All right. I'm Stephen Willey, one of the senior biotech analysts here at Stifel, and glad to have with us from MEI Therapeutics, CEO David Urso. David, thanks for joining us here today. Not sure if you wanna make any kind of opening statement before we jump into Q&A. I know you've had a fairly busy month here with respect to some incremental announcements coming from the pipeline.
Yeah. No, thanks for having us. It's always good to, to speak with you. We have had a lot going on recently. I guess just at the top, I would say that we just had our annual, strategic board session. And it's been really gratifying that we've got the management team and the, and the board really aligned on what the plan going forward is for both the programs, and we've had recent press releases, articulating all of that. But in a, in a nutshell, you know, and we'll get into all the details, I'm sure, later on in our talk, but, we saw, we saw interesting activity with 344, interesting clinical activity, and it exceeded the bar that we had internally set, which was like a quasi-utility analysis to get to the next 20 patients.
But in the grand scheme of things, we thought it would just be a better use of resources, and really it would create a better opportunity for the drug to move to a new formulation that we're developing in order to really get the drug on board for more days throughout the cycle, and get that synergy with VEGF inhibition that we've been, you know, hypothesizing that's at play in the indications that we've been pursuing. So that's, you know, that's what we've decided to do there. And we can get into, like, the ramifications for a dividend that was tied to that decision also, we can speak to that. And then with voruciclib, where we are right now is, you know, there's a lot of enthusiasm with the investigators, and they keep, you know.
Our cohorts just fill in as soon as they are open. There's a huge unmet need in the relapsed AML population that we're addressing. So I'd love to speak about that, but we are doing a two-week on, two-week off expansion cohort right now. In addition to that, we're going to be looking at a three-week on administration of voruciclib, and we'll have the data from both those cohorts in the second half of the year. So you know, that's, I think, some really exciting data that's gonna be coming out for us. And then based on that data, we've got a plan to really, for voruciclib, generate phase II data by the end of 2025.
And along with some of the core clinical work that we have to do and CMC development work to get a phase III-ready drug product, basically by the end of 2026, be ready for phase III. So we feel like we can move very quickly, relatively inexpensively to create a lot of value. It'll all be gated by, you know, the requisite data and financing. But you know, I feel like it's an exciting opportunity for the company, especially given kind of the real disconnect with what we perceive the value in the assets is and where the stock's trading. So I'd say in a nutshell, that's kind of where we are right now.
Okay, great. Maybe we can start with ME-344.
Sure.
So I know you characterized this as an inhibitor of mitochondrial oxidative phosphorylation. And I guess before we get to some of the data and some of the next steps of the asset that you alluded to, maybe you can just kind of expand upon, you know, what the preclinical data tells you this drug is mechanistically doing at the mitochondrial level.
Sure.
And then why you're looking to specifically leverage this mechanism in combination with an anti-angiogenic like bev-
Mm-hmm
I n an indication-
Mm-hmm
L ike colorectal?
Yeah. So this was based on a lot of work that Miguel Quintela-Fandino from CNIO in Madrid did with us, and he showed in various models using PET scan, that if you administer a VEGF inhibitor, it inhibits the production of ATP through glycolysis. But tumors are very plastic, and they'll move to the mitochondria to produce ATP through oxidative phosphorylation. And vice versa, if you just, if you gave 344, you can, you know, the tumors take a little bit of a near-term hit, but they're very comfortable, and with the Warburg effect, they're very comfortable producing energy through glycolysis. So, what he did was then he put both end mechanisms together and really flatlined these tumors.
That was very intriguing to us, and he did it with multiple TKIs in addition to 344 and in multiple tumor models. And so we decided. Well, the next step in the development was to work with him because he's a breast cancer physician. In Spain, women, when they want to have a mastectomy, there's a two- or three-month waiting period before they can have surgery, and so he used this kind of window of opportunity to administer one cycle of 344 in addition to Avastin before the women received mastectomy, and we tracked Ki-67 scores. And this, all this data is in our presentation that's posted on our website.
But it showed, you know, in a controlled manner in 40 patients, that there was a significant decrease in Ki-67 when you, when you administer both agents together versus just Avastin alone. So after that piece of data, we went, and we looked to see where's Avastin used, and where's the most, you know, rational place for us to go to prove the concept in patients? And we had some advisory boards, and the, the guidance really was go into, you know, relapsed/ refractory CRC. There's huge unmet need there. There's not good prognosis for those patients. Avastin is used kind of throughout as a treatment paradigm paired with various, you know, other, treatments, and so. And, and the physicians were very confident that they could see a difference over just, you know, what Avastin alone would look like in a fourth-line colorectal patient.
So that's the study we just set up. We just did the first cohort of 20, and basically what we saw was definitely activity that everybody can perceive. Like I said, we set the bar at four patients going out, four of 20 going out, four months progression free, and we saw five, almost six. But really what it looks kind of like when you look at the data right now, you know, the OS data is still evolving, but the median PFS data kind of looks like regorafenib, I would say. And, you know, like in baseball, singles, there's never a bad time for a single in baseball, right? But in small-cap biotech, that's really not the case, where we can't. We're not hitting singles. We're always, like, trying to hit the cover off the ball.
We just felt like, honestly, to do another 20 patients, we wouldn't really learn that much more, and the resources would be better utilized turning toward formulation work that we've been doing with the drug. Also, extending our runway and putting money in, you know, further resources into voruciclib, our CDK9 inhibitor. So, the one challenge with the way that 344 is currently formulated is it's got a very short half-life, and you know, we've been working for a while now on the formulation.
I don't wanna, like, say too much about it because we're still, you know, in the middle of it, but we feel like we're going to have the potential to dramatically expand the area under the curve and the amount of, you know, time the drug's on board through a course of the cycle, and make it much more convenient for patients. And, you know, in the end, if we're successful, just enlarge the commercial opportunity for the drug. And just change the PK so much that we think there could be a real potential change in the efficacy profile, and for not a lot of money.
'Cause really what we're gonna do over this next stretch of time is work on this formulation, prove it in the same animal models that we're already in, and then get it IND-enabled so that we'll be ready to get back into phase I, you know, in the relatively near term, while this next phase of voruciclib work is going on. So that's kind of the, what the strategy in a nutshell for 344 is.
Okay. So it sounds like the formulation efforts are kind of multifold in terms of wanting to increase exposure, improve patient convenience.
Yeah.
Does that mean that you'll have to functionally press the reset button on dose escalation, or are you gonna be able to bridge PK data to-
Yeah, that's a great question.
Formulation.
I think we will be starting over in a way just because the exposure's gonna be so different. Like, we've gotta make sure not only there's, y ou know, we've gotta see what the new tox profile of this different, you know, PK profile is. But that's not to say that we can't leverage some of the other work that's already been done with the same API. So that's a conversation with the FDA that we're gonna have to have, to know exactly how much we're gonna be able to leverage and, you know, what additional work we can do, we have to do.
But we feel like it fits nicely within the next, you know, period of time while we're creating value in voruciclib, so that we would, you know, end up, if we, you know, see the data we wanna see with voruciclib, get the finance we wanna do, we could end up at the end of that with, you know, phase III-ready asset and a phase I-ready asset with a completely, you know, new PK profile, and hopefully opportunity to not only address CRC, but really any disease where tyrosine kinase inhibitors are being used right now. VEGF are these tyrosine kinase inhibitors.
Okay. And I think you've talked about having, you know, established biomarkers for this mechanism that provides evidence of on-target activity, and I'm assuming that you can lean on those to help you guide your reformulation efforts. Is that a fair assumption?
I'd say we're working on it. We're still really working on exactly the protein target. We know it's doing pyruvate biosynthesis is being affected. We know that OXPHOS 1 is being affected, but we're, you know, creating mutant strain cell lines to really hone in on the protein target, and we're doing metabolomics in the patients that we just dosed. So the work is ongoing to really figure out exactly the protein target there. I would say with voruciclib, we've got a much better idea of exactly how the drug's working, and we've got nice data showing that it's going just as we had hypothesized.
Okay. So maybe with respect to voruciclib, you can, you know, elaborate a little bit on the mechanism-
Yeah
O f action.
Sure.
And then, I guess, why you've chosen to combine this with venetoclax within-
Yeah.
Within the formulation.
So venetoclax is a really important drug. It's being used, you know. Almost everybody who's elderly unfit in AML is getting it in combination with aza or maybe decitabine. It's being, you know, investigated even in the young and fit population on top of 7+ 3. It's also used in B-cell malignancies, you know, when you get progression after one or two BTK TK inhibitors. So it's a very important drug, but where it's not working is once you've progressed on venetoclax in AML, the treatment options are really dismal. So there's various things, standard of care range, like the response rates rarely you know, they kind of range from 6%-12% once you've progressed on venetoclax in relapse AML, and so that's roughly half the patient population.
So there's a lot of value and great enthusiasm around some of the very mutationally directed therapies like Menin inhibitors and FLT3 inhibitors and IDH inhibitors in AML right now. But, you know, our approach would, you know, take the rest of the half of that population. Like, that's basically half the population, and the other half, you know, we would be addressing. And at some point, even with those specific therapies, patients are gonna progress, and you're gonna need something else, so it's even really bigger than that half. So we think it's a big commercial opportunity. Now, as far as the biology goes, venetoclax increases MCL-1, and MCL-1 is a known resistance mechanism to BCL-2 inhibition, inhibiting apoptosis. And so.
And what's really nice, you know, we don't have the slides today, but they're in the deck that is with the conference presentation. And what you can see very nicely is in our trial design, because of FDA wanting to make sure that they could control for any kind of like CYP inhibition, which we haven't seen any problems with drug-drug interactions whatsoever, but we start off on venetoclax, and then we bring our drug on board. And what you can see in the patients is MCL-1 levels increasing when they're just on venetoclax, and then when we bring on board voruciclib, they dive.
Then, unfortunately, like when we take the pedal off the gas after two weeks, you see that, you know, like you see blast counts, and the need for transfusions coming up again. So that's why we think 2 weeks on is really. W e're seeing a lot of interesting biology. We're seeing complete responses, we're seeing patients go transfusion-free, we're seeing blast counts getting driven down. But we think that we really need to be on board three, three weeks a cycle, not just two weeks a cycle. But as far as the biology goes, we're binding RNA Pol II. That's the direct target. That's inhibiting the transcription of MCL-1. MCL-1 is going down, and you also see data in our deck showing, for the best responses, you see the most decrease of MCL-1.
So the biology is really correlating nicely with what we're seeing in the clinic, and we think we're just, like, on the precipice now of just needing to have the drug on board longer during the course of the cycle, and then we're gonna see the clinical responses that we really wanna see. And we think that bar is, you know, somewhere, or like I said, the standard of care right now is around 12%. So if you see something like a doubling of that, somewhere 20%-25%, I think all the clinicians would be very happy with complete response rates in there in this population, and anything over that is just, you know, fantastic. So that's what we're shooting for, and we'll have that data at the end in the second half of this year.
We'll have first a look at a bigger cohort of patients, 12 patients with just the two-week on dosing regimen, and then we're going to be immediately starting dose escalation with three weeks on. So we'll have that, you know, coming in the second half of the year, too. So some really interesting data points to be looking at in the second half of this year with respect to voruciclib.
Okay. Maybe a couple safety-related questions. So, I guess this drug is potent against CDK9.
Yeah.
But there is, I think, some preclinical data that suggests that it's also potent against some of these other-
Mm-hmm
C DK isoforms, like four and six, and, I guess we haven't really seen any of that kind of classical four and six toxicity manifest, at least in development thus far. And maybe that's just a function of not having the drug on board long enough. So I guess the first question is, you know, how do you think about, you know, circumventing some of that four, six toxicity-
Yeah
I n contrast to kind of what the preclinical data says?
Yeah.
And then the second question: you know, I think there's been a couple of high-profile MCL-1 inhibitors that have run into cardiotox issues.
Mm-hmm.
Do you think that that's a mechanism-associated side effect? Is that something that you're proactively looking for, or do you think that the cardiotox that was seen with those is specific to the scaffolds of those, competitor molecules?
No, I think it's mechanistic for the cardiotox.
Mm-hmm.
Those were only antibodies or direct inhibitors of MCL-1. MCL-1's expressed in cardiac tissue, so that's the problem there. We're not directly inhibiting MCL-1, we're inhibiting the transcription of MCL-1, so it's a completely different approach.
Mm-hmm.
That's why we think we're not seeing the cardiotox. And then as far as the difference with four, six, it's really about residence time. We're just, like, not on. We're just on nine much longer than we're on four and six, and at the doses that we're dosing for these hem malignancies, it's just, you know, we don't. We just don't think we're hitting four, six hard enough to see those toxicities. We did see. We didn't, but the previous owner, Piramal, when they originally developed the drug, they were going after solid tumors, and they were dosing, as I said before, like they were going up to 650 mgs, and we're like at. We're maxing out at 300.
When you go that high, you can overcome that delta between, you know, the residence time for six, four, and nine. And so, you do see, like, GI toxicities and things like that.
Mm-hmm.
But we're not seeing it, you know, at the doses that we're giving it, and especially with that week off, and I think it's just because it's just much more avidly binding, nine to four, six.
Okay. So again, you talked about, you know, migrating from the two weeks on, two week off schedule to-
Mm-hmm
A three, three on, 1 off.
Mm-hmm.
I guess maybe another two-part question. So one, you know, what are the PK properties of this drug that allow for intermittent dosing without diminishing target engagement and clinical benefit?
Yeah.
And then too, is the pursuit of just more frequent dosing, is that just a function of the safety margin that you've seen to date, or is that informed by biomarker data? Would just be kinda curious about.
Yeah, I mean, it's kind of both. I mean, you know, we have seen at higher and higher doses, more and more reduction in MCL-1. But we've also seen peripheral blast counts after two weeks of voruciclib, and you take it away, boom, they shoot up. So personally, I think it's more about keeping the drug on board longer through the cycle than it is, like, increasing the dose.
Mm-hmm.
So that's why we're moving, you know, to the... And we're gonna find out because we're gonna start. You know, FDA asked us to start at 150 for three weeks on, so we're gonna do 150, 200, 250. At 250 is when we get the incremental exposure to the patient. And so I think that'll sort that out with that data set. And then the other question you had for me was what?
I guess just whether or not that has been. I think you just answered the safety and biomarker data. I guess the other question was just surrounding the PK properties of the drug that allow for intermittent dosing.
Yeah, the PK. So it's got a very high volume of distribution, even higher than zandelisib had, if you'll recall, you know, our PI3K, a pure PI3K delta inhibitor. So for solid tumor, that's incredibly valuable. But it also has a very long half-life of, like, 20 hours. So when we, like, model, basically, after we stop dosing it, you got a week where the drug's still hanging around, and then you, like, when we're doing two weeks on, two weeks off, the last week, it's the patient's totally clear. So that's why we think it's gonna be really interesting to see the three week on, because the drug will still be around for the. You know, obviously, we're dosing.
It'll be around for the week off, but, and you know, we won't be dosing it, but it'll still be around, and then we'll start up again. So we get even higher coverage through the cycle, and the toxicity looks really manageable right now. So we're really- we're not concerned about it at all. It's playing very nicely with venetoclax, like, we haven't seen any drug-drug interaction. There was some, like, you know, concern that you might see, either because of CYP3A4 inhibition, you might see something, and the two drugs are just playing really nicely together, actually. So we're not, you know, concerned about that.
Okay. Maybe just in the last couple of moments here, you can, you can kinda walk us through the efficacy update you provided last month.
Mm-hmm
M aybe you can just kinda contextualize that relative to, you know, what expectations are with respect-
Yeah
T o retreatment post-progression with venetoclax. I know-
Yeah
I know you've been using, you know, a fraction of the approved maintenance dose of Venetoclax, so presumably-
Well, yeah, I mean, so that's not exactly the right-
Mm
W ay to phrase it. So it's the approved dose when, you know, you're combining with a CYP3A4 inhibitor or the CYP3A4-
Mm
CYP3A4 inhibitor. So it's, it's the legal dose. It's just if there's this, you know, CYP3A4 inhib- potential for CYP3A4 inhibition. And so... But, you know, we'll see going forward where that's gonna come out because FDA has agreed with us that we're not seeing any DDI. So, but that is what we're gonna do with the three-week-on, we're gonna maintain that. It's gonna be the same thing. And in the- and then in the last dose, in the last week of the cycle, where we're, we're not dosing anything with the three-week-on, regimen, will go up again to 400 mg of venetoclax, just like we've been doing. So that'll be interesting to see how that all plays out. But it's, it's not like a unlabeled dose. It's a labeled dose if you're administering a CYP3A4 inhibitor.
So, yeah, so that's, that's that. And then, sorry, what was the last thing you said?
I guess the retreatment rate that is expected of venetoclax-
Yeah
T he post venetoclax.
Yeah.
So-
So the, I mean-
Right, 'cause these patients all have higher-
Which is true? O f what's been given these patients once they progress. You know, it really depends on what their mutational status is. If they got, like, a FLT3 up front, then they wouldn't get it. If they didn't, then they would. I mean, people are getting venetoclax again. Like, everybody in our cohort had received at one time venetoclax.
Mm-hmm.
Like I said, the only data that exists in the relapse population, I think we talked about this in November, where it was studied with venetoclax, it was in a completely venetoclax-naive population, obviously, 'cause they were just developing the drug. And even there, it had a 20% response rate. And so nobody knows what the true response rate of just venetoclax in this patient population would be today in a completely, you know, venetoclax-exposed population. But we know with those, we have a slide in the deck of the standard of care, and like I said before, it ranges between response rates of 6%-12%. But what I love about the data we've generated is that it's we know what's going on is not because of venetoclax.
Because of all the correlative work we said, we can see MCL-1 in the beginning of the study, in a way, like FDA kind of did us a favor by saying, like, "You can't start both at the same time with just start venetoclax," 'cause we see MCL-1 driving up when they're just on venetoclax. And then when we bring in voruciclib, we see MCL-1 tanking, and so that's really nice to see, like, the theory getting played out in actual data there. So the drug's working like it's supposed to, and again, like I said, and this is in the deck also, if you look at, you know, patients that don't respond, have stable disease, and then do respond, and obviously the ends are still smaller in phase I, but the biggest decreases in MCL-1 are correlated with the best clinical responses.
So we think that it's very powerful data saying this is not at all due to venetoclax, and it's clear that it's due to our drug. And I think, you know, we have very convincing data showing that.
Okay. Very good. That is it for time, David, but-
Hey, thanks.
I appreciate it.
I really appreciate it. You always ask great questions, and we really appreciate you, you know, having your interest in the company, so thank you.
We appreciate the time. Thanks everyone for listening. Have a great day.