SOHO 2026 | Phase IIa trial of ofirnoflast, a first-in-class allosteric NEK7 inhibitor, in ESA-refractory LR-MDS

Yeah, so I’m very excited actually by it. I do have some bias. You know, my first mentor, Alan List, like this is really his pioneering work for several decades and actually kind of a pivotal publication was now way back in 2016 in Blood that really shows that the NLRP3 inflammasome is essentially central to the pathogenesis of lower-risk MDS. So lots of different mutations, lots of different inflammatory events ultimately lead to this being activated. This then leads to what is called pyroptosis, which is inflammatory cell death. This also leads to elaboration of pro-inflammatory cytokines that kind of feed this whole thing. So we’ve wanted to target this literally now for a decade. There’s only been one prior agent, this is with Novartis or DFV890, which does target NLRP3 through a very different way. But the concern is it only inhibits the inactive form and not the active form of NLRP3. And unfortunately, and these data been presented by Dr Garcia Manero, really had zero efficacy, and that program has essentially been abandoned.

So this is an allosteric inhibitor of NEK7, which is essentially involved in the structure of NLRP3, and at least preclinically, and this is done by Amit Verma, as well as the company, rapidly dissolves these ASC specs, which basically show this kind of, it’s like a prion-like structure of a bunch of active NLRP3. This can actually further activate the whole process. So it makes them go away. It prevents new NLRP3 activation from happening. So preclinical data, great. What’s really cool is this is an oral drug, you know, from that, whereas, of course, luspatercept sub-Q, you know, every three weeks. And then we have imetelstat IV every four weeks. This is a once-daily drug. On the trial was five days on, two days off. Probably every day is how it would be done in the future. And so it was tested in a Phase I trial in India. And this was in essentially ESA relapses/refractory or intolerant patients. So low-risk only after ESA, a mixture of both transfusion-dependent and non, and response rates were about 50% and durable through the 32 weeks of study. So unfortunately on the study, kind of everybody ended at the end of that 32 weeks. So we don’t have long-term follow-up, although anecdotally some of these patients may still be responding from that perspective. But I would say, yeah, very high response rate and the magnitude of benefit is high. So actually the average hemoglobin improvement or the median was almost five grams per deciliter. So I think sometimes that’s been a struggle on luspatercept is what the delta has been. Imetelstat can get there, but maybe in a smaller percentage of patients. So really impressive, both response rate of transfusion independence, as well as the magnitude of it. And it seemed to be across all subsets. The only group that maybe did a little bit worse, I think they had about seven patients that were EPO greater than 500, which has predicted poor responses to other therapies. That was a little bit less, but very small numbers. And so where we are now at is essentially a dose optimization stage. So really, what is the perfect dose? We’re going to look across some dose levels. And then because our product optim, have sort of a randomized component where we’ll look at one of two doses. I think if we can validate anything close to what has been done in the original study, then I think it’s a guarantee that it would ultimately be a positive trial in Phase III. Of course, this will take us some years to answer. But I think the most exciting part is this next step. It’s coming to the multicenter, you know, US study opening like as we speak. And so hopefully in a year or two at the most, but somewhere in that ballpark, we will have the dose. And do we see the exact same data? We do see some cool correlative on-target effects, but really could be a game-changer in our low-risk MDS space. Still probably LUSPA is very solidified as frontline, but kind of in that second-line trial. And that’s what’s nice. We wrote this trial. You could have ESA, LUSPA, imetelstat. So not this only after one line of therapy. It’ll be easy to accrue from that perspective. We just don’t allow HMA exposure.

Yeah, so I would say the majority of responses, so for example, that were eight weeks, were at least durable through 16 weeks, I think was about 70 to 80%. So the challenge is how durable. And again, I think that was one of the negatives of the study, given patients, you know, essentially, you know, did come off on trial. So I think that will be, I think it’s at least, it’s at least durable in the fact that we think that 16-week TI matters, you know, in the updated IWG guidelines, that is the new, you know, the new change. So maybe about 40% of patients had at least 16-week, you know, TI, maybe a little bit higher than that. So I think it is durable, but how durable, and is it durably different than LUSPA, imetelstat, other options in the setting? We can’t answer that question. I think that will be a key consideration in the next step. I think to your question as far as sequencing, I may allude it a little bit to it. I think, you know, we are in this kind of SF3B1 mutant, you know, yes or no. If we take most low-risk trials, about two-thirds of patients have been SF3B1 mutant. Actually, very interesting, in the ofirnoflast study, it was only about 15%. And whether or not there’s a different frequency of SF3B1 in India, some of these questions have come up, or chance or whatever is a little bit unusual. But I do think, and we’ll answer that in the next part of the trial. But I do think for SF3B1, LUSPA, because survival is improved, is really no question frontline therapy. So I think it would be positioned as second line, potentially second line post LUSPA. I mean, imetelstat would be a consideration. And I think there could be pros and cons depending on what the data show. I think in the wild type, there’s still some unanswered. Some people still feel, hey, LUSPA for all, that was the primary endpoint of the commands. And it’s not that it was worse. I do think the EPO levels matter from that perspective as well. Like if EPO levels less than 100, ESA may be reasonable. So I think in the long-winded, I think in the wild type, I think this is still probably a second line. But whether or not it’s second line post ESA, post LUSPA, or maybe even post imetelstat in patients, let’s say, with the EPO level greater than 500. Probably this is a great, that great next option. I do think as we, let’s say, we’re excited by the dose optimization, it validates what we saw with the first Phase I study. We go into a pivotal Phase III, let’s say, after one to three lines of therapy. Then, of course, the question is, why not add this drug to everything else? This is a completely different mechanism of action, has nothing to do with erythroid maturation, has nothing to do with targeting telomerase. And so I could very clearly see, you know, could we do an add-on approach of, for example, LUSPA ofirnoflast for all patients? I think that could be a very cool concept. And so I think first will be get it established as second line, second or third line. And then next step would be probably more combination to be considered to get it part of frontline, more because LUSPA has really established itself there.

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