EHA 2026 | Results from a first-in-human study of a Type II JAK2 inhibitor (AJ1-11095) in myelofibrosis

The AJAX study is a first in human phase 1 dose escalation study of AJ1-11095. So this is a type 2 JAK inhibitor. So it’s very different than the four approved type 1 JAK inhibitors in that it binds the inactive conformation of JAK2, thereby at least pre-clinically extinguishing JAK-STAT signaling and clonal persistence of the cells. So it is a different angle of trying to more potently suppress a pathway that we believe drives the disease process. And it’s the first of its kind. So it’s kind of exciting because it is really credentialing what we saw in the laboratory in murine models where we see much more effect of a type 2 inhibitor in terms of controlling the clonal burden and reducing disease process in JAK2-mutant mice. 

So we did this phase 1 study 25 all the way to 125 milligrams once daily of the drug. There was no maximally tolerated dose. There were really no DLTs. Probably the biggest toxicity that we saw, which was anticipated, was myelosuppression, which was manageable with dose reduction, so anemia, manageable toxicity. And maybe most excitingly, we’re seeing that signal of activity even within the first 24 weeks in terms of very deep spleen responses. These are in patients who’ve already seen a type 1 inhibitor. So deep spleen responses. About 70% of patients at any time had an SVR 35 or second line. And actually, the median number of cycles was two prior to coming out of therapy. And then 65% of patients had a 50% or greater TSS reduction. So very deep spleen and symptom responses. 

And then early biomarkers of disease modification in terms of reduction in driver mutation. This is JAK2, CALR, and MPL, so the drug was active across the three, as one would expect. But we saw about, you know, maybe about 60% of patients had a 20% or greater reduction in their allele burden. In 24 weeks, 35% had a 50% or greater. So already seeing very early evidence of disease modification as well as reduction in cytokines that are also implicated in the disease. So we are excited to continue to expand at the recommended phase 2 dose of 75 milligrams daily of 11095 and then also look at other disease cohorts high-risk PV, JAK inhibitor naive MF. So the program is going to continue to expand. Lilly just took over the Ajax program, so it’s really skyrocketing. Very exciting approach. A novel twist on a theme that we’ve been looking at for over a decade. 

A lot of it really is to the credit of Ross Levine and his lab that has shown that when you use a type 1 JAK inhibitor that binds the active confirmation of JAK2, you still allow for heterodimerization with other proteins, with other enzymes. So there’s still activity. You don’t fully quench that pathway, which is fundamental to disease biology. Whereas with the type 2 inhibitors, you’re able to overcome that. So he showed very nicely in the lab that if you took JAK2 inhibitor exposed and now persistent clones, that you can rescue that and inhibit proliferation with a type 2 inhibitor going after it. In fact, in murine modeling, actually the best spleen responses and reduction of disease burden were in mice, that first saw RUX and then got 11095, the type 2 inhibitor. So, you know, it took that from the lab and translating it right into humans who’ve seen JAK inhibitors. We know that the mechanism of resistance is not by acquired JAK2 mutations, but by persistence of activated JAK2. So it really, it should work. I think we’re seeing it already in this phase one study in terms of spleen and symptom responses. So the rationale really follows very nicely.

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