P0163 - The Impact of Age on Microbiome Diversity and Engraftment of Fecal Microbiota Spores, Live (FMS) in Patients With Recurrent Clostridioides difficile Infection
University of Houston College of Pharmacy Houston, Texas
Anne J.. Gonzales-Luna, PharmD1, Kevin D.. Litcofsky, PhD2, Timothy J. Straub, MS2, Dina Hot, PhD3, Brooke Hasson, PhD2, Matthew Sims, MD, PhD4, Jennifer R. Wortman, MS2, Matthew R.. Henn, PhD2, Barbara McGovern, MD2 1University of Houston College of Pharmacy, Houston, TX; 2Seres Therapeutics, Cambridge, MA; 3Aimmune Therapeutics, a Nestlé Health Science Company, Brisbane, CA; 4William Beaumont University Hospital and Oakland University William Beaumont School of Medicine, Royal Oak, MI
Introduction: Patients (pts) >65 yr of age have a higher risk of recurrent Clostridioides difficile infection (rCDI) than younger pts, possibly due to poor microbiome resilience after antibiotic discontinuation. In a post hoc analysis of two Phase 3 trials in adults with rCDI (ECOSPOR III and ECOSPOR IV), we analyzed effects of age on compositional/functional microbiome changes after treatment with fecal microbiota spores, live (FMS; formerly SER-109), an FDA-approved, oral, microbiota-based therapeutic comprised of Firmicutes spores given after standard-of-care antibiotics.
Methods: Stool samples were obtained from pts with rCDI following symptom resolution after antibiotics at baseline (pre-dose) and Week 1 post-treatment in the randomized, controlled ECOSPOR III trial and open-label ECOSPOR IV trial. Microbiome profiles were generated from whole metagenomic sequencing data using MetaPhlAn2. Microbiome diversity was reported with Shannon diversity, and engraftment was defined as newly appearing dose species from baseline (before FMS). Concentrations of secondary bile acid (2°BA), which inhibit vegetative C. difficile bacterial growth, were measured via targeted LC–MS panel. Subgroup differences (age, < 65 vs ≥65 yr) were analyzed with linear mixed models. Data from the placebo arm are included in the figures as a reference, but not included in the statistical models.
Results: A total of 362 baseline and 249 Week 1 stool samples were available for analysis. . At baseline, Shannon diversity was not significantly different between age groups and increased at Week 1; similar increases in diversity were observed (Fig. 1A). Engraftment magnitude after FMS was comparable between subgroups (Fig. 1B). Baseline 2°BA concentrations were comparably low in age groups in ECOSPOR III; 2°BA concentrations were significantly lower in ECOSPOR IV in those ≥65 yr (Fig. 1C). Concentrations of 2°BA were comparable between subgroups 1 week after FMS. Consistent with these compositional/metabolic changes, of 349 FMS-treated pts in ECOSPOR III or ECOSPOR IV, rCDI rates at Week 8 were low in both age groups (< 65 yr, 4.2% [95% CI, 1.7-8.5]; ≥65 yr, 14.2% [95% CI, 9.5-20.1]), while placebo rates in ECOSPOR III were 30.8% and 46.3% in pts < 65 and ≥65 yr, respectively.
Discussion: Pts in both age groups responded similarly, suggesting treatment with the oral microbiome therapeutic, FMS, may be beneficial in early restoration of microbiome diversity/function, regardless of age.
Figure: Figure 1. Microbiome data for ECOSPOR III and ECOSPOR IV patient samples by age subgroup (<65 years vs ≥65 years). (A) Shannon diversity at baseline and Week 1, (B) engraftment of newly appearing dose species at Week 1, and (C) 2°BA concentrations at baseline and Week 1 (shown on a logarithmic scale). *P=0.021. Abbreviations: 2°BA, secondary bile acid; FMS, fecal microbiota spores, live (formerly SER-109); ns, not significant (P>0.1). For additional study detail: ECOSPOR III: Feuerstadt P, et al. N Engl J Med. 2022;386-220-229; ECOSPOR IV: Sims MD, et al. JAMA Network Open. 2023;6(2):e2255758.
Disclosures:
Anne Gonzales-Luna: Cidara Therapeutics – Grant/Research Support, Payment to institution. Ferring Pharmaceuticals – Independent Contractor, Personal fees. Innoviva Specialty Therapeutics – Independent Contractor, Personal fees. Paratek Pharmaceuticals – Grant/Research Support, grant payment made to institution. Seres Therapeutics – Grant/Research Support, grant payment made to institution.
Kevin Litcofsky: Seres Therapeutics – Employee, Stock Options.
Matthew Sims: AstraZeneca – Grant/Research Support, principal investigator or coinvestigator. ContraFect – Grant/Research Support, principal investigator or coinvestigator. Crestone – Grant/Research Support, principal investigator or coinvestigator. Curetis GmbH – principal investigator or coinvestigator. DiaSorin Molecular LLC – Grant/Research Support, principal investigator or coinvestigator. Epigenomics Inc – Grant/Research Support, principal investigator or coinvestigator. EUROIMMUN US – Grant/Research Support, principal investigator or coinvestigator. Finch Therapeutics – Grant/Research Support, principal investigator or coinvestigator. Genentech USA Inc – Grant/Research Support, principal investigator or coinvestigator. Janssen Research & Development LLC – Grant/Research Support, principal investigator or coinvestigator. Kinevant Sciences GmbH – Grant/Research Support, principal investigator or coinvestigator. Leonard-Meron Biosciences – Grant/Research Support, principal investigator or coinvestigator. Lysovant – principal investigator or coinvestigator. Merck – Grant/Research Support, principal investigator or coinvestigator. OpGen – Grant/Research Support. Pfizer – Grant/Research Support, principal investigator or coinvestigator. Prenosis – Advisory Committee/Board Member, Grant/Research Support. Prenosis – principal investigator or coinvestigator. QIAGEN Sciences CLC – principal investigator or coinvestigator. Regeneron Pharmaceuticals – Grant/Research Support, principal investigator or coinvestigator. Roche – principal investigator or coinvestigator. Seres Therapeutics – Grant/Research Support, principal investigator or coinvestigator. Shire – Grant/Research Support, principal investigator or coinvestigator. Summit Therapeutics – Grant/Research Support, principal investigator or coinvestigator. Venatorx Pharmaceuticals – Advisory Committee/Board Member.
Jennifer Wortman: Seres Therapeutics – Employee, Stock Options, Stock-publicly held company(excluding mutual/index funds).
Matthew Henn: Aimmune Therapeutics – study funder, medical writing. Life Sciences Cares – leadership or fiduciary role in other board, society, committee or advocacy group (unpaid). Seres Therapeutics – study funder, study conduct, data generation, analysis of all included content, Stock Options.
Barbara McGovern: Seres Therapeutics – Employee, Stock Options.
Anne J.. Gonzales-Luna, PharmD1, Kevin D.. Litcofsky, PhD2, Timothy J. Straub, MS2, Dina Hot, PhD3, Brooke Hasson, PhD2, Matthew Sims, MD, PhD4, Jennifer R. Wortman, MS2, Matthew R.. Henn, PhD2, Barbara McGovern, MD2. P0163 - The Impact of Age on Microbiome Diversity and Engraftment of Fecal Microbiota Spores, Live (FMS) in Patients With Recurrent Clostridioides difficile Infection, ACG 2023 Annual Scientific Meeting Abstracts. Vancouver, BC, Canada: American College of Gastroenterology.
