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. 2024 Oct;13(10):2105-2121.
doi: 10.1007/s40121-024-01007-z. Epub 2024 Jun 28.

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

Colleen S Kraft  1 , Matthew Sims  2   3 , Michael Silverman  4 , Thomas J Louie  5 , Paul Feuerstadt  6   7 , Edward S Huang  8 , Sahil Khanna  9 , Charles S Berenson  10 , Elaine E L Wang  11 , Stuart H Cohen  12 , Louis Korman  13 , Christine Lee  14 , Colleen R Kelly  15 , Alberto Odio  16 , Paul P Cook  17 , Bret Lashner  18 , Mayur Ramesh  19 , Princy Kumar  20 , Ananya De  11 , Asli Memisoglu  11 , David A Lombardi  11 , Brooke R Hasson  21 , Barbara H McGovern  11 , Lisa von Moltke  11 , Darrell S Pardi  9 ; ECOSPOR III and ECOSPOR IV investigators
Collaborators, Affiliations

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

Colleen S Kraft et al. Infect Dis Ther. 2024 Oct.

Erratum in

Abstract

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.

Methods: VOS or placebo [ECOSPOR III only] (4 capsules once daily for 3 days). Integrated analysis of treatment-emergent adverse events (TEAEs) collected through week 8; serious TEAEs and TEAEs of special interest collected through week 24; and rates of rCDI (toxin-positive diarrhea requiring treatment) evaluated through weeks 8 and 24.

Results: TEAEs were mostly mild or moderate and gastrointestinal. Most common treatment-related TEAEs were flatulence, abdominal pain and distension, fatigue, and diarrhea. There were 11 deaths (3.2%) and 48 patients (13.8%) with serious TEAEs, none treatment-related. The rCDI rate through week 8 was 9.5% (95% CI 6.6-13.0) and remained low through 24 weeks (15.2%; 95% CI 11.6-19.4). Safety and rCDI rates were consistent across subgroups including age, renal impairment/failure, diabetes, and immunocompromise/immunosuppression.

Conclusions: VOS was well tolerated and rates of rCDI remained low through week 24 including in those with comorbidities. These data support the potential benefit of VOS following antibiotics to prevent recurrence in high-risk patients.

Trial registration: ClinicalTrials.gov identifier, NCT03183128 and NCT03183141.

Keywords: Clostridioides difficile infection; Microbiome; Microbiome therapeutics; Recurrent C. difficile infection.

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Conflict of interest statement

Colleen Kraft reported serving on the scientific advisory board for Seres Therapeutics and serves as a consultant for Rebiotix/Ferring. Matthew Sims reported serving as an advisory board member for Prenosis, consultant for Applied BioCode, CorMedix, and Venatorx, and also reported serving as a principal investigator or co-investigator for the following companies: AstraZeneca, ContraFect, Crestone, Curetis GmBH, Pfizer, DiaSorin Molecular LLC, Epigenomics Inc, EUROIMMUN US, Finch Therapeutics, Adaptive Phage Genetics Biotest AG—PI, Dompe, Pfizer, Genentech USA Inc, Janssen Research and Development, LLC, Kinevant Sciences GmBH, Leonard-Meron Biosciences, Merck, Prenosis, QIAGEN Sciences LC, Regeneron Pharmaceuticals, Roche, Seres Therapeutics, Shire, and Summit Therapeutics. Christine Lee reported receiving grants from Rebiotix/Ferring, Seres, Merck and Summit Therapeutics to conduct clinical trials. Paul Feuerstadt reported serving as a consultant for Merck and Co. and also reported serving on the speakers bureau and on consulting/advisory boards for the following companies: Seres Therapeutics, Ferring/Rebiotix, and Takeda Pharmaceuticals. Sahil Khanna receives research support from Rebioitx/Ferring, Vedanta, Finch, Seres and Pfizer and serves as a consultant for ProbioTech, Takeda, Niche and Immuron. Colleen Kelly reported serving as a site investigator for Seres Therapeutics and Finch Therapeutics; serving as a clinical advisory board member (unpaid) for Openbiome; as well as serving as a consultant for Sebela Pharmaceuticals. Princy Kumar reported serving as an investigator/receiving research funds from ViiV, Gilead, Merck, and Theratechnologies; serving as a consultant for Viiv, Gilead, and Merck; serving on the Advisory Committee/Board for GSK, Gilead, and Merck; and is a shareholder of Pfizer, GSK, Gilead, and Merck. Brooke Hasson and Lisa von Moltke are employees and shareholders of Seres Therapeutics. Lisa von Moltke is an employee and shareholder of Seres Therapeutics and is also a shareholder and serves on the Board of Directors for Cara Therapeutics. Barbara McGovern, Ananya De, Elaine Wang, Asli Memisoglu, and David Lombardi are all former employees of Seres Therapeutics. Darrell Pardi reported receiving research grants from the following companies: Seres Therapeutics, Vedanta, Finch, Takeda, Applied Molecular Transport and also reported serving as a consultant for: Seres Therapeutics, Vedanta, Immunic Therapeutics, Abbvie, Otsuka, Ferring, Rise Therapeutics, Boehringer Ingelheim, and Summit. Paul Cook is a principal investigator for Gilead, Pfizer, Abbvie and the National Institutes of Health. Louis Korman, Charles Berenson, Mayur Ramesh, Bret Lashner, Alberto Odio, Edward Huang, and Stuart Cohen were study investigators. No other disclosures were reported.

Figures

Fig. 1
Fig. 1
Phase 3 clinical studies included in the integrated analysis of VOS safety and efficacy. RCT randomized controlled trial. Patients in ECOSPOR III who experienced CDI recurrence prior to 8 weeks post-treatment (indicated by rectangular box) were eligible to rollover into ECOSPOR IV. The same VOS treatment regimen (3 × 107 spore colony forming units [SCFUs] in four capsules once daily for three consecutive days) was administered in both ECOSPOR III and ECOSPOR IV. Blue solid lines indicate data included in the integrated datasets. Placebo data (dashed blue lines) were not included in the integrated datasets. Integrated data was available from 349 unique patients treated with at least one VOS dosing regimen (90 patients from ECOSPOR III [note that 4 of these patients received a second regimen in ECOSPOR IV], 25 placebo rollover patients in ECOSPOR IV, and 234 de novo patients in ECOSPOR IV
Fig. 2
Fig. 2
Integrated CDI recurrence rate in patients who received at least one dose of VOS in ECOSPOR III and/or ECOSPOR IV
Fig. 3
Fig. 3
Durability of response at 24 weeks among patients without recurrence through 8 weeks in patients who received at least one dose of VOS in ECOSPOR III and/or ECOSPOR IV. Among those patients with non-recurrence through week 8 (316/349; 90.5%), 93.7% (296/316) maintained a durable response through week 24
Fig. 4
Fig. 4
CDI recurrence rates in subgroups. CDI Clostridioides difficile infection; PPI proton pump inhibitor; VOS VOWST™ oral spores. Two patients enrolled in ECOSPOR III had missing or negative assay results for the qualifying episode and are not included. Two patients were enrolled in ECOSPOR IV on the basis of a positive loop-mediated isothermal amplification assay result and are also not included. One rollover patient in ECOSPOR IV was diagnosed by PCR alone; however, in the integrated analysis, all baseline information for rollover patients was recorded from ECOSPOR III and this patient is therefore included in the category “qualifying episode defined by toxin with/without PCR”. Four patients had missing CCI scores; 12 patients had missing baseline creatine clearance rate; one patient had missing data for number of prior CDI episodes. [1] Charlson Comorbidity Index (CCI) scores adjusted for age [20]
See this image and copyright information in PMC

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