Safety and Tolerability of SER-109 as an Investigational Microbiome Therapeutic in Adults With Recurrent Clostridioides difficile Infection
Authors: Sims Matthew D. , Khanna Sahil , Feuerstadt Paul , Louie Thomas J. , Kelly Colleen R. , Huang Edward S. , Hohmann Elizabeth L. , Wang Elaine E. L. , Oneto Caterina , Cohen Stuart H. , Berenson Charles S. , Korman Louis , Lee Christine , Lashner Bret , Kraft Colleen S. , Ramesh Mayur , Silverman Michael , Pardi Darrell S. , De Ananya , Memisoglu Asli , Lombardi David A. , Hasson Brooke R. , McGovern Barbara H. , von Moltke Lisa ,   ECOSPOR IV Investigators, Hemaidan Anmar , Kumar Princy , Misra Bharat , Nathan Richard , Nguyen Hien , Pullman John , Williams Jeffrey , Acosta Idalia , Odio Alberto , Tran Huy , Smith Kent , Weinstock Leonard , Hansen Val , Georgetson Michael , Sheikh Aasim , Garcia-Diaz Julia , Arimie Calin , Andrade Gladys , O'Marro Steven , Esfandyari Tuba , Ritter Timothy , Mcnicol Baird Ian , Colman Ronald , Patel Meenakshi , Hernandez Lilliam , Adams Atoya , Walton Marie , Arsenescu Razvan , Shapiro Max , Cook Paul , Heuer Marvin , Bogdanovich Tatiana , Grimard Doria , Steiner Theodore , Butt Debra , Daley Peter , Gauthier Stephanie , Guimont Chantal , Kreines Michael , Berman Larry , Bennett Michael , Fogel Ronald , Moises Gutierrez Juan Carlos , Pedersen Peder , Bressler Adam , Nadar Venkatesh , Newton Eric , Diaz Jorge , Abbas Jalal , DuPont Herbert , Jamal Aamir , Talreja Neetu , Benjamin Sabrina , Ayub Kamran , Oguchi Godson , Pinero Jose , Ramesh Gowrappala , Sepe Paul , Brook Loren , Ruthardt Frederick , Surace Lindsey , Hussain Ayub , Rutland Travis , Schmalz Micahel , Degala Gourisankar , Phillips Raymond , Stock Kent , Bullock Jeffrey , Onwueme Kenolisa 
Published: February 2023

ImportanceA 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.ObjectivesTo evaluate the safety and rate of CDI recurrence after administration of investigational microbiome therapeutic SER-109 through 24 weeks.Design, Setting, and ParticipantsThis phase 3, single-arm, open-label trial (ECOSPOR IV) was conducted at 72 US and Canadian outpatient sites from October 2017 to April 2022. Adults aged 18 years or older with recurrent CDI were enrolled in 2 cohorts: (1) rollover patients from the ECOSPOR III trial who had CDI recurrence diagnosed by toxin enzyme immunoassay (EIA) and (2) patients with at least 1 CDI recurrence (diagnosed by polymerase chain reaction [PCR] or toxin EIA), inclusive of their acute infection at study entry.InterventionsSER-109 given orally as 4 capsules daily for 3 days following symptom resolution after antibiotic treatment for CDI.Main Outcomes and MeasuresThe main outcomes were safety, measured as the rate of treatment-emergent adverse events (TEAEs) in all patients receiving any amount of SER-109, and cumulative rates of recurrent CDI (toxin-positive diarrhea requiring treatment) through week 24 in the intent-to-treat population.ResultsOf 351 patients screened, 263 were enrolled (180 [68.4%] female; mean [SD] age, 64.0 [15.7] years); 29 were in cohort 1 and 234 in cohort 2. Seventy-seven patients (29.3%) were enrolled with their first CDI recurrence. Overall, 141 patients (53.6%) had TEAEs, which were mostly mild to moderate and gastrointestinal. There were 8 deaths (3.0%) and 33 patients (12.5%) with serious TEAEs; none were considered treatment related by the investigators. Overall, 23 patients (8.7%; 95% CI, 5.6%-12.8%) had recurrent CDI at week 8 (4 of 29 [13.8%; 95% CI, 3.9%-31.7%] in cohort 1 and 19 of 234 [8.1%; 95% CI, 5.0%-12.4%] in cohort 2), and recurrent CDI rates remained low through 24 weeks (36 patients [13.7%; 95% CI, 9.8%-18.4%]). At week 8, recurrent CDI rates in patients with a first recurrence were similarly low (5 of 77 [6.5%; 95% CI, 2.1%-14.5%]) as in patients with 2 or more recurrences (18 of 186 [9.7%; 95% CI, 5.8%-14.9%]). Analyses by select baseline characteristics showed consistently low recurrent CDI rates in patients younger than 65 years vs 65 years or older (5 of 126 [4.0%; 95% CI, 1.3%-9.0%] vs 18 of 137 [13.1%; 95% CI, 8.0%-20.0%]) and patients enrolled based on positive PCR results (3 of 69 [4.3%; 95% CI, 0.9%-12.2%]) vs those with positive toxin EIA results (20 of 192 [10.4%; 95% CI, 6.5%-15.6%]).Conclusions and RelevanceIn this trial, oral SER-109 was well tolerated in a patient population with recurrent CDI and prevalent comorbidities. The rate of recurrent CDI was low regardless of the number of prior recurrences, demographics, or diagnostic approach, supporting the beneficial impact of SER-109 for patients with CDI.Trial RegistrationClinicalTrials.gov identifier: NCT03183141