Geron Corporation (GERN) Earnings Call Transcript & Summary

Hello, and welcome to the Geron Virtual R&D Investor Event Call. [Operator Instructions] I would now like to turn the conference over to Aron Feingold. Please go ahead.

Good morning, everyone, and welcome to our Investor event. I am Aron Feingold, Geron's Vice President of Investor Relations and Corporate Communications. I'm thrilled to be joined today by 2 key opinion leaders in hematologic malignancies and leading investigators of our imetelstat clinical study. Professor Uwe Platzbecker, M.D. University Hospital, Leipzig; and Professor Rami Komrokji, Moffitt Cancer Center as well as the members of Geron's management team. Dr. John Scarlett, Chairman and Chief Executive Officer; Olivia Bloom, Executive Vice President and Chief Financial Officer. Dr. Faye Feller, Executive Vice President and Chief Medical Officer; and Anil Kapur, Executive Vice President of Corporate Strategy and Chief Commercial Officer. These speakers will cover the agenda topic shown on this slide. As you can see, we will speak to the latest IMerge Phase III data presented recently at ASCO and EHA, provide an imetelstat clinical pipeline overview and share some thoughts around the lower-risk MDS market potential. At the end of the prepared remarks, we will have an open Q&A session with Drs. Platzbecker and Komrokji as well as members of management taking your questions. Before we begin, please note that during the course of this presentation and question-and-answer session, we will be making forward-looking statements regarding future events, performance, plans, expectations and other projections including those relating to the therapeutic potential and potential regulatory approval of imetelstat, anticipated clinical and commercial events and related time lines, the sufficiency of Geron's financial resources and other statements that are not historical fact. Actual events or results could differ materially. Therefore, I refer you to the discussion under the heading Risk Factors in Geron's quarterly report on Form 10-Q for the quarter ended March 31, 2023, which identifies important factors that could cause actual results to differ materially from those contained in the forward-looking statements. Geron undertakes no duty or obligation to update our forward-looking statements. With that, I'll turn the call over to Chip. Chip?

Thanks, Aron. Good morning, everyone, and thanks for joining us today. I'd also like to extend a very special welcome to Professor Uwe Platzbecker; and Professor Rami Komrokji. Both of these gentlemen are imminent hematologists who have been important contributors to the developments in imetelstat as well as outstanding presenters and discussions for imetelstat data recently presented at both ASCO and EHA. I attended both conferences with my colleagues from Geron, and I think we were all very inspired by the attention and enthusiasm shown within the hematology community for emerging treatment options in lower-risk MDS, including, of course, imetelstat. We have a really ambitious program today, which Aron has already briefly described for you. I'll have a few concluding remarks at the end of the presentation and before Q&A. But for now, let's turn the call over to our Chief Medical Officer, Faye Feller, to provide brief remarks on telomerase inhibition mechanism and an imetelstat overview. Faye?

Thank you, Chip, and good morning to everyone on the call. I'd like to start today by reminding everyone about the uniqueness of the telomerase target in oncology, which not only differentiates imetelstat from other treatments, but also underlies the efficacy and safety results we have been observing in our clinical studies of hematologic malignancies. In hematologic malignancies such as lower-risk MDS, myelofibrosis and acute myeloid leukemia, malignant hematopoietic stem cells, or HSCs give rise to uncontrolled proliferation of malignant blood cells. Malignant HSCs rely on continual upregulation of telomeres to support uncontrolled proliferation making telomerase a novel target in malignantly transformed HSCs. As you can see on this next slide, when imetelstat inhibits telomerase activity, it limits the uncontrolled proliferation of malignant stem and progenitor cells, leading to selective killing and apoptosis of these cells responsible for malignant hematopoiesis thus enabling recovery of the bone marrow and normal blood cell production. That is normal hematopoiesis. This mechanism of action, telomerase inhibition, is very powerful and underlies the efficacy and safety data we have reported today, including the potential disease-modifying activity. Next slide. Here is our pipeline in which we are trying to explore the broad potential of this mechanism. Today, we are going to focus on our clinical programs in lower-risk MDS, MF and AML. I'm honored to turn the call over to Drs. Platzbecker and Komrokji who, as Chip commented, are both very experienced investigators and professional colleagues whom we have been privileged to work with for many years. Uwe, let's start with you.

So my name is Uwe Platzbecker, I'm a Professor of Hematology at the University Hospital Leipzig in Germany, and I'm also a PI of the imetelstat program for lower-risk MDS patients, and it's a great pleasure to be here and to discuss with you the current evidence, the scientific evidence on imetelstat in lower-risk MDS patients. Next. This is actually the patient journey of a typical lower-risk MDS patient. These patients are, in general, above the age of 70 years when it comes to the first diagnosis. And you see that many of these patients, if not the majority, more than 80% actually develop anemia, get transfusion-dependent. And by achieving transfusion dependence, they also have a deterioration of quality of life with a lot of transfusion support, also iron chelation comes into play. And after a journey of 2 to 5 years, depending on the genetics of the disease, these patients also develop higher-risk MDS or even AML with a still very short survival, irrespective of current therapeutic opportunities. Next, so what I will do now is I will give you a short wrap-up of the EHA presentation I had the honor to give at the last Congress here in Frankfurt. You see it's on behalf of all the co-authors of this study, which was in a Phase II, Phase III program, evaluating imetelstat as a monotherapy compared to placebo in lower-risk MDS patients being heavily transfusion-dependent, but also relapsed or refractory to hematopoiesis or stimulating agents or so-called ESAs. Next, this is a slide which shows the mode of action of imetelstat in lower-risk MDS patients. It is a first-in-class direct and competitive inhibitor of telomerase activity, which is known to be activated predominantly in malignant cells. This has also been shown for MDS, but also AML patients. The Phase II part of the IMerge study investigated imetelstat monotherapy in ESA relapsed -- refractory or ineligible non-del(5q) but also naive to LEN and HMA patients being red blood cell transfusion dependent. And in this study, which was published in the JCO a couple of years ago, an RBC-TI rate, the red blood cell transfusion independence rate of 42% with a median duration of 86 weeks was reported, and this was then the backbone for the Phase III program, which you see on the next slide, where you see that patients with the disease characteristics of lower-risk MDS based on IPSS were randomized 2:1 imetelstat every 4 weeks IV infusion versus placebo with the primary endpoint being 8-week red blood cell transfusion independence rate. On the next slide, you see the baseline characteristics of patients MDS cohort, given the median age. You also see that almost 40% of the patients had an RS- phenotype at study entry. Also the red blood cell transfusion burden was pretty high with 48% of the patients getting more than 6 units within 8 weeks and only a minority of patients predominantly RS+ patients had been exposed to prior luspatercept therapy. On the next slide that is showing the IPSS-R and the IPSS-M for the patients at study entry. You'll see that the majority is 73%, 74% of the patients actually where IPSS-R low. The same was also true for the recently published IPSS-M score, which also includes molecular characteristics of these patients. So this is a typical lower-risk MDS cohort within the IMerge Phase III program. On the next slide is the treatment exposure and disposition after 18 months. You see that treatment discontinuation occurred in the majority of patients, but with the difference with regards to lack of efficacy, which was the reason in 42% of the patients in placebo and 23.7% in the imetelstat arm. The same is also vice versa true for loss of response as a reason for the end or stop of imetelstat or placebo therapy. On the next slide is the primary endpoint. So the study met its primary endpoint with a significant and superior response rate for imetelstat compared to placebo, which I think is a very good sign and very important and also confirms the Phase II study results, which I summarized in my first slide. The next slide shows the durability of response, 16 weeks, 24 weeks, even 1 year. And you see that with imetelstat 64% of 24-week responders also achieved 1 year red blood cell transfusion independence, which I think is stunning, given the high transfusion burden and prior ESA therapy in this low-risk segment of patients. The next slide shows the 8-week red blood cell transfusion responders with regards to duration of transfusion independence. You see a significantly longer 51.6 weeks versus 13.3 weeks in favor of imetelstat. The next slide depicts an analysis with regards to subgroups for the primary end point and you see that across all important subgroups in lower-risk MDS patients, including RS status, transfusion burden, IPSS and so on. All of those analysis actually showed that there was no disadvantage for imetelstat in any of these subgroups. So all of these subgroups actually had a benefit from imetelstat therapy. The achievement of red blood cell transfusion independence is one thing, but I think especially for patient reported outcomes, quality of life, the increase of hemoglobin is very important. And I think this is also, therefore, a very important slide showing that the median hemoglobin rise in imetelstat arm compared to placebo, which was 3.6 gram per deciliter. So some patients even normalized the hemoglobin levels, which I think is a very important finding also of this study. The next slide goes along those lines with a greater reduction in mean red blood cell transfusion units over time, which also favored imetelstat versus placebo. The next slide shows you the HI-E rates based on the IWG 2018 criteria, which were also part of the protocol. And you see that only numerically a low number of patients with low transfusion burden actually were included into the study, but the HI-E response here was 33%, and it was 30.9% and 44.3% with regards to major or minor HI-E response in the HTB patient population. The next slide now looks again for the subgroup analysis for the 24-week RBC-TI rate. And again, there's a benefit favoring imetelstat across all subgroups, which I introduced to you in one of the previous slides. This also includes RS+, but also RS- patients, which I think is a very important finding. On the next slide is the same analysis now for the mutation burden. So no mutation or more than 1, 2, 3, lower-risk risk mutations, you see that in all of those subgroups it was actually my favorite application in this study where all of these subgroup patients benefited for a translational work with regards to RBC-TI rate at 24 weeks. We also look to the telomerase activity and telomerase length and hTERT expression at baseline. And again, this the breakdown here we met that median or about the median again, all subgroups actually had a benefit from imetelstat compared to placebo with regards to the 24-week RBC-TI rate. What about side effects? On the next slide, you see only 1 predominant side effect due to induction of Grade 3, Grade 4 thrombocytopenia and neutropenia, which occurred in 62% and 68% to patients, respectively and I'll come to this in one of the next slides, just mentioning that liver toxicity, which was actually not observed, but it was not different in imetelstat versus placebo. On the next slide, you see the duration of Grade 3, Grade 4 Cytopenia, median duration of Grade 3 to 4 of thrombocytopenia and neutropenia in less than 2 weeks and more than 80% of the events were actually reversible to Grade less or equal to 2 within 4 weeks after starting to 1 cycle dose. Also growth factors were actually allowed in this study and were used in some patients. On the right side, you see that there was 0.8% of patients in the imetelstat arm, which had Grade 3 febrile neutropenia. So the clinical consequence of this side effect were rather low. The next slide shows how the AEs were managed and most AEs actually leading to dose modification were, as I said before, neutropenia and thrombocytopenia. Although 74% of patients treated with imetelstat had dose modifications due to AEs, and less than 15% of patients discontinued treatment due to these treatment when it was given. So the next slide is the conclusion, which is a heavy slide, but I think number 1 is trial met its primary endpoint with a superior and clinically meaningful RBC-TI rate of 40% median-duration approached 1 year though it also included significant increase of hemoglobin level in these patients. The rate of 24-week RBC-TI rate was achieved and what was higher with the imetelstat across all subgroups of patients shown so far and has higher rate of 24-week responses was observed regardless of the number of mutations, but of the telomerase activity, and hTERT expression. Safety results were consistent with prior imetelstat clinical experience with no new safety signals and Grade 3, 4 cytopenias were that was common side effects. What I haven't shown is that we also saw disease-modifying activity with a significant reduction of [ variant allele ] of known MDS specific mutations like SF3B1 which also correlated with the RBC-TI rate but also the duration. And I think most importantly, the durability of response with the project here with the imetelstat treatment was not previously observed with other treatment, imetelstat-treated patients. And last but not least, I would like to mention that Dr. Komrokji will actually review within this meeting the disease-modifying activity of imetelstat which I briefly mentioned in my conclusion slide. So what I will briefly do now is to summarize the analysis of patient reported fatigue, and -- in the IMerge Phase III trial. And I think this is a very important analysis because in recent approvals of agents like luspatercept and lower-risk MDS actually showed that the hemoglobin levels go up or patients actually achieve transfusion independence, but at least for luspatercept no improvement of quality of life has been validated out of the Phase III program. So therefore, we're very curious how the IMerge study actually would read out with regards to PROs and especially fatigue. And this is -- actually it has been done in the Phase III program. As you can see here on the first slide, a 13-item questionnaire measured during daily activity, the FACIT-Fatigue scale was actually performed in patients within the clinical study in order to monitor, especially with the focus on fatigue in the IMerge Phase III trial. The next slide shows the fatigue endpoint, the way it was done. So this was an assessment of the proportion of patients in each treatment group reporting any episode of sustained or meaningful deterioration of improvement in fatigue. As you can see, this was done in the way Figure 2 shows so an episode of sustained meaningful deterioration or an episode of sustained meaningful improvement of fatigue reported at least 2 consecutive non-missed treatment cycles was performed in order to assess changes, significant changes with at least 3-point increase in the FACIT-Fatigue scale or based on the PRO assessment in order to assess whether a patient had an improvement or a deterioration of fatigue within the clinical trial. The next slide shows patient disposition, which is exactly what you would expect from the data of the clinical trial. And this is also why we had very good completion rates throughout the study, more than 85% of the PROs were actually assessed in the patient population, and I think gives you a very good snapshot of what the drug can do in the given patient population. So the next slide shows a lower deterioration in the FACIT-Fatigue score for imetelstat versus placebo. In fact, the sensitivity analysis showed that 43% of patients in either group experienced any episode of meaningful deterioration in fatigue for at least 2 consecutive cycles. In the PRO population, 67% of patients at either group reported any episode of meaningful deterioration in the fatigue for at least or more than 1 cycle. And most importantly, a lower percentage of imetelstat-treated patients experienced any episode of sustained meaningful deterioration than the placebo group, while imetelstat-treated patients slower to report sustained meaningful situation in fatigue than in the placebo group. The next slide shows actually the sustained meaningful improvement in the facet fatigue score with imetelstat versus placebo. You see on the left side, a sustained improvement which was significantly higher for imetelstat for more than 2 cycles, but also there was an improvement for at least or more than 1 cycle. Imetelstat-treated patients also had quicker to report sustained meaningful improvement in fatigue than those receiving placebo and compared to placebo imetelstat treatment resulted in more frequent reports of improvement in fatigue after week 12, which is also shown on the right side here. So the next slide shows the association of improvement in fatigue and clinical responses with imetelstat versus placebo also similar plot shown here where the majority of the 8-week RBC-TI responders in the imetelstat group consistently have sustained meaningful improvement in the FACIT-Fatigue scores through the durable TI intervals. And on the right side, you see a higher proportion of imetelstat-treated patients with 8-week RBC-TI or even longer or an HI-E response reported actually a sustained meaningful improvement in fatigue versus the nonresponders. And such an association also given the small amount of responders in non -- in the placebo arm was not observed in the placebo arm. The next slide shows the improvement in the FACIT-Fatigue score over time with imetelstat versus placebo and this was based on a complex model, which is depicted here, there were actually significant differences between the treatment groups, which again favored imetelstat versus placebo. So the conclusion on the next slide shows that, in fact, IMerge Phase III is the first randomized global trial of lower-risk MDS patients with baseline transfusion burden of at least 4 units over 8 weeks where actually sustained and meaningful improvement in PRO fatigue was observed when treated with imetelstat versus placebo. Imetelstat-treated patients reported also a lower rate of sustained meaningful deterioration in fatigue than placebo while also receiving fewer red blood cell transfusion units over time. Also, a higher percentage of imetelstat-treated patients reported any episode of sustained meaningful improvement in fatigue than placebo. So the rest, I think, of the summary is what I basically just reported in the previous slide. And I think the take-home message here is that this drug not only leads to red blood cell transfusion independence rate also sometimes sustainable in a substantial number of patients, but also reduces fatigue in patients with a high transfusion burden.

Hi. I'm Dr. Rami Komrokji, I'm the Vice Chair of Malignant Hematology Department at Moffitt Cancer Center and the lead investigator for the MDS program here. I have been honored to be part of the investigators developing imetelstat in myelodysplastic syndrome as well as myelofibrosis. I'll be summarizing a few abstracts starting first about the disease modification activity of imetelstat in patients with myelodysplastic syndrome. This was presented by Dr. Santini just this week at EHA meeting. Next slide, please. As you heard from Dr. Platzbecker, IMerge was really associated with impressive hematological responses, transfusion and dependency and hemoglobin increase, but what was really unprecedented is really seeing a lower-risk MDS patient cytogenetic responses that we have not seen with other drugs short of Lenalidomide in patients with deletion (5q) so in this study, we saw Cytogenetic responses in almost 1/3 of the patients in the imetelstat group that included patients with complete cytogenetic response, almost 19% of the patients as well as partial cytogenetic responses. And the cytogenetic responses did correlate with a hematological improvement or red blood cell transfusion independency. Next slide, please. And also one of the biomarkers of the disease is the ring sideroblast on this study, around 60% of the patients had MDS with ring sideroblast and a higher percentage of patients treated with imetelstat had more than 50% reduction in marrow ring sideroblast. And again, according to our knowledge, this is the first product to demonstrate a reduction in ring sideroblast which will consider a biomarker of the disease. So in around 40%, 41% of the patients, we saw that reduction and that also associated with transfusion independent of response. Next, we looked at variant allele frequency of several genes, including SF3B1, TET2, DNMT3A and ASXL1, those are commonly mutated abnormalities. SF3B1 is the hallmark we see with -- in patients with MDS with ring sideroblast. And again, we saw a reduction in the allele burden of all those mutations. Again, this is another piece suggesting of disease-modifying activity that, again, has not been observed with other treatments, including luspatercept that's approved for patients with MDS ring sideroblast. When we look at the percentage of the patients, roughly around 1/3 of the patients had reduction in those mutations. ASXL1 mutation is known to be resistant to hypomethylating agents as well. And even with patients treated with hypomethylating agents they either don't respond or the variant allele frequency of this mutation does not go down. Again, this is really suggesting of a disease-modifying activity of imetelstat. Next, we looked at the sustained reduction in the SF3B1 and we saw that this was not just like a fluctuation that this was a real reduction in the allele frequency. And when we tried to look at the reduction in the allele burden with SF3B1 more than 50% and the primary endpoint which is red blood cell transfusion independency, we saw a nice correlation between the 50% reduction in the SF3B1 variant allele frequency and the red blood cell transfusion at different time points, 8, 24 weeks and even up to 1 year. Similarly, when we looked at patients with TET2 mutation, those that had a 50% or more reduction in the TET2 variant allele frequency had higher transfusion independency at different time points as well. We also looked at the reduction in all those mutations, the SF3B1, TET2 and DNMT3A and that correlated with a longer red blood cell transfusion independency. Suggesting, again, that the disease modification is what's really leading back to restoration of effective hematopoiesis in those patients. And we also looked at the hemoglobin level as summarized by Dr. Platzbecker hemoglobin increase was around 3.6 grams per deciliter in the study. Again, one of the most robust hemoglobin increase following Lenalidomide and del(5q) and we saw a very nice correlation in the reduction of the allele burden of those mutations and the blood transfusion or the hemoglobin increase in this case. Finally, we looked at all those variables in terms of 8- and 24-week transfusion independency and all those disease-modifying biomarkers correlated with the primary endpoint as well as the longer duration of red blood cell transfusion independency, a reduction ring sideroblast, cytogenetic responses, a reduction in the allele frequency of the SF3B1, TE2, DNMT3A and ASXL1 all correlated with both the 8- and 24-week red blood cell transfusion independency. I think the importance of this data, this is one of the few drugs short of Lenalidomide in the recent (5q) which is 5% of MDS patients to suggest that we have a medication that could alter the natural history of the disease. So we saw cytogenetic responses. We saw a reduction in the ring sideroblast. We saw a reduction in the somatic mutations, including the SF3B1 to ASXL1. So this will be very exciting for the researchers in the field also to obtain the longer-term follow-up with this disease modification activity to correlate that with outcomes such as overall survival as well as leukemia-free survival. So again, this suggests that imetelstat restored effective hematopoiesis and Erythropoiesis through altering the natural history of the underlying biology of the lower-risk MDS patients. Next, I would like to discuss the ongoing trials in patients with myelofibrosis. So myelofibrosis is another disease of unmet need. This is probably even more complicated than MDS. The hallmark of this disease is the activation of the JAK/STAT pathway, patients have a cytokine release, excess cytokine they have cytopenias, but they could also have constitutional symptoms and splenomegaly. 10% to 20% of those patients eventually will transform to acute myeloid leukemia. And the only standard of care are JAK2 inhibitors which are mostly used for symptom management, namely reduction of constitution symptoms and spleen reduction. Roughly 40%, 50% of the patients would respond to those treatments on an average duration of 3 years, sometimes shorter in patients with higher-risk mutations. Our group and our colleagues from MD Anderson had published previously that at time of ruxo failure patient survival, those patient's unfortunately, is in the range of 14 to 16 months. So previously, we've looked in the Phase II trial on -- with imetelstat in patients with myelofibrosis there were 2 arms, 1 with the 9.4 milligram dosing and the other 1 with the lower dose that actually showed that the higher dose was associated with pain reduction, symptom improvement, but what was most important is the study was a lower dose had not much activity and further as a controller arm we saw a signal suggesting of improved survival in patients treated with imetelstat. So the median overall survival was 29 months compared to 14, 15 months in the lower dose and what I just mentioned historically known. We also later on, conducted a real-world data and met with the patients treated with that study. And again, showed that there was a survival signal in that Phase II even compared to real-world data. And that was true even in a very hard subset to treat, so we name them -- we call them triple negative disease. So based on that, we have this ongoing exciting study in patients with myelofibrosis looking at patients with higher risk myofibrosis that had relapsed or refractory after JAK2 inhibitors, randomized to either imetelstat at the 9.4-milligram kilogram dosing every 3 weeks versus best available therapy. This is the only study in patients with myelofibrosis with a primary endpoint of overall survival. However, we still will be assessing the classical endpoint in myelofibrosis such as symptom response and pain response. The study is ongoing and hopefully, again, will lead to a benefit to our patients. Also, as we note this activity that imetelstat could be disease-modifying both in MDS and myelofibrosis it makes sense to consider moving this earlier and combine it with the JAK2 inhibitors. So we have a study plan and ongoing of combining ruxolitinib with imetelstat. This is the IMproveMF study looking at, again, moving imetelstat in the upfront setting, where we'll be treating patients with intermediate 1 intermediate 2 and higher risk with Ruxolitinib plus imetelstat, first to assess the Phase II recommended dose and then a Phase II study to expand and evaluate the efficacy and the safety of this combination. With that, I'll turn it back to Dr. Platzbecker. Thank you very much for listening.

So this is all about the IMpress study, which is planned, but I have the pleasure to say ongoing now. Phase II investigator-led study of single agent Imetelstat in post HMA relapse/refractory AML. This is a study within the European MDS network M score and is performed not only in Europe, but also together with our friends in Australia. So there's an unmet medical need in high-risk MDS and AML failing HMA-based first-line therapy. That's at least in the European Union, there's not so much available with regards to standard of care for these patients. So therefore, there's a medical need to evaluate novel agents. And I think imetelstat has a very good and excellent preclinical rationale to investigate it in this segment of patients. The way the study is designed is that patients with relapsed/refractory or intolerant to HMA, high-risk MDS and AML can be included. And these patients actually are given imetelstat at the dose shown here, preferentially in an outpatient segment every 4 weeks with the endpoint being overall response rate according to IWG criteria and the study is powered to include roughly 45 patients at 2 continents. And I'm happy to say that last week, the first patient was actually dosed and there are a couple of more now already in screening. So we hope that the trial will fill up pretty soon.

Uwe, Rami, thanks so much. I'm sure the audience will have many questions for you. Let me now give a brief update on regulatory activities with imetelstat in lower-risk MDS. Our new drug application to the FDA in lower-risk MDS is still on track to be submitted this month. As a reminder, we have fast track designation in lower-risk MDS, which has enabled a rolling review of our submission along with the final module of the NDA being submitted, we also plan to request priority review. As we have explained in the past, we expect to receive a response from the FDA on the status of our submission including whether it will be reviewed under priority or standard basis, approximately 60 days after our completed submission. On the EU regulatory front, we still expect to submit the MAA in the second half of 2023. With that, I'll turn the call over to Anil, our Chief Commercial Officer. Anil?

Thank you, Faye, and good morning, everyone. As you've heard from our clinicians, the data supporting Imetelstat in both lower-risk MDS and relapsed/refractory myelofibrosis as well as the science behind telomerase inhibition is robust. We believe that imetelstat can play a meaningful role in the treatment of patients in both of these indications. These indications offer large, addressable patient populations for imetelstat which represents significant commercial opportunity for Geron. Today, I'll be sharing our perspective on the market dynamics in lower-risk MDS, how we view our commercial opportunity, recent market research and physician perspectives and a brief update on progress towards commercial launch. This next slide shows the current treatment landscape in lower-risk MDS. First, most patients with symptomatic anemia received ESA treatment. However, not all patients respond to or are eligible for ESAs. Even among responders, responses typically last between 18 to 24 months. There also remains very high unmet need in frontline patients who are ESA ineligible given their high baseline serum EPO levels. Treatment options are limited for patients who have failed or are ineligible for ESAs and may include HMAs and luspatercept, which is approved for ring sideroblast positive patients. RS- patients represent approximately 75% of all low-risk MDS patients and treatment options in this setting do not offer evidence of durable and continuous transfusion independence. Therefore, we believe this market in ESA relapsed/refractory and ESA ineligible lower-risk MDS patients is undersaturated and ripe for innovation for a durable treatment that has a potential to be broadly used across MDS subtypes. Thus, we see a substantial and compelling commercial opportunity for imetelstat as depicted in the red boxes. Next slide. When shown the Phase III IMerge data, several key attributes of imetelstat resonated strongly with both community and academic hematologists. Specifically, with regards to efficacy, physicians perceive a strong totality of clinical benefit and meaningful durability of response. This was attributable to compelling TI rates across RS subtypes, sustained reduction of red blood cell units and continuous rise in hemoglobin levels. Further, 16- and 24-week transfusion independence data was regarded as more robust than current standards of care. With regards to safety, physicians perceive the AE profile is predictable with manageable cytopenias. Given the familiarity of the adverse event profile with transient cytopenias, physicians expect to use imetelstat in their lower-risk MDS patients across both community and academic edits. As shown on this next slide, our market research, reflecting interviews with over 30 hematologists from U.S. and key European markets in both academic and community settings indicates that hematologists perceive imetelstat's benefit risk profile, provides a compelling treatment option across RS subtypes and in high-transfusion burden patients. First, in the RS-, ESA relapsed/refractory low-risk MDS patients, physicians communicated that imetelstat would be strongly preferred treatment of choice regardless of level of transfusion burden with enthusiasm for the efficacy improvements observed from clinical studies as well as dissatisfaction with current treatments. Next, in the ESA relapsed/refractory RS+ patient segment, hematologists considered the reported durability of imetelstat transfusion independence, compelling and would provide significant improvement in long-term response over available options. Furthermore, physicians noted that gaining more clinical experience with the drug, may increase conviction to prescribe imetelstat ahead of currently available options. Lastly, physicians stated that imetelstat's efficacy profile was significantly differentiated in high-transfusion burden patients which further bolsters their opinion that imetelstat may be a compelling option over currently approved therapies. Next slide. We also conducted market research with 56 practicing hematologists in the U.S. across both community and academic settings to understand how they would use imetelstat if available, as compared to other therapies. We asked them about future treatment paradigms across 3 key patient segments, second-line patients who may receive ESA in the frontline setting, second-line patients who may receive luspatercept in the frontline setting and frontline patients who are ESA ineligible due to serum EPO levels being greater than 500. Their responses indicate strong enthusiasm for imetelstat to be integrated across these 3 different patient segments in the low-risk MDS treatment landscape upon potential approval. This next slide shows the responses about future treatment paradigm across the same 3 patient segments. Second-line usage in ESA experienced patients, second-line usage in luspatercept experienced patients and frontline usage in ESA ineligible patients. These data are now further segmented for RS-positive and RS-negative patients within these subgroups. As you can see here, their responses indicate that imetelstat is not only expected to be broadly adopted for the treatment of lower-risk MDS as we saw on the previous slide. But that it is especially likely to become the new standard of care for RS- patients. As a reminder, RS- patient segment is approximately 3x larger than the RS+ patient segment and treatment options for RS- patients remains suboptimal. Holistically, we believe this market research emphasizes the significant unmet need across the lower-risk MDS patient population, which is also supported by the comments provided by our clinicians this morning. Therefore, we continue to believe that imetelstat can play a meaningful role in the treatment paradigm of lower-risk MDS moving forward. I would like to close by saying how very pleased I am by the tremendous effort across Geron as we prepare for a highly successful U.S. commercial launch of imetelstat. Our goal is to prepare imetelstat, the lower-risk MDS market, and Geron is an organization so that we can deliver a seamless customer experience to all stakeholders, while ensuring broad reimbursement for imetelstat. Efforts, which necessitates deep collaboration across the organization. I'm pleased to report that we are on track across all of our pillars shown on this slide to achieve launch readiness in early 2024. Regulatory submissions are on track, community and channel engagement efforts are well underway. U.S. commercial distribution blueprint and third-party logistics are finalized and we have onboarded our deeply experienced medical affairs and commercial teams. Our build-out and hiring of the sales force will occur in a stage-gated approach aligned to our future PDUFA date when identified. We are extremely pleased with our progress to date and look forward to sharing updates in the future. I'll now turn the call back to Chip for closing remarks. Chip?

Thanks, Anil, and thanks to everyone on the call for joining us today. And again, a special thanks to Uwe and Rami for joining us to present the IMerge data and review the other clinical studies in our imetelstat pipeline. From an investor perspective, this slide depicts our overall strategy for building value with imetelstat over the next several years. And bringing the conversation back full circle to lower-risk MDS if I were to leave you with just 1 key point that's come out of the talks given today, it would be that we believe in imetelstat approval will change the standard of care for treatment of transfusion dependence in low-risk MDS patients by providing them with the following: long-term continuous relief from the burden and complications of red blood cell transfusions; an improvement in fatigue and hopefully, other PRO measures of clinical benefit elucidated by further study and analysis; and the potential for changing the natural history of MDS through reduction of the uncontrolled proliferation of the malignant clone responsible for the underlying disease. With that, let's turn the call back to the operator for a live Q&A.

[Operator Instructions] Your first question comes from the line of Kalpit Patel of B. Riley.

Maybe I'll start with a couple for the KOLs on the call. Now that we have ASCO and EHA updates for both the IMerge study and the COMMANDS study, how are you thinking about the positioning and sequencing of luspatercept and imetelstat in the treatment landscape?

Uwe or Rami, either of you can take that.

I can start if you want me to start. So thank you very much for the question, which I think is certainly valid. So at this stage, luspatercept is approved for ring sideroblast patients being relapsed/refractory or not eligible to ESA therapy. So the label at the moment is restricted to ring sideroblastic patients. So as of now, if the label would stay like it is, I think the story is pretty clear for non-ring sideroblastic patients where luspatercept doesn't have a label so far, where I think that luspatercept would be the valid second-line therapy. For the ring sideroblastic patients, I think the community would go for the sequence EPO followed by luspatercept, followed by imetelstat. You know that the COMMANDS study has shown superiority for the global trial with regards to the primary endpoint, including RS+ and RS- patients. In the subgroup analysis, the RS- patients did not seem to benefit with regards to superiority of the response rate, although study was not powered maybe to show that difference, but that's as the data looked like. So I think it depends a little bit on the view of the authorities and how they interpret the data whether luspatercept will get a flat first-line approval for RS-positive and RS-negative patients. Of course, I'm not the FDA, and neither the EMA. So the decision, I think, is pending. But let's say this way, if there will be a full approval for non-RS and RS patients. Then I think the community -- this is, of course, my anticipation. I cannot foresee the future. But I think since it's a easy to give growth factor maturating agent I think majority of patients would get probably luspatercept first, followed by imetelstat. It may be different for maybe the subset of patients with high transfusion burden, where we know that luspatercept is not very active or transiently active, but the strength, I think, of imetelstat is definitely in this patient segment. And then, of course, patients being exposed or not eligible to ESA therapy, may go directly to imetelstat therapy.

Thank you.

And Doctor, you mentioned that the high transfusion burden patients might not get luspatercept. So what would those patients get? Would they get ESAs? Or would they get imetelstat perhaps off label in the frontline setting?

No. I mean I'm talking about patients being -- with a high transfusion burden who have been exposed to ESA therapy, and then the treatment choice is either luspatercept or imetelstat and where we know that the -- the luspatercept had some activity there. Yes, it has. But transiently and many patients only reduce their transfusion burden, but don't get transfusion independent. The situation is different for imetelstat where even patients with a high transfusion load and burden can get transfusion independent with an increase of hemoglobin levels for a long period of time.

Yes, and if I may add to Dr. Platzbecker. So the transfusion burden is also predictive of response to ESA so we don't expect those patients to be responding higher to ESA as well. But as mentioned, with Luspa, the transfusion burden is probably the most important predictor of response. And in high-transfusion burden patients probably the best we can achieve is transfusion reduction, that's actually dose-dependent, so those patients need way higher dose of luspatercept or the maximum dose.

Your next question comes from the line of Robert Driscoll of Wedbush Securities.

Just a couple of questions for Dr. Platzbecker. Can you put the imetelstat FACIT-Fatigue data into context of what is seen, I guess, your clinical experience with other therapies used for LR-MDS such as luspatercept?

Yes. Thank you for the important question, which addresses actually quality of life as a meaningful endpoint in clinical trials with low-risk MDS patients. So fatigue is not only very common in low-risk MDS patients, sometimes independent of the transfusion burden and also the extent of anemia, but it's also -- it can be also a side effect of treatment. And we know that luspatercept in a small subset of patients, though, but can also induce a side effect fatigue, which sometimes dose-dependent can be managed quite easily in the majority of the patients, but this is something we need to consider. We also know from luspatercept that although the primary endpoint of MEDALIST trial and also the COMMANDS trial was met, at least on the MEDALIST trial the quality of life data did not show a superiority or improvement of quality of life in the global patient population, although the transfusion independence is achieved and sometimes also an increase of hemoglobin levels. So the situation is fortunately different to imetelstat where fatigue was improved in the pivotal IMerge Phase III trial, which I think is, of course, maybe multi-factoral. But I think 1 reason why we saw this improvement in fatigue maybe the significant increases of hemoglobin levels in patients with high transfusion burden. We -- as you have seen in the presentation we gave at ASCO and EHA there was a significant increase of hemoglobin levels sometimes to normal value. So I personally have seen patients with high transfusion burden where actually the hemoglobin levels normalized and not only stayed at a level of, let's say, 9 or 10 grams per deciliter so really normalized. I think this could explain why imetelstat also improved quality of life, which I think, is a very important thing and also from the authorities, and I can speak here because I'm part also of the assessment in Germany, also in line with the with the people who assess approval of drugs and reimbursement, that quality of life improvement or changes become a very important assessment tool with regards to the reimbursement strategy of drug in low-risk MDS.

Thanks very much, Dr. Platzbecker. I think -- Rob, sorry, I think we're going to need to move on to give everybody a shot here, we're short on time.

Your next question comes from the line of Stephen Willey of Stifel.

Maybe just a couple for the KOLs. I guess the first would be why do we seem to see such a skied representation of RS-positive patients across all lower-risk MDS trials that are ongoing. I think is there some kind of underlying dynamic here just with respect to how these patients are getting referred in the clinical trials?

This is Rami. I may take a shot on this and Dr. Platzbecker can add. So I think there are 2 parts. Partly, there is probably some physician bias enrolling patients on trials because people like knew that more activity of Luspa and imetelstat. But I think part of it is also related to the disease biology. We just presented data at EHA about the incidence of those RS patients or SF3B1, which is really around 15%. However, those patients have an excellent median overall survival in the range of 8 to 10 years. So they are prevalent in any practice. So any lower risk practice get enriched by patients with ring sideroblast because the major issue is this ineffective erythropoiesis transfusion dependency. So they live longer, but they are in need for therapy. So by that, the trials get enriched by those patients.

Thanks, Rami. Any other comments from Uwe or shall we move on to the next question? Okay.

I can. But in the sake of time, I may not.

Your next question comes from the line of Gil Blum of Needham & Company.

So it looks like the activity in EPO and eligible was not as strong as you would expected from some of the other patients. Do you believe this is due to just powering, do you think this could be potentially restrictive of the label? I mean, a similar trend was also seen in the COMMANDS study as well. So I'd love your comments here.

Rami, do you want or I can...

You can go ahead, Uwe.

Yes. So I think the short answer is the numbers are too small to make final conclusions. I don't think that there is a scientific or preclinical rationale why these patients may have not benefited. And again, it was a very small number. So I don't think this is -- we can make a clear conclusion from these results.

Your last question then comes from the line of Joel Beatty of Baird.

ASCO in the discussion session or the discussion raised the question for lower-risk MDS patients with previous ESA exposure would you use imetelstat or DNA methyl transferase inhibitors. Could the docs address that?

Yes. So first, I would like to say that the use of the JAK inhibitors or what we call them hypomethylating agents is really only available in the U.S.A., in Canada and Europe those -- and Australia, those drugs are not approved for lower risk. However, even in the lower risk we've been trying to move the use of those medications later in the line preserved for patients with higher risk because we see this kind of bone marrow failure post hypomethylating agents. We've published previously that the median survival, even if the lower-risk patients after HMA failure is somewhere around like 18 months. So -- and their activity is really not even higher what's reported, all over responses are in the range of 30% again. So from my perspective, I would move use of luspatercept and imetelstat prior to hypomethylating agents even in the lower risk. But this is strictly a U.S.A. phenomenon where there is no approval anywhere else in the world for hypomethylating agents for lower-risk MDS.

I would like to add -- can I just say 4 sentences. Number one, even if it would be approved in my country, which is not, I would favor imetelstat because the activity is based on a Phase III positive trial. HMA has never been proven in a Phase III trial to be active, more active than any other treatment in low-risk MDS.

Thank you very much for that important comment. Well, we are definitely out of time. I want to thank again both Dr. Platzbecker and Dr. Komrokji for their generous time and their outstanding contributions to this program. They've been really valued contributors and we look forward to many more years of working with them. Thank you to all of the excellent questions from the group listening, and I wish everyone a very, very nice day. I appreciate all of your attendance here.

Thank you. And this concludes today's conference call. You may now disconnect.