Tag Archives: C Diff Clinical Trials

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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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/.

 

 

Crestovo Doses Recurrent C. diff. Infection Patients In PRISM 3 – A Phase 2 Clinical Trial Testing CP-101 Microbiota

Crestovo doses recurrent Clostridium difficile infection (C. difficile) patients in PRISM 3, a phase 2 clinical trial testing CP101 (Microbiota).

The company is developing a Full-Spectrum Microbiota that harnesses the human gut microbiome. CP101, a first-in-class, lead microbiome therapy, is an encapsulated, single dose, orally-administered medicine that contains the full complement of functional microorganisms that may help restore the dysbiotic microbiota to a normal, functioning gut microbial community.

As Published in MD Mag :  http://www.mdmag.com/medical-news/phase-2-clinical-trial-tests-cp101-in-subjects-with-recurrent-c-diff

“CP101 has the potential to be the first therapy seeking FDA-approval utilizing the human gut microbiome,” Joseph Lobacki, chief operating officer, interim chief executive officer, Crestovo, said.

PRISM 3 is a multicenter, randomized, placebo-controlled trial evaluating the efficacy and safety of Microbiota in approximately 240 patients with recurrent C. difficile at clinical sites throughout the US.

Primary outcomes include a proportion of patients with no recurrence of symptomatic, laboratory confirmed C. difficile infection through 8 weeks, following administration of Microbiota, compared to the placebo, as well as a proportion of participants with adverse effects assessed by CTCAE v4.0 through 8 weeks mapped to system organ class.

Secondary outcome measures include a proportion of subjects sustaining clinical cure by a C. difficile subtype; through week 8, time to first recurrent C. difficile during the study at week 8 and 24; and a proportion of patients with no recurrence of symptomatic, laboratory confirmed infection at week 24.

Study arms include high dose full spectrum Microbiota, low dose full spectrum Microbiota and a placebo.

Inclusion criteria includes the ability to provide written informed consent, men or women 18–85 years age, a current diagnosis of a recurrence of non-severe, non-complicated C. difficile, and a clinical response to a standard course of oral vancomycin therapy to treat the current episode of recurrent C. difficile.

Top-line data from PRISM 3 is expected to release in December 2018.

Rebiotix Reports Topline Results From a Controlled Open-label Phase 2 Trial of RBX2660 (PUNCH Open Label) For the Prevention of Recurrent Clostridium difficile (C. diff.) Infection (rCDI)

In The News

April 2017

 

 

Rebiotix Inc., a clinical-stage microbiome company focused on harnessing the power of the human microbiome to treat challenging diseases, today announced topline results from a controlled open-label Phase 2 trial of RBX2660 (PUNCH Open Label) 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). RBX2660 is a broad-spectrum microbiota suspension that is designed to rehabilitate the human microbiome by delivering live microbes into a patient’s intestinal tract to treat disease.

Lee Jones, president and CEO of Rebiotix, stated, “The 78.8% treatment success achieved in this open label Phase 2 trial demonstrates the potential of RBX2660, a broad spectrum microbiota drug product, to rehabilitate the gut microbiome and break the cycle of C. diff. recurrence. These results, coupled with the safety and efficacy data observed in our prior Phase 2b and Phase 2 clinical trials, position Rebiotix to advance RBX2660 into Phase 3 clinical development, solidifying our standing as the most clinically advanced microbiome company in the industry.”

PUNCH Open Label was designed as a prospective, multicenter, open-label, controlled Phase 2 study to assess the efficacy and safety of RBX2660 for the prevention of recurrent C. diff.

The primary efficacy endpoint involved a comparison of patients treated with RBX2660 to a closely matched set of antibiotic only treated historical controls through 56 days. There were 31 active treatment sites and four control sites in the US and Canada. 132 RBX2660 and 110 historical control subjects were included in this topline analysis.

Actively treated patients, after determining eligibility, were administered two doses of RBX2660; the first at day one and the second at day seven. Patients were then monitored for eight weeks to determine whether there was a recurrence of C. diff.

Top line results from the trial, which examined responses from 132 patients versus a historical control of 110 patients, indicated a treatment success rate of 78.8% as compared to a historical control of 51.8% (p<0.0001). Overall, RBX2660 was generally well-tolerated with the most commonly reported adverse events being gastrointestinal, including diarrhea, abdominal pain, flatulence, constipation and distension.


About Rebiotix Inc.

Rebiotix Inc. is a clinical-stage microbiome company focused on harnessing the power of the human microbiome to revolutionize the treatment of challenging diseases. Rebiotix is the most clinically advanced microbiome company in the industry, with its lead drug candidate, RBX2660, expected to enter Phase 3 clinical development for the prevention of recurrent Clostridium difficile (C. diff.) infection. Previously, RBX2660 was the subject of three Phase 2 trials in recurrent C. diff, including a Phase 2b randomized, double-blind, placebo-controlled trial (PUNCH CD2), with data indicating the drug was well-tolerated and demonstrated statistically significant treatment efficacy. RBX2660 has been granted Orphan Drug status, Fast Track status and Breakthrough Therapy Designation from the FDA for its potential to prevent recurrent C. diff. infection.

Rebiotix’s development pipeline includes multiple formulations targeting several disease indications and is built around its pioneering Microbiota Restoration Therapy (MRT) platform. MRT is a standardized, stabilized drug technology that is designed to rehabilitate the human microbiome by delivering a broad spectrum of live microbes into a patient’s intestinal tract via a ready-to-use and easy-to-administer format.

For More Information About C. difficile Clinical Trials In Progress : 

https://cdifffoundation.org/clinical-trials-2/

 

For more information on Rebiotix and its pipeline of human microbiome-directed therapies, visit www.rebiotix.com

 

Source:  Rebiotix 4/17

Summit Therapeutics plc Outlines Phase 3 Program for Novel C. difficile Infection Antibiotic Ridinilazole

Clostridium difficile Treatment – Phase 3 program outline —

 

SUMMIT OUTLINES PHASE 3 PROGRAMME FOR NOVEL CDI ANTIBIOTIC RIDINILAZOLE FOLLOWING FDA AND EMA REGULATORY MEETINGS

Oxford, UK, On 1 February 2017 – Summit Therapeutics plc
the drug discovery and development company advancing therapies for Duchenne muscular dystrophy and C. difficile infection (‘CDI’),  outlines its Phase 3 programme for its novel antibiotic, ridinilazole, following recent regulatory meetings with the US Food and Drug Administration (‘FDA’) and European Medicines Agency (‘EMA’).

With input from the FDA and EMA, Summit intends to design the Phase 3 clinical programme to evaluate superiority of ridinilazole over standard of care in the treatment of C. diffiicle Infection (CDI).

A positive Phase 3 result on superiority has the potential to support the commercial launch of ridinilazole as a differentiated therapy that can both treat initial CDI and reduce disease recurrence.

Mr Glyn Edwards, Chief Executive Officer of Summit commented: “The constructive end of Phase 2 meetings with the US and European regulators have enabled us to design a Phase 3 programme that focuses on evaluating ridinilazole’s superiority over standard of care. This is something we believe would help differentiate our novel class antibiotic from currently marketed CDI treatments and those in late-stage development. Superiority in the combined measure of treatment of initial infection and importantly, reduction in recurrence, could position ridinilazole for front-line treatment of CDI.”
Summit discussed its Phase 3 development programme with the FDA at an End of Phase 2 meeting and through a scientific advice process with EMA. With input from both agencies, the Phase 3 programme is expected to include two trials evaluating ridinilazole as compared to the standard of care, vancomycin, each of which would enrol approximately 700 patients with CDI with the primary endpoint being superiority in sustained clinical response (‘SCR’). Other planned endpoints will include health economic outcome measures. The Phase 3 trial designs are consistent with the successful proof of concept Phase 2 trial, CoDIFy, in which ridinilazole achieved statistical superiority over vancomycin in SCR. SCR is a combined endpoint that measures cure at the end of treatment and a lack of recurrence in the 30 days after treatment. FDA also confirmed that ridinilazole would be eligible for Priority Review based on its QIDP designation.
Mr Edwards continued: “As we continue to evaluate our options to maximize the value of ridinilazole, our stronger financial position following the DMD programme partnership with Sarepta Therapeutics, Inc. means Summit has more time to fully explore all options. These include potentially entering into a collaboration with a third party or securing meaningful non-dilutive funding from government and charitable organizations. In parallel, activities

About Ridinilazole
Ridinilazole is an orally administered small molecule antibiotic that Summit is developing specifically for the treatment of CDI.

In preclinical efficacy studies, ridinilazole exhibited a narrow spectrum of activity and had a potent bactericidal effect against all clinical isolates of C. difficile tested. In a Phase 2 proof of concept trial in CDI patients, ridinilazole showed statistical superiority in sustained clinical response (‘SCR’) rates compared to the standard of care, vancomycin. In this trial, SCR was defined as clinical cure at end of treatment and no recurrence of CDI within 30 days of the end of therapy. Ridinilazole has received Qualified Infectious Disease Product (‘QIDP’) designation and has been granted Fast Track designation by the US Food and Drug Administration. The QIDP incentives are provided through the US GAIN Act and include an extension of marketing exclusivity for an additional five years upon FDA approval.

About Summit Therapeutics
Summit is a biopharmaceutical company focused on the discovery, development and commercialization of novel medicines for indications for which there are no existing or only inadequate therapies. Summit is conducting clinical programs focused on the genetic disease Duchenne muscular dystrophy and the infectious disease C. difficile infection.

Resources:

http://www.summitplc.com/media/press-releases/