¹Universitätsklinikum Jena, Institut für Krankenhauspharmazie, Jena, Germany
²Universitätsklinikum Jena, Klinik für Innere Medizin IV, Jena, Germany

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Background: Developing innovative therapeutic strategies to restore gut microbiota has gained significant interest across various conditions, including gastrointestinal, metabolic, neurologic, hematological, inflammatory, neoplastic and infectious diseases. The approach of faecal microbiota transplantation (FMT) has emerged as a promising method to rebalance the intestinal microbial diversity and functionality by transferring a complex collection of microorganisms from healthy donors to patients. Dysbiosis in gut microbiota is increasingly recognized as one key contributor in the pathogenesis and activity of ulcerative colitis. Meta-analyses have shown, that FMT significantly improves remission rates in ulcerative colitis patients [1], [2]. However, colonoscopic delivery of FM cannot provide continuous, long-term administration and is associated with safety concerns for patients, limiting its widespread use.

Materials and Methods: Faecal microbiota (FM), faecal microbiota filtrates (< 0.2 µm, FMF) or placebo (0.9 % NaCl, PL) are double encapsulated in enteric-coated hypromellose capsules (Vcaps entericTM, Lonza). Donors undergo extensive screenings to exclude potential pathogens, in accordance with safety requirements from the Federal Institute for Drugs and Medical Devices (BfArM). To increase the transferred microbial diversity, a multi-donor strategy is used by pooling capsules from different donors. The frozen capsules are orally administered in patients enrolled in the FRESCO study [3] – a randomized, double-blind, placebo-controlled, three-arm, multicentre trial in patients with mild to moderate active ulcerative colitis.

Results: The investigational medicinal products (IMP) – double-encapsulated faecal microbiota (FM), faecal microbiota filtrates (FMF), and placebo (PL) – are classified as medicinal products that require a manufacturing licence. Therefore, a quality management system has been implemented covering all manufacturing and quality control processes in accordance with Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP) including comprehensive qualification and validation of the equipment used and the processes. In the setting of the FRESCO trial, each patient receives 600 capsules (FM, FMF or PL) over a period of 12 weeks by two successive supplies. More than 150 IMPs, corresponding to more than 90.000 capsules, have been released since the start of the study in 2023.

Conclusion: The encapsulation of fecal microbiota represents an innovative development in microbiome therapies, offering a convenient and effective method of treatment that simplifies application, improves patient safety, and may enhance compliance in comparison to colonoscopic application. Here, we present the qualified process of manufacturing frozen capsules according to GMP requirements and certified by inspections of the State Authority of Thuringia (TLV). The FRESCO study contributes to assess long-term clinical efficacy and safety of frozen multi-donor FMT in active ulcerative colitis.

Literatur

[1] Paramsothy S, Paramsothy R, Rubin DT, Kamm MA, Kaakoush NO, Mitchell HM, Castaño-Rodríguez N. Faecal Microbiota Transplantation for Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2017 Oct 1;11(10):1180-1199. DOI: 10.1093/ecco-jcc/jjx063.
[2] Feng J, Chen Y, Liu Y, Lin L, Lin X, Gong W, Xia R, He J, Sheng J, Cai H, Xiao C. Efficacy and safety of fecal microbiota transplantation in the treatment of ulcerative colitis: a systematic review and meta-analysis. Sci Rep. 2023 Sep 3;13(1):14494. DOI: 10.1038/s41598-023-41182-6
[3] Stallmach A, Grunert P , Stallhofer J, Löffler B, Baier M, Rödel J, Kiehntopf M, Neugebauer S, Pieper DH, Junca H, Tannapfel A, Merkel U, Schumacher U, Breternitz-Gruhne M, Heller T, Schauer A, Hartmann M, Steube A. Transfer of FRozen Encapsulated multi-donor Stool filtrate for active ulcerative Colitis (FRESCO): study protocol for a prospective, multicenter, double-blind, randomized, controlled trial. Trials. 2022 Feb 22;23(1):173. DOI: 10.1186/s13063-022-06095-1