Good afternoon, everyone. Welcome to the Geron Investor Event. I am joined today by Dr. John Scarlett, Geron's Chairman and Chief Executive Officer, Dr. Aleksandra Rizo, Geron's Executive Vice President and Chief Medical Officer, and Anil Kapur, Geron's Executive Vice President of Corporate Strategy and Chief Commercial Officer. In addition, we are honored to have present three key opinion leaders in hematologic malignancies: Dr. John Mascarenhas, Associate Professor of Medicine at the Icahn School of Medicine at Mount Sinai, Dr. Uwe Platzbecker, Director of the Medical Clinic University Hospital, Leipzig, and Dr. Swami Iyer, Professor of Medicine at the MD Anderson Cancer Center. These speakers will cover the agenda topics shown on this slide. 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 of and potential regulatory approval of imetelstat, anticipated clinical and commercial events and related timelines, the sufficiency of Geron's financial resources, and other statements that are not historical fact. Actual results and events 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 September 30, 2021, 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. I will turn the call over to Dr. Scarlett. Chip. Thanks, Olivia. Good afternoon, everyone, and welcome to the Geron Investor Event of 2021. I'm Chip Scarlett, the Chairman and CEO of Geron Corporation. By way of an overview for this investor event, let me begin by saying that Geron's vision is to become a leader in the treatment of hematologic malignancies. We believe we can achieve this vision by focusing on the development of drugs that target telomerase. As Dr. Mascarenhas will discuss shortly, telomerase is an enzyme that's continuously upregulated in malignant cells, enabling their rapid, uncontrolled proliferation and accumulation in the bone marrow and other organs, ultimately resulting in the clinical manifestations of disease. Geron's first-in-class telomerase inhibitor, imetelstat, selectively kills these malignant cells with the cytogenetic, molecular, and clinical data from our phase two studies, providing strong evidence of disease modification potential. As Dr. Platzbecker and Dr. Mascarenhas will discuss further, the imetelstat phase two studies showed that imetelstat was able to successfully address patients' current unmet medical needs. This included the need for durable transfusion independence in lower-risk MDS, and improved overall survival in JAK refractory MF. We have ongoing phase three studies in these indications that are intended to be pivotal registration trials, the design of which will also be discussed. Of great importance is that the first of these phase three readouts in lower-risk MDS is expected to occur in early January of 2023. In addition, our phase three study in refractory MF is currently enrolling. An interim analysis for this study is expected in 2024, while a final analysis is expected in 2025. We have high hopes for both of these studies. To complete the first part of this investor event, Anil Kapur, our Chief Commercial Officer, will review the commercial opportunity in lower-risk MDS and refractory MF, in addition to providing details around our U.S. commercial readiness efforts. Based on our expectations for a unique, highly differentiated imetelstat product profile, similar to what we saw in our prior phase two studies, we expect the commercial opportunity for the combined lower-risk MDS and refractory MF indications in the U.S. and EU five countries will reach an annual peak market potential of over $3 billion. In the second part of this investor event, we're also announcing several new initiatives intended to further strengthen our telomerase franchise. One of these new initiatives is a next-generation telomerase inhibitor discovery program. I'll give a brief update on this program, which we started about a year ago. Then our Chief Medical Officer, Dr. Aleksandra Rizo will take over from me. Alex will introduce these new initiatives that will explore the use of imetelstat in other indications, both as a single agent and in combination with other therapies. She'll also introduce the principal investigators for the studies being described. These studies include a phase I Geron-sponsored study of imetelstat in combination with ruxolitinib in frontline myelofibrosis, a phase II investigator-sponsored study of single agent imetelstat in relapsed refractory acute myeloid leukemia and higher-risk myelodysplastic syndromes, a phase I/II investigator-sponsored study of imetelstat in combination with HMA s or venetoclax in relapsed refractory acute myeloid leukemia, and a preclinical program in lymphoid malignancies. We'll conclude this investor event with a panel of our KOL guests, as well as the members of Geron management who have participated in the event, and we'll be happy to take questions at that time. With that, thank you for your attention, and let me turn the meeting over to Dr. Mascarenhas. John. Thanks, Chip. Moving along, here I'm showing the myeloid malignancies that are a group of clonal hematologic cancers derived from a hematopoietic stem and progenitor cell population, include myelodysplastic syndromes, myeloproliferative neoplasms, and acute myeloid leukemia. These diseases share commonalities such as the acquisition of chromosomal and genetic alterations that contribute to expansion of the myeloid malignant hematopoietic stem cell population and increased production of blood cells, as is the case of MPNs and AML overproduction, and in the case of MDS, ineffective production. These clonal diseases also negatively regulate normal hematopoiesis, so the end result is often cytopenias and the consequences of anemia, infections, and bleeding. The goal of therapeutic development in the myeloid malignancy space is effective targeting and depletion of the malignant stem cell population to achieve long-term remission and cure. To this point, we are interested in targets that are preferentially or differentially expressed in the malignant hematopoietic stem cell population, and this is why telomerase is a key target in these diseases. Telomerase is an enzyme that adds DNA repeats to the ends of chromosomes, thusly allowing for continued cell division, and this enzyme is constitutively expressed in the malignant hematopoietic stem and progenitor cell population, and only transiently in normal hematopoietic stem cells. Next slide. Imetelstat is an oligonucleotide that competitively binds and antagonizes the active site of telomerase RNA template region, thereby inducing apoptosis preferentially in the malignant cell population, and this relatively spares normal hematopoiesis, and therefore allows the potential recovery of normal blood counts. This mechanism of action and relevance in myeloid malignancies is supported by multiple preclinical studies. Next slide. What makes imetelstat very exciting is not only the mechanism of action, which is unique and first-in-class, but also that the data at hand in both MDS and MF suggests disease-modifying potential. In both phase two studies, we have seen on-target engagement with reduction in telomerase activity, and MPN and MDS hematopoietic stem cell depletion as evidenced by elimination of the abnormal clones marked by molecular and cytogenetic responses, and very importantly, reinforced as clinically meaningful by correlation with clinical benefits in both MDS and MF, such as anemia responses in MDS and reduction in bone marrow fibrosis and myelofibrosis that can even more so be correlated with survival benefit for the first time in myelofibrosis. Thank you, Dr. Mascarenhas, for this introduction. I will now cover in the next couple of minutes lower-risk MDS, disease characteristics, unmet medical need, and also the putative role of imetelstat in the treatment landscape. I will start a little bit to talk about MDS, especially lower-risk MDS. MDS per se is a malignant stem and progenitor cell disorder which comes with so-called ineffective hematopoiesis, so ineffective production of red blood cells, white blood cells, and also platelets. The primary clinical presentation, however, is chronic anemia, and many of these patients actually get red blood cell transfusion dependent. There are several subgroups also defined by molecular characteristics, but one of the largest subgroups actually are the so-called ring sideroblast- positive and the ring sideroblast- negative patients. The current treatment paradigm in the majority of the patients being anemic at the first presentation is to start with so-called erythropoiesis- stimulating agents, ESAs or EPO. However, only roughly 40% of patients respond to these therapies, and the majority also fail after two years of successful treatment. Therefore, patients relapse or refractory to ESA treatment are an unmet medical need, and many of these patients actually still do not have any treatment options. Serial red blood cell transfusions on the other side can only in part improve or maintain the quality of life. They are also associated with significant costs. Iron overload and also transfusion dependency has been linked to shorter survival and higher risk of AML transformation in these patients. Apart from ESA, we have also other treatment options. For instance, luspatercept is registered, but only for the subset of ring sideroblast-positive low-risk MDS patients, and at least not in the European Union, but in the U.S., HMAs, hypomethylating agents, and also lenalidomide are a valid option for these patients. However, also in the majority of these patients, responses are not very high and not long-lasting. To summarize, I think there's an unmet medical need for patients with lower-risk MDS who are actually transfusion dependent, and you see that the patient population at the moment is pretty big. 70% of all MDS patients are basically lower-risk. This is roughly more than 100,000 patients in the European Union as well as in the U.S., and more than 25,000 low-risk MDS patients are currently diagnosed annually in both continents. On the next slide, you will see now the treatment results with imetelstat, which are basically meaningful and also lead to durable transfusion independence. You see the eight-week transfusion independence with imetelstat given once a month as a single infusion is 42.1%. Twenty-four-week transfusion independence is 31.6%, and I think very meaningful also for these patients is the one-year transfusion independence rate, which is almost 30%. Pretty durable response rate is in these heavily transfused patients, at least in the phase two trial, the majority of the patients had at least four units of red blood cells within eight weeks prior to study treatment. Also, transfusion independence comes with a rise of hemoglobin. You see 75% of patients showed a hemoglobin rise of at least three grams per deciliter during the transfusion-free interval compared to the pretreatment hemoglobin levels. Is there any subgroup of patients, and this is now the next slide, who may preferentially benefit from imetelstat treatment, lower-risk MDS? This is an analysis among common subgroups. For instance, the RS positive versus RS negative, also transfusion burden, did not show any impact on the likelihood to basically achieve a transfusion independence for at least eight weeks. In contrast to luspatercept, which is actually primarily active in ring sideroblast-positive patients, imetelstat seems to have a very broad activity across different subtypes of lower-risk MDS patients. The next slide actually describes the disease modification potential of imetelstat in lower-risk MDS patients. Many of these patients actually have also a clonal burden, so several mutations which can be detected by next-generation sequencing, and in the first figure on the left side, figure A, you see the change in the allelic frequency, the allelic burden of the so-called SF3B1 mutation, which actually is associated and linked to the ring sideroblastic phenotype. You see that baseline and post-imetelstat, there's a significant decline of the allelic burden, so a disease-modifying activity of imetelstat in these low-risk MDS patients, and on figure B, you see that the greater SF3B1 variant allelic frequency reduction also correlates with a longer duration of transfusion independence, which is given on the x-axis. Some patients actually do not display mutations, but rather have cytogenetic abnormalities, and also in the figure C, you see that patients with abnormal cytogenetics at baseline also had a reduction of their clones and also long-lasting transfusion independence, which was correlated with this reduction of the cytogenetic abnormality. Again, all of this suggesting that in contrast to agents like ESA or also luspatercept, where not a disease-modifying activity has been described so far, imetelstat is not only inducing high rates of transfusion independence, but it's also doing or has also a disease-modifying activity and potential, which makes it, I think, quite interesting. The next slide describes the imetelstat safety profile, and I think to make a long story short, you can have a look at the non-HEM AEs, which were rather rare and of very low grade. I think the majority of the patients displayed HEM toxicity, as you can see here, grade three, grade four, thrombocytopenia, neutropenia occurred in roughly 55%-61% of the patients. Median time to this cytotoxicity was actually four weeks, median duration less than two weeks, and in more than 85% of the cases, this toxicity resolved within four weeks. It was therefore manageable with dose hold or modification, and also had limited clinical consequences, 5% grade three, four febrile neutropenia, 8% grade three, four bleeding. I think this is an important statement. I think HEM toxicity is something I think we are pretty aware of as hematologists. We can manage it pretty well, but I think especially in lower-risk MDS patients at this grade, it's important to monitor and also to watch it, but I think also, as we know from the phase two trial, it's possible, it can be easily managed, and is not harmful to the majority of the patients. The next slide actually describes the IMerge phase three clinical trial. The top line results actually to be expected in early 2023. This trial actually completed enrollment in October 2021, so a couple of weeks ago, and actually included low or intermediate one-risk MDS patients with non-del(5q) MDS being transfusion dependent and relapse refractory or also not eligible to ESA treatment. One hundred seventy patients were randomized in a two-to-one fashion to imetelstat given every four weeks versus placebo, and you see the primary endpoint is red blood cell transfusion independence of at least eight weeks. Key secondary are transfusion independence of at least 24 weeks, but also patient-reported outcomes and many others. I think this is an important study because it had a broad patient enrollment, not only ring sideroblast-positive patients, but also negative patients, also including ESA ineligible, and most importantly, luspatercept, of course, has been recently launched, and therefore also this study allowed luspatercept-experienced or relapsed refractory patients to be included. The next slide summarizes the key efficacy results of the IMerge phase two trial, which investigated imetelstat in lower-risk MDS patients and compared it. Of course, this is not a fair comparison here, but I think just to give you a little bit of direction where imetelstat could stand in the future, the comparison to basically the MEDALIST phase three luspatercept being only in ring sideroblast-positive patients. You see the transfusion independence rate 42% in the imetelstat versus 32% in the luspatercept MEDALIST trial, and also the duration of response, 88 weeks versus 31 weeks. The available data so far, of course, always being cautious because it's a comparison of a phase two with a phase three study, suggests that the imetelstat is inducing a high rate of transfusion independence, and most importantly, this is also very durable in a substantial amount of patients. With that slide, I would now like to hand over to Dr. Mascarenhas. Thank you, Dr. Platzbecker, for allowing me to continue with imetelstat in relapsed refractory myelofibrosis, unmet need, and role in treatment landscape. MF, as we have discussed, is a hematopoietic stem cell and progenitor cell malignancy akin to a chronic leukemia with a median survival of approximately five to six years and a risk of progression to AML, which has a dismal survival of approximately three to five months. MF is interesting as it also is associated with a robust inflammatory component that drives symptoms and splenomegaly and promotes bone marrow fibrosis. JAK inhibitors have been developed as potent anti-inflammatory therapies that downregulate the JAK stat signaling pathway and result in inflammatory cytokines with symptom and spleen relief, but unfortunately do not deplete that clone and therefore do not reliably change the natural history of disease. Approximately 15% of myelofibrosis patients are refractory to JAK inhibitors upfront, and the majority by five years have discontinued with a median time to discontinuation of three years. The survival after ruxolitinib failure by five independent studies is approximately 12-15 months, and no approved therapies exist for these unfortunate patients with limited survival, and this defines an unmet need in myelofibrosis. Next slide. From the EMBARK randomized phase two trial of imetelstat at 9.4 and 4.7 mg per kg IV every three weeks in intermediate-2 and high-risk myelofibrosis after ruxolitinib failure, we saw impressive efficacy outcome measures when comparing the two dose levels with a median survival of 28 months in the high-dose arm and 43% of patients having at least one-grade reduction in bone marrow fibrosis, with 42% of treated patients with at least a 25% or greater reduction in driver mutation variant allele frequency. This really points to the disease modification beyond symptom and spleen responses, which was also seen at this dose, but is not the most pressing treatment objective in the Rux failure state. Next slide. The graph on the left shows the Kaplan-Meier survival curves between the two arms, with the blue arm indicating the 9.4 milligram per kg dose, and the reason the curves touch eventually is that the lower-dose arm was closed as it did not meet pre-specified criteria to continue, and these patients had the option to cross over to the active arm. There's a clear survival advantage seen here that again compares favorably to historical controls. On the right is a recent published analysis using a real-world data set from Moffitt of 38 patients from their database that had ruxolitinib failure and 57 patients from the 9.4 mg per kg arm that were matched by propensity scoring to try and replicate a prospective randomized study. Remarkably, and I would say consistently with the literature, the median overall survival in the imetelstat treated patients was 33 months, and this compared very favorably to the real-world data set with a median overall survival of 12 months. Next slide. When looking at biomarkers of response, reduction of at least one grade of bone marrow fibrosis by blinded central review was seen in 41% of the active arm treated patients, and this was associated with a median overall survival of 32 months compared to 25 months in those patients who did not attain reduction in bone marrow fibrosis. I should mention this is the first study that I'm aware of that correlates bone marrow fibrosis reduction with survival as shown in the graph on the right. Next slide. 46% of imetelstat treated patients at the 9.4 mg per kg arm achieved at least a 20% reduction in driver mutation VAF, indicating modification of the clonal burden of disease, and this was also associated with prolongation in survival as shown by the Kaplan-Meier curve on the right. To highlight the anti-clonal activity beyond driver mutation burden reduction, the figure here shows the mutational complexity and enrichment in high molecular risk mutations indicated by the arrows in this population of patients after ruxolitinib failure that confirms this is a very poor risk population. More so, it shows in bright green these patients who attained a complete molecular remission of individual mutations as a surrogate for clonal response with imetelstat, including bad players such as ASXL1, TP53, and RUNX1, all of which are recognized as adverse prognostic mutations in this disease, as well as MDS and AML and throughout myeloid malignancies. Next slide. Imetelstat has expected myelosuppression, which was dose-dependent and reversible and not associated with serious adverse clinical outcomes such as febrile neutropenia, bleeding, and infection, which were at a very low rate. The non-hematologic toxicity was rarely grade three, four, and not a major reason for discontinuation. The median time to cytopenias was approximately three cycles, and given that the drug is dosed every three weeks, it is reversible and easily manageable in a clinical setting. Next slide. This leads us to the current randomized phase three registration trial of imetelstat at 9.4 mg per kg in intermediate two and high-risk myelofibrosis patients that have specifically met JAK inhibitor refractory criteria and excludes those patients that may be intolerant to JAK inhibitor therapy. The patients are randomized in a two-to-one fashion to imetelstat at 9.4 mg every three weeks or best available therapy, which excludes a JAK inhibitor. The primary endpoint is overall survival, which is the first trial of its kind in myelofibrosis, and as an investigator and physician who treats these patients, this is extremely exciting and encouraging that we are moving beyond spleen and symptom endpoints. The interim analysis planned after 70% or more of the final analysis events have occurred is expected to result in 2024, and the final analysis is planned after 50% of those events have occurred, which is expected in 2025. I believe that the company will now review its future plans in MDS and MF. Thanks, Dr. Mascarenhas, and good afternoon, everyone. As you have heard from our clinicians, the phase two clinical data supporting imetelstat in both lower-risk MDS and refractory MF, 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. Today, I'll be sharing our perspective on these markets and where we expect imetelstat to be used. We believe there are large addressable patient populations for imetelstat, which represents significant commercial opportunity for us. First, let's look at the lower-risk MDS market, where the vast majority of patients are treated in the community setting. Looking at the schematic representation of the MDS landscape, you see that lower-risk MDS represents approximately 70% of the total MDS patient population. Erythropoietin stimulating agents, or ESAs, are the mainstay of frontline treatment in 90% of patients who have symptomatic anemia without 5q deletion. Not all patients respond to or are eligible for ESAs. Even among responders, responses typically last between 18-24 months. Despite the availability of luspatercept, patients who have failed or are ineligible for ESAs have limited treatment options. Luspatercept was approved in 2020 for ESA-failed patients who are ring sideroblast- positive, or RS positive. It has been well received in the US market, validating the high unmet need and the lack of innovative therapies in lower-risk MDS. Hypomethylating agents, or HMAs, may also be used but are not a preferred option given their limited benefits. Also, they are not broadly approved across Europe for this indication. I want to point out that this RS positive segment covers only 25% of patients, leaving a significant unmet need for effective therapies for the remaining approximately 75% of lower-risk MDS patients who are RS negative. As seen by our phase two data, imetelstat has activity across different lower-risk MDS subtypes, indicating an opportunity to treat a significantly broader set of patients, which represents a compelling market opportunity. Now, moving on to imetelstat's expected target product profile. In our recent market surveys, hematologists reaffirmed the unmet needs in lower-risk MDS that were discussed by Dr. Platzbecker and highlighted how the strengths of imetelstat can address those needs. We also found that there was a higher level of awareness among the providers for patients' RS status, given the recent approval for luspatercept. Importantly, hematologists had a strong desire for approved treatment options for RS negative patients, and they cited this as an area of serious unmet need. In addition, the 24-week and one-year RBC-TI data from our IMerge phase two trial provide strong evidence of the durability of transfusion independence, which resonated very well with physicians as they felt these outcomes to be more clinically relevant than eight-week transfusion independence. We expect a highly differentiated position for imetelstat at launch based on these data, as well as the novel mechanism of action and the disease modification potential for the drug as described by Dr. Platzbecker. We expect to significantly penetrate this attractive market and eventually become part of the standard of care in lower-risk MDS. The next slide describes the potential market segmentation in more depth. We expect imetelstat patients to come from four main groups highlighted here. All of these patient groups were eligible to be enrolled in our IMerge phase three trial. The first group and our key focus is the ESA relapsed and refractory RS negative patients where patients do not today have an approved therapy. This is the largest opportunity of addressable patients, and if IMerge phase three study is positive, we expect imetelstat will become the standard of care in this segment. The second group is the ESA relapsed and refractory RS positive patients. We expect imetelstat to compete favorably with luspatercept in this setting. The third group is drawn from the first line lower-risk MDS patients with high endogenous serum EPO levels greater than 500 milliunits per mL who are ineligible for ESAs. This group currently remains underserved with poor prognostic outcome. Finally, the fourth group of patients for imetelstat will come from those who have been previously treated unsuccessfully with luspatercept. The ultimate size of this segment is yet to be determined, and we expect it to grow over time. Based on our current commercial assumptions and assuming regulatory and fair access to the four patient segments I just described, we expect imetelstat to become part of the standard of care in lower-risk MDS and exceed $1.2 billion in potential peak revenue across the U.S. and the five largest European markets. Now, let's take a look at the second indication for imetelstat, myelofibrosis, and the unique profile of imetelstat that can address key areas of unmet needs presented earlier by Dr. Mascarenhas. We all know that over the past decade, there has been a dearth of new agents approved in myelofibrosis. While ruxolitinib is the standard of care in frontline patients today, it is still limited to addressing the patient's spleen and constitutional symptoms. We also know that over 50% of the patients discontinue this therapy within three years, and they have limited alternative treatments available to them. As Dr. Mascarenhas pointed out, these patients have a dismal survival prognosis. When presented with the profile of our phase two data to community-based oncologists who treat the vast majority of myelofibrosis patients, they found the improvement in overall survival and potential for disease modification to be most impactful. The clinicians were also highly enthusiastic on learning about imetelstat's unique mechanism of action and that our ongoing phase three trial in refractory MF is the first trial in myelofibrosis with overall survival as a primary endpoint. They also cited that the demonstration of an improvement in overall survival in the phase three trial would significantly impact treatment choice towards imetelstat. Let's now look at the MF opportunity for imetelstat. The decade-old JAK inhibitor therapy ruxolitinib has been a very successful drug in the MF market and has established itself as the standard of care and the backbone of frontline therapy. We know patients do not stay on this drug long-term. As part of the natural evolution of this market, we expect to see significant expansion over the next decade as more drugs are developed to give clinicians more choices to offer tailored patient treatment options. These will include single-agent or combination approaches where appropriate. We believe imetelstat will play an important role in the treatment of JAK-experienced patients who need alternative therapies. Commercially, I draw a parallel to the evolution in the multiple myeloma space where over the last decade, we have seen a significant expansion with multiple lines of treatment now common, and it has become a fast-growing multi-billion dollar market. We feel strongly that the MF market is headed towards a similar dynamic, and this is fantastic news for patients who deserve new innovative treatment options to fight this disease. We believe that the opportunity in MF is driven by the expectation that all JAK inhibitor-treated patients will become unresponsive to JAKs over time and therefore become eligible for imetelstat. This suggests that there is an expected imetelstat addressable patient population in the U.S. and top five European Union countries of approximately 18,000 patients. We believe this translates to $1.8 billion in potential peak revenue across the U.S. and the five largest European markets. Lastly, this next slide addresses our commercial efforts. MDS is the near-term opportunity for imetelstat. With top-line results expected in early January 2023 and assuming priority review, we could potentially launch in the U.S. market in the first half of 2024 and in Europe in the second half of 2024. Given that we are at the cusp of commercialization, we are taking measured steps to ensure commercial success. Our efforts are milestone-driven and stage-gated to ensure fiscal discipline. We plan the bulk of our commercial investments to occur after top-line results are available from the IMerge phase three study. We are working on pre-launch market preparation activities to increase product awareness and provide seamless patient access to drive market uptake and adoption at launch. With a customer-centric mindset, we are engaging extensively with all of our customers from key opinion leaders, providers, payers, and patient advocacy stakeholders. We have made senior leadership hires in medical affairs and market access functions with deep industry knowledge and operational experience. We will continue to build out the commercial organization in a phased manner with the goal of hiring talent with deep oncology and U.S. market experience. The commercial supply chain planning and infrastructure is stage-appropriate to ensure sufficient commercial drug supply upon regulatory sign-off. To finish, I'll make a few comments on Europe as it represents a critical and important market for imetelstat. The majority of commercial value in Europe is concentrated within five European countries, which helps prioritize our effort. We plan to leverage our extensive network of European clinical investigators with their experiences in treating patients with imetelstat as part of local reimbursement discussions and to increase product awareness. Given that securing reimbursement in European markets is critical, we sought payer feedback on imetelstat in lower-risk MDS. These payers specifically cited the importance of durability of transfusion independence in their decision-making. As such, the 24-week transfusion independence data from our phase two study was of particular interest and received positively. We are currently evaluating our EU commercial entry options. As always, we remain open to partnership opportunities that can help us fully harness the commercial potential of imetelstat and bring this highly differentiated therapy to patients. I will now hand the call over to Chip. Thanks very much, Anil. We'll now move into part two of our program, the planned expansion of our imetelstat and telomerase inhibitor franchise. I'm going to start off with a brief description of our next-generation telomerase inhibitor program. We started this program over a year ago as the cytogenetic, molecular, and clinical data from our phase two studies began to provide such strong evidence of the potential for disease modification. We commissioned a worldwide search and assessment of existing telomerase inhibitor programs, including early-stage drug candidates, as well as promising chemistry platforms. Based on the insights we gained, we felt it was highly appropriate to begin a next-generation telomerase inhibitor program of our own. To do so, we began a collaboration with a talented medicinal chemistry group. The goal of the program is to discover and develop novel small molecules based on chemistry platforms that can be proprietary to Geron, in which these new compounds bind to the active site of the telomerase molecule and directly inhibit telomerase activity. Our aspirations are to identify compounds of high potency and selectivity, suitable for oral delivery, with a strong potential for combinability. Using several different chemistry scaffolds, identification of potential lead compounds is underway. Because of the very competitive and proprietary nature of this work, we're not in a position at this time to make more specific comments. We plan to make additional information public when and if we declare a lead compound and can give a line of sight to a possible IND. With that, let's move on to some of the new imetelstat initiatives. Our discussion in this exciting area will be led by our Chief Medical Officer, Dr. Aleksandra Rizo. Alex? Thanks, Chip. Good afternoon, everyone. I'm truly excited to be able to speak to the addition of new preclinical and clinical studies to our pipeline to potentially expand the treatment applications for imetelstat in hematologic malignancies. When planning this pipeline expansion, we took a two-pronged approach. First, the disease-modifying potential of imetelstat to affect the malignant clones as early as on a stem cell level gives us confidence that imetelstat can play a larger role in treatment of multiple hematologic malignancies beyond relapsed refractory myelofibrosis and lower-risk MDS. Second, we have generated and published robust preclinical data on combination of imetelstat with other oncology drugs. Further to this, we have now characterized the safety profile of imetelstat based on data from our phase two studies. Given the evolving treatment landscape towards combination therapies and the knowledge on how to best approach combination treatment with imetelstat, we believe this is the next logical step for us to take. Based on this two-pronged approach, and as presented on this slide, in addition to the two phase three registration studies, we are initiating a company-sponsored phase one study in frontline myelofibrosis as a combination therapy. I will read you the study in the next few slides. In addition, we're supporting two investigator-initiated clinical studies in relapsed refractory AML and high-risk MDS, one using imetelstat as a single agent and one as a combination therapy. Dr. Mascarenhas and Dr. Platzbecker will speak to this. On a preclinical level, we have signed a collaboration agreement with MD Anderson Cancer Center to explore the role of imetelstat outside of the myeloid space. More specifically, we're conducting experiments in multiple T and B- cell lymphomas using imetelstat both as a single agent and as a combination therapy. As Chip already covered, we also have an ongoing discovery research program to identify a next-gen telomerase inhibitor. We have a lot of interesting activities happening on top of the important work on our ongoing phase three trials. Let's move on to more details around the upcoming phase I study in frontline myelofibrosis. Next slide, please. The preclinical data summarized on this and the next slide have been generated in collaboration with Dr. Hoffmann's team at Mount Sinai. One of the key findings of the experiment was that the sequential treatment of ruxolitinib followed by imetelstat had a selective inhibitory effect on the malignant myelofibrosis stem cells, while the normal stem cells were spared. This finding holds great potential for clinical application as the combination treatment would have selective killing of the malignant cells without harming the normal cells. Even more important, it differentiates the mechanism of action of imetelstat from any other drug currently approved or in development for myelofibrosis treatment. Next slide. If we now focus only on the effect of the malignant stem cells, you can notice that the sequential treatment of ruxolitinib followed by imetelstat had additive and synergistic inhibitory effect on the growth of these cells when compared to, first, the control group, second, to the effect that each of the drugs had alone, or third, when the two drugs were given at the same time. These data served as a basis for our new clinical study of combination therapy with ruxolitinib and imetelstat. Next slide, please. This is the design of the phase one study, which we expect to start in the first half of next year. It is a single-arm, open-label study consisting of two parts where patients with frontline myelofibrosis will be enrolled. Part one will enroll up to 20 patients with the objective to identify the safe dose for the combination of imetelstat and ruxolitinib, while efficacy data is also being collected. In part two, we plan to enroll about 20 patients as well with the objective to confirm the dose identified in part one and further collect safety and efficacy data. Guided by the preclinical work I just summarized, patients will receive first ruxolitinib followed by imetelstat. I look forward to seeing and reporting the data from this study. I would now like to hand over to Dr. Platzbecker. Dr. Platzbecker? Thanks, Aleksandra. I will now introduce a little bit of preclinical data and also rationale to use single-agent imetelstat in AML. You all know that AML is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells. Selective targeting of these leukemia stem cells, therefore, is a promising approach actually for treating these AML patients and also to prevent potential relapse after successful induction of remission with, for instance, chemotherapy. The AML field, however, has seen some recent advances in the treatment paradigm after many years of actually research. However, there's still tremendous need for novel agents, especially in the relapsed refractory setting. There are actually multiple preclinical publications from the past years that describe the role of telomerase in AML, but the most comprehensive work actually has been performed and done by Dr. Steve Lane's lab. The paper here referred, it's actually on the left side, showed that inhibiting telomerase in both mouse and human AML models targets not only, but also potentially depletes leukemic stem cells and also impairs their leukemic progression and by doing so delays relapse following chemotherapy. On the left-hand side of this slide, I'm showing a snapshot of the key data from this paper, namely the colleagues performed experiments where mice were transplanted with cells from AML patients in so-called patient-derived xenografts or PDX. Half of the mice were actually left untreated, and the other were treated with imetelstat. What you can see is that the imetelstat-treated mice had significantly longer survival compared to the control. This demonstrates also that imetelstat obviously potentially and very selectively eradicated the leukemic stem cells treated mice, and this also, of course, now has potential clinical implication and is the rationale also to go for clinical trials with imetelstat in the AML setting. On the next slide, you will see the clinical trial we are planning from our European platform together with our colleagues and friends in France and Australia. It's a phase two open-label single-arm multicenter trial in MDS, high-risk MDS and AML patients failing first-line hypomethylating agents. Imetelstat will be given at the standard dose, and the objective of the study is actually to evaluate the efficacy of single-agent imetelstat in this rather frail and older population. Now I'll let Dr. Mascarenhas review the AML study of imetelstat in combination with other treatments. Dr. Mascarenhas? Thanks, Dr. Platzbecker. Preclinical data of combination ABT-199, a selective BCL-2 inhibitor, with imetelstat results in increased cell death of AML cell line cells in a dose-dependent fashion. In an AML xenograft, the combination results in prolongation of survival and even potentially cure at the two highest doses evaluated. This again goes back to the potential MPN or AML stem cell effect of imetelstat, which appears to synergize nicely with the BCL-2 inhibitor. The case of venetoclax has dramatically changed the treatment paradigm of AML in combination with either chemotherapy or hypomethylating agent. Below is preclinical data showing synergistic killing of AML cells with combination azacitidine and imetelstat. Of course, azacitidine is frequently used as a therapy to treat patients with relapsed refractory AML. Next slide. Here I show the study schema for the telomere study, which is imetelstat with venetoclax or azacitidine in acute myeloid leukemia in relapse. This is an investigator-initiated study that will be conducted over multiple sites. We're hoping to start the study in the first half of 2022. It will randomize patients with relapsed refractory AML after azacitidine and/or venetoclax exposure to two arms, plus azacitidine versus imetelstat plus venetoclax, with the ability to cross over with a disease that is progressive in nature. This is the phase one component of the study, which the objective is to determine the recommended phase two dose of imetelstat in combination with venetoclax or azacitidine and to describe the safety profile of both combinations. The phase two portion is shown to the right and has two stages. Again, combining imetelstat with azacitidine or imetelstat with venetoclax in approximately 50 patients in a Simon's two-stage design, looking at efficacy as the primary endpoint in this phase two part of the trial. Onto hematologic malignancies outside of the myeloid space. Dr. Iyer, I think it's your turn now. Thank you, Dr. Mascarenhas. I will speak on the imetelstat and lymphoid malignancies. Let's go to the next slide, which talks about the T-c ell lymphomas in general. T- cell lymphomas represent at least 27 recognized entities as categorized by the WHO in 2017. In this slide, you can see the diversity and heterogeneity. What you see here are the commonly represented types with a variable clinical manifestation, such as the angioimmunoblastic T- cell lymphoma, abbreviated as AITL, anaplastic large cell lymphoma, abbreviated as ALCL, and ATLL, and the rare varieties such as hepatosplenic T- cell lymphoma. Now, they have varied clinical manifestation, and obviously, it's a challenge to treat this as one entity. We shall go to the next slide, which talks about the unmet medical need in lymphoid malignancies. In addition to the diversity and the heterogeneity, it's poorly understood, and 30-50% of T- cell lymphomas are misclassified as not otherwise specified with the current diagnostic approaches. It's an increasing incidence of all lymphomas, even though it represents 10% of all NHLs, that for increasing age and due to increasing exposure, perhaps there is the need to study the biology better. More importantly, the most common subtypes have inferior outcomes because they are mostly refractory, and there's very limited therapeutic options. Even if you see here, the five-year overall survival for ALCL, which is 70%, drops down to 14% for ATLL, and that's a pretty dismal outcome for a lymphoma diagnosis. The next slide, as we move on to, shows some of the preclinical work. The reason for this, I explained the dismal outcome. Obviously, you need novel drugs with different mechanisms of action. There are several new pathways and medicines available, and we all know that telomerase activity is a hallmark of cancer. Hence, telomerase inhibition might be a potential new treatment option that warrants further investigation. Looking at the literature, it suggests that telomerase inhibition might have a role in T- cell lymphomas. There are reports suggesting that telomere length, TL, and telomerase activity play a big role compared to healthy individuals. In this particular slide, which is a lab correlate of a skin lymphoma called mycosis fungoides, MF or CTCL, we can see that patients with Sézary syndrome, which is the component of the T cell lymphoma in the blood and the viscera, and the mycosis fungoides have significantly shorter TL, and the telomerase activity is significantly shorter compared to the healthy individuals. Both of these examples suggest that these diseases are excellent candidates for treatment with imetelstat. The next slide shows a little bit more data on what a drug like imetelstat can do. This is, of course, using RNAi inhibition with hTR+ hTERT. On the left-hand side, you see CTCL cell lines, and when they have been downregulated with the RNAi with hTR+ hTERT, the growth is inhibited tremendously. On the right-hand side in the top, you see the colony-forming assays are completely inhibited with the downregulation. All of these suggest that if the cells are treated with imetelstat, growth inhibition and killing of malignant cells might be expected. In the next and the final slide to show you is the correlation of hTR expression and overall survival in T- cell lymphoma. A study that was done not too long ago shows that the PDCL and OS and several other T- cell lymphomas had comparisons for the TERT levels, and the expression of TERT made a difference in terms of overall survival. You can see the survival curve is very different for those that express TERT versus the ones that do not express TERT. This is critically important in a situation where these T- cell lymphomas have been teased out based on the cell of origin. As you all know, B- cell lymphomas are more common, and we are trying to extrapolate a lot of the information that happens in B- cell lymphomas to T- cell lymphomas. In the cell of origin and B- cell lymphoma, a lot of the drugs, including imetelstat, works in the stem cells and the progenitors. Our focus on the cell of origin on the right-hand side that you see is very indicative of the possibility that telomerase activity plays a huge role, and imetelstat is a very good way to embark on as a new therapeutic approach for lymphoid malignancies in general. I want to show in the next slide some of the ongoing and planned experiments to define the role of imetelstat in lymphoid malignancies. In the interest of time, I'll just summarize this rationale for T- cell lymphomas. However, based on the published data, B- cell malignancies, it's definitely possible that a lot of these are also going to be performed in B- cell lymphomas and extrapolated vice versa. Following the success of the myeloproliferative neoplasms, we are very happy that this collaboration work with Geron will lead to data in the lymphoid space. If you look at the in vitro experiments that are planned, including apoptosis assays, colony-forming assays, cytokine assays, and measurement of TA TL and hTERT, and some of the in vivo experiments include the mouse studies in T and B- cell lymphoma models, including primary samples, which we selected based on the in vitro data. Aleksandra, I think you wanted to provide some final thoughts about all of these programs, and I'm just going to hand it over to you to take it from here. Thank you. Thanks, Dr. Iyer. And thanks to both Dr. Mascarenhas and Dr. Platzbecker for your presentation. As a physician researcher, you can imagine how excited I am about these new programs and the rest of the company as well. We look forward to sharing news about the new studies as developments occur. We believe these new programs can extend imetelstat's potential treatment application to improve the lives for many patients in need. Chip, back to you. Thanks, Alex. That concludes our prepared remarks for today. We will now open up the line to questions for our KOL panel as well as the management team. Thank you. Ladies and gentlemen, at this time, we will conduct our question-a nd- answer session. If you would like to ask a question, please press star one on your telephone keypad. A confirmation tone will indicate that your line is in the question queue. You may press the star key followed by the number two if you would like to remove your question from the queue. For participants using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. Once again, to ask a question, press star one on your telephone keypad. We will pause for a few moments while we pull for questions. Thank you. Our first question comes from Joel Beatty with Baird. Please state your question. Hi, thanks for taking the question, and thanks for the detailed presentation today. My first question is on the lower-risk MDS opportunity, and in particular, the RS negative setting. This seems like a setting that luspatercept struggled with and ultimately decided not to pursue for approval, even though it is a much larger opportunity than the RS positive setting. Yeah, imetelstat's phase three is targeting all of these patients, both RS positive and RS negative. I guess the question is, could you help us think about the opportunity for the RS negative population for imetelstat and how that compares with luspatercept? Dr. Platzbecker, maybe you'd like to take that. Yeah. Thanks for the important question. As you nicely summarized, the current phase three trial actually includes all the patients not only with RS positive but also RS negative MDS. And we know from the phase two data that the agent has actually chemical activity irrespective of the RS status. It is actually expected that also in the phase three, this will be the same way. This imetelstat may be an agent then in the future which can be used irrespective of the RS status in patients with lower risk MDS. Since you referred also to luspatercept, the current COMMANDS trial by BMS Celgene actually explores head-to-head comparison in patients with RS, but also RS positive, but also RS negative patients being ESA naive. Of course, the jury is out whether this trial will actually show superiority in the segment of non-RS patients, because as we know from the PACE trial, from the phase two luspatercept study, the activity was rather modest and much lower in the RS negative segment. Thank you very much, Dr. Platzbecker. Perhaps before we go on to the next question, Anil Kapur might have a comment or two about the market size. Yeah. And Joel, just as an FYI, as we know that RS positive is approximately 25% of the patients, and the much larger segment with currently no approved therapy is the RS negative. As you correctly stated, we are going to pursue a broad label across both of these indications. Thank you. Okay. Maybe if I could ask one follow-up question. Sure. This question is on MF, and the new indication disclosed today for the frontline combination and combination with Rux, can you help us think ahead towards what would ultimately be a good profile to be approved and adopted in that frontline setting? Would it need to be an OS study like the ongoing study for relapse resistant, or are there other paths to approval? Great question, Joel. Thank you. John, do you want to take a crack at that? Sure. I'd be happy to. I think the way the paradigm is shifting in myelofibrosis is one of combination therapies and typically treating earlier on the disease rather than waiting for the disease to progress and become harder to treat with worse outcomes. That's exemplified by the current trials that are conducted by Constellation with their pan-BET inhibitor pelabresib, in combination with Rux in the upfront setting, as well as navitoclax and avapritinib in the upfront setting, and even Incyte's parsaclisib PI3 kinase inhibitor in the upfront setting. It is a trend that's caught on. We recognize that if you wait too long with Rux, inevitably by a median of three years, you have treatment discontinuation and a survival that's poor, measured on an order of a year. Really, the benefit of combination in my mind is not really, can we get more spleen and symptom benefit, although that's not uninteresting. The more interesting and important question is, can we get a longer duration of therapeutic benefit with a JAK inhibitor backbone and progression-free survival? I think overall survival would be an enviable endpoint to look at, would be harder perhaps in a phase three setting. Progression-free survival, time to discontinuation of Rux, and it would be endpoints of interest because we know that the outcomes are poor once you get to JAK inhibitor failure. I think I'm excited, very excited to see imetelstat move not just from the relapsed refractory setting in which it's desperately needed, but also to the upfront setting in which we're trying to capitalize on this theme and hopefully get deeper, longer-lasting, durable responses that would be meaningful to patients. Great. Thank you. Thanks, Thanks very much, Dr. Mascarenhas. Joel, any other questions? No. I'll get back in queue. Thank you. Okay. Thank you very much. We'll go ahead and take the next question up in the queue. Thank you. Our next question comes from Gail Bloom with Needham & Company. Please state your question. Hi. Good evening, everyone. Also just a couple of questions from me as well. Kind of going back to the MDS, particularly the SF3B1 VAF reduction, is there any evidence that those clones are driving the disease, or this could be a carrier mutation? Thanks, Gail. Dr. Platzbecker, comment about the SF3B1 clones? Yeah. I think there are several seminal papers showing that the SF3B1 mutation is actually initiating mutation in the early progenitor stem cell. It is also the, let's say, the mutation which drives also the phenotype, the ring sideroblastic phenotype. It is not a passenger or minor mutation. It is really the one which drives the disease, and therefore the modulation of SF3B1 by imetelstat, I think, is an important observation and also shows the disease-modifying activity of this agent. Thanks for the clarification. Now kind of jumping to MF, is there any evidence of Rux-limited mediated reduction in fibrosis in MF? Has that ever been shown? It looks like there's some correlation between reduction in fibrosis and overall survival, as Dr. Mascarenhas pointed to. Can this be considered a potential surrogate endpoint at some point with enough data coming out? Thank you. Dr. Mascarenhas? Yeah, I would love to answer this question because the first part of the question in terms of Rux-limited ability to reduce fibrosis is minimal. It's minimal in clinical trial evidence. At five years follow-up from the COMFORT studies, there were a handful of patients, a very small minority of patients who had one and even two-grade reduction in fibrosis. What we see with some of the newer trials, like the combination trials, is in a shorter period of time, you can get 30-40% of patients can have at least one-grade reduction in fibrosis. Now, what's important to realize is that the fibrogenic stimulation is probably TGF beta driven from megakaryocyte sites, and it's probably complex in nature, but it's not clearly due to clonal fibroblast activity. I question sometimes with certain medications whether if you dampen the inflammatory response and get some degree of fibrosis, if that's actually clinically meaningful to the patient and maybe an epiphenomenon. What's exciting, I think, about the imetelstat data that's been presented is it's the first time that I'm aware of where there's been a more clear association between reduction in fibrosis and endpoints of importance, particularly survival, which would lead me to believe that imetelstat is doing something genuinely more stem cell directed and disease-modifying, which may not always be the case. I guess what I'm trying to get at is that maybe not every case of bone marrow fibrosis reduction may have the same implication. I suspect that after long exposure of a JAK inhibitor and some reduction in fibrosis from downregulating inflammatory cytokine expression levels may have a very different impact or significance than targeting the stem cell clone itself and a more rapid reduction, which is what you tend to see with imetelstat, for example. All right. Thank you. Thank you Thank you for taking our questions. Okay. Great. We're coming towards the end here. Let me ask Dr. Iyer a question. Dr. Iyer, since lymphoid malignancies are a new story, at least to many of the folks following Geron, maybe you could expand on the treatment needs in lymphoid malignancies and what you would see as approval thresholds within that disease. That'd be very helpful if you could comment about that. Thank you for the question. I think it's an important one and it's also a rapidly evolving one, I should say. If you look at the therapeutic developments in lymphomas, they've been all confined to the largest sets, such as the diffuse large B- cell and follicular lymphoma, whether it's the monoclonal antibodies, the small molecule inhibitors, or CAR-Ts. Right? At the same time, I think we are looking at a phenomenon, the most common subtypes where the lymphomas get treated, not just with chemotherapy, but with some of these targeted therapies, are CAR-Ts. You also have patients who have failed many of these things. We have all these options, and it's not been a home run all the way. There are patients who relapse. It's the biology that dictates some of these needs. What we're finding out in many of these patients is that there are pathways that are completely changed, either because of the immune microenvironmental interactions between CAR-Ts and the immune therapies, if you will. Newer targets are required and needed in this patient population. You also have to take into consideration patients with comorbidities and patients above the age of 65 who cannot tolerate chemotherapy or CAR-T for that matter. You definitely need therapy. If you look at the most common varieties, there is an unmet need there. You have marginal zone and mantle cell where I think you still have patients who relapse frequently, and it is not a curable situation. As you come down the line in T- cell lymphomas, the median survival, as I showed you, is about 15 months. The threshold for drug development is very low. You only have three drugs which have at the very best palliative benefits. In other words, you have a lot more opportunities in T- cell lymphomas, in marginal zone lymphomas, in mantle cell, and in relapsed diffuse large B- cell post-CAR-T. Depending on the subtype you take, there's still a huge unmet need. There are a large number of patients who will need novel pathways and pathways that look at the biology and the hallmarks of cancer. Thanks very, very much. I think we have time for one more question, and it's directed to you, Dr. Platzbecker. Dr. Platzbecker, could you expand on what you've been observing in your patients treated with imetelstat in terms—in your patients treated with imetelstat in terms of disease modification? Yeah. I think what we observed was quite striking because the SF3B1 mutation is, as I said before, a disease-initiating mutation which you can also detect in blood and marrow at a high allele burden in the majority of the patients. I actually witnessed also patients I treated myself with in the phase two study becoming transfusion independent and who almost cleared actually the SF3B1 mutation in their blood and in their bone marrow. Actually, this was also sustainable for several months in some patients. I think this is something we have not observed before with, let's say, standard maturation or growth factors which are used to treat anemia or transfusion dependence in these patients. Also, I think outpatient treatment every four weeks is very convenient for these sometimes heavily transfusion dependent patients, which does not require weekly injections. Just getting two hours infusion, I think, is also very convenient for the elderly MDS scores. Thanks very much, Dr. Platzbecker. I think that we're going to begin to wrap this up. On behalf of my colleagues at Geron, I'd really like to thank Dr. Mascarenhas, Dr. Platzbecker, and Dr. Iyer for really wonderful presentations and a great Q&A session. Thank you. Honestly, we couldn't ask for more committed or expert collaborators than the three of you. You're deeply appreciated. Thank you. I'd also like to thank all of our clinical investigators and patients who really come from many countries around the world. Their enthusiastic participation in our clinical programs obviously are critical, and we're immensely grateful to all of them. I would be completely remiss if I didn't thank all of our Geron team members who continue to work tirelessly to bring imetelstat to the market and to these patients. As we conclude today, I have just a few key comments and thoughts that I'd like to leave you with. I think we've seen today that the discovery and development of imetelstat represents a powerful application of deep scientific insights into fundamental cancer biology. As a pioneer in the therapeutic use of telomerase inhibition, we're committed to pursue the imetelstat clinical programs discussed today, as well as the advancements in the development of next-generation telomerase inhibitors. Geron's made remarkable progress over the last few years, and we're now deep in the midst of transitioning from a clinical stage to a commercial stage company. We have never been more excited by our vision of Geron becoming a leader in the treatment of hematologic malignancies and in doing so positively impacting the lives of patients with these diseases. Thank all of you for participating in this very interesting, I hope stimulating and thoughtful event, and I hope everyone has a great rest of the day and evening. Bye-bye.