Geron Corporation

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 1 on your telephone. If you require any further assistance, please press star 0. I would now like to hand the conference over to Olivia Bloom, Jerome's Chief Financial Officer. Thank you. Please go ahead, ma'am.

Olivia Bloom 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, Jerome'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 slash 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 Jerome'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 eMERGE Phase III and IMPACT-MS clinical trials and submission of an MBA, the potential for positive outcomes from eMERGE Phase III and IMPACT-MS, potential approval of IMS HealthStats by regulatory authorities and commercialization of IMS HealthStats, the expectation that Geron's current financial resources will be sufficient to fund its operations until the end of 2022, and that Imatel's set has the potential to be disease-modifying and alter the course of MBS and MS. These and other forward-looking statements involve risks and uncertainty 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 timeline for eMERGE Phase III and IMPACT-MF due to COVID or otherwise, that in the Phase III clinical trials, Imatelset 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 IMITEL-STAT on a timely basis or at all, and may not approve it for commercialization, and that JIRA may need additional financial resources before the end of 2022 for the development and commercialization of IMITEL-STAT. Detailed information on the above risks and uncertainties and additional risks, uncertainties, and factors that could cause actual results to differ maturely 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 that speak only after 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 IMMERGE 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-Delphi-Q and relapsed-actor or refractory tube prior treatment with an erythrocrease-stimulating agent, or ESA. She will also provide an update on our impact MS-based retrial, which is in a population of patients with intermediate to or high-risk myelofibrosis who are refracted to prior treatment with a JAK inhibitor, which we call refractory MF. Alexander 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 MS HealthSeth'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 MS markets and IMITEL staff 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. Chip?

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 Geraldine, 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 the end, we presented compelling and differentiating data from our eMERGE Phase II lower-risk MDS trial. These data showed high rates and exceptional durability of transfusion independence. Of any study in non-DEL5q lower-risk MDS patients who relapsed in a refractory to a EFA, the 20-month median duration of transfusion independence in eMERGE Phase II was the longest reported to date. In our eMERGE Phase III lower-risk MBS study, enrollment gains continued with over 50% enrollment achieved by the end of the year. We also presented exceptional overall survival data from our EMBARQ Phase II trial in JAK-I relapsed or refractory MF patients. In this trial, in the Telstat-treated patients had a median OS of 28 months, which is almost twice the median OS reported in medical literature. Based on these and other supporting data, and after conferring with FDA, we opened IMPACT-MF, our Phase III trial, and JAKI refractory MF patients. IMPACT-MF is the first and, to date, only Phase III trial with overall survival as the primary endpoint. We also presented strong results of disease-modifying activity in our patients with low-risk MDS and relapsed refractory MF. In both indications, we saw reductions in key driver mutations of the underlying disease. Furthermore, Imatel sets 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 and low-risk MDS and improvement in MS. Such correlations have given us even greater confidence in the potential positive outcomes for our ongoing A3M. Okay. This doesn't stand out as important accomplishments in 2020. The first was that we successfully established our global Imatel stat 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. effect on clinical trial . 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 eMERGE 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 eMERGE being inadequately prioritized by investigators. In our interactions with them, our investigators remain enthusiastic about our Immatelt stat data and are committed to enrolling their patients in this trial. Based on the information we currently have, we expect eMERGE Phase 3 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 Emerge Phase 3 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 Phase 3 pandemic. She'll also update our activities in the conduct of Impact MF. We currently expect the interim analysis for IMPACT-MF to occur in 2024 and the final analysis to occur in 2025. Looking ahead, our plan strategic priorities for the next three years and commercially launching this highly differentiated drug in lower risk MDS. Now I'd like to hand the call. I'd like to hand the call over. Go ahead.

I'm sorry. You were breaking up a bit just back there, just right before for Alexandra.

Okay. So we currently expect the interim analysis for Impact MS 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 eMERGE Phase III, gaining regulatory approval of Imatelstat and commercially launching this highly differentiated drug in lower 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?

Thank you, Chip. As of December 31, 2020, we had approximately $260 million in cash, cash equivalent, 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 and 12 months ended December 31, 2020, were generally higher in comparison to the same periods in 2019 due to headcount increases in 2019 and 2020 across the company, increased activity for the eMERGE Phase III clinical trial in low-risk MDF, startup activities for the IMPACT MS Phase III clinical trial in refractory MS, and costs associated with ongoing ImatelSAT manufacturing. These increased costs were partially offset by lower costs related to purchases of raw materials, drug substance, and drug products, and completion of the IMPACT clinical trial. Regarding financial guidance for 2021, We expect our operating expense burn to range from $108 million to $112 million, which includes costs for two ongoing phase three clinical trials, production of validation batches of Imatel stat at contract manufacturers to enable future production of Imatel stat 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 3 clinical development activities. Alexandra? Thanks, Olivia. Good afternoon, everyone. As Chief mentioned, we have now achieved 65% enrollment in our eMERGE Phase 3 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 eMERGE Phase 3. 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 eMERGE 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 Emerge Phase 2 trial in low-risk MDS, on which I would like to expand on briefly. These data are very encouraging, and they continue to differentiate Imatelstat from other currently approved or investigational treatments. Foremost is that Imatelstat 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 metastatic 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 dependence of 20 months. That compares very favorably to the most recent available data we've seen from Nusplatercept, 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 eMERGE Phase III, we believe imatelostats will be highly differentiated and very competitive treatment for the lower risk MBS patient population. Moving on to myelofibrosis. In his earlier remarks, Chip mentioned that in the EMBARQ Phase II trial, the median overall survival was 28 months. compared very favorably to the median OS of 13 to 16 months in the medical literature. The median OS also compared favorably to the OS of 12 months observed in real-world data analysis of relective fractal MS patients who were treated with best available therapy and they were carefully matched with our Matelstat treated patients in INDAR. In addition to the overall survival, patients in INBARC experienced other important clinical benefits, including symptom improvement, screen 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 IMPACT-MS in December, which was one quarter earlier than expected. As mentioned, the IMPACT-MS is the first and to date only MS Phase III trial with overall survival as the primary endpoint, which will be a key differentiating feature compared to other drugs in main stage development for this population of patients. The same dynamics affecting enrollment in eMERGE Phase 3 are also affecting enrollment in IMPACT-MS. And in addition, we've seen startup of numerous other clinical trials in MS that will compete with IMPACT-MS for patients. We're using enrollment boosting strategies for IMPACT-MS similar to those we have employed in eMERGE Phase 3. These include expanding the number of countries and sites engaging more clinical science liaison, and utilizing a social media campaign. And the 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 this timeline. The reason that 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 death events. Since these events will accrue 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 up my remarks by noting that we reported a very important data linked to the mechanism of action of the Natel study that made her responsible for these remarkable disease-modifying activity of the drug we've seen in our Phase II trials in both low-risk MDS and in MS. In low-risk MDS patients, we've observed reductions in key driver mutations at a molecular level and decrease of cytogenetic abnormalities. that indicate hematelstat kills malignant stem and progenitor cells by targeting telomerase. These molecular data were directly correlated with a clinical benefit of transfusion independence, providing strong evidence of disease-modifying activity of hematelstat. And in BARC, we also saw significant dose dependence of key driver mutations for MS, as well as improvement in bone marrow fibrosis. These data were also correlated with improved overall survival observed in the EMBARQ trial, further strengthening the evidence of the disease-modifying activity of hematostatic. We believe that the clinical benefits of durable transfusion independence in low-risk MDS and improvement in overall survival in MS, along with the molecular data and their correlations, highlight the magnitude of Imatelstat's unique mechanism of action of telomerase inhibition, and provide strong evidence that Imatelstat alters the course of MBS and MS. As a result, we have further confidence that we will have potential success in both Emerge Phase 3 and Impact MS. I'd like to now hand the call back to Chip to review the current MBS and MS marketplaces. Chip? Chip, 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 and lower-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 named Reblazil, and lower-risk MDS. The U.S. approval took place in April 2020 based on a Phase III trial in non-Delphi-Q lower-risk MDS patients who were relapsed or refractory to ESAs and naive to HMAs. This trial enrolled only RS-positive patients. The launch of Revlozil 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 eMERGE phase two 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 imitelpstat to play a significant role for this lower-risk MDS patient population. For the MS landscape, jacofi, 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 MS 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, Intelstat 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 eMERGE Phase 3 are supported, we plan to submit the completed MDA in 2023. In planning for those events on that timeline, in 2021, we've begun MDA readiness activities for Imatelstat and lower-risk MDS. That includes starting long lead time activities to validate drug substance and drug product manufacturing processes that are needed to keep standards for regulatory approval and to enable the future commercial production of the Mattel stat. We'll also begin drafting non-clinical content for the application this year. In addition, we'll invest in building the appropriate infrastructure to support a high growth in commercial stage companies. Other 2021 Preliminary commercial activities include preparing the market by increasing awareness of Inatel STEP'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 eMERGE. 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 eMERGE Phase III trial, advance clinical site initiation and patient enrollment in the IMPACT-MF trial, present further data and analyses from the Phase II eMERGE 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 in the Telstat development and transition to the commercial stage, and having the financial resources to support our plans, we strongly believe our efforts will help establish Giron as a leader in hemologic malignancies, thus creating long-term shareholder value. And with that, we'd 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 1 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. Can we just start with a little bit of drill down on COVID impact, you know, Everything you said about patients and sites obviously makes a lot of sense what's going on in the world today. But in your prepared remarks, Chip, 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, you know, 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. But 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 question. She's in rather constant contact with these sites and our team is, of course. So, 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. And the second one is really the availability of side personnel who appear to be busy maintaining trials with, again, multiple procedures during COVID time. So it's a really mixture of these two variables. You know, we do expect that as we spoke, as the COVID pandemic winds down and with the vaccinations, you know, hopefully patients feel again comfortable to come to clinical, to come to the clinic and participate in clinical trials. But those are the two key reasons.

Yeah. Okay. Yeah. Thanks. Thanks. That makes a lot of sense. And then this next one, well, I definitely have a comment. Maybe there's a question in there. So it's really interesting that, you know, especially when we hear about your ASH data and you talk about justifying OS as the OS benefit that you've seen. And I get it. It's single arm. So maybe the justification comes with kind of validating it. in that context. But 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. So I guess that was the comment. And then the question, and you guys, you touched on this a little bit, but I mean, you know, Talk a little bit more, and I know MS is such a unique disease in terms of the endpoints that are looked at for JAK inhibitors and other standard of care therapies. But, you know, 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 Alexander 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 uh commentary on this uh 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 three trial that will in fact use os as an outcome and uh it takes uh some courage to do that right if these are long trials uh you've heard the the the dates um they require fairly large number of patients and 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. But what you don't see are the real benefits of changing the course of the disease. And 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. So that's 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. So I hope that that puts it in some context. Alexander, 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, look, 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 Reilly Security.

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 MS physicians and patients for new treatment options and how they reacted to Imatel's profile? Right.

Well, 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 researches here that will really drive into those points, Justin. But 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 have very high transfusion burdens, and that's an area that can be particularly difficult for these physicians to get traction with. Now, they've certainly adopted or they're in the process of adopting luspatercept. And we, 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, 12 years ago. So I think that the rapid uptake has been good. But there's a lot of room left for a drug like in a Telstat that does a bunch of things. 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, repeat it, the durability, the durability of NHL stats 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 these pattercepts. So 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. Alexander, do you want to comment on the specifics of investigator interaction and KOL interaction? Because you're very close to it.

sure i can i can talk uh about that i mean we we obviously are in uh in very close contact with uh participating pis uh as well as uh key opinion leaders so and i i can just reiterate there's really a great enthusiasm for a drug that works across um different subtypes of low risk MDS. That's to start with, right? So for them, there's just the fact that they don't need to subtype whether you're RS positive or off RS negative. It makes their clinical and everyday work very, very easy, right? I mean, we were not subtyping for RS positivity prior to Roblosio's approval, let's put it that way. So this kind of is one convenience for them, right? And then, I mean, the fact that we have durability of 20 months versus the seven months of an already approved drug that is doing very well on the market is really another convenience, if you will, for patients. You know, you don't have to come back to the clinic for multiple transfusions to which they're used to prior to treatment. And I have to say something, and we often discuss this internally. I mean, what really makes these investigators excited is the molecular data. It's really, and this was, you know, that's maybe even the best reason or why the paper ended up in JCO, you know. So it's really the, you know, decrease in not only SF3B1, SF3B1 is just an example that we are using here to illustrate the effect, but it's really multiple mutations that we've seen and also cytogenetic decrease in these patients that make believe our care of NPIs that Mattel studies really altering the cause of disease in low risk MDS patients. Same goal as you answered for MBS. I don't know, Justin, if you want me to cover for MS, but it is the same as much as really the molecular data. And I mean, and Chad, also a little bit to go to your question, right, about DOS. I mean, data has been evolving and the agencies have been more receptive to different endpoints, right? We started with SVR as the coffee was on the market for so long. But as new data with new compounds show that we can improve anemia with one drug. We can improve symptoms. New endpoints have been established, and now we come with OS without a question, the crown of the endpoints. I mean, it's the ultimate endpoint of every clinical trial. So when you show such data, Granted, at the moment, it's just from two different doses of Hematelstat. 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. So 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. But 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. So, one, can you maybe quickly just remind us of how many of the low-risk MDS patients are RS-positive versus RS-negative? And do you think that there could be potential for patients to use lupatercept and imipelstat in sequence if they fail therapy with one or the other?

So typically, the numbers for RS-positive patients in the literature range anywhere from 10% to 25%. It depends which paper you take. So let's say at most, a quarter of the patients are RS-positive. So a lot of the patients are RS-negative. And again, as we've spoken multiple times, we work across both subtypes. So I think that was one question. And can you remind me what was the second part of your question?

Yes. Is there potential to use this cataclysm and help that in sequence?

So for RS positives, patients, right? Potentially, right? But, you know, for patients that are heavily transfused, you know, I really don't know, right, what would be, you know, the clinical preference, I would say. Okay.

Thank you very much. That's it for me. Okay. Thanks. Thanks, Justin.

Your next question is from Stephen Wiley with Stiefel.

Yeah, good afternoon. Thanks for taking the questions. Maybe just with respect to the impact, MF guidance. So I'm just kind of curious as to, you know, 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-Rux patients, I guess, specifically just given the number of trials we're kind of seeing within that setting.

Yeah, that's a great question, Steve. Just as we announced the study, there had been three new trials, three trials in MS that had been started. Competition is really high. For us, at this moment, it's difficult to give a very precise guideline. But as you can imagine, we have conducted a study feasibility. And that feasibility takes into account COVID as well as competitive trials. So that's how, based on the current knowledge we have and our current planning assumptions are that we will reach the full enrollment in 2024, which is a different guidance than what we've given so far.

Okay. And maybe just going back to eMERGE for a minute, Chip, you had made the comment with respect to Liz Patterset's availability potentially impacting patient enrollment into the study. So is there a scenario whereby eMERGE maybe ends up representing kind of an over-enrichment of RS negative patients? And do you think that there's any potential labeling or ramifications as a result of that? I'm just kind of curious to to get your opinion there and just whether or not, you know, 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're seeing.

Thanks. Again, I think Alex is in the best position to answer those questions.

Go ahead, Alex. Yeah. So I'll start with the last one, Steve. 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? So it's very difficult to, not very difficult, it's impossible to comment or to know what patients are enrolled. Now, your first question, if whosparisept might or whosparisept approval might have impact so whosparisept usage right might have impact in in a way that we now in large positive patients only um Sorry, RS negative patients, the other way, because they will be treating. I don't think so. Remember, Luspiracept has just been approved. It is used. Now patients, I assume, you know, for the RS positive patients, they would initially be treated with Luspiracept and only then they'll put them on our trial. So I honestly do not think, right. that we will end up in reaching for one or for another patient population. And therefore, I don't see a problem in the labeling at the moment.

Steve, I think also we should comment that when we talk to investigators, their views are that these are really quite different drugs, right? 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 two comparisons to phase three comparisons between the two drugs. So 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. And I think we'll be surprised. But we don't know yet, and we'll see.

And I was just, as you were talking, Chip, sorry, Steve, I just wanted to add, listen, I mean, we involved about 50% on our trial before the spot effect became available or reimbursed in the European countries where most of our sites are. So I bet we do have sufficient number, you know, 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.

Our next question is from Tom Schrader with VTIG.

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 lespatercept or probably did get almost nothing out of lespatercept. 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. And 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. So 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 Muspatercept has this effect and appears to have this effect, a big enough effect that Acceleron and Celgene decided to really restrict their phase three, their initial phase three trial metal study to RS positive. But what I can tell you is that when we look at our data, it doesn't really matter whether you're RS positive or RS negative, you get very similar results. So I think that's the real bottom line for us. And I think that will show equally good results in either group.

Okay, and then there's kind of an interesting comment about a reasonable 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 tea leaves?

Yeah. No, I mean, let's just say this. I don't know that the R&D bill necessarily reflects that, but what it does reflect is a maturing development organization for a drug that's going to be on the market in however many years. and 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. So we'd be crazy not to try to take advantage of that. And 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. But we certainly have... are 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 relapsed-retractor MF, for that matter. So I think that you can assume that we have a very keen interest in that, but 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.

Well, 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, and we will talk to you again shortly 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.