Geron Corporation (GERN) Earnings Call Transcript & Summary

Good morning, everyone. Welcome to the Geron Corporation call for Top Line Results from IMerge Phase III. I'm Olivia Bloom, Geron's Executive Vice President of Finance and Chief Financial Officer. I'm joined today by the following members of Geron's management team: Dr. John Scarlett, Chairman and Chief Executive Officer; Dr. Faye Feller, Executive Vice President and Chief Medical Officer; and Anil Kapur, Executive Vice President of Corporate Strategy and Chief Commercial Officer. 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, timelines, expectations and other projections, including those relating to imetelstat's therapeutic potential and potential regulatory approval of imetelstat, our plans to submit regulatory applications for marketing approval in the United States and EU, potential market opportunities, anticipated clinical plans and commercial events, the sufficiency of Geron's financial resources and other statements that are not historical fact. Actual results or events could differ materially. These factors, together with those that are described under the heading Risk Factors or other similar headings found in documents we file from time to time with the Securities and Exchange Commission, including our quarterly report on Form 10-Q for the quarter ended September 30, 2022, may cause actual results performance or achievements to differ materially and adversely from those anticipated or implied by our forward-looking statements. Geron undertakes no duty or obligation to update our forward-looking statements. Today, we are very excited to be announcing the top line results from the IMerge Phase III study in lower risk MDS. Our press release describing these results was distributed this morning. Both the press release and the slide deck we are using for today's call are available in the Events area of the Investors section of our newly redesigned website at www.geron.com/investors. The agenda for today's conference call will be as follows: our CEO, Dr. John Scarlett, will make introductory remarks; our Executive Vice President and Chief Medical Officer, Dr. Faye Feller, will discuss the top line efficacy and safety results from IMerge Phase III as well as our plan for including these data as part of regulatory submissions in the U.S. and EU for imetelstat in low-risk MDS; Anil Kapur, our Executive Vice President of Corporate Strategy and Chief Commercial Officer, will discuss the unmet medical need and lower risk MDS and imetelstat's market opportunity; and Dr. Scarlett will close the call with concluding remarks before going to a Q&A session for participants on this call. With that, I will turn the call over to Chip.

Thanks, Olivia. On behalf of Geron and all our stakeholders, I'm very proud and very excited to tell you that we have positive top-line results from our IMerge Phase III study of imetelstat in lower risk MDS. At a glance, we saw a statistically significant and clinically meaningful improvements in the imetelstat-treated patients compared to the placebo control arm. First, the trial met its primary 8-week transfusion independence endpoint and its secondary 24-week TI endpoint. We saw substantial increases in both hemoglobin levels and reductions in transfusions. We also saw efficacy across key subtypes, including both RS+ and RS- patients. The safety results were consistent with prior imetelstat clinical experience and the trial provided clinical and molecular evidence supporting imetelstat's potential for MDS disease modification. Based on these very gratifying results, we plan to submit a U.S. new drug application in mid-2023 and an EU marketing authorization application in the second half of 2023. Assuming regulatory approvals, we are preparing for an imetelstat at U.S. commercial launch in lower risk MDS in the first half of 2024 and in the EU by the end of 2024. If I might reflect for a moment, these results, above all, make it a great day for patients with lower risk MDS for their caregivers and for those who provide their health care. We look forward to further collaboration with patient advocacy groups, many of whom we've been working with for some time. These organizations work tirelessly to bring better outcomes to patients and their families affected by this difficult disease, and we acknowledge their contributions with gratitude. It is also a great day for our shareholders, for our employees and for our many collaborators past and present, who've supported the remarkable scientific and clinical journey to reach this outstanding Phase III milestone that we're showcasing today. In addition, we also celebrate today the myriad of other individuals, including Geron collaborators who have labored over decades to further explicate the role of telomerase in cancer. With today's top-line results, telomerase can now be considered a clinically relevant and meaningful oncology targets with potential application across multiple hematologic malignancies. Finally, I also want to recognize the many Geron employees, past and present, who over the course of several decades, discovered and are developing imetelstat at Geron as a first-in-class telomerase inhibitor. True innovation is a lot harder than it sounds like. And this isn't the ultimate victory lab today. We still have a long way to go in getting imetelstat across the approval and launch finish lines. But with this positive Phase III study, we believe we've taken a very meaningful step forward and that the results we're reporting today support the belief many of us have had in telomerase as a target, in imetelstat as a potential drug and in Geron itself. With that, let me hand the call over to Faye Feller, our Chief Medical Officer, to walk you specifically through the top-line results of our IMerge Phase III study. Faye?

Thank you, Chip. Good morning, everyone. I am honored and excited to be here today to share the top-line results from IMerge Phase III. IMerge is a Phase II/III study initiated in 2015 and for which we have previously presented the results of the single-arm Phase II portion. The Phase III portion was a placebo-controlled, double blind, randomized study in transfusion dependent, lower risk MDS patients. The Phase III was conducted in 118 clinical sites in 17 countries and was truly a unique global effort spanning continents. The patient population had low or intermediate-1 risk MDS by IPSS and were relapsed or refractory to erythropoietin-stimulating agents or ESA treatment or were ineligible for ESA treatment due to EPO levels over 500 million units per mL. Additionally, these patients were transfusion dependent requiring at least 4 units of red blood cells over 8 weeks, assessed within the 16-week period prior to randomization. Eligible patients were randomized on a 2:1 basis for treatment with either imetelstat at a dose of 7.5 milligram per kilogram IV every 4 weeks or placebo IV every 4 weeks. The primary endpoint assessed the rate of transfusion independence or TI for at least 8 weeks at any time on study. Secondary end points we have identified as key include the rate of 24-week TI, duration of TI and hematologic improvement erythroid or HIE. The Phase III study had the same patient enrollment criteria as the Phase II, specifically the subset of 38 lower risk MDS patients without del(5q) and without prior treatment with lenalidomide or hypomethylating agents. In addition, Phase III endpoints were the same as the Phase II, and approximately 80% of the clinical sites from Phase II also participated in the Phase III portion of IMerge. Today, I will be sharing top-line results from the primary analysis of the Phase III. A total of 178 patients were enrolled and randomized in the study with 118 assigned to imetelstat treatment and 60 to placebo. One patient randomized to placebo did not receive treatment and thus was not included in the safety analysis. This Phase III study enrolled the first patient in October 2019. The clinical cutoff for the primary analysis results being presented today was October 2022. The median follow-up for imetelstat-treated patients was 19.5 months and the median treatment duration was 7.8 months. Moving along to the baseline disease characteristics of the patients on the study. The protocol specified stratification by red blood cell transfusion burden and IPSS risk category resulted in a balance between the imetelstat and placebo arms, as expected. Additionally, both imetelstat and placebo arms were well balanced with respect to the number of enrolled patients in the RS+ and RS- categories. Similarly, the pretreatment median hemoglobin levels were comparable. Please note, the median transfusion burden of these patients prior to receiving study treatment was 6 units over 8 weeks. To put this transfusion burden in context, these lower risk MDS patients would have been seen by their providers, had labs done and spent time in the infusion center approximately 3 or 4 times over the period of 2 months. This represents a considerable amount of time and effort for patients and caregivers and also a substantial impact on health care resources. Here, we show that at the time of the clinical cutoff in October, after a median 18-month follow-up, treatment discontinuation rates were similar in both arms, although discontinuations attributed to lack of efficacy were almost double in patients treated with placebo versus imetelstat. Discontinuations associated with adverse events occurred in 16% of imetelstat-treated patients with less than 10% of discontinuation due to cytopenias. This compares favorably to the greater than 20% rate of AE discontinuations observed in the IMerge Phase II study. I'd also like to point out that discontinuations due to transformation to AML were infrequent, less than 2% and equal on the imetelstat and placebo arms. And now let's move on to the efficacy results. 40% of imetelstat-treated patients achieved the primary endpoint of 8-week TI compared with 15% of placebo-treated patients. This result is highly statistically significant with a p-value of less than 0.001, clinically meaningful and consistent with Phase II findings. Also consistent with our Phase II findings, we see sustained periods of TI in imetelstat 8-week responders, as shown in the swimmer plot. Over 80% of 8-week TI responders had 1 continuous TI period, uninterrupted by red blood cell transfusions. We also see here imetelstat patients with transfusion independence for up to 125 weeks or nearing 2.5 years. This continuous durable TI is not seen with placebo-treated patients with the exception of the second placebo-treated patient, who despite hemoglobin values on study of less than 6.5 grams per deciliter for the majority of the placebo treatment period, was never transfused. Durability of transfusion independence is further demonstrated with the Kaplan-Meier estimate of median TI duration or 8-week TI responders displayed here. Imetelstat-treated responders had a median TI duration approaching 1 year, which is highly statistically significant with a hazard ratio of 0.23 and a p-value of less than 0.001, compared with a median TI duration of 13 weeks for placebo responders. This median 1-year durability of TI has yet to be demonstrated with any treatment in this ESA-relapsed, refractory and ineligible population and is highly clinically meaningful. Adding to the evidence of long durable TI achieved with imetelstat treatment, the 24-week TI rate for imetelstat-treated patients was 28% compared with 3.3% for placebo. This again is highly statistically significant with a p-value of less than 0.001. Please note, the median duration of transfusion independence for the imetelstat patients who achieved 24-week TI was 80 weeks and that approximately 70% of patients treated with imetelstat who achieved an 8-week TI went on to achieve a 24-week TI. This next slide shows TI response rates from 8 weeks to 1 year. After a median follow-up of approximately 18 months, you can see the previously mentioned 8-week imetelstat TI rate of 40% and 24-week imetelstat TI rate of 28%. In addition, we have added the TI rates for at least 16 weeks and 1 year. The TI rates for the 8 weeks, 16 weeks and 24 weeks are highly statistically significant in comparison to placebo rates. The early data for 1 year TI is quite impressive. However, since the clinical cutoff for the primary analysis was exactly 1 year after the last patient was enrolled, this outcome for the 1-year TI rate is preliminary. We expect to present more mature 1-year TI data at a future medical conference. For all imetelstat-treated patients, there was a highly statistically significant increase over time of mean hemoglobin levels compared with placebo. Looking specifically at patients who achieved at least 8-week TI and during the periods of TI, there was a median hemoglobin rise of 3.6 grams per deciliter on imetelstat with a median peak hemoglobin of 11.3 grams per deciliter, compared with only 0.8 grams per deciliter and 8.9 grams per deciliter median hemoglobin rise and peak, respectively, in placebo-treated patients. Corresponding to the improvement in hemoglobin, there was also a statistically significant decrease in mean number of red blood cell units transfused for imetelstat-treated patients versus placebo. For example, after 41 weeks on study, imetelstat patients had a mean decrease of over 4 RBC units transfused compared to a mean of 1 unit for placebo patients. This slide shows response rates for the secondary efficacy endpoint of HI-E. Using the most recent 2018 IWG HI-E criteria, there was a highly statistically significant and clinically meaningful benefit for imetelstat-treated patients; 42% of patients achieving HI-E compared with 13% on placebo. Benefit is seen with imetastat in both components of HI-E, the 16-week TI rate and transfusion reduction by at least 50% over 16 weeks. The original IMerge protocol was finalized in 2015 and using the older IWG 2006 criteria from that time, there was not a statistically significant benefit to imetelstat treatment versus placebo. However, in 2018, the IWG criteria was changed to put greater emphasis on durability by measuring responses for at least 16 weeks and is more clinically meaningful for the assessment of HI-E in this disorder. Consistent with the imetelstat's mechanism of action that is selective for the malignant hematopoietic stem and progenitor cells in MDS, subtype analysis in patients who achieved 8-week TI demonstrates broad activity across all 3 subtypes called out in the protocol, including statistically significant improvements in 8-week TI rates compared to placebo, irrespective of ring sideroblast status, prior RBC transfusion burden and IPSS risk category. Additionally, imetelstat treatment had a comparable magnitude of clinical benefit across all subtypes. This slide looks more deeply at the response rate and median duration of TI in the RS+ and RS- patients. The 8-week TI rate was 45% in imetelstat-treated RS+ patients and 32% in RS-, with a median TI duration of approximately 1 year in both subtypes. The 24-week TI rate was 33% in imetelstat-treated RS+ patients and 21% in RS-, with a median TI duration of 88 weeks and 123 weeks in RS+ and RS- subtypes, respectively. These rates of 8-week and 24-week TI are statistically significant for both RS+ and RS- imetelstat-treated patients compared to placebo. We consider these results in RS- patients to be especially encouraging because such patients are known to have particularly poor outcomes. Lastly, for efficacy, we are fortunate to have early data available to perform an analysis of mutation burden reduction and exploratory end points. This slide shows the percentage of patients treated with imetelstat who had a reduction by at least 50% variant allele frequency or VAS and MDS-associated mutations while on treatment. The rate of reduction in SF3B1 VAS for imetelstat patients was highly statistically significant compared to placebo and reductions of at least 50% VAS in TET2, DNMT3A and ASXL1 were also seen to a greater extent in the percent of patients treated with imetelstat compared to placebo. Reductions in VAS for acquired mutations associated with MDS are also consistent with the reduction in the clonal burden of malignant stem and progenitor cells in the bone marrow and suggestive of the selective effect of the mechanism of action of imetelstat. These molecular data, together with the clinical outcomes presented earlier, provides evidence for the potential of imetelstat to modify the disease. We expect to present further data from these types of molecular analysis at future medical conferences. In summary, the trial demonstrated highly statistically significant and clinically meaningful improvements for imetelstat in 8-week TI, 16-week TI and 24-week TI rates versus placebo. A median TI duration for imetelstat-treated 8-week TI responders approaching 1 year. Highly statistically significant and clinically meaningful increases in mean change for hemoglobin levels over time were observed for all imetelstat-treated patients versus placebo patients. HI-E per IWG 2018 criteria demonstrated a highly statistically significant and clinically meaningful improvement for imetelstat-treated patients versus placebo. Statistically significant and clinically meaningful 8-week TI rates were achieved for imetelstat-treated patients with high and very high transfusion burdens, low and intermediate-1 risk IPSS and perhaps most notably, RS+ and RS- compared with placebo. Finally, we report both clinical and molecular evidence supporting the potential for MDS disease modification with imetelstat. This includes a 1-year median TI duration for imetelstat 8-week TI responders, a median rise of 3.6 grams per deciliter in hemoglobin levels in those same patients, and importantly, 50% and greater VAS decreases in SF3B1, TET2, DNMT3A and ASXL1 mutations. Now let's move on to the safety results, which were generally comparable to the Phase II data. Treatment emergent adverse events that were not hematologic in nature and occurred in greater than 10% of patients on either arm were generally low-grade and consistent with prior clinical trials of imetelstat. Please note, slightly higher rates of asthenia, headache and ALT increase with imetelstat and slightly higher rates of constipation and pyrexia with placebo. As shown on this slide, treatment-emergent liver function test, LFT, lab abnormalities were generally low-grade and occurred with similar frequency imetelstat and placebo-treated patients. Low-grade elevations of the alkaline phosphatase and AST occurred more frequently in imetelstat-treated patients. Notably, Grade 3 LFT abnormalities were generally infrequent and occurred at similar frequencies on imetelstat and placebo. No Grade 4 LFT abnormalities occurred on study. Grade 3 LFT elevations on imetelstat were short in duration with a median duration less than 2 weeks and more than 80% resolved to Grade 2 or lower within 4 weeks. As a reminder, all LFT lab abnormalities and liver-associated adverse events were evaluated in both the IMerge Phase II and Phase III studies by a hepatic expert committee. Their assessment concluded, there were no cases of Hy's Law or drug-induced liver injury in either of the studies. Consistent with prior imetelstat trials and expected with imetelstat's mechanism of action, after a median treatment duration of 8 cycles, the most frequently reported treatment-emergent adverse events with imetelstat were hematologic with thrombocytopenia and neutropenia occurring most frequently. In this Phase III study, Grade 3 and 4 thrombocytopenia and neutropenia were experienced by 62% and 68% of imetelstat-treated patients, respectively. These AEs, however, are primarily laboratory values and importantly, have minimal clinical consequences. Grade 3 and higher bleeding events occurred in 2.5% of imetelstat-treated patients. And there were no Grade 3 or higher bleeding events in the setting of Grade 3 or 4 thrombocytopenia. On imetelstat, 3 patients experienced Grade 3/4 infections in the setting of Grade 3/4 neutropenia. All 3 were sepsis that resolved and only 1 was considered related to imetelstat. Only 1 patient experienced Grade 3 febrile neutropenia. The febrile neutropenia occurred at study day 33, lasted 8 days and was assessed as possibly related to imetelstat. The patient went on to achieve transfusion independence for over 40 weeks and remains on imetastat treatments at the time of data cutoff. On this slide, we provide additional information about the cytopenias. The median duration of thrombocytopenia and neutropenia with imetelstat treatment was less than 2 weeks and over 80% of cytopenia events resolved to Grade 2 or lower within 4 weeks or within a treatment period. We believe the short median duration and the reversibility of high-grade cytopenias indicate that imetelstat treatment does not generally lead to persistent prolonged periods of myelosuppression, and therefore, there is not an increased risk of clinically severe or significant bleeding or infection events. In summary, we believe the safety profile of imetelstat is favorable in the lower risk MDS patient population studied and consistent with prior imetelstat clinical experience. Before concluding my prepared remarks about top-line results, I would like to personally, and on behalf of my general colleagues, express my deepest gratitude and appreciation to all the patients and caregivers, study investigators, research support staff and all the past and present Geron employees for their commitment and collaboration. Because of the contributions of all of the above, we have reached this milestone today. Now with our positive top-line results from the IMerge Phase III are available, I have a few brief comments on our plans for regulatory submissions. Based on these top-line results from the IMerge Phase III, we continue towards execution of our plan to submit a U.S. New Drug Application, or NDA, in mid-2023. The request for rolling submission enabled by our Fast Track designation in lower risk MDS has been granted. We also continue to plan to submit the EU Marketing Authorization Application or MAA in the second half of 2023. Updates to these plans or information regarding any regulatory interactions will occur once definitive outcomes have been reached. I thank you all for your attention this morning and turn the call over to my colleague, Anil, for discussion of the unmet need in lower risk MDS and imetelstat's potential market opportunity. Anil?

Thank you, Faye, and good morning, everyone. I share the same tremendous excitement about today's results, which my colleagues have expressed, especially because of the important difference that imetelstat could make in the lives of our patients who live with lower risk MDS. All of us at Geron are looking forward to the day when imetelstat will be widely available to help our patients. In my prepared remarks today, I'll provide our perspective regarding 2 topics related to lower risk MDS: the current unmet needs and the market dynamics that we believe make for an exciting potential commercial opportunity for imetelstat. Lower risk MDS is predominantly a disease of the elderly. Patients typically present with anemia and many experienced no symptoms in the early stages of the disease. Over time, the disease continues to progress and the majority of patients develop symptomatic anemia. Supportive care, predominantly red blood cell transfusions, remain an important component of patients treatment, but exposes patients to insufficient correction of anemia and other risks, including alloimmunization and organ-iron overload. Erythropoietin-stimulating agents remain the first-line treatment of choice in lower risk MDS with lenalidomide and HMAs being used in some patients as well. There is significant unmet need for new therapeutics in this setting, as patients typically fail frontline treatments become dependent on frequent red blood cell transfusions, have poor quality of life, heightened risk of transformation to acute myeloid leukemia and shortened survival. Looking at the schematic representation of the MDS landscape, you see the 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 the patients who have symptomatic anemia without 5q deletion. But not all patients respond to or are eligible for ESAs. Even among responders, responses typically last between 18 to 24 months. Treatment options are limited for patients who have failed or are ineligible for ESAs and may include hypomethylating agents or HMAs, and luspatercept, which is approved for ring sideroblast-positive patients. These treatments do not offer evidence of durable and continuous transfusion independence. Thus, there remains high unmet need in lower risk MDS and a need for innovative therapies. As you saw from Faye's presentation, 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. These include frontline ESA ineligible patients, ESA-failed, RS+ and ESA-failed RS- patients. Now moving on to imetelstat expected profile at launch. In our recent market surveys and advisory boards, hematologists have reaffirmed the unmet needs in lower risk MDS that I highlighted earlier and identified how the strengths of imetelstat could 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 of luspatercept. Importantly, hematologists had a strong desire for approved treatment options for RS- patients, and they cited this is an area of serious unmet need. In addition, the 24-week and the 1-year RBC-TI data from our IMerge Phase II trial provided strong evidence of durability of transfusion independence, which resonated very well with physicians, as they felt that these outcomes were more clinically relevant than the 8-week transfusion independence. Physicians also expressed dissatisfaction with currently approved therapies because they do not offer continuous and durable transfusion independence for their patients. Given the top-line results from the Phase III trial being reported today and the potential for disease modification, we expect a highly differentiated position for imetelstat at launch. Thus, we expect to significantly penetrate this attractive market and eventually become part of the standard of care in lower risk MDS. This next slide describes the potential market segmentation in more depth. We expect imetelstat patients to come from 3 main groups, all of whom were enrolled in our IMerge Phase III trials. The first group is drawn from the first-line lower risk MDS patients with high endogenous serum EPO levels greater than 500 mill units per mL who are ineligible for ESAs. This group has an addressable patient opportunity of approximately 3,700 patients in the U.S. and the 5 largest European markets. The second group and one of our key focus areas is the ESA relapse and refractory RS- patients. This is the largest opportunity of about 22,000 addressable patients in the U.S. and 5 largest European markets. These patients currently do not have effective approved therapies available to them. Given our IMerge Phase III trial results, we expect imetelstat will become part of the standard of care in this setting. The third group is the ESA relapsed and refractory RS+ patients. This group has an addressable patient opportunity of approximately 7,000 patients in the U.S. and the 5 largest European markets. Note also that this is where luspatercept is currently approved. We expect imetelstat to compete favorably with luspatercept in this setting, especially in patients with higher baseline transfusion burdens such as greater than 4 units per 8 weeks, which is more than 50% of the population in this segment according to our analysis. In addition, the durability of transfusion independence demonstrated in our Phase III IMerge trial will provide further differentiation to luspatercept in this patient segment and also in the RS- patient segment I just described. Based on our current commercial assumptions and assuming regulatory and fair access to the 3 patient segments, we expect a potential peak global revenue opportunity for imetelstat in lower risk MDS to exceed $1.2 billion. Lastly, I would like to make a brief comment today regarding our commercial activities, which are ongoing. Given that we are at the cusp of commercialization, we are taking important steps to ensure commercial readiness at launch. We have made multiple senior commercial leadership hires with deep industry knowledge, launch and operational experience. As part of the execution of our go-to-market plan, we are focused on 3 important pillars: our value proposition and how we best communicate to our stakeholders, product and marketplace readiness and company readiness. Our prelaunch market preparation activities include building an in-depth understanding of our customer base, to ensure smooth flow of imetelstat through the U.S. health care system across all touch points and provide for seamless patient access to drive market uptake and adoption at launch. We are engaging extensively with all our customers, from key opinion leaders, providers and payers to patient advocacy stakeholders to ensure the same. Our supply chain remains stage-appropriate for commercial launch, and we are executing on long lead time activities, including 3PL selection and state licensing efforts. With our commercial leadership now onboarded, 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. We expect to provide more details later this year. With that, I will now hand the call back over to Chip. Chip?

Thanks, Anil. As we complete the MDA for imetelstat, assuming imetelstat is approved in lower risk MDS and become a commercial company, Geron is entering into a very exciting period. In addition to the IMerge Phase III data you've just heard about, we have several additional studies underway. Two, in particular, have the potential to change the treatment landscape in another indication, myelofibrosis. IMpactMF is our Phase III study of imetelstat versus best available therapy in JAK inhibitor relapsed and refractory myelofibrosis patients. This is the largest MF study done to date in such patients and the first MF study using overall survival as the primary endpoint. We expect an interim analysis for IMpactMF in 2024. We've also initiated IMproveMF, an early phase study, exploring the safety and potential value in frontline MF of combining a JAK inhibitor with imetelstat. I expect Geron will continue to evolve and hopefully extend the scientific journey of telomere science and of imetelstat and potentially a next-generation telomerase inhibitor, as we reach for yet more important outcomes for patients with hematologic malignancies. I can't wait to see what's around the next bend. Operator, you can open the call to questions.

[Operator Instructions] Your first question comes from the line of Gil Blum from Needham & Company.

Allow me to congratulate you on strong results and for highly anticipated study. One question I do have, it seems there was a higher placebo effect than anticipated earlier. Do you guys have any commentary around that for potential reasons for why that would have happened?

Thanks a lot Gil. I appreciate the thoughts. Well, for those who have any doubt, of course, the highly statistically significant results take into account the placebo rate as well as the effect size of the imetelstat arm. Faye, do you have anything else you want to add on -- thoughts around placebo?

Sure. Patients were motivated to remain on the study on IMerge, even retrospectively having been treated with placebo, given that it provided them access to supportive care, medical treatment, laboratory testing, and we believe this speaks to the highly unmet need in this patient population and that the limit -- the treatment options are limited.

All right. And this is a bit of an older question relating to the thrombocytopenia. Was there any potential of physicians realizing that their patients were on drug due to the relatively high incidence of thrombocytopenia and imetelstat-treated patients? I know this has been addressed in the past, but I'd love to hear your comments again.

Unfortunately, I can't comment on behalf of the investigators in the trial. I don't know.

As you know, these are pretty objective endpoints by and large, so I think it's hard to speculate about that, Gil.

All right. And maybe a last one. We did see a really nice molecular information on VAF reduction. Did you guys also see VAF reductions associated with responses? I know this analysis was done on the Phase II study.

Yes. We have not had the opportunity yet to have that analysis performed, but we will hope to demonstrate that at a future medical conference.

We [indiscernible] the VAF into the sort of the top line data, but there's more to come on analyses at least.

Your next question comes from the line of Kalpit Patel from B. Riley.

Yes. Faye, congrats on the impressive data set here. Maybe starting with a question on the enrolled patients in the Phase III. It looks like the trial enrolled more RS+ patients than what the epidemiology would suggest. I guess can you speculate why this may be the case? Does it have to do with the high transfusion burden patients being primarily RS+ or is there anything else that might explain the gap?

We -- it's likely not due to the high transfusion burden. It's most likely due to the fact that there are limited treatment options for RS- patients. So they often go on to receive HMAs or lenalidomide, which would make them ineligible for this study. And given that they have worse outcomes, they tend to receive those at higher frequency. So we have some enrichment for the RS+ population as a result.

Kalpit, we've seen that in other studies in the same ESA-relapsed and refractory population. So I think this has been a finding in multiple studies now.

Okay. Okay. And then if we look back into Phase II, imetelstat showed a median duration of TI of 88 weeks. And then in the Phase III, it was closer to 1 year. Was there anything in the patient demographics in the Phase III that might explain this difference? And should we expect the median duration of TI to increase over time with additional follow-up?

We don't -- there are no baseline characteristics or any other characteristics of the Phase III that have the different -- led to the different median duration of TI. It's -- the data is fairly mature with 18 months, approximately 18 months overall follow-up. So we don't anticipate that to shift much.

And maybe 1 last question for Anil, for market opportunity. You had a slide, I believe Slide 39 showed a breakdown of all the patients that could be potentially eligible for imetelstat. I guess the segments of those patients, does that only include high-transfusion burden patients or is that -- are those numbers inclusive of both low and high transfusion-burden patients?

So thank you, Kalpit. I think it's a great question. Vast majority of low-risk MDS patients obviously are transfusion burdened. Our research indicates about half of those patients are high transfusion burdened. So those are the patients, which would be part and parcel of our population remains again, very high unmet need. And also, we are seeing from our real-world data, which is maturing that the transfusion burden is only increasing in the patient population. So we are addressing the patient population, which we believe today is largely reflective of the real-world population, and that's what IMerge Phase III study able to demonstrate a big benefit.

[Operator Instructions] Your next question comes from the line of Joel Beatty from Baird.

Congrats on the data. First question is, could you explain how there's no clinical effects from the hematologic AEs, despite the trend that were seen on the AEs and the biomarkers there? And then relatedly, due to this effect, could this lead to a lower dropout rate in the real world?

So Joel, I'm not sure we got the first part of your question. Could you just restate it, you broke up a little bit?

I'm sorry, could you explain the lack of clinical effects from hematologic AEs despite the trend in the biomarkers?

So I'm not sure about the trend in the biomarkers. You want to comment about the relative lack of clinical consequences is what you're asking about, right, Joel?

Yes.

Yes.

Sure, Joel. Thanks for the question. Because imetelstat -- the thrombocytopenia and the neutropenia caused by imetelstat is short-lived and reversible, these patients don't experience long periods of prolonged myelosuppression and don't have unnecessarily an increased risk of bleeding events or infections. And we believe that this Phase III data now with the placebo, we can see that our rates are very similar to the background rates and the placebo rates in this disorder.

Yes, and I'll just add, I think that it's pretty clear that the -- certainly, the SF3B1 data, which is strong and then the supportive but not statistically significant decreases in VAS and the other mutations, certainly support the whole story for potential disease modification and more selective hitting of the malignant stem and progenitor cells. How that ultimately plays out in the precise question that you asked, I think, needs a little more explication than we can give today. But it's pretty clear that that's all working together and likely with a predominant effect on the malignant cells as opposed to the nonmalignant cells.