved with FMT,” Johnson said.

The study, “Vancomycin Taper and Pulsed Regimen with careful Follow up for Patients with Recurrent Clostridium difficile Infection,” was published in the journal Clinical Infectious Diseases.

Norman B. Javitt, M.D. Is Welcomed As a Member Of the C Diff Foundation, R & D Committee

We are pleased to welcome
Norman B. Javitt, M.D. to the
C Diff Foundation.

Dr. Javitt has an extensive professional career in health care.  New York University Medical Center: Instructor, then Assistant Professor Medicine where his career was devoted mostly to research in liver disease, specifically in inborn errors of cholesterol metabolism affecting newborns, and to teaching medical students.

Cornell University Medical School-New York Hospital:  Associate Professor of Medicine, then Professor of medicine and Chief, Division of Gastroenterology the research program continued to grow, attracting many fellows from all over the world.  Also provided care for private patients, both children and adults, with difficult liver problems.

New York University Medical Center:  Professor of Medicine and of Pediatrics, Division chairman Hepatic Diseases April, Research professor 2015-presnt.  At NYUMC Dr. Javitt has been focusing on C. difficile research  and teaching medical students and house staff.  His research interest has also expand to many areas of cholesterol synthesis and metabolism other than just liver disease.

Dr. Javitt has published research papers in age-related macular degeneration, in vitro fertilization, and Alzheimer’s disease.  He has also published more than 150 research papers, in addition to several books and review articles, and presented work at numerous professional meetings and symposia throughout the world.  His work has been supported by the National Institutes of Health, by private foundations and Pharmaceutical companies.  Dr. Javitt is welcomed by fellow researchers in the Research and Development Committee Chaired by Professor Simon M. Cutting, Ph.D…

C. diff. May Carry Risks in Preoperative and Postoperative Patients

 

There are risks for acquiring a C. difficile infection (CDI).

The risks range from the overuse of Antibiotics, Immunosuppressed patients, prolonged hospital stays, being a patient in a long-term care facility, and for the senior population.

There may also be a risk for the surgical patients and the following study explains the study and the results:

To read the article in its entirety please click on the following link: https://cdifffoundation.wordpress.com/wp-admin/post-new.php

A lengthy study of four surgical specialties has determined that Clostridium difficile infection (CDI) is a major risk factor for postoperative patients, although incidences varied.

Although it has been shown that CDI is associated with increased cost, morbidity and mortality in patients after surgery, this is the first to examine C. difficile rates across multiple surgical specialties (Infect Control Hosp Epidemiol 2017:1-4. doi: 10.1017/ice.2017.158).

“This study has great importance as the landscape of repayment for elective surgical procedures changes,” said the study’s lead author, James Bernatz, MD, a surgeon with the Department of Orthopedics and Rehabilitative Medicine at University of Wisconsin Hospital and Clinics, in Madison. “With more surgeries being reimbursed as bundled payments, hospitals are pressured to limit costs. As C. diff infection has been found to increase length of stay by one week and double the cost of care, it is clearly a postoperative complication to be avoided.”

Dr. Bernatz and his colleagues conducted the study at a 592-bed tertiary care academic center. They used the hospital’s quality improvement database to review admissions to the orthopedic surgery, neurosurgery, trauma surgery and general surgery units from January 2014 through July 2016. Those patients who underwent an inpatient surgical procedure, and did not meet the exclusion criteria, were surveyed.

Case patients were defined as those who underwent an inpatient procedure and subsequently developed a health care–associated CDI, which was defined as a positive polymerase chain reaction (PCR) test result for C. difficile toxin gene recorded more than 72 hours after admission and within 12 weeks of discharge.

They found 52 cases of CDI among 11,310 surgical admissions to four hospital units: general surgery, neurology, orthopedics and trauma. In all 52 cases, patients had a PCR-positive test result more than 72 hours after admission and within 12 weeks of discharge, making the incidence rate 0.80 cases per 1,000 patient-days. The trauma unit had the highest rate at 9.5 CDI cases per 1,000 admissions (11 cases over 1.160 admissions during the study period). General surgery had 30 cases among 3,447 admissions for a rate of 8.7; orthopedics had six cases among 4,339 admissions for a rate of 1.4; and neurology had five cases among 2,364 admissions for a rate of 2.1.

A number of risk factors were surveyed, including the use of antibiotics.

Regarding antibiotic use, the researchers found that the odds of CDI increased 3.34-fold when the perioperative antibiotic is continued more than 24 hours after surgery, outside of the perioperative window. Antibiotic use, other than the perioperative antibiotic, while in the hospital also was associated with 2.2 times greater odds of CDI. And exposure to antibiotics as long as six months before surgery increases the odds of CDI more than threefold.

“Although the surgeon cannot necessarily control the antibiotics prescribed to their patients in the year leading up to surgery, they can control antibiotic administration in the perioperative and postoperative period,” Dr. Bernatz said. “Antibiotics should be limited to one prophylactic preoperative dose, unless 24 hours of antibiotics are indicated. In the immediate postoperative period, antibiotics should be used judiciously.”

Other significant risk factors included number of hospital admissions in the past year and proton pump inhibitor or histamine type 2 receptor blocker use in the previous six months. “Previous studies have shown a correlation between CDI and hospital admission in the previous 3 months,” the researchers wrote. “Our study reports that this association extends to 12 months. We found that the number of hospital admissions in the past year increases the odds of CDI by 133% for each admission.”

A higher American Society of Anesthesiologists (ASA) physical status classification also was a significant risk factor for CDI; ASA IV or V patients were 15 times more likely to develop CDI than those with ASA class I or II disease, according to the researchers.

Dr. Bernatz said additional research is needed to further reveal these links. “Other studies could examine the rate of C. diff infection between operations within one subspecialty to determine if certain operative variables or patient characteristics affect the postoperative risk of C. diff infection,” he said.

The Latest Developments in C. diff Research and Treatment

 

 

 

 

 

The Program Podcast is Now Available —

Listen at your leisure as our guest, Dr Mary Beth Dorr, PhD, Clinical Director, Clinical Research, Infectious Diseases, and he product development team lead for bezlotoxumab, Merck & Co., Inc.  provided us with an overview of a C. diff. infection, the challenges of recurrence, the latest clinical research overview, current treatment landscape, and pending new C. diff infection treatment guidelines from the Infectious Diseases Society of America (IDSA) that are anticipated to be released fall of 2017.

Click on the C. diff. Spores and More Logo to be connected to the podcast