Pooled Fecal Allogenic Microbiotherapy for Refractory Gastrointestinal Acute Graft-<i>Versus</i>-Host Disease : Results from Early Access Program in Europe

Introduction Acute graft-versus-host disease (aGvHD) is a major source of mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Fecal microbiotherapy has shown promising results in several pilot studies in patients with refractory gastrointestinal (GI)-aGvHD. Here we report long-term clinical outcomes of 154 patients diagnosed with refractory GI-GvHD treated with the pooled allogeneic microbiotherapy MaaT013 within an Early Access Program (EAP) in Europe. Patients and methods One hundred and fifty four patients (incl. two pediatric patients aged 12 and 15years) with steroid-refractory (SR) or -dependent (SD) GI-aGvHD (classical n=93, late onset n=16, chronic or overlap syndrome n=25, hyperacute n=20) were treated with MaaT013 as part of the EAP in Europe (France, Germany, Spain, Italy, Austria). These patients had previously failed 1 to 6 systemic aGvHD treatment lines (median 3; 134/152 received ruxolitinib). Most patients had grade III to IV aGvHD (13% grade II, 47% grade III, 40% grade IV). For each patient, a total of 3 MaaT013 administrations were planned every 7 +/- 2 days (median dose administered 3, range 1-3). Each dose comprised 30 g of feces in 150 mL of solution from 4 to 8 healthy donors administered by enema (except for 1 patient by nasogastric tube). Treatment response was calculated among treated patients based on aGvHD grading at day 28 (D28) compared grading at the time of the EAP request. Results At D28, the GI-overall response rate (ORR) was 51%: 46 complete response (CR 30%), 23 very good partial response (VGPR 15%), 9 partial response (PR 6%). GI-ORR was higher in grade II &amp; III GvHD patients compared to grade IV (65% in grade II, 64% in grade III, 30% in grade IV) and higher in SD versus SR (81% versus 45%). ORR considering all organs (n=154) was 49%, including 41 CR, 19 VGPR and 15 PR. At D56, GI-ORR was 44% with 50 CR, 13 VGPR and 3 PR, ORR was 42% with 47 CR, 12 VGPR and 5 PR (n=151). Administration of MaaT013 in the two pediatric patients was well tolerated. One patient was in VGPR at D28 (baseline grade IV, stage 0 skin and liver, stage 4 GI-aGVHD), the other was in complete response of GI and skin symptoms up to 12 months (baseline grade IV, stage 3 skin, stage 2 liver, stage 4 GI) but liver symptoms were not resolved at D28 (stage 2 liver, stable disease). Liver stage improved from month 6 (M6) without additional therapy. Overall survival (OS) was 53% at M6, 47% at M12, and 42% at M24. The median follow-up among surviving patients was 418 days (range, 27-1644).OS was significantly higher in patients achieving at least GI-PR at D28 (Responder, R; n=78) compared to patients in treatment failure (Non-responder, NR; n=76): 73% versus 34% at M6, 68% versus 24% at M12 and 58% versus 24% at M24 (Log-rank test p&amp;lt;0.0001). Median survival duration in R was 290 days versus 71 days in NR. Interestingly, in the subgroup of 58 patients previously treated with ruxolitinib as 2nd line and MaaT013 as 3rd line GI-ORR was improved being 59% at D28 (48% CR) and 54% at D56 (53% CR). ORR was 55% (43% CR) at D28 and 56% (53% CR) at D56. OS was 54% at M6, 49% at M12, and 40% at M24. OS was significantly higher in R patients, when compared to NR patients (79% versus 17% at M6, 75% versus 11% at M12, 61% versus 11% at M24) for R and NR, respectively, Log-rank test p&amp;lt;0.0001). Median survival duration in R was 444 days versus 42 days in NR. MaaT013 displayed a good overall safety profile in the EAP population: 37 serious pharmacovigilance cases were reported in 34 patients, including 24 cases reported in 23 patients considered possibly related to MaaT013 either by the physician or the company: infections/ bacteremia in 13 patients, sepsis in 6, rectal bleeding/ anorectal disorder in 3, C. difficile colitis in 1. 83 deaths have been reported. The causes of death were GvHD in 34 patients, severe infection in 30 (incl 5 COVID-19), relapse of underlying malignancy in 11, hemorrhage in 2, neurological complications in 2, cardiac arrest in 2, acute respiratory distress in 1 and natural death in 1. Conclusion Overall, EAP clinical data showed that MaaT013 was a safe and effective treatment of refractory GI-aGvHD especially in patients having previously received ruxolitinib. Interestingly, the response to MaaT013 correlates with increased OS, suggesting a strong favorable benefit-risk profile for MaaT013. A Phase 3 trial is currently ongoing to confirm these results in ruxolitinib-refractory patients (NCT04769895).