EHA 2021 | Sabatolimab plus HMAs in high-/very high-risk MDS and ND-AML

Sabatolimab, or MBG453, is an anti-TIM-3 antibody that is being explored in combination with azacitidine or decitabine for the treatment of MDS or AML. It’s an interesting molecule. It binds to TIM-3, which is an immune receptor that is involved both in T-cell recognition of potential antigens, as well as maybe apparently expressed on leukemic cells themselves. And sabatolimab, as we’re understanding, may have a role both in the immune response to a tumor-like acute leukemia or MDS, as well as it may somehow interact with leukemic progenitors to limit their self-renewal.

And so, in this study, we have combined sabatolimab with azacitidine or decitabine, given the standard dosing and at various dose levels. And the current abstract is looking at a subgroup of patients who have either very high-risk or high-risk MDS, or newly diagnosed AML, who had not received hypomethylating agent before and received this combination. They’re generally higher risk patients, and one of the things we wanted to look at in this cohort, specifically, was mutation profiles, as well as whether there was an impact on high-risk mutation profiles for the response rate.

The responses have been presented previously. In general, we’ve seen that there’s a reasonably favorable response rate and safety profile for these patients. One of the things that we looked at in this current abstract is the duration of responses. And so, the durability of response, one of the mechanisms that we think that TIM-3 innovation might play, is by prolonging your response. If you can engage the immune system to maintain longer responses, then we should see that in more durable responses. And we saw median duration of response of around 21 months in those patients who achieved a complete remission with MDS. And it was actually very similar in the AML group. So, of the 25% of patients who achieved a CR, the median duration of that response was about 23 months.

We are also starting to look at [inaudible] to understand what is mediating this. There is a signal suggesting that IL-1β is regulated differently when exposed to sabatolimab, and whether that plays a role or explains some of the findings that we’re seeing with possible immune engagement of this compound.

Similarly, there’s lot of interest in looking at high-risk cohorts of patients. There are some groups of MDS and AML for which we really don’t have great therapeutic options. TP53 being the most well-known of that group. And so, we did look at some of both TP53 mutated patients, as well as looking at cohorts of patients with ELN high-risk disease. The overall response rate seems similar in these groups, as it did in the overall cohort, suggesting that even in this group that traditionally has very poor responses and duration of response, perhaps there’s something that we’re seeing with improvement here.

And so, I think that in general, the data that we’re presenting at EHA suggests sort of an ongoing reason to explore this combination in high-risk MDS and in AML, particularly AML that has some features of high-risk MDS. So, AML that has ELN high-risk mutations, or the so-called oligoblastic AML, that has overlapping features with myelodysplastic syndromes. And to see if in subsequent Phase II and III studies, if we continue to see these patterns and if sabatolimab has a role in improving the quality of responses, the percentage of patients who achieve a response and also the duration of response, to standardize [inaudible] in the future.