GMP Fecal Studies with Custom Chamber and Sterilization Port

Abstract

Fecal microbiota transplant (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI) but has undefined composition and poor scalability. In vitro manufactured live biotherapeutic products (LBP) enable both scalability and defined strain composition but with higher manufacturing complexity, resulting in few LBP clinical trials. Here we show how an accessible platform to produce human-grade LBPs could accelerate LBP development. We provide regulatory documentation and manufacturing protocols to facilitate translating microbiome advances to human trials. With this platform, we conduct the first direct comparison of the same bacterial strains from donor sourced FMT compared to an in vitro manufactured 15-strain LBP drug product MTC01 for the treatment of recurrent Clostridioides difficile infection. In a phas 1b randomized controlled trial, 18 of 20 screened patients met eligibility and were randomized equally to one of four arms: low dose FMT (N=4), high dose FMT (N=5), low dose MTC01 (N=4), or high dose MTC01 (N=5) with a 5:1 female to male ratio. The primary outcome of safety was met with 10 adverse events across 8 patients, evenly spread across MTC01 (5 events)n and FMT (5 events) recipients and no treatment-related adverse events across all four groups. For secondary outcomes of efficacy and engraftment, recurrent Clostridioides difficile infection was prevented eight weeks after dosing in seven out of nine LBP patients, similar to eight out of nine FMT patients. Strain engraftment was high and durable for both FMT and MTC01 with a dose effect for the LBP ClinicalTrials.gov identifier: NCT05911997.