End-to-end donor screening and manufacturing controls: complementary quality-based strategies to minimize patient risk for donor-derived microbiome therapeutics.

Advances in microbiome therapeutics have been motivated by a deeper understanding of the role that the gastrointestinal microbiome plays in human health and disease. The FDA approval of two stool-derived live biotherapeutic products (LBPs), REBYOTA® 150 mL enema (fecal microbiota, live-jslm; formerly RBX2660) and VOWST® oral capsules (fecal microbiota spores, live-brpk; formerly SER-109), for the prevention of recurrent CDI in adults following antibiotic treatment for recurrent CDI provides promise and insights for the development of LBPs for other diseases associated with microbiome dysfunction. Donor-derived products carry risk of disease transmission that must be mitigated through a robust donor screening program and downstream manufacturing controls.

Integrated Safety and Efficacy Analyses of Phase 3 Trials of a Microbiome Therapeutic for Recurrent CDI.

Introduction: Recurrent Clostridioides difficile infection (rCDI) often occurs after standard-of-care antibiotics. VOWST oral spores (VOS, previously SER-109), an FDA-approved orally administered microbiome therapeutic, is indicated to prevent rCDI following antibiotics for rCDI.

Objective, Design, And Patients: To evaluate safety and efficacy of VOS from two phase 3 trials, (randomized, placebo-controlled [ECOSPOR III: NCT03183128] and open-label, single arm [ECOSPOR IV: NCT03183141]) of 349 adults with rCDI and prevalent comorbidities.

Impact of a Purified Microbiome Therapeutic on Abundance of Antimicrobial Resistance Genes in Patients With Recurrent Clostridioides difficile Infection.

Background: The gastrointestinal microbiota is an important line of defense against colonization with antimicrobial resistant (AR) bacteria. In this post hoc analysis of the phase 3 ECOSPOR III trial, we assessed impact of a microbiota-based oral therapeutic (fecal microbiota spores, live; VOWST Oral Spores [VOS], formerly SER-109]; Seres Therapeutics) compared with placebo, on AR gene (ARG) abundance in patients with recurrent Clostridioides difficile infection (rCDI).

Methods: Adults with rCDI were randomized to receive VOS or placebo orally for 3 days following standard-of-care antibiotics.

Manufacturing Processes of a Purified Microbiome Therapeutic Reduce Risk of Transmission of Potential Bacterial Pathogens in Donor Stool.

Background: Although fecal microbiota transplant has been used to prevent recurrent Clostridioides difficile infection (rCDI), documented pathogen transmissions highlight inherent safety risks of minimally processed stool. We describe manufacturing processes for fecal microbiota spores, live (VOWST; VOS, formerly SER-109), a microbiota-based oral therapeutic of Firmicutes spores.

Methods: Bacterial inactivation kill curves were obtained after ethanol exposure for 4 model organisms spiked into process intermediates.

Prevalence of Comorbid Factors in Patients With Recurrent Clostridioides difficile Infection in ECOSPOR III, a Randomized Trial of an Oral Microbiota-Based Therapeutic.

Background: Although comorbidities are risk factors for recurrent Clostridioides difficile infection (rCDI), many clinical trials exclude patients with medical conditions such as malignancy or immunosuppression. In a phase 3, double-blind, placebo-controlled, randomized trial (ECOSPOR III), fecal microbiota spores, live (VOWST, Seres Therapeutics; hereafter "VOS," formerly SER-109), an oral microbiota therapeutic, significantly reduced the risk of rCDI at week 8. We evaluated the efficacy of VOS compared with placebo in patients with comorbidities and other risk factors for rCDI.

Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection: A Phase 3, Open-Label, Single-Arm Trial.

Importance: A safe and effective treatment for recurrent Clostridioides difficile infection (CDI) is urgently needed. Antibiotics kill toxin-producing bacteria but do not repair the disrupted microbiome, which promotes spore germination and infection recurrence.

Objectives: To evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.

Assessment of Quality of Life Among Patients With Recurrent Clostridioides difficile Infection Treated with Investigational Oral Microbiome Therapeutic SER-109: Secondary Analysis of a Randomized Clinical Trial.

Importance: Recurrent Clostridioides difficile infection (CDI) is a debilitating disease leading to poor health-related quality of life (HRQOL), loss of productivity, anxiety, and depression. The potential association of treatment with HRQOL has not been well evaluated.

Objectives: To explore the association of SER-109 compared with placebo on HRQOL in patients with recurrent CDI up to week 8.

SER-109, an Oral Microbiome Therapy for Recurrent Infection.

Background: Current therapies for recurrent infection do not address the disrupted microbiome, which supports spore germination into toxin-producing bacteria. SER-109 is an investigational microbiome therapeutic composed of purified Firmicutes spores for the treatment of recurrent infection.

Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled trial in which patients who had had three or more episodes of infection (inclusive of the qualifying acute episode) received SER-109 or placebo (four capsules daily for 3 days) after standard-of-care antibiotic treatment.

Quilting emergent advanced practice nursing educator identity: an arts-informed approach.

Objectives: Arts-informed pedagogy in the graduate nursing classroom is used to support the integration of theory with advanced practice nursing (APN) competencies (Canadian Nurses Association, 2008, 2019).

Methods: Using the patterns of knowing (Carper, 1978; Chinn & Kramer, 2018), Iwasiw & Goldenberg's curriculum development model (2015) and practice development (McCormack, Manley, & Titchen, 2013), two course professors facilitated the delivery of an innovative arts-informed approach in a nursing graduate program, the Quilt.

Results: The Quilt was meant to invite graduate students to critically reflect and create a visual depiction of their emergent identities as advanced practice nurse educators (APNEs).

A Phase 1b Safety Study of SER-287, a Spore-Based Microbiome Therapeutic, for Active Mild to Moderate Ulcerative Colitis.

Background & Aims: Firmicutes bacteria produce metabolites that maintain the intestinal barrier and mucosal immunity. Firmicutes are reduced in the intestinal microbiota of patients with ulcerative colitis (UC). In a phase 1b trial of patients with UC, we evaluated the safety and efficacy of SER-287, an oral formulation of Firmicutes spores, and the effects of vancomycin preconditioning on expansion (engraftment) of SER-287 species in the colon.

The Efficacy and Safety of Fecal Microbiota Transplant for Recurrent Infection: Current Understanding and Gap Analysis.

The leading risk factor for () infection (CDI) is broad-spectrum antibiotics, which lead to low microbial diversity, or dysbiosis. Current therapeutic strategies for CDI are insufficient, as they do not address the key role of the microbiome in preventing spore germination into toxin-producing vegetative bacteria, which leads to symptomatic disease. Fecal microbiota transplant (FMT) appears to reduce the risk of recurrent CDI through microbiome restoration.

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

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.

Interferon Lambda 4 Genotype Is Associated With Jaundice and Elevated Aminotransferase Levels During Acute Hepatitis C Virus Infection: Findings From the InC3 Collaborative.

Symptomatic acute HCV infection and interferon lambda 4 (IFNL4) genotypes are important predictors of spontaneous viral clearance. Using data from a multicohort database (Injecting Cohorts [InC3] Collaborative), we establish an independent association between host IFNL4 genotype and symptoms of acute hepatitis C virus infection. This association potentially explains the higher spontaneous clearance observed in some patients with symptomatic disease.

A Novel Microbiome Therapeutic Increases Gut Microbial Diversity and Prevents Recurrent Clostridium difficile Infection.

Background: Patients with recurrent Clostridium difficile infection (CDI) have a ≥60% risk of relapse, as conventional therapies do not address the underlying gastrointestinal dysbiosis. This exploratory study evaluated the safety and efficacy of bacterial spores for preventing recurrent CDI.

Methods: Stool specimens from healthy donors were treated with ethanol to eliminate pathogens.

Dosing Recommendations for Concomitant Medications During 3D Anti-HCV Therapy.

The development of direct-acting antiviral (DAA) agents has reinvigorated the treatment of hepatitis C virus infection. The availability of multiple DAA agents and drug combinations has enabled the transition to interferon-free therapy that is applicable to a broad range of patients. However, these DAA combinations are not without drug-drug interactions (DDIs).

Underascertainment of acute hepatitis C virus infections in the U.S. surveillance system: a case series and chart review.

Background: In 2010, the incidence of hepatitis C virus (HCV) infection in the United States was estimated to be 17 000 cases annually, based on 850 acute HCV cases reported to the Centers for Disease Control and Prevention by local public health authorities. Absence of symptomatic disease and lack of a specific laboratory test for acute infection complicates diagnosis and surveillance.

Objective: To validate estimates of the incidence of acute HCV infection by determining the reporting rate of clinical diagnoses of acute infection to the Massachusetts Department of Public Health (MDPH) and Centers for Disease Control and Prevention.

Hepatitis C Virus Reinfection and Spontaneous Clearance of Reinfection--the InC3 Study.

Background: We aimed to characterize the natural history of hepatitis C virus (HCV) reinfection and spontaneous clearance following reinfection (reclearance), including predictors of HCV reclearance.

Methods: Data were synthesized from the 9 prospective cohorts of the International Collaboration of Incident Human Immunodeficiency Virus and HCV in Injecting Cohorts study, which evaluated HCV infection outcomes among people who inject drugs. Participants with primary HCV infection were classified as having achieved viral suppression if they had negative results of at least 1 subsequent HCV RNA test.

Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine.

Background & Aims: Hepatitis C virus (HCV)-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy.

Methods: This was a phase II, multicenter, open-label, single-arm study in treatment-naïve or peginterferon/ribavirin treatment-experienced HCV genotype 1-infected patients on methadone or buprenorphine±naloxone.

Patterns of hepatitis C virus RNA levels during acute infection: the InC3 study.

Background: Understanding the patterns of HCV RNA levels during acute hepatitis C virus (HCV) infection provides insights into immunopathogenesis and is important for vaccine design. This study evaluated patterns of HCV RNA levels and associated factors among individuals with acute infection.

Methods: Data were from an international collaboration of nine prospective cohorts of acute HCV (InC3 Study).

Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial.

Importance: Patients co-infected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are at high risk for liver disease progression. However, interferon-based treatments for HCV infection have significant toxicities, limiting treatment uptake.

Objective: To assess the all-oral 3 direct-acting antiviral (3D) regimen of ombitasvir, paritaprevir (co-dosed with ritonavir [paritaprevir/r]), dasabuvir, and ribavirin in HCV genotype 1-infected adults with HIV-1 co-infection, including patients with cirrhosis.