ASH 2023 | Canakinumab plus darbepoetin in patients with LR-MDS following ESA failure

So for lower-risk MDS, I think now, for almost eight years, there’s been a ton of data supporting that this inflammatory cell state called pyroptosis, which is an inflammatory cell death, is quite central to the pathogenesis of MDS patients. And essentially multiple things can trigger this pathway activation, including gene mutations, and you ultimately get the enumeration of pleural inflammatory cytokines such as interleukin 1 beta. 

So canakinumab is this monoclonal antibody that basically targets interleukin 1 beta. It’s actually approved for very rare periodic fever syndromes. And given that this is potentially the critical cytokine, we ran a clinical trial with this in combination with darbepoetin for lower-risk MDS patients. I think from a translational side, we see exciting data in that we can decrease ASC specks, which is really showing the decreased activation of the inflammasome pathway. A couple of other correlatives suggest that we are hitting target both in peripheral blood and bone marrow. But I think unfortunately we’ve not really had the efficacy. So, so far, we have not had any patients with an objective response. And this builds upon a little bit Dr Garcia-Manero’s presentation now from last year, where they looked at single-agent canakinumab, with a relatively low hematologic response. 

I think the challenge is targeting a single cytokine may not be enough, and you may need to hit multiple pathways such as NLRP3, IRAK, and others. So, I think, could this be combined with other novel therapies in the lower-risk MDS space is an open question. The other one is, potentially this is molecular subset-driven, so TET2 or isolated epigenetic mutation patients may have the most upregulation of these pathways. Those patients are somewhat hard to find, but we are in expansion now and looking to treat some of those patients and see if efficacy can improve.