Tolerability and Pharmacokinetics of SYN-004, an Orally Administered β-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies

Roberts, Tracey; Kokai‐Kun, John F.; Coughlin, Olivia; Lopez, Barbara Valero; Whalen, Heidi; Bristol, J. Andrew; Hubert, Steven; Longstreth, James; Lasseter, Kenneth C.; Sliman, Joseph

doi:10.1007/s40261-016-0420-0

Cited by 28 publications

(25 citation statements)

References 24 publications

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“…Based on these encouraging data, ribaxamase was advanced into human clinical testing. Phase 1 clinical studies demonstrated that ribaxamase was well tolerated (Roberts et al 2016), Phase 2a studies confirmed that ribaxamase degraded CRO in the human GI tract (Kokai-Kun et al 2017), and a double-blind, placebo-controlled Phase 2b study designed to assess the ability of ribaxamase to prevent C. difficile-associated disease and antibioticassociated diarrhoea by protecting the gut microbiome from CRO-mediated changes is in progress (clinicaltrials.gov 2016).…”

Section: Introductionmentioning

confidence: 99%

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

et al. 2017

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Aim: To evaluate an antibiotic inactivation strategy to protect the gut microbiome from antibiotic-mediated damage. Methods and Results: SYN-004 (ribaxamase) is an orally delivered betalactamase intended to degrade penicillins and cephalosporins within the gastrointestinal tract to protect the microbiome. Pigs (20 kg, n = 10) were treated with ceftriaxone (CRO) (IV, 50 mg kg À1, SID) for 7 days and a cohort (n = 5) received ribaxamase (PO, 75 mg, QID) for 9 days beginning the day before antibiotic administration. Ceftriaxone serum levels were not statistically different in the antibiotic-alone and antibiotic + ribaxamase groups, indicating ribaxamase did not alter systemic antibiotic levels. Whole-genome metagenomic analyses of pig faecal DNA revealed that CRO caused significant changes to the gut microbiome and an increased frequency of antibiotic resistance genes. With ribaxamase, the gut microbiomes were not significantly different from pretreatment and antibiotic resistance gene frequency was not increased. Conclusion: Ribaxamase mitigated CRO-mediated gut microbiome dysbiosis and attenuated propagation of the antibiotic resistance genes in pigs. Significance and Impact of the Study: Damage of the microbiome can lead to overgrowth of pathogenic organisms and antibiotic exposure can promote selection for antibiotic-resistant micro-organisms. Ribaxamase has the potential to become the first therapy designed to protect the gut microbiome from antibiotic-mediated dysbiosis and reduce emergence of antibiotic resistance.

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Section: Introductionmentioning

confidence: 99%

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

et al. 2017

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“…Animal studies further showed that SYN‐004 was capable of degrading ceftriaxone in the GI tract of dogs and reduced microbial changes in the gut of pigs treated with ceftriaxone . Two phase I clinical trials showed that SYN‐004 was well tolerated and remained localized to the intestines . Two phase II clinical trials confirmed that SYN‐004 is capable of degrading systemically administered β‐lactam antibiotics that enter the intestines .…”

Section: Areas For Improvement and Targets For Emerging Therapiesmentioning

confidence: 95%

“…44 Two phase I clinical trials showed that SYN-004 was well tolerated and remained localized to the intestines. 45 Two phase II clinical trials confirmed that SYN-004 is capable of degrading systemically administered ␤-lactam antibiotics that enter the intestines. 46 A recently completed phase II clinical trial studied the ability of SYN-004 given orally in a 150 mg dose to prevent CDI in patients with a lower respiratory tract infection receiving IV ceftriaxone (NCT02563106).…”

Section: Prevention Of CDImentioning

confidence: 99%

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

Dieterle

Rao

Young

2018

Annals of the New York Academy of Sciences

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Clostridium difficile is the leading infectious cause of antibiotic-associated diarrhea and colitis. Clostridium difficile infection (CDI) places a heavy burden on the health care system, with nearly half a million infections yearly and an approximate 20% recurrence risk after successful initial therapy. The high incidence has driven new research on improved prevention such as the emerging use of probiotics, intestinal microbiome manipulation during antibiotic therapies, vaccinations, and newer antibiotics that reduce the disruption of the intestinal microbiome. While the treatment of acute C. difficile is effective in most patients, it can be further optimized by adjuvant therapies that improve the initial treatment success and decrease the risk of subsequent recurrence. Lastly, the high risk of recurrence has led to multiple emerging therapies that target toxin activity, recovery of the intestinal microbial community, and elimination of latent C. difficile in the intestine. In summary, CDIs illustrate the complex interaction among host physiology, microbial community, and pathogen that requires specific therapies to address each of the factors leading to primary infection and recurrence.

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“…[40][41] This agent degrades unmetabolised antibiotic in the host intestine in order to protect the gut microbiota from dysbiosis and is well tolerated. 42 Animal studies have demonstrated safety without interference with the systemic pharmacokinetics of ceftriaxone. 41 A phase 2 double-blind placebo-controlled study is ongoing and will examine safety and whether ribaxamase can reduce CDI risk.…”

Section: Difficile Infection Prophylaxismentioning

confidence: 99%

New and emerging therapies for Clostridium difficile infection

Martin

Wilcox²

2016

Current Opinion in Infectious Diseases

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(max 200 words)Purpose of review: Clostridium difficile infection has attained high prominence given its prevalence and impacts on patients and healthcare institutions. Multiple new approaches to the prevention and treatment of CDI are undergoing clinical trials. Recent findings:Bezlotoxumab is a monoclonal antibody against toxin B that has successfully completed phase three studies, demonstrating a significant reduction in recurrent CDI when given with standard of care antibiotics. Antibiotics under development include cadazolid and ridinilazole, while surotomycin has had disappointing phase 3 results. Multiple live biotherapeutics are being developed, including freeze thawed and encapsulated versions of faecal microbiota transplantation to improve the practicality of treating patients with recurrent CDI. Alternatives to faecal microbiota transplantation, that aim to improve safety, including a microbial suspension, RBX2660, and a complex spore formulation, SER-109, have progressed to phase 2 studies. A non-toxigenic C. difficile strain has also shown promise to prevent recurrent CDI. In addition, three C. difficile vaccines have progressed to phase 2/3 clinical trials. Summary:The diverse approaches to treating and preventing CDI offer substantial promise that new treatment options will soon emerge, particular ones that reduce the risk of recurrences.3

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Tolerability and Pharmacokinetics of SYN-004, an Orally Administered β-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies

Abstract: SYN-004 was well tolerated up to a single oral dose of 750 mg and multiple doses of 300 mg every 6 h for 7 days. The pharmacokinetic results support that SYN-004 remained localized in the intestine.

Cited by 28 publications

References 24 publications

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

SYN-004 (ribaxamase), an oral beta-lactamase, mitigates antibiotic-mediated dysbiosis in a porcine gut microbiome model

Novel therapies and preventative strategies for primary and recurrent Clostridium difficile infections

New and emerging therapies for Clostridium difficile infection

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