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ASH 2021 | Pooled allogenic FMT for the treatment of steroid-refractory intestinal acute GvHD

Beyond steroid therapy, there are very few options available for the treatment of intestinal acute graft-versus-host disease (aGvHD). Several immunosuppressive approaches have failed to show benefit in this setting and thus, novel approaches to treatment are a great unmet need. Mohamad Mohty, MD, PhD, Saint Antoine Hospital, Paris, France, shares the findings from a trial of fecal microbiotherapy (FMT) for the treatment of gastrointestinal (GI) aGvHD, an approach aiming to improve microbial diversity and functionality to restore immune balance. The Phase IIa HERACLES trial (NCT03359980) treated 24 patients with grade 3-4 steroid refractory GI aGvHD with MaaT013, an investigational pooled allogenic fecal microbiotherapeutic. An additional 52 patients were treated in an expanded access program (EAP). The overall response rates were 38% and 60% in HERACLES and the EAP, respectively. Treatment response was associated with a significantly higher overall survival, compared to non-responders. The treatment was very well tolerated and microbiome analyses showed that MaaT013 successful increased microbiota diversity. These promising results endorse further investigation of the MaaT013 product. This interview took place at the 63rd ASH Annual Meeting and Exposition congress in Atlanta, GA.

Transcript (edited for clarity)

Hi, I’m Mohamad Mohty from the Sorbonne University at Saint-Antoine Hospital in Paris, in France. And it is my great pleasure today to give you a brief summary about a study we presented during the last ASH 2021 annual meeting in Atlanta. And this is about the use of pooled fecal microbiota transfer for the treatment of steroid refractory acute GvHD patients. And for the sake of introduction, I’d like to kindly remind all of you that steroid-refractory acute GvHD is a truly a big unmet need...

Hi, I’m Mohamad Mohty from the Sorbonne University at Saint-Antoine Hospital in Paris, in France. And it is my great pleasure today to give you a brief summary about a study we presented during the last ASH 2021 annual meeting in Atlanta. And this is about the use of pooled fecal microbiota transfer for the treatment of steroid refractory acute GvHD patients. And for the sake of introduction, I’d like to kindly remind all of you that steroid-refractory acute GvHD is a truly a big unmet need. And the mortality in this group of patients is very high and we really need new treatment options. For several decades, different immunosuppressive agents have been tested and unfortunately failed. Recently, we’ve seen the results of ruxolitinib, which is now approved in some countries. And the ruxolitinib is becoming an interesting and important option for many patients with steroid refractory acute GvHD.

However, we also know that it didn’t solve all the problems, and this is why we need novel and innovative approaches. Especially maybe moving beyond or moving away from the immunosuppressive activity and trying to restore the immune homeostasis, or immune balance. And this is exactly the principle, the rationale, behind using fecal microbiota transfer. And here in this communication at ASH 2021, we reported the results of the Phase II HERACLES multicenter European trial in patients with gut steroid refractory grade 3 and 4 acute GvHD. So these are the most severe patients, they’re hard to treat, but we also know that the prognostic of these patients is clearly linked to this GI involvement. And the patients here in this Phase II trial received the MaaT013 investigational product. So this is a drug made of a pooled donor, actually fecal microbiota, and it is developed and manufactured according to all state of the art, I would say, criteria.

And what is quite impressive is the very high overall response rate at day 28, because day 28 is the established, usually, endpoint you need to look for in this population with a high rate of complete remission, but also VGPR roughly around 40%. And we were also able to show through some very nice translational studies the proof of concept clearly showing that the use of this MaaT013 FMT product is able to engraft in the gut of these patients and the diversity is really improving. And there is clearly a correlation between the response and actually the engraftment of the product, but also what’s really interesting is that the survival of the patients who responded is really amazing compared to what you would expect in this population. And based on these important and very appealing results, we have also reported another series of 52 patients who received this investigational product, MaaT013, as part of an early access program.

And these were patients who were not necessarily eligible to the HERACLES trial. The inclusion criteria, of course, are different because cortico-dependent, for instance, patients were authorized, but also these were more advanced patients because most of them received other lines of therapies, including almost half of them receiving ruxolitinib. And here in this cohort of early access program patients, actually the response rates are really impressive, even better, I would say. Although, of course there’s no comparison there, but the results are really very exciting, further confirming what we have seen in the prospective trial. And most importantly, the responses have been seen very high in the ruxolitinib resistant and refractory patients. So in summary, it looks like that this MaaT013 product is clearly a new tool towards improving the outcome of these patients. Now we have dozens of patients being treated. The safety profile is excellent, no safety signal, no severe adverse events directly related to the use of the drug.

And obviously the next step is to move into a Phase III trial, which is about to start very soon. So clearly the field of acute GvHD is moving in the right direction. And I believe the modulation of the microbiota is now opening new perspectives, not only in the GvHD field, but I think beyond the GvHD field because we also know that the microbiota diversity and composition is playing a major role when it comes to the efficacy of chemotherapy, when it comes to response to CAR-T cells, but also when it comes maybe to improving wide spectrum of complications after treatment. So really very, very exciting era. And the modulation of the microbiota is likely to become a pillar of the interventions we do in hematology patients, and in cancer patients in general.

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