Ladies and gentlemen, thank you for standing by and welcome to the Fourth Quarter 2020 Geron Earnings Conference Call. At this time, all participants are in the listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one on your telephone. If you require any further assistance, please press star zero. I would now like to hand the conference over to Olivia Bloom, Geron's Chief Financial Officer. Thank you. Please go ahead, ma'am. Thank you, Erica, and good afternoon, everyone. Thank you for joining us for today's conference call. I'm joined today by Dr. John Scarlett, Geron's Chairman and Chief Executive Officer, and Alexander Rizzo, our Chief Medical Officer. After the market closed today, we announced our fourth quarter and year-end 2020 financial results and operational highlights via press release, which is available on our website under geron.com/investors. In addition, a live webcast of this call is available on our website, and an archive will be available for 30 days. Before we begin, please note that this presentation and question-and-answer session will contain forward-looking statements relating to Geron's plans, expectations, timelines, beliefs, statements of potentiality, and projections. These include, without limitation, those regarding the expected timelines for completion of enrollment and the results from the IMerge phase III and IMpactMF clinical trial and submission of an NDA, the potential for positive outcomes from IMerge phase III and IMpactMF, potential approval of imetelstat by regulatory authorities and commercialization of imetelstat, the expectation that Geron's current financial resources will be sufficient to fund its operations until the end of 2022, and that imetelstat has the potential to be disease-modifying and alter the course of MDS and MF. These and other forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. These risks and uncertainties include, without limitation, those regarding that the company may be unable to overcome all the enrollment, clinical, safety, efficacy, technical, scientific, operational, manufacturing, and regulatory challenges to meet the expected timelines for IMerge phase III and IMpactMF due to COVID or otherwise, that in the phase III clinical trials, imetelstat may not prove to be as safe or efficacious as in the phase II trials and may not demonstrate that it is safe, efficacious, and disease-modifying, that regulatory authorities may not permit the further development of imetelstat on a timely basis or at all, and may not approve it for commercialization, and that Geron may need additional financial resources before the end of 2022 for the development and commercialization of imetelstat. Detailed information on the above risks and uncertainties and additional risks, uncertainties, and factors that could cause actual results to differ materially from those in the forward-looking statements are explained under the heading Risk Factors in Geron's Annual Report on Form 10-K for the year ended December 31, 2020, filed with the Securities and Exchange Commission. Undue reliance should not be placed on forward-looking statements. They speak only as of the date they are made, and the facts and assumptions underlying the forward-looking statements may change. On today's call, Dr. Scarlett will make a few introductory comments, after which I will cover the fourth quarter and year-end financial results, as well as guidance for 2021. Dr. Rizzo will provide clinical development updates on the ongoing IMerge phase III trial in our target patient population with low or intermediate one risk myelodysplastic syndrome, which we call low-risk MDS, who are transfusion-dependent, non-del(5q), and relapsed after or refractory to prior treatment with an erythropoietin stimulating agent, or ESA. She will also provide an update on our IMpactMF phase III trial, which is in a population of patients with intermediate two or high-risk myelofibrosis who are refractory to prior treatment with a JAK-inhibitor, which we call refractory MF. Alexandra will also discuss how the data and analyses we reported at the American Society of Hematology Annual Meeting in December 2020 have deepened our understanding on imetelstat's mechanism of action and its effect on the underlying cause of the disease and the indications we're pursuing. Dr. Scarlett will then comment on the evolving low-risk MDS and MF markets and imetelstat's positioning in those markets, given its potentially highly differentiated product profile. He'll finish the call with closing remarks on planned milestones for 2021. I'll now turn the call over to Dr. Scarlett, Geron's Chairman and CEO. John? Thanks, Olivia. I'd like to welcome everyone to our fourth quarter and year-end 2020 conference call. Let me start by sharing our vision for Geron, which is to become a leader in the treatment of hematologic malignancies by changing the course of these diseases, thereby improving and extending the lives of patients. As I look back on 2020, we made significant progress towards realizing this vision. To begin, we presented compelling and differentiating data from our IMerge phase II low-risk MDS trial. These data showed high rates and exceptional durability of transfusion independence. Of any study in non-del(5q) low-risk MDS patients who relapsed and were refractory to ESAs, the 20-month median duration of transfusion independence in IMerge phase II was the longest reported to date. In our IMerge phase III low-risk MDS study, enrollment gains continued, with over 50% enrollment achieved by the end of the year. We also presented exceptional overall survival data from our IMbark phase II trial in JAK- inhibitor relapsed or refractory MF patients. In this trial, imetelstat-treated patients had a median OS of 28 months, which is almost twice the median OS reported in the medical literature. Based on these and other supporting data, and after conferring with FDA, we opened IMpactMF, our phase III trial in JAK-inhibitor refractory MF patients. IMpactMF is the first and, to date, only phase III trial with overall survival as the primary endpoint. We also presented strong evidence of disease-modifying activity in our phase III of low-risk MDS and relapsed refractory MF. In both indications, we saw reductions in key driver mutations of the underlying disease. Furthermore, imetelstat's the only drug in development to establish a correlation of these and other measures of disease modification with key clinical outcomes, including durability of transfusion independence in low-risk MDS and improvement in MF. Such correlations have given us even greater confidence in the potential positive outcomes for our ongoing phase III IMpactMF. It stands out as important accomplishments in 2020. The first was that we successfully established our global imetelstat supply chain, ensuring uninterrupted drug supply for clinical trials and permitting inclusion of Geron-manufactured materials in our two phase III trials. Second, we raised over $175 million in new capital from both an underwritten public offering and a new loan facility. As a result, we expect our current cash will be sufficient to fund our operations through the end of 2022. All of these accomplishments were made despite the challenges posed by the ongoing COVID pandemic and the effect on clinical trial activities. Through trial all of the end of the year, and as of today, we've achieved 65% enrollment. As a result of the COVID pandemic, ongoing enrollment continues to be challenging. These enrollment challenges have been due primarily to the reluctance of patients to participate in clinical trials, as well as delays in opening new sites. These effects of the pandemic appear to be true for many oncology trials, not just ours. In addition, we believe enrollment in IMerge phase III may be starting to be impacted by luspatercept becoming more widely available as a treatment for patients who are RS positive in low-risk MDS. From everything we can see, the enrollment constraints in this trial are not a result of IMerge being inadequately prioritized by investigators. In our interactions with them, our investigators remain enthusiastic about our imetelstat data and are committed to enrolling their patients in this trial. Based on the information we currently have, we expect IMerge phase III to be fully enrolled in the second half of 2021. Depending on the exact timing when that full enrollment is achieved, we expect top-line results from IMerge phase III to be available from the end of 2022 to the first half of 2023. Alexandra will discuss in more detail the initiatives we put in place to improve enrollment in the face of the pandemic. She'll also update our activities in the conduct of IMpactMF. We currently expect the interim analysis for IMpactMF to occur in 2024 and the final analysis to occur in 2025. Looking ahead, our planned strategic priorities for the next three years in. John. Commercially launching this highly differentiated drug in low-risk MDS. Now, I'd like to hand the call. I'd like to call and hand the call over. Go ahead. I'm sorry. You were breaking up a bit just back there just right before for Alexander. Okay. We currently expect the interim analysis for IMpactMF to occur in 2024 and the final analysis to occur in 2025. Looking ahead, our planned strategic priorities for the next three years include achieving top-line results in IMerge phase III, gaining regulatory approval of imetelstat, and commercially launching this highly differentiated drug in low-risk MDS. Now, I'd like to hand the call over to Olivia to discuss our fourth quarter and year-end financial results and financial guidance for 2021. Olivia. Great. Thank you, John. As of December 31, 2020, we had approximately $260 million in cash, cash equivalents, and current and non-current marketable securities. Our cash position reflects net proceeds of approximately $140 million from a public offering in May 2020 and approximately $24 million in initial net proceeds from a non-dilutive $75 million loan facility that we closed at the end of the third quarter last year. Based on current planning assumptions, we estimate our current financial resources to be sufficient for our operations until the end of 2022. Overall, the financial results for the fourth quarter and year-to-date period were in line with our expectations and our operating expense guidance. Operating expenses for the three months and four months ended December 31, 2020, were generally higher in comparison to the same period in 2019 due to headcount increases in 2019 and 2020 across the company, increased activity for the IMerge phase III clinical trial in low-risk MDS, startup activities for the IMpactMF phase III clinical trial in refractory MF, and costs associated with ongoing imetelstat manufacturing. These increased costs were partially offset by lower costs related to purchases of raw materials, drug substance, and drug product, and completion of the IMbark clinical trial. Regarding financial guidance for 2021, we expect our operating expense burn to range from $108 million-$112 million, which includes costs for our two ongoing phase III clinical trials, production of validation batches of imetelstat at contract manufacturers to enable future production of imetelstat for clinical and commercial purposes, and preparatory activities for NDA and commercial readiness. Financial guidance is based on a set of assumptions at a point in time, and if the company's plans change, causing assumptions to be revised, then we will update guidance at that time. With that, I will now turn the call over to Alexandra to provide an update on our phase III clinical development activity. Alexandra? Thanks, Olivia. Good afternoon, everyone. As Chief mentioned, we have now achieved 65% enrollment in our IMerge phase III trial. Also, the first meeting of the Independent Data Monitoring Committee was held in December, and the IDMC recommended that the trial continue without modification. We expect the enrollment-boosting activities we started last year to become more effective as COVID cases decline and as clinical operations begin to hopefully return to normal over the next several months. As a result, we believe the clinical science liaisons we engaged in the beginning of last year will be able to interact with clinical sites more easily and with greater frequency to help alert site personnel and patients to the potential benefits of participating in IMerge phase III. In addition, we believe our social media campaign will help drive patient recruitment. Over the next few months, we expect all of the approximately 20 additional sites for IMerge will be open, bringing the total number of sites in this trial to approximately 120. Of course, the best boost to enrollment should come as vaccinations proceed, the number and severity of COVID cases decline, and patients again become more comfortable leaving their homes to participate in clinical trials. Earlier in this call, Chief mentioned some of the more mature clinical data from our IMerge phase II trial in low-risk MDS, on which I would like to expand on briefly. These data are very encouraging, and they continue to differentiate imetelstat from other currently approved or investigational treatments. Foremost is that imetelstat elicits remarkable durability for transfusion independence. In addition to the 42% of patients that achieved the primary endpoint of eight-week transfusion independence, 32% of the imetelstat treated patients were transfusion-free for 24 weeks, which was a key secondary endpoint. Furthermore, 29% of the patients were transfusion-free for over a year. We also reported a median duration of transfusion independence of 20 months. That compares very favorably to the most recent available data we've seen from Reblozyl, in which a median duration of transfusion independence of seven months was recorded. I'd also like to emphasize that these results have come from a patient population with very heavy baseline transfusion burden, and that the results were similar for both RS negative as well as RS positive patients. If similar results are obtained in our IMerge phase III, we believe imetelstat will be highly differentiated and very competitive treatment for the low-risk MDS patient population. Moving on to myelofibrosis. In his earlier remarks, Chief mentioned that in the IMbark phase II trial, the median overall survival was 28 months. This compares very favorably to the median OS of 13-16 months in the medical literature. The median OS also compares favorably to the OS of 12 months observed in real-world data analysis of relapsed refractory MF patients who were treated with best available therapy, and they were carefully matched with our imetelstat treated patients in IMbark. In addition to the overall survival, patients in IMbark experienced other important clinical benefits, including symptom improvement, spleen volume reduction, and bone marrow fibrosis improvement. These clinical benefits have been correlated to the improvement in overall survival. Based on these data and after conferring with FDA, we opened IMpactMF in December, which was one quarter earlier than expected. As mentioned, the IMpactMF is the first and to date only MF phase III trial with overall survival as the primary endpoint, which will be a key differentiating feature compared to other drugs in late-stage development for this population of patients. The same dynamics affecting enrollment in IMerge phase III are also affecting enrollment in IMpactMF, and in addition, we've seen startup of numerous other clinical trials in MF that will compete with IMpactMF for patients. We're using enrollment-boosting strategies for IMpactMF similar to those we have employed in IMerge phase III. These include expanding the number of countries and sites, engaging more clinical science liaisons, and utilizing a social media campaign. Under current planning assumptions, we expect that IMpactMF will reach full enrollment in 2024 and that the interim analysis may also occur in 2024 and the final analysis in 2025. Let me expand a bit on these timelines. The reason the interim analysis could occur in 2024 is because the primary endpoint of the study is overall survival. As a result, the timing of the interim analysis will be based on reaching a certain number of test events. Since these test events will occur throughout the enrollment period, it is possible that the number of events required to conduct the interim analysis could occur before enrollment is complete. I'd like to end my remarks by noting that we're reporting very important data linked to the mechanism of action of imetelstat that may be responsible for this remarkable disease-modifying activity of the drug we've seen in our phase II trials in both low-risk MDS and in MF. In low-risk MDS patients, we've observed reductions in key driver mutations at a molecular level and decreasing of cytogenetic abnormalities that indicate imetelstat kills malignant stem and progenitor cells by targeting telomerase. These molecular data were directly correlated with the clinical benefits of transfusion independence, providing strong evidence of disease-modifying activity of imetelstat. In IMbark, we also saw significant dose-dependent reductions in the mutation burden of key driver mutations for MF, as well as improvement in bone marrow fibrosis. These data were also correlated with improved overall survival observed in the IMbark trial, further strengthening the evidence of the disease-modifying activity of imetelstat. We believe that the clinical benefits of durable transfusion independence in low-risk MDS and improvement in overall survival in MF, along with the molecular data and their correlations, highlight the magnitude of imetelstat's unique mechanism of action of telomerase inhibition and provide strong evidence that imetelstat alters the course of MDS and MF. As a result, we have further confidence that we will have potential success in both IMerge phase III and IMpactMF. I'd like to now hand the call back to Chief to review the current MDS and MF marketplaces. Chief? Chief, we cannot hear you. There's something with your line. Let's try it again. Thanks, Alexandra. Historically, there have been few new treatments for hematologic malignancies, especially myeloid heme malignancies. However, in 2020, we saw a new approval for luspatercept in low-risk MDS and several new approaches being tested for MF, including many combination therapies. First, let's discuss last year's approval of luspatercept, trade name Reblozyl, in lower-risk MDS. This approval took place in April 2020 based on a phase III trial in non-del(5q) lower-risk MDS patients who were relapsed or refractory to ESAs and myelitis to HMAs. This trial enrolled only RS-positive patients. The launch of Reblozyl by Celgene and BMS appears to be strong, which validates the high unmet need and the market potential for these RS-positive lower-risk MDS patients. We expect a highly differentiated profile for imetelstat at launch in the lower-risk MDS market. In the patient population of our IMerge phase II trial that we targeted, as described by Alexandra, we've seen clinically meaningful transfusion independence across multiple MDS subtypes, including both RS positive as well as RS negative patients, low and high transfusion burdened patients, and patients with low and high EPO levels. Because of this differentiated and advantageous profile, we continue to expect imetelstat to play a significant role for this lower risk MDS patient population. For the MF landscape, Jakafi, ruxolitinib, remains the primary frontline treatment. Although the number of investigational treatments, including combination therapies, has increased over time, these treatments are either another JAK-inhibitor or a combination with a JAK-inhibitor. They continue to be focused on spleen symptoms or anemia improvements. These are certainly helpful, but do not address the fundamental problem of continued disease progression in these patients, which results in dismal survival. Eventually, the majority of MF patients are or become non-responsive to a JAK-inhibitor. As such, there remains a key unmet need of overall survival in JAK-inhibitor non-responsive patients. As the only therapy in development that is not a JAK-inhibitor or used in combination with a JAK-inhibitor, imetelstat has a clearly differentiated profile due to its potential to extend the lives of patients who either are or have become non-responsive to a JAK-inhibitor. Next, I'd like to say a few words on our pre-commercial planning and activities. With top-line results expected to be available from the end of 2022 to the first half of 2023, and assuming the results of IMerge phase III are supportive, we plan to submit the completed NDA in 2023. In planning for those events on that timeline, in 2021, we've begun NDA readiness activities for imetelstat in lower risk MDS. That includes starting long lead time activities to validate drug substance and drug product manufacturing processes that are needed to meet standards for regulatory approval and to enable the future commercial production of imetelstat. We'll also begin drafting non-clinical contents of the application this year. In addition, we'll invest in building the appropriate infrastructure to support a high-growth and commercial stage company. Other 2021 preliminary commercial activities include preparing the market by increasing awareness of imetelstat's differentiated profile and building our commercial team and internal infrastructure to support commercialization. However, spending on our commercial launch plan is stage-gated to positive top-line results in IMerge. In conclusion, before opening the call to questions, I'd like to reiterate our commitment to Geron's vision of being recognized as a leader in the treatment of heme malignancies. In support of that vision, in 2021, our plan is to complete enrollment in the IMerge phase III trial, advance clinical site initiation and patient enrollment in the IMpactMF trial, present further data and analyses from the phase II IMerge trial at medical conferences, and begin the NDA and commercial readiness activities I just described. With a strong team in place that has the expertise to advance imetelstat development and transition to the commercial stage, and having the financial resources to support our plans, we strongly believe our efforts will help establish Geron as a leader in hematologic malignancies, thus creating long-term shareholder value. We would now like to answer your questions, so I'll turn the call back over to the operator. As a reminder, to ask a question, you'll need to press star one on your telephone. To withdraw your question, press the pound key. We'll take our first question from Chad Messer with Needham. Great. Thanks. Thanks for the update. Thanks for taking my questions. Maybe we'll just start with a little bit of drill down on COVID impact. Everything you said about patients and sites obviously makes a lot of sense what's going on in the world today. In your prepared remarks, Chief, you talked a little bit about the primary problem kind of being patients showing up for sites, and then in the press release, there's some additional discussions about site personnel, I guess, site personnel issues. I was wondering to what extent these two things are playing off relative to each other. I mean, to me, and maybe I'm naive, it seems the patient interest in showing up is the most obvious to normalize with COVID, and that site things may be more complicated. I could even be wrong about that. am just wondering if you could give a little bit more insight on the relative impact of those two things, which are both, in my mind, logically impacted by COVID. Yeah. That's a really perceptive question. Thanks, Chad. I think I'm going to turn it over to Alexandra, who's certainly the closest of all the people on the call to the questions she's in, rather constant contact with these sites and our team is, of course. Alexandra, maybe you'd like to comment on these two different variables that Chad brought up. Sure. Thanks for the question, Chad. I mean, you are spot on. The two main issues that we are seeing is really the patient reluctance to participate in clinical trial, which actually may require more frequent visits to the hospital, right, than they would like to during COVID times. The second one is really the availability of site personnel who appear to be busy maintaining trials with, again, multiple procedures during COVID time. It is a really mixture of these two variables. We do expect that as we spoke, as the COVID pandemic winds down and with the vaccinations, hopefully, patients feel again comfortable to come to the clinic and participate in clinical trials. Those are the two key reasons. Yeah. Okay. Yeah. No, thanks. Thanks. That makes a lot of sense. This next one, I definitely have a comment. Maybe there's a question in there. It's really interesting that, especially when we hear about your ASH data and you talk about justifying the OS benefit that you've seen. I get it. It's single arms, so maybe the justification comes with kind of validating it in that context. With things like spleen volume and symptom scores, in one way of thinking, spleen volume and symptom scores should be out there justifying their value in terms of OS, in my mind. I guess that was the comment. The question, and you guys touched on this a little bit, I mean, talk a little bit more. I know MF is such a unique disease in terms of the endpoints that are looked at for JAK-inhibitors and other standard of care therapies. Why is it that we have to work so hard here to convince people that OS benefit is important? I'll take the first part, and then I think Alexandra, again, would like to probably comment on this. I don't think we feel that there's any need to justify the OS benefit. I think it's plain and simple and incredibly obvious. I think we make the point, and perhaps our continued commentary on this could be taken the wrong way, but I think we're trying to make the point that we're the only drug that we're aware of that is actively engaged in a phase III trial that will, in fact, use OS as an outcome. It takes some courage to do that, right? These are long trials. You've heard the dates. They require a fairly large number of patients. It's breaking out of the mold. Most people just do a landmark analysis at a certain number of months after being treated with a combination, usually containing a JAK-inhibitor and a new drug or simply a new JAK-inhibitor alone, and you're kind of done. What you don't see are the real benefits of changing the course of the disease. Chad, we think that that's the big news, the big story, and frankly, the big benefit of this drug. I don't think anybody else has any kind of data like we do in that regard. That has been our primary focus on why we've tried to talk about OS more than anyone else, and we also have the correlations of the changes in the course of the disease, both clinical and, more importantly, perhaps in some ways molecularly, with the actual improvement in OS in our phase II study. I hope that that puts it in some context. Alexandra, I don't know if there's anything else to add, or Chad, if you would like to jump back in, that's fine. No. Those are really helpful comments and context. Thank you. Sure. Anything else? Nothing from me. Thank you. Okay. Go ahead. Your next question is from Justin Walsh with B. Riley Securities. Hi. Thanks for taking the question. Can you provide any color on feedback that you've received from your initial marketing research and outreach efforts? How eager are MDS versus MF physicians and patients for new treatment options, and how have they reacted to imetelstat's profile? Right. I'm going to let Alexandra talk about the individual physicians that we've spoken to. We've done market research, and we're in the process of planning for additional market research this year that will really drive into those points, Justin. I think that the benefits of MDS in MDS are really quite evident to a lot of physicians, particularly those who take care of more ill patients. Remember that all of our patients had very high transfusion burdens, and that's an area that can be particularly difficult for these physicians to get traction with. They've certainly adopted or they're in the process of adopting luspatercept, and again, we call that out, and we think that's good because prior to luspatercept coming on the market, there hadn't been anything new since the HMAs over 10 years- 12 years ago. I think that the rapid uptake has been good, but there's a lot of room left for a drug like imetelstat that does a bunch of things. One, we treat RS negative patients as well as RS positive. Two, we can treat patients with very high baseline transfusion burdens and still get excellent outcomes. Three, the durability—the durability. The durability of imetelstat's activity in these patients is really dramatic and far greater than anything we've seen, at least in print or at meetings from the folks studying luspatercept. I think that those then factor into the underlying cause of all of this, which is when we see decreases in SF3B1 and decreases in cytogenetic abnormalities, it's pretty clear that we have disease-modifying activity going on. I won't characterize other products in low-risk MDS, but all of those are really powerful differentiating factors, and I think that they'll play very, very well. Alexandra, do you want to comment on the specifics of investigator interaction and KOL interaction because you're very close to a number of these folks? Sure. Sure. I can talk about that. I mean, we obviously are in very close contact with participating PIs as well as key opinion leaders. I can just reiterate, there's really a great enthusiasm for a drug that works across different subtypes of low-risk MDS. That's to start with, right? For them, just the fact that they don't need to subtype, whether you're RS positive or RS negative, makes their clinical and everyday work very easy, right? I mean, we were not subtyping for RS positivity prior to Reblozyl's approval, let's put it that way. This kind of is one convenience for them, right? I mean, the fact that we have your ability of 20 months versus the 7 months of an already approved drug that is doing very well on the market is really another convenience, if you will, for patients. You don't have to come back to the clinic for multiple transfusions to which they're used to prior to treatment. I have to say something, and we often discuss this internally. I mean, what really makes these investigators excited is the molecular data. This was that maybe it's even the best reason or why the paper ended up in JCO. It's really the decrease in not only SF3B1. SF3B1 is just an example that we are using here to illustrate the effect. It's really multiple mutations that we've seen and also cytogenetic decrease in these patients that make believe our KOLs and PIs that imetelstat is really altering the cause of disease in low-risk MDS patients. Same goes with your answer for MDS. I don't know, Justin, if you want me to cover for MF, but it is the same pretty much. It's really the molecular data. I mean, and Chad, also a little bit to go to your question, right, about the OS. I mean, data has been evolving, and the agencies have been more receptive to different endpoints, right? We started with SVR as Jakafi was on the market for so long, but as new data with new compounds, right, showed that we can improve anemia with one drug. We can improve symptoms, right? New endpoints have been established, and now we come with OS without a question. The crown of the endpoint, I mean, is the ultimate endpoint of every clinical trial, right? When you show such data, granted, at the moment, it's just from two different doses of imetelstat, enthusiasm is high. I don't think we had the need to justify the OS as an endpoint to any of our investigators nor to regulators so far. We remain enthusiastic. It's long, and that's what makes it a challenge. It's a long study, right? It's a different endpoint. Other than that, there's really, really no other reason to believe that we have any questions about the data. Thank you. That's very helpful. Maybe just a quick follow-up to that. One, could you maybe quickly just remind us of how many of the low-risk MDS patients are RS positive versus RS negative? Do you think that there could be potential for patients to use luspatercept and imetelstat in sequence if they fail therapy with one or the other? Typically, the numbers for RS positive patients in the literature range anywhere from 10%-25%, right? It depends which paper you take, right? Let's say at most, a quarter of the patients are RS positive, right? A lot of the patients are RS negative. As we've spoken multiple times, we work across both subtypes. I think that was one question. Can you remind me what was the second part of your question? Yes. Is there potential to use luspatercept and imetelstat in sequence? For RS positive patients, right, potentially, right? For patients that are heavily transfused, I really don't know, right, what would be the clinical preference, I would say, by. Okay. Thank you very much. That's it from me. Okay. Thanks. Thanks, Jus. Your next question is from Stephen Willey with Stifel? Yeah. Good afternoon. Thanks for taking the questions. Maybe just with respect to the IMpactMF guidance. I'm just kind of curious as to there's obviously a lot of competitive happenings within the space, and I'm just kind of curious as to how the guidance, if at all, contemplates the competitive environment in terms of competition for some of these post-ROSC patients, I guess, specifically just given the number of trials we're kind of seeing within that setting. Yeah. That's a great question, Stephen. I mean, just since we announced the study, there have been three new trials, phase III trials in MDS, right, that have been started. Competition is really high. For us, at this moment, it's difficult to give a very precise guideline. As you can imagine, we have conducted a study feasibility, and that feasibility takes into account COVID as well as, right, as well as competitive trials. That's how, based on the current knowledge we have and our current planning assumptions, we will reach the full enrollment in 2024, which is a different guidance than what we've given so far. Okay. Maybe just going back to IMerge for a minute, I know, Chip, you had made the comment with respect to luspatercept's availability potentially impacting patient enrollment into the study. Is there a scenario whereby IMerge maybe ends up representing kind of an over-enrichment of RS negative patients? Do you think that there's any potential labeling or ramifications as a result of that? I'm just kind of curious to get your opinion there and just whether or not you have kind of real-time insight into the baseline characteristics of patients that are coming into the study and if that's something that you've seen. Thanks. Again, I think Alex is in the best position to answer those questions. Go ahead, Alex. Yeah. I'll start with the last one, Stephen. I mean, we have no insight into what type of patients are being enrolled in the study because it's a double-blind placebo-controlled study, right? It's very difficult to—not very difficult, it's impossible to comment or to know what patients are enrolled. Now, your first question is luspatercept might, or luspatercept approval might have impact. luspatercept usage, right, might have impact in a way that we now enroll RS positive patients only, sorry, RS negative patients, the other way, because they will be treating. I don't think so. Remember, luspatercept has just been approved. It is used on our patients. I assume for the RS positive patients, they would initially be treated with luspatercept and only then we'll put them on our trial. I honestly do not think, right, that we will end up enriching for one or for another patient population. I don't see a problem in the labeling, I mean, at the moment. Stephen, I think also— I don't know. Yeah. Yeah. Yeah. Stephen, I think also we should comment that when we talk to investigators, their views on the—or that these are really quite different drugs, right? I mean, the effects of imetelstat in high transfusion burden patients, greater than four units and especially greater than six units, is quite dramatically different, at least if you look at sort of the phase II comparisons to phase III comparisons between the two drugs. I think that there's probably so many different ways to cut this. I agree with Alexandra. I think we'll be surprised to see a meaningful enrichment of one RS positive versus RS negative. I think we'll be surprised. But we don't know yet, and we'll see. As you were talking, Chip made a—sorry, Stephen, I just wanted to—I mean, we invoked about 50% on our trial before luspatercept became available or reimbursed in the European countries where most of our sites are. I bet we do have sufficient numbers in those patients that are RS positive as well as RS negative. Very good. That's a fair point. Thanks for taking the questions. Sure. Thank you. Your next question is from Tom Shrader with BTIG. You kind of just talked about my question, but you see no reason to stratify for RS positive versus RS negative. Kind of, Chip, to your point, that these patients either physicians would know are going to get almost nothing out of luspatercept or probably did get almost nothing out of luspatercept. Is that accurate? You just don't think it confounds your study much? I think the question, if I understand it, Tom, is whether we're stratifying in the analysis for RS positive versus RS negative. Stratification in this case usually would mean if you were stratifying in the randomization. We're not stratifying as far as I know, at least in the randomization. Will we look at the effects of the subtypes? Absolutely. Of course, we will. We'll look at it, but we're not preferentially making sure that we take a specific group. I mean, I need to say this. We don't completely understand why luspatercept has this effect and appears to have this effect, a big enough effect that Acceleron and Celgene decided to really restrict their phase III, their initial phase III trial meta-study to RS positive. What I can tell you is that when we look at our data, it does not really matter whether you are RS positive or RS negative. You get very similar results. I think that is the real bottom line for us. I think that we will show equally good results in either group. Okay. There is kind of an interesting comment about a reasonable RNA R&D build going forward. Are you still looking for a way forward in AML? Is that still on the table? Are you looking for a subgroup that makes a lot of sense, or am I misreading the key leads? No. I mean, let's just say this. I don't know that the R&D build necessarily reflects that. What it does reflect is a maturing development organization for a drug that's going to be on the market in how many years. One that we think has a very unique mechanism of action as well and has properties and capabilities that aren't shared by other products. We'd be crazy not to try to take advantage of that. I think that's kind of the real answer. I don't think we're prepared to talk today about the specifics of what the next indication would be or when it would come or how much it will cost or any of that or how many people will be required to support it. We certainly have our going through the cafeteria line of hematologic malignancies, we're certainly interested in putting more on our plate than simply low-risk MDS and MF and relapse refractory MF for that matter. I think that you can assume that we have a very keen interest in that. We'll just have to wait a little bit longer for us to really come out and have the commentary that I think you're looking for, Tom. Okay. Great. Thank you. Sure. This concludes our Q&A session. I will now turn the call back over to Dr. Scarlett for closing remarks. Thanks a lot. That was a very spirited discussion, which I think we really appreciate and thank everyone who participated. We thank all the people who listened to the call, and we hope you have a good rest of this week and onward. We will talk to you again surely at the next quarterly earnings call. Thank you all very much for participating. Bye-bye. Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.