Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

Background

Failure of gastrointestinal acute graft-

Methods

This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980).

Findings

Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters.

Interpretation

Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation.

Funding

MaaT Pharma.

Informations de copyright

© 2023 The Author(s).

Déclaration de conflit d'intérêts

FM reports honoraria from Therakos/Mallinckrodt, Sanofi and Novartis. TC reports consulting fee from Celgene, Abbvie, Jazz Pharma, Roche, Novartis, Agios and Servier and honoraria from Novartis, Amgen, Astellas, Celgene/BMS and Gilead/Kite. ED report payment for expert testimony from Astellas and support for attending meetings and/or travel from Neovii and Novartis. MJGTV report grants or contracts from MSD, Heel, Biontech and Roche, consulting fees from MaaT Pharma, Tillots, MSD/Merck, Roche and EUMEDICA and payment or honoraria from Merck/MSD, 3M, Ferring, Astellas, Uniklinik Karlsruhe, Uniklinik Köln, Akademie für Infektionsmedizin, Klinikum Essen, Pfizer, Universitätsklinikum Heidelberg, Uniklinik Frankfurt, Landesärztekammer Hessen, Janssen, Intitur Merieux, Forum für medizinische Fortbildung Gmbh, Universitätsklinikum Freiburg, Berliner Dialy Seminar, ADKA, Falk Foundation, St. Johannes Hospital, DiaLog Service, CED Service, Ärztekammer Niedersachsen, St. Josef Hospital, Limbach Gruppe SE, SUMIT OXFORD Ltd. EUMEDICA Kit Kongress, Tillots Pharma, Helios Kliniken, Lahn-Dill-Kliniken, GILEAD and Klinikum Leverkusen. CEB report honoraria from Astellas. EH report grants from Medac, payment for expert testimony from Novartis, participation on Advisory Board of Maat Pharma and Pharmabiome. JD is cofounder and member of the advisory board of MaaT Pharma, report consulting fees from MaaT Pharma, support for attending meetings and/or travel from MaaT Pharma and shares from MaaT Pharma. EPr, CG and EPl are MaaT Pharma employees and have patents as part of company inventor compensation policy MM reports grants and consulting fees from Sanofi, Novartis, and Janssen, honoraria from Sanofi, Novartis, Janssen, and MaaT Pharma, participation on Advisory Board of Janssen and leadership role in The European Group for Blood & Marrow Transplantation. All other authors declare no competing interests.