The results of the expanded access program using MaaT013 for steroid-refractory GI GvHD

Gastrointestinal acute graft-versus-host disease (GI aGvHD) is a serious complication of stem cell transplantation (SCT). Once a patient with GI aGvHD becomes resistant to steroids, ruxolitinib is the only approved therapeutic option. However, almost 40% of patients with GI aGvHD fail to respond to ruxolitinib and therefore, there is a pressing unmet medical need to identify new treatments. One solution could be using a standardized fecal microbiota transplant (FMT) product, as this circumvents the problem of donor sourcing. During the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, GvHD Hub Steering Committee member Florent Malard presented a talk about the novel microbiota therapeutic, MaaT013.¹

MaaT013 is a standardized, high-diversity, pooled-donor therapeutic microbiota product, which is manufactured under Current Good Manufacturing Practices conditions, with strict screening tests based on EU consensus recommendations. It is thought to work by restoring microbial networks and homeostasis. This leads to increased microbial diversity in the gut, which aids the restoration of epithelial intestinal barrier integrity. As a result, this product will increase competition among different bacterial species and could help in the eradication of multidrug-resistant bacteria in the gut. In addition, there would be an increase in production of short chain fatty acids, such as butyrate, which has a protective effect on gut endothelial cells and downregulates the immune response.

Key points

In an expanded access program for MaaT013, a total of 48 patients with steroid-dependent or steroid-resistant chronic or aGvHD with gut involvement at any time were treated. The 29 patients eligible for assessment are presented here.

These patients were given one dose of MaaT013 consisting of 10¹¹ colony-forming units (CFU) on Days 1, 8, and 15 by enema (except one patient who received treatment by nasogastric tube), and the response was assessed on Day 28. The patient characteristics of those included in this extended access program are shown in Table 1. Most patients had SR classical aGvHD, and 93% of patients had Grade III aGvHD at the time of FMT request.

Table 1. Patient baseline characteristics¹

For these patients, the median number of previous treatments for aGvHD was three (range, 1−5). MaaT013 was administered a median of three times (range, 1−3).

Efficacy

At Day 28, 59% of patients reported achieving at least a partial response overall, with 31% achieving a complete response (Table 2). In terms of the best GI response achieved until Day 28, 69% achieved at least a partial response. Results were similar in ruxolitinib resistant patients.

Table 2. Response to treatment¹

With a median follow-up in all patients of 111 days (range, 6−654 days), overall survival (OS) at 6 months was 52% (range, 31−69) reducing to 46% (range, 27−66) at 12 months. Similarly, in patients with ruxolitinib-resistant aGvHD, OS was 47% at 6 months and 39% at 12 months.

Safety

The 29 patients in this study received a total 71 doses of MaaT013. Overall, it was well tolerated, with only one possibly related case of sepsis in a patient occurring a day after their third dose. No pathogen was identified in blood cultures and the patient subsequently made a full recovery after a course of antibiotics. A case of C. difficile diarrhea was recorded 24 hours after the patient’s first dose, but it was suspected to be a nosocomial infection.

A phase II clinical trial HERACLES (NCT03359980) is currently ongoing to treat 24 patients with steroid-refractory Grades III−IV GI aGvHD with MaaT013 as first line treatment after corticosteroids. A total of 24 sites have been opened in four countries (France, Poland, Italy, and Germany) and 27 patients were enrolled. The last patient entered the trial in February 2020 and 58 enemas have been administered in total. There were five serious adverse events reported in two patients, however, the isolated strains were not detected in the MaaT013 product. Results will be presented at a major congress by the end of 2021.

Conclusion

In this small study in patients with steroid-refractory and steroid-dependent GvHD, MaaT013 induced promising responses even after ruxolitinib failure and proved to have the potential to become an effective therapy in this difficult to treat group of patients. Furthermore, MaaT013 was demonstrated to be safe in highly immunosuppressed patients, with only one case of sepsis that may have been related to treatment.