MaaT013 for ruxolitinib-refractory acute graft-versus-host disease with gastrointestinal involvement: Results from the ARES phase III trial

Abstract Introduction Refractory acute graft-versus-host disease (aGvHD) is a significant cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). Fecal microbiotherapy has shown promising results in several pilot studies involving patients with refractory aGvHD with gastrointestinal involvement (GI-aGvHD). Here we report primary efficacy and safety results from ARES (NCT04769895), a multicenter, open-label, pivotal, phase III study exploring the pooled allogeneic microbiotherapy MaaT013 in participants with refractory GI-aGvHD previously treated with systemic steroids and ruxolitinib. Methods AlloHCT recipients diagnosed with GI-aGvHD and identified as refractory to steroids and either refractory or intolerant to ruxolitinib (Mohty et al., 2020) were eligible for inclusion. The treatment period included a preparatory course of 2-day oral vancomycin [250 mg 4 times a day (D)] followed by rectal administration of 3 MaaT013 doses (on D1, D5 and D10). Each bag of MaaT013 (150 mL) contained a minimum of 1.35 × 1011 viable bacteria (109 viable bacteria per mL). A single supplementary MaaT013 dose was authorized in case of relapse after D28 if subject achieved at least a very good partial response (VGPR) by D28. The primary endpoint was GI overall response rate (GI-ORR) at D28 assessed by an independent review committee and based on the Mount Sinai Acute GvHD International Consortium (MAGIC) criteria. Secondary endpoints included all-organ ORR at D28, D56 and Month 3 (M3), GI-ORR at D56 and M3, overall survival (OS), and safety analysis. Here, we report primary analysis results after all participants completed at least the D28 visit or discontinued earlier, with a data cut-off (DCO) of 11-Nov-2024. Results At the DCO date, 66 adult subjects with grade II-IV GI-aGvHD received at least one MaaT013 dose (median number of doses=3; range, 1-4). Median age at informed consent was 55.5 years (range, 24-76); 53% (n=35) were male. Most subjects presented with grade III (58%, n=38) or IV (33%, n=22) aGvHD; 86% (n=57) were steroid-resistant and 14% (n=9) steroid-dependent, all were resistant to ruxolitinib. 77% (n=51) of patients had exclusive lower GI (LGI) involvement, 17% (n=11) had LGI and skin involvement, 3% (n=2) had LGI and liver involvement and 3% (n=2) had LGI, skin and liver involvement. The study met its primary endpoint, with a D28 GI-ORR of 62% (n=41), significantly higher than the pre-established 22% threshold (p<0.0001; 95% CI, 0.49 to 0.74). Most subjects achieved D28 GI-complete response (CR: 38%, n=25) or GI-VGPR (20%, n=13), while 5% achieved GI-PR (n=3). Responses for all-organ ORR were similarly frequent with D28 ORR of 64% (n=42), including 36% (n=24) with CR and 18% (n=12) with VGPR. At D56 and M3, GI-ORR was maintained in 49% (31 of 63 subjects; 95% CI, 0.36 to 0.62) and 44% (27 of 62 subjects; 95% CI, 0.31 to 0.57) of subjects, respectively, with a prevalence of GI-CR (37% and 36%, respectively). Average duration of response was 6.4 months (95% CI, 4.8 to 8.0). Up to the DCO date, with a median follow-up of 140.5 days, the median OS was not reached. The estimated OS was 59% at M6 and 54% at M12, exceeding the previously reported 12-month OS of 15% (Abedin et al., 2021). Importantly, the estimated OS was significantly higher in responders (i.e., achieving at least GI-PR at D28, n=41) compared to non-responders (n=25): 75% versus 28% at M6; 67% versus 28% at M12, respectively (Log-rank p<0.0001). The median OS of responders was not reached while it was 54 days in non-responders (95% CI, 24.0 to 116.0). MaaT013 demonstrated an acceptable safety profile despite the vulnerability of subjects with refractory GI-aGvHD. 34 treatment-related adverse events (AEs) were reported in 19 (29%) subjects. Of these, 7 events in 6 subjects (9%) were considered serious. Out of 26 fatal AEs, one was deemed related to MaaT013. Conclusion Results from the ARES study demonstrate that MaaT013 induces frequent and deep responses translating into prolonged survival and an acceptable safety profile in patients with aGvHD who previously failed both systemic steroids and ruxolitinib, a population characterized by poor clinical outcomes with limited therapeutic options. These positive primary analysis results support MaaT013 as the first microbiome-based therapy for the treatment of refractory aGvHD.