Welcome, everybody. Thanks so much for joining us. We have Geron here with us. Jim, hi. Before I jump into the nitty-gritty questions, why don't you take a minute or two? I'd love to hear what's happening, what's coming in 2024, what are you excited about, and where are we positioned heading into the new year? Great! Well, thanks an awful lot. I'm flattered to be here and appreciate the opportunity to chat with you. Look, 2024 is gonna be a transformative year for our company. After many years of developing the whole science of telomerase, telomerase inhibition, developing imetelstat as a telomerase inhibitor, the first and certainly first in class because it's the only telomerase inhibitor currently here. We completed our phase III and our lead indication, which was lower risk MDS, earlier this year. Outstanding results. On the basis of that, we filed an NDA in the mid part of the year, and then we also filed an MAA a couple of months thereafter. So we have both an NDA and an MAA pending. We have a PDUFA date, that is, in mid-2024, in mid-June, and we are preparing to become a commercial company. So there's lots going on. We also have a second indication, which is relapsed and refractory myelofibrosis. That's been a long time coming as well. We actually kind of started out at that space, had some really interesting phase II data that caused us to discuss with regulators, as well as many, many, many KOLs, the right approach to developing that very-- this very unique product for that space. We have an ongoing study that, as far as I know, is the only overall survival study in MF, and we expect to have, hopefully, in the first half of 2025, we hope to have an interim analysis that is, and that we have allocated sufficient sufficient statistical power, that if that were positive, we'd be able to file on that as well. So lots coming, and excited to be here and excited for this opportunity for the company. Excellent. Well, a very exciting 2024, it sounds like. Yeah. Let's start with the recent Phase 3 data, low-risk MDS. Yeah. You obviously show a great positive durability, good transfusion results. What's the key metric for commercial adoption in this market? And what are you gonna be messaging on once you launch? Assuming of course you get approved. Yeah. Yeah, wonderful question. Thank you. Yeah, so let's just do a quick tour back into where the market has been, how it's evolved to where it is, and where we expect it to evolve, and how we expect to be part of that evolution. So the low-risk MDS prior to the approval of luspatercept a couple of years ago was pretty much a quiet, not particularly well-served market. A lot of patients, you know, these. The principal problem for these patients, so everybody understands, is that they have a malignancy in the bone marrow, which actually causes red blood cell formation to be compromised. Malignant clones, malignant hematopoietic stem cell clones compromise all of that, and at the end of the day, they become transfusion-dependent. Transfusions, I will just leave it to well-described literature and every company that's developing a drug- Mm-hmm ... in any of these spaces to tell you how bad transfusions are. So, what we, when we first started developing the product, we saw that there-- we knew that luspatercept was coming, but beyond that, you basically had two, drugs that were out there, two types of drugs. One was, Revlimid, which is only used really effectively in a very small proportion of the low-risk MDS population, the so-called del(5q) population, and, is not terribly effective in, in the rest of it. It causes-- It's very important to note also some of the downsides of the existing products, because we'll come back and talk about them in the context of our data. You also, Revlimid is certainly known to cause prolonged myelosuppression. In fact, I would say a feature of all of the drugs that interact with the bone marrow are that in some way, shape, or form, the majority of them, not all, but the majority, do cause myelosuppression. And the second drugs were hypomethylating agents, HMAs, decitabine, azacitidine. They didn't even get approved in this indication, by the way, specifically for lower risk MDS, and they didn't really get approved on the basis of transfusion independence. They got approved in the use of high-risk MDS- Mm-hmm ...which kind of got, everything kind of got smushed together, and increasing hemoglobin levels in patients who had lower risk MDS. So it was a very undifferentiated, market. Luspatercept has done a great job of sensitizing this market to some of the possibilities. Good, you know, but relatively brief transfusion-free intervals, good safety profile. And they also, sensitized the market to the distinction between patients who are ring sideroblasts positive or RS positive- I was just gonna ask about that next. ... and ring sideroblasts negative. Those ring sideroblasts are structures in the bone marrow that you can use as a characterization of an important subgroup. Another important characterization of the way to look at these patients as we've become more sophisticated about it is where are they in their transfusion burden? It's really different to have somebody who's getting two units of red blood cells every eight weeks and somebody who's getting twelve. It's a really big difference, and it vastly impacts the ongoing survival of patients. Patients who receive large numbers of transfusions have a lower survival. They have you know end organ damage from the excess iron, and so forth and so on. So where we ended up with our phase III data was, first of all, we studied patients who were ESA, meaning EPO, right? ESA, relapsed and refractory. And we had a couple of really outstanding looks. The first one we showed outstanding durability of transfusion independence. If you look at the patients, the top line, you know, the primary outcome, efficacy measure was eight-week TI, but the patients who achieved eight-week TI in this study at the top-line data had a year of TI, actually. So they might have tripped the, the eight-week number, but then they went on. But really it was- Yeah, it was a year. It was a median of a year. We now have patients reported, and you can come to ASH, and we've already, you know, seen all the ASH abstracts that are out. At ASH, we are showing patients with a year TI, which is unprecedented. Especially in post-EPO setting. Exactly. And, but there they have a median of two years of TI, and the hemoglobin levels in those patients are responding incredibly. That's another feature of this drug. We saw in the patients who met the primary analysis, they had serum hemoglobin rises of 3.5, 3.6 grams per deciliter, much greater than any other drug out there. Now, we're seeing 5 grams per deciliter in that smaller responding patients who go over a year. Now, I wanna be clear. I think you were showing about 40% eight-week TI- That's correct. -levels. What proportion of patients are getting out past a year? What proportion of patients are truly stable? Yeah. So, eight-week TI, again, really a year, but eight-week, they clip the eight-week number, that's 40%. The 24-week is 28%, and then the year is 18%. Those, those are the actual numbers. Of the overall numbers. Yeah, of the overall numbers. And patients, of course, who don't have an eight-week TI still have what was always considered a very good outcome, which is you still see increases in hemoglobin, you still see decreases in transfusion burden. They just don't all become transfusion independent. But those numbers are really quite, those numbers are, again, very dramatically different compared to other products in the marketplace. Much, really, again, I'll use the word unprecedented in durability. Now, separately, if we look at the subgroup analyses, very important, again, market sensitized to RS positive and RS negative. So, in the second-line setting, the MEDALIST study for luspatercept, they didn't even study RS-negative patients. Mm-hmm. They knew that they were not gonna win there. They knew they were effective. They knew they were not gonna win there. And so we included both RS positive and RS negative patients, and the summary is we see the same effects in RS positive and RS negative. So the drug is, in effect, agnostic to whether they're RS positive or RS negative. Can you talk a little bit about the difference between those patients? Mechanistically, what is luspatercept missing that's keeping them out of RS negative patients? Well, I'll leave luspatercept's mechanism of action to the BMY folks to describe, because I don't wanna be accused of shortchanging them in that. But I will say that in general, erythrocyte maturation agents and as well as even EPO, they sort of promote immature cells, red cells to the right, to mature cells, and overcome what has been described as a maturation deficit. But that's very different. We're actually addressing the underlying disease itself- The malignancies. and the malignant hematopoietic stem cell clones that are mutated, and we can follow what happens. Just a quick commercial for this, it's not really a, you know, per se, a clinical outcome, although it's all highly correlated with clinical outcomes. But we can follow what happens to the malignant clones because they carry with them acquired mutations, and we can measure in the circulating daughter cells that come from those clones, white cells. We can actually measure the proportion of cells that carry that, those mutations, and we can also look, by the way, at the prognostic value of those mutations. We know some mutations are worse than others across many different malignant malignancies. But what we can tell you is this: the variant allele frequency, the proportion of cells, goes down substantially, more than 50%, in many, many patients who receive imetelstat. Yeah. Critically, if we're talking about removing some of these cells- Yeah. From the bone marrow, we have to go back to that cytopenia issue. Sure. Now, we have to talk about safety here. Yep. Obviously, you have some transient thrombocytopenia, but can you talk a little bit about the safety differentiation here, for a bone marrow activation? Yeah. So if you want to, if part of the, part and parcel of actually affecting the underlying disease is likely going to be effects on that are kind of predictable if you have a newer appreciation for what's going on in the marrow. So the way we put it together is this: that you have malignant hematopoietic stem cell clones. They're in the marrow. They're making red cells, white cells, and platelets. They may not work particularly well, but they are making them. They get counted. And then you have normal coexisting normal hematopoiesis normal stem cell clones. They coexist, but the highly proliferative malignant clones are requiring telomerase activation in order to maintain their replicative immortality. When you shut that off by giving a telomerase inhibitor, like imetelstat, those malignant clones apoptose and die. That causes the fall in the daughter cells, that the platelets and the white cells. But then the normal hematopoiesis picks that back up again, and you have very transient dips in both thrombocytopenia and neutropenia and- Now, one thing that you skated right over that, but I think is a very important point, is that the normal stem cells in the bone marrow here are less dependent on telomerase- Yeah. which is something that maybe is less familiar to folks who had a high school education on what stem cells were. Like I did when I started. Yeah. Yeah, so telomerase, you know, subject of a Nobel Prize, right? This is really big time science, now finally getting to the clinic. Woo-hoo! Many, many years later. What we see is that in normal stem cells, when they have to propagate and make their daughter cells, which we all have to do, telomerase is an enzyme that turns on very briefly and allows those stem cells to proliferate without shortening the telomeres. Every time a cell proliferates, every time a cell divides, the telomeres shorten, and if you don't turn on telomerase, it will eventually go through 30, 40 doublings, and boom, you're done, the cell apoptoses and dies. In the case of these heme malignancies, they constitutively turn on, Rather than pulsatile. -telomerase, rather than being pulsatile, as you said. That you can think of it as a square wave function, and it's that continually turned on telomerase that makes them susceptible to a telomerase inhibitor. Mm-hmm. That is what the differentiation is between a malignant and a normal cell or stem cell in this case, and that's why we don't see killing off the rest of the marrow. We only see a differential effect on the malignant cells. All right. I wanna talk a little bit about the regulatory, the ongoing regulatory review before we move to, Sure ... MF. But, obviously, as a first-in-class agent, you can expect a reasonable amount of scrutiny. That'd be pretty standard at the M- Absolutely ... at the FDA. What do you expect the ODAC to focus on? And in particular, do any of these transient neutropenias, thrombocytopenias, are they likely to be an issue for the agency? Yeah. So for just a couple of high-level comments about this. Number one, we tell the same story to everybody. We tell the same story to investors, we tell the same story to investigators, we tell the same story to regulators. It's, it's a story, and it's the story of the efficacy that we went over in quite some detail, the beautiful outcomes with the various subgroups, the ability to plug into the white space, in the existing drugs that are out there, that we can now do something to help patients. So that's the positive side. On the safety side and the mechanistic side of it, we point to a couple of really important things. Number 1, the real issue that every hematologist understands is what are the clinical consequences of thrombocytopenia and neutropenia? Do you have bleeding? Do you have associated infections? What are the numbers? How worried do I have to be? The answer is, it's very, very, I won't say minimal, I'll just simply say it's really, very manageable. So if you look, first of all, at a statistical level, if you look between the placebo arm and the imetelstat arm in our phase three, there were really no meaningful differences between the incidence of actual AEs associated with any of these. The second one is part of the narrative that we are evolving and will be telling, as we, you know, head into the commercial space, is: Well, what really happens? Okay, I've got a patient with grade three/four thrombocytopenia. Does that patient actually have bleeding? Majority don't. Take it the opposite way. I've got a patient who had some form of bleeding. Do they have thrombocytopenia at that time? Not necessarily. So you have to be careful with all of this. We think grade three/four, we always know what that means. Grade three/four thrombocytopenia, neutropenia, just those are just ways of characterizing what, what the actual levels are. It's a laboratory value. It's a laboratory value, and then you've got to look at what the AEs are- Does- and the AEs are dramatically not as impressive as the laboratory. Do these laboratory imbalances functionally unblind the study? Like, I can't imagine- Oh, that's a great, that's a great question. ... transfusion independence has a lot of- No, the reason that they don't is because they occur in the natural history of the disease. So if you look at our placebo arm, again, you see patients with grade three/four neutropenia and thrombocytopenia. Any one investigator only has a couple of patients. They sit there and they look, and they go: "Well, okay, somebody's got a grade three thrombocytopenia. Well, but I see that all day long in my practice. I don't know what that patient is on." And we were very, very careful with all the rest of the blinding procedures and, you know, and infusions, so on. So I, I don't, we do not believe that's an issue. Well, I wouldn't expect that there's a lot of placebo effect in transfusion independence, but... So, there's a little tiny bit. There's one guy who had a very prolonged placebo-associated, but he actually had this... He was an elderly gentleman in another country, and he loved coming into the clinic every week. And so he came in for a long period of time and kept refusing. He didn't really need anything, and by the time his hemoglobin finally got to five, somebody said- Right ... "Maybe you really need a transfusion here. Fair enough. In our last couple seconds- Sure. I do wanna touch on myelofibrosis. Yeah. We don't have a ton of time to go through. Yeah ... the Phase 2 results, but can you just touch on the choice of OS as an endpoint relative to spleen volume, which is much, much more common in these? Yeah in these trials? Well, it's because of the mechanism of action, this drug, we can do OS. I think, you know, spleen volume reductions, improvements in total symptom score, which we also see, by the way, in total symptom score. But reductions, these are really a function of interrupting with JAK inhibitors, the JAK-STAT pathway, and some of the products that come out of that. What we're really after is obviously being able to go after the underlying cause of the disease, and at the end of the day, the way to show that is with an overall survival. So we can do it. We're doing it. I think, we have very high hopes for this study, and of course, that's the ultimate, killer app, as it were, or golden BB, whatever, analogy you'd like to say, if you have overall survival. It's the only study that I'm aware of that is out there in overall survival in MF. Now, I will point out, we're going into passing time, but I'm gonna do it anyway, because I don't think there's anybody in this room after us. So I can ask you, you are starting in post-JAK setting. Yes. If you are addressing the underlying cause of disease, what's your feeling about the first line setting in competition with JAKs? So, first of all, I think that we saw this big prevalence population of people who had virtually nothing else available to them. And so, you know, part of your goal as a drug developer and a physician drug developer is to actually make sure that what you're doing is treating patients who really don't have other alternatives first. That's why many oncology applications go to the back end first. So that's where we went, and we showed very, very good Phase II results, and hence the Phase III program there. Frontline, we do have an interest in the frontline. I think frontline is very filled right now. The spigot got turned on about five years ago. We now have multiple recent JAK approvals. It's a fairly crowded space. We'll see what happens with the MorphoSys drug. Mm-hmm. We'll see what happens. We know that the add-ons, the BCL-2, and the- JAK inhibitors. - inhibitors, they maybe didn't do as well as some people thought they would. We have a small study, which is in the frontline. It's a mostly a safety study, looking at the effects of Rux plus imetelstat to see if we can combine effectively and safely, mostly safely, safety right now. But I think there is a compelling argument to bring disease modification, if you can achieve it- Mm-hmm ... forward into the, you know, earlier lines of therapy. And we have really good preclinical data that suggests that if you sort of sensitize the cell with JAK inhibitor, you can also then have a better improvement in, in the outcome if you add imetelstat. So we're very interested in that. Excellent. But that will be a while from now. Well, I didn't get to ask you about preparation for commercialization. I didn't get to ask you about a lot more of the phase III program in MF, but we are now well over time, and- Well, you just have to invite us back, and we'll be happy to talk about all that. Well, next year it'll be post facto. But, thank you so much for coming.