Geron (NASDAQ:GERN) Q1 2020 Earnings Call

0:00 Ladies and gentlemen, thank you for standing by and welcome to the Q1 2020 Geron Earnings Conference Call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you'll need to press star one on your telephone. If you require any further assistance, please press star zero. I would now like to hand the conference over to your speaker today, Head of Investor Relations, Suzanne Mafferi. Thank you, please go ahead. Thank you, Chantel, and good afternoon, everyone. Thank you for joining us for today's conference call. I am joined today by Dr. John Scarlett, Jones Chairman and Chief Executive Officer, and Olivia Bloom, the company's Chief Financial Officer.

0:45 Also joining me today are Alexandra Rizzo, our Chief Medical Officer, and Anil Kapoor, our Head of Corporate Strategy and Chief Commercial Officer. After the market closed Today, we announced our first quarter 2020 financial results via press release. It is available on our website under www.geron.com slash investors, as well as several other press releases announcing recent developments in the month of May. In addition, a live webcast of the call is available on our website and will be archived for 30 days. Before we begin, please note that this presentation and question and answer session will contain forward-looking statements relating to GERON's plans, expectations, timelines, beliefs, statements of potentiality, and projections.

1:35 These include, without limitation, those regarding the timelines for completion of enrollment of and the results from the ongoing Phase III eMERGE and planned refractory MF clinical trials, that GERON's existing financial resources will be sufficient to fund operations into the second half of 2022, potential revenues, and that Jaron's 2020 operating expense burn will be in the range of 70 to $75 million. These and other forward-looking statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. These risks and uncertainties include, without limitation, those regarding that the company may be able to overcome all the clinical, safety, for their advocacy, technical, scientific, operational, manufacturing, and regulatory challenges to enable the expected timelines for the eMERGE and CLAND refractory MF clinical trials.

2:37 That regulatory authorities may not permit the further development of Immatelsta on a timely basis or at all. That the COVID-19 pandemic may significantly impact the timelines for both the enrollment and the results of the clinical trials and or drug supply. that competition or other factors result in lower than projected revenues and that there may be unexpected operating expenses or events or changes in John's plans that cause the 70 to 75 million 2020 financial guidance to be revised. Detailed information on the above risks and uncertainties and additional risks, uncertainties and factors that could cause actual results to differ materially from those in the forward-looking statements are explained under the heading Risk Factors in Jaron's quarterly report on Form 10-Q for the quarter ended March 31, 2020, filed with the SEC.

3:35 Undue reliance should not be placed on forward-looking statements which speak only as of the date they are made and the facts and assumptions underlying the forward-looking statements may change. I will now turn the call over to Dr. John Scarlett, Jaron's Chairman and CEO. Chip? Thank you, Suzanne. I'd like to welcome everyone to our first quarter 2020 conference call. On today's call, I'll have some introductory remarks. Olivia will cover Q1 results, 2020 guidance, and the recent financing, and Alexandra will discuss recently announced clinical development activities in MF and MDS. To start our call today, I'd like to share with you my conviction that Geron today is a fundamentally different company. It's a company in which all the pieces necessary to become a leader in the treatment of hematologic myeloid malignancies are now in place. We have a novel drug and a unique target.

4:35 Meaningful clinical activity and indications with significant unmet need. Two phase three trials, one ongoing and another planned, both based on compelling phase two data. A highly experienced team to execute all aspects of drug development. and financial resources to reach significant value inflection points. We've known for many years that Imatelstat has a unique mechanism of action. In malignant stem, progenitor and blood cells, telomerase is continuously upregulated resulting in malignant hematopoiesis. Imatelstat selectively targets malignant cells with continuously upregulated telomerase inducing their apoptosis or cell death and enabling potential recovery of normal hematopoiesis.

5:21 As we continue to treat and follow patients in our Phase II eMERGE trial in lower-risk MDS, data continue to mature and improve. We have an increasingly differentiated profile of Imatelstat compared to other agents, with a high rate of transfusion independence that is similar in both RS-positive and RS-negative patients, a remarkable durability of transfusion independence, even in patients with high baseline transfusion burdens, and substantial rises in hemoglobin levels that suggest potential recovery of normal hematopoiesis in patients treated with Imatelstat. The phase three trial in low risk MDS continues to enroll patients and enrollment is currently expected to be completed by the end of the first quarter of 2021 with top line results expected in the second half of 2022.

6:10 Imatelstat also represents a highly differentiated therapy designed to address the current unmet need in patients with intermediate to or high risk myelofibrosis unresponsive to JAK inhibitor therapy. In the Telstat treated MF patients who were relapsed or refractory to JAK inhibitors in our phase two Embark trial exhibited a median overall survival that compares very favorably to both historical controls and to a real world data analysis of closely matched patients who discontinued JAK inhibitors and were treated with best available therapy. Based on these analyses and our data and the regulatory clarity we have from our recent interactions with the FDA, we've designed a randomized phase three trial in refractory MF patients with overall survival as a primary endpoint and a control arm of best available therapy that excludes JEC inhibitors.

7:02 We expect that trial to be open for screening and enrollment in the first quarter of 2021. Both the lower risk MDS and refractory MF indications represent very substantial medical need. And if we are successful in bringing Imatelstack to the market for both indications, we believe they represent a combined annual revenue potential of approximately $1.25 billion in the United States and approximately $2.5 billion worldwide. To execute successfully on our plans in these indications, we'll be relying on our very experienced dedicated in-house professional drug developers. This extraordinary group includes individuals who are key team members working with Imatelstat at Janssen, including our Chief Medical Officer, Dr. Alexandra Rizzo, and our Chief Commercial Officer, Anil Kapoor.

7:50 These individuals have followed Imatelstat to Jira, bringing with them years of experience in clinical science, regulatory affairs, statistics, clinical operations, and commercial strategy. We've also recruited other talented professionals with experience from other very successful companies in those areas. as well as others in drug safety, manufacturing, and quality operations. And finally, due to our successful recent public offering, today we have the money to achieve our development plans in two phase three indications. It was particularly gratifying to see the response of investors to this transaction, especially leading biotechnology specialist investors such as Eco R1, Great Point, NEA, RA Capital, and Sansara.

8:36 They joined with other investors in making a very significant investment, which we believe provides strong affirmation for both Immatelstat and Geron. Perhaps that's a good segue to Olivia's discussion of the financing and our updated financial guidance. Olivia? Thank you, Chip, and good afternoon, everyone. Before discussing the recent public offering, I will briefly summarize our financial results for the first quarter of 2020. Overall, the financial results are in line with our expectations. Operating expenses are generally higher in comparison to the first quarter of 2019 due to increases in headcount across the company as well as increasing activity for the Emerge Phase 3 clinical trial in lower-risk MDF.

9:27 As of March 31, 2020, we had approximately $133 million in cash, cash equivalents, and current and non-current marketable securities. Our spending in the first quarter of 2020 reflected normal business activities into March and then a curtailment of certain costs due to the impact of the COVID-19 pandemic. Although certain external vendor costs related to the eMERGE Phase III clinical trial are estimated to be lower in the second quarter of 2020 as a result of a reduction in clinical trial activity limited by the COVID-19 pandemic, We expect much of our personnel related expenses will continue in line with the first quarter of 2020, with some decline as a result of travel restrictions.

10:14 However, we project expenses will increase in the future as we begin to support two phase three clinical trials of IMITEL steps, the ongoing eMERGE phase three clinical trial and the planned phase three clinical trial in refractory MF. Regarding financial guidance for 2020, We expect our operating expense burn to range from $70 to $75 million. The guidance reflects cash conservation measures implemented in April due to the COVID-19 pandemic, such as suspending travel and postponing a planned IMITEL-STAT proof of concept study. It also includes new costs for startup activities associated with the planned Phase III clinical trial in refractory MF and additional costs for the expansion of clinical sites for the eMERGE Phase III clinical trial.

11:03 Financial guidance is based on a set of assumptions at a point in time, and if the company's plans change, causing assumptions to be revised, then we expect to update guidance at that time. Yesterday, we closed an underwritten public offering of common stock and warrants. Due to the strong demand, not only was the offering upsized, but it was also oversubscribed. We expect the estimated net cash proceeds to GERON from the public offering to be approximately $140 million after deducting the underwriting discount and estimated offering expenses payable by the company. Based on current planning assumptions, we estimate that these net proceeds, together with our existing financial resources, will provide sufficient funds for our operations into the second half of 2022 when we expect top-line results for the eMERGE Phase III clinical trial in low-risk MDS and completion of patient enrollment for our planned Phase III clinical trial in refractory MF.

12:08 With that, I will now turn the call over to Alexandra to provide details around our clinical development activities. Alexandra? Thanks, Olivia, and good afternoon, everyone. Due to its novel mechanism of action, the Mattel study remains unique in comparison to the currently available treatments in myelofibrosis. as well as other investigational agents in Phase III clinical trials today. The overall survival data from our EMBARQ Phase II clinical trial in intermediate II or high-risk MS patients relapsed or refractory to JAK inhibitor highlights the potential clinical benefit achievable with the Matelsa treatment and indicates the potential disease-modifying activity of the drug.

12:54 Today, there are limited treatment options available for patients who become relapsed or refractory to JAK inhibitors and discontinue ruxolitinib. Approximately 75% of patients discontinue treatment with ruxolitinib, as you might know, within five years. And median survival after discontinuation is dismal and has been reported to be 14 to 16 months. Meanwhile, as we have previously reported, The median overall survival in INBARC was 28.1 months and it was similar for both refractory and rehab patients. This potential improvement in overall survival associated with Metelza treatment was further corroborated by rigorous real-world data analysis from patients treated with best available therapy at the Moffitt Cancer Center.

13:48 who were closely matched for demographic and disease characteristics with the Metelstad-treated patients from Embark. In those analyses, the patients treated with VAT had a median overall survival of approximately 12 months compared to the Metelstad-treated Embark patients who had an overall survival of approximately 30 months. A few weeks ago, we announced that three abstracts were accepted for poster presentations at the upcoming European Hematology Association or IHA Annual Congress. These abstracts report recent INBARC data analysis and provide further support to the OS results from INBARC. In one of the abstracts, the new data analysis suggested that the improvement in overall survival in INBARC correlate with other clinical benefits observed in this trial, most notably with fibrosis improvement, as well as symptom and screening response.

14:51 The second abstract reports improvement in OIS in triple negative MS patients treated with the Mattel study in Embark. Triple negative patients represent a patient subpopulation that affects the three driver mutations in myelofibrosis and that have a poor prognosis. The third abstract reports biomarker data indicating on-target dose-dependent inhibition of selomerase after treatment treatment at CalSTAT, and these correlated with the improvement in overall survival in EMBARC. Taken together, we believe that the 3-MF abstract substantiates the OS data observed in EMBARC and supports the plan to complete three clinical trials in this factory model of approaches.

15:40 We now discuss the Planned Phase III trial in a bit more detail. Firstly, disclosed, we discussed this trial design with the FDA, and they agreed that we could move forward. This will be an open label, one randomized Phase III trial of Imatelstat compared with best available therapy in approximately 320 patients with intermediate to or high-risk MS who are refractory to JAK inhibitor treatments. Patients eligible for the trial will be required to be refractory to a JAK inhibitor defined as patients who have had an inadequate spleen response or symptom response after treatment with a JAK inhibitor for at least six months and who had received an optimal dose of a JAK inhibitor for at least two months during the treatment period with a JAK inhibitor.

16:39 Given this definition, we believe that refractory MS patients meeting these criteria will not benefit from further JAK inhibitor treatment, which is why the control arm of best available therapy will exclude JAK inhibitors. In the Imatelstad treatment arm, 9.4 mg per kg of Imatelstad will be administered intravenously every week. As Chip mentioned, the primary endpoint for the trial is planned to be overall survival. And we believe this is the first trial in refractory myelofibrosis to use overall survival as primary endpoint. Planned key secondary endpoints include symptom response, spleen response, progression-free survival, complete and partial response, clinical improvements, duration of response, safety, pharmacokinetics, and patient-reported outcomes.

17:39 The trial has been designed to have more than 85% power to detect a 40% reduction in the risk of death for metastatic patients. In making these power calculations and setting the trial size, we assumed a hazard ratio of 0.6 and a one-sided alpha of 0.025. For example, We made the assumption that the best available therapy arm will have a median overall survival of 14 months and the MatelSAT arm will have a median overall survival of 23 months. The final analysis for OS is planned to be conducted after more than 50% of the total enrolled patients have died. An interim analysis of OS in which the alpha spend is expected to be approximately 0.01 is planned to be conducted after approximately 70% of the total projected number of deaths for the final analysis have occurred.

18:45 At the interim analysis, if the pre-specified statistical OS criterion is met, then we expect such data may support registrations in a tel-setting refractory MS. If the pre-specified OS criterion is not met at an interim analysis, The trial will continue to the final analysis. Currently, we expect to engage over 150 sites across North America, South America, Europe, and Asia. Startup activities have already begun, and we plan to open the trial for screening and enrollment in the first quarter of 2021. Under current assumptions, we expect to complete patient enrollment in the second half of 2022, to conduct an interim analysis in the first half of 2023 and to conduct a final analysis in the first half of 2024.

19:45 However, both the interim and the final analysis are event-driven and could occur on a different timeline than currently expected. We believe that if this planned phase three trial in refractory MS is successful, will be the first track to demonstrate a survival benefit in this poor prognosis patient population. Moving on to the ongoing eMERGE Phase 2-3 clinical trial in lower risk MDS. As of the end of April 2020, approximately 68% of the regionally planned clinical sites for the eMERGE Phase 3 clinical trial in lower risk MDS are open for enrollment. As we previously announced, COVID-19 has had a significant impact on site initiation and enrollment in this trial. We are doing everything we can to ensure we meet our enrollment goals and emerge. This has included consistent contact with our clinical investigators and working with our CRO on enrollment boosting activities.

20:50 Now, on top of those activities, we are currently evaluating the addition of potentially six new countries and approximately 40 new clinical sites for participation in the trial, which could result in a total of up to approximately 135. As for top-line results, the protocol-defined final analysis will be conducted 15 months after the last patient is enrolled, and that's based on our updated enrollment assumptions. We expect top-line results to be available in the second half of 2022. Compelling data from the Phase II portion of eMERGE continue to highlight the dissociating effect of hematelstat in lower-risk MDS patients.

21:38 First, our data indicate meaningful transfusion independence, or CI, achievable with hematelstat treatment, as 42% of patients achieved the primary endpoint of 8-week CI, and 68% achieved hematologic improvement at risk for it. Second, similar rates of clinical benefit, including CI, have been observed in both RS-positive and RS-negative patient subgroups. RS-positive patients represent approximately 10 to 25% of low-risk MDS patients, while RS-negative patients represent approximately 75 to 90% of the low-risk MDS patients.

22:25 Being able to show transfusion independence across these patient subgroups allows IMATEL-STAT to potentially address a broad patient population. Third, and the most significant differentiator of IMATEL-STAT in low-risk MDS, which is observed to date, is the durability of transfusion independence. Namely, this year's IHA-ASTRAG, which was accepted for an oral presentation, reported a 24-week TI rate of 32%. For the first time, we're now reporting a one-year TI rate of 29%, representing patients being transfusion-free for at least one year, with the longest transfusion-free period being 2.7 years.

23:13 In addition, the new median duration of transfusion independence is 88 weeks, which is, to our knowledge, the longest reported to date in the non-Delphi skill lower risk MDL setting. Finally, 75% of the eight-week RBCTI responders showed a hemoglobin rise greater than three grams per deciliter during the transfusion-free interval when compared to their pretreatment level. A hemoglobin rise of this magnitude is not achievable with a blood transfusion or growth factor treatment. We believe that the increase in hemoglobin, together with the durability of TI, is indicative of the disease-modifying activity with Imatelstar treatment, which aligns with Imatelstar's mechanism of action. As a telomerase inhibitor, Imatelstar has potential to inhibit the uncontrolled proliferation of malignant stem and progenitor cells and potentially enable recovery of normal hematopoiesis.

24:17 Now, I'd like to hand the call back to James. Chip, are you maybe on mute? Thank you. The trials and tribulations of the era. So thank you, Alexander. With all the pieces now in place to capture the value from two significant indications, we believe we have strategically positioned Jira on to become a leader in the treatment of hematologic myeloid malignancies. And perhaps with that, we'd like to answer your questions, so I'll turn the call back to our operator. Operator? As a reminder, to ask a question, you'll need to press star one on your telephone.

25:06 To withdraw your question, press the pound or hash key. Please stand by while we compile the Q&A roster. Your first question comes from Charles Duncan with Cantor Fitzgerald. Your line is open. Thank you. Hi Chip and team. Thanks for taking my question and congratulations on the recent equity raise as well as the planned route forward in myelofibrosis in addition to MDS. I had a couple of questions on the pipeline and just one operational. So first question is regarding the pipeline in MDS. You know, I'm not sure if I'm reading this right, but in the corporate debt, it looked like there's 29% of patients or so achieved a 24-week red blood cell transfusion independence.

26:04 But in the EHA abstract, it seemed longer. And I think Alexander just addressed this, but I'm assuming these are the same patients. Please correct me if I'm wrong. And in addition, I'm wondering if you could compare the patient sample characteristics and durability of treatment or of transfusion independence to that of the emerging agent Luspatracept. Thanks, Charles. While Alexandra perhaps compares some of those numbers, which I'm confident are correct, I'll take the Luspatracept comments.

26:50 I think that the things that really distinguish the imital stat in low-risk MDS are, first of all, that we are treating both RS-positive and RS-negative patients. The RS-positive, as you recall, are somewhere around 20-ish, 25%, quoted as anywhere from 10% to 25% of patients with low-risk MDS. and that is both the limitation within the accepted labeling for the U.S. for leucocytosept to RS positive patients and the CHMP positive opinion also mentions that. We include both RS positive and RS negative patients in our studies and would anticipate heading in that direction from a submission perspective. The second is that we had significantly higher baseline transfusion burden in our Phase II study compared to the MEDALIST Phase III study. The median baseline translation burden was eight units per eight weeks compared to five for MEDALIST.

28:00 And the interesting feature about MEDALIST was that they did include patients in MEDALIST who had Thank you very much. eight-week RBCTI rates of 42% for Emerge and 32% for METALIST. And as we commented earlier, the 24-week RBCTI rate of 32% and 29% for the one-year RBCTI rate have not, for Imatel said, those rates, the 24-week and the one-week, have not been reported for the METALIST study anywhere we've been able to find.

29:02 Finally, the last point is that if you look at the median duration of RBC-TI, it's 88 weeks for the eMERGE data in the Phase II, and it was 31 weeks for the median duration of the TI in METALYST. Now, I would hasten to add that the eMERGE study was a Phase II study, and METALYST was, of course, Phase III. And second, I would make the point that Metalyst has a very, I would say, benign side effect profile. So the drugs are not entirely comparable, but I think that when you look across the opportunity, I think we feel very good about where Imatel stacks up, particularly in the higher transfusion burden and the RS negative as well as RS positive patients.

29:57 Alexandra, did you have any other further comments about numbers? No, Chip, I think you covered everything. Charles, please let us know if there's anything to be answered. Yeah, no, I think that was very clear, and I appreciate the added color. My second question was regarding the myelofibrosis protocol, which I think is pretty interesting because I believe it's quite well suited to show mechanistically driven differentiation of clinical profile for imetelstat relative to standard of care. However, for the planned control arm, which is best available therapy since it does not include a JAK inhibitor, how would you characterize what BAP is if in any way?

30:51 And then given that it's an open label study, You know, I know overall survival is probably pretty hard to fake, but in terms of some of the secondary endpoints like some of the patient reported outcomes, how do you plan to maintain some level of control regarding patient communication? So why don't you start off and I'll supplement if needed. I can take. Yes, for sure. Let me start with the question around the best available therapies. So we have defined the patient population in our study very carefully and the patient population as such has exhausted or has had the chance to respond to a JAK inhibitor treatment They would have had, as I mentioned, six months of treatment for the JAK inhibitor and two months of those would have been on a stable dose for the JAK inhibitor. Therefore, with this definition, patients would not need a further treatment with a JAK inhibitor. Therefore, the BAP arm can exclude the JAK inhibitor. Now, in this setting, The BETR will include most likely agents like hydroxyurea, steroids, damazol, emits, potentially

32:23 HMAs, right? So we believe that with this we've addressed the need for the defined patient population. I believe that... And then relative to the secondary endpoints, you know, just kind of I guess exercising some control around patient communication and how those read out given it's an open label study. So that's a fair question. It's a question that has an overall survival as an endpoint, you know, applies to any study with an overall survival endpoint. and as you mentioned, the primary endpoint, you cannot fake. It is what it is.

33:13 And for the symptom assessment or some of the PROs, we will just ensure that they're taken with a high compliance and report the data as such. It's difficult. It's a problem of every survival study. Got it. And last question, operational. Do you have sufficient quantities of IMITEL staff for both studies? And if not, I assume you've contemplated that with regard to the balance sheet and if you need to do additional manufacturing? Yeah, we have sufficient to complete the MDS study and to go at least very far into the MF study. Alexandra, I don't know if you have any update on that or not.

34:10 No, that's accurate, Chip. That's well said. Yeah. So we have multiple years' worth of drug supply at this point and a very well-established manufacturing process. This is Olivia. What I would add to that, Charles, because you asked about the spend, is that in the guidance I gave does include costs for CMC. As you know, Imatel said is contract manufactured out. And so we have been validating all those vendors as part of the process in readiness for potential not only for phase three trial supply, but also for potential commercialization down the road. And so those activities are ongoing right now.

34:58 OK, thanks for taking my questions. Thank you. Thank you very much. Your next question comes from Chad Messer with Needham & Company. Your line is open. Thanks for taking my questions and my congratulations on all the progress, particularly with getting this MS protocol worked out and things moving forward there. It's just wondering if there's one thing You can maybe share your thoughts on with me with regards to MS. And that's, you know, all other drugs approved or late stage development are kind of getting away with a sort of hybrid off their endpoint. And you guys are kind of being held to the sort of high bar of OS.

35:47 But 20, do you have any thoughts on why that may be and whether or not your really strong OS data from the Phase 2, smallish though it may be, is somehow ironically working against you. Well, let me take that first of all, and then I'll invite Alex to make additional comments. I would actually look at it differently. I think that we view the ability, the confidence we have in a potential OS development Thank you very much. to our drug, to Emet-Elstat. So far from viewing it as something that we were gonna be held to a higher standard than anyone else.

37:00 It may be true that it's a higher standard. It takes a little bit longer and it takes substantial resources to do. But on the other hand, coming out at the other end of this, I think we expect to have the only drug that will have been through the, the only drug in Jack Refractory patients who make up a very substantial part of the market. The only drug that will have actually demonstrated a survival benefit in such patients and a survival benefit in fact chat is a primary outcome measure. So this is actually new ground but with new ground also comes high barriers to entry potentially and also a great differentiation. I can tell you the investigators that we engaged in working through the details of this type of approach were just simply extremely excited about the possibility of getting a drug that would have this type of benefit demonstrated.

38:01 So that was our real approach to it and I think we feel pretty terrific about the opportunity to go there. Did I leave anything out, Alex? Yeah, maybe I can just reinforce, Chip, I mean, we love the fact that we have a drug that can, you know, improve overall survival in these relapsed refractory settings. There's no other drug, as Chip mentioned, that has shown that. And as you know, right, other drugs are having primary endpoints. that are addressing the symptom of the disease, whether that's a spleen or a symptom response or an anemia improvement or a combination of the above. So what we have here is an overall survival, and I think that we have the possibility or the chance to have a paradigm shift in the thinking of how you approach treatment with myelofibrosis.

39:03 I appreciate that perspective and certainly don't disagree with anything you're saying. It's the go big or go home approach. Maybe just with regards to the upcoming EHA, congrats on the strong sort of top line one-year data that came out in the abstract. What other analyses, are there any other analyses that you would recommend sort of highlight you should be looking out for in the full oral presentation? In the model fibrosis presentation, there is one key, I guess, data that I would definitely want to bring to the attention, and that's the correlation that we are now showing of fibrosis improvement with the significantly longer overall survival in these patients, right?

40:04 So it is the first time ever that in myelofibrosis is being the fact that if you have an improvement of fibrosis, you have a better chance to live longer. So I guess that would be the data that I would really highlight from the myelofibrosis abstract. In terms of the MDS, it will certainly be the durability, right? The one-year transfusion-free period. Great. Thanks. I'll be looking out for those. Thanks, Chad. Again, if you would like to ask a question, press star 1 on your telephone keypad. Our next question comes from Andrew DeSilva with B.

40:50 Reilly FBR. Your line is open. Yeah, thanks for taking my questions and congrats on the progress. So, you know, lots to unpack here. I'll just start as far as Embark, the MF Phase 3, and connecting, you know, the recent abstracts and the benefits seen in overall survival in patients that experience other clinical benefits. And then, you know, tying that into the stronger results that we're seeing in the triple negative patient group that further aligned with the other clinical benefit statement. Are you looking to have protocols designed in the phase three in a manner where we should expect triple negative patients to be a focal point of the enrollment criteria?

41:41 Alex? Yes, the answer to that is yes. However, our focus and priority of the moment is the Phase 3 study in refractory myelofibrosis patients. I think Andy might have been asking, within the Phase 3 study, within the refractory Phase 3 study, will there be a particular focus on triple negative patients within that broader patient population? And In other words, is there either a major stratification for triple negative or do we have particular focus on that? Go ahead, Alex. Well, triple negative patients will be also allowed to enter the current, the refractory study.

42:30 At the moment, if that was the question, we have not planned for stratification for triple negative patients. Right. There's no particular focus on them, Andy. Okay, thank you for that. And then you noticed that enrollment, or you noted that enrollment from a bat standpoint would exclude JAK inhibitors. Did the real-world data Moffitt ran with their bat population also exclude JAKs? Yes. Yes, the VAT in the Moffitt patients did not include also, excluded JAK inhibitors. So it's a fairly clean comparison then as far as, okay, okay, good.

43:19 As far as the outcomes expected, yes. Okay, okay, perfect. And then this last question for me, as far as guidance goes, you know, no change really from a number standpoint. Can you help me crosswalk how it's different today than it was in March? Obviously, you're increasing spend with MF and then reducing enrollment or just enrollment is going slower, MDS due to COVID-19, and you're pushing out proof of concept studies a little bit. Could you help me get to the same number as far as where the gives and takes are there?

44:06 Yeah, Andy, this is Olivia. Sure, I can. So you're right. Overall, the range is the same as what we guided earlier this year. But you're right. There's kind of pluses and minuses in many areas. And then we ended up in the same range. So I would say that the composition of the guidance is relatively same. Again, there were some pushing from one category to another. as the different expenditures were going along. So just to let you know, for the current guidance and the composition, the clinical trial costs, which include the startup activities that I mentioned for the refractory MF trial, as well as the ongoing support for the eMERGE Phase III, that probably represents a little less than a fifth of the total guidance. FTE costs are a little over a third.

45:04 The manufacturing cost that I mentioned earlier when we were talking with Charles, that's a little over a fourth. And then overall, G&A, you know, kind of supporting the public company, that kind of thing is a little less than a fifth. Okay. Great. Thank you very much. I'll take everything else offline. Best of luck going forward this year. Thank you. Your next question comes from Paul Schrader with VTIG. Your line is open. Good afternoon. I'd like to echo the sentiment. It's been an amazingly long poll. Congratulations on getting this to this stage. I know it's not been easy. So my first question is the MS control arm. Does Fidratinib, is that a complexity for you?

45:51 They have retreatment data. I know it's highly contentious. But is it a worry for you that, as you talk to clinicians, that they would want to try Fidratinib and Ruxvilliers? Alex, did you get the question? Go ahead. Right. I mean, I don't know. It is not a worry, right? Again, taking the definition of the patient population in our study, we do believe that, you know, patients or PIs, investigators, would not want to treat patients with a JAK inhibitor. So I don't think we see that as a worry. Okay. And then kind of a So I'm intrigued by your EHA abstract with the telomere length. My memory is that that's been very difficult to measure historically and in fact I think didn't correlate with early data because you couldn't measure it. Is it now a robust assay and you could actually look at all MS patients as a function of telomere length irrespective of treatment and you might have a subgroup? Just your thoughts on is that a new assay and how robust is it because my memory is Telomere length was historically nearly impossible to measure.

47:08 You are correct. Telomere length is very difficult to measure, especially due to the fact that you're mixing potentially malignant as well as normal cells. However, as Alfredo indicated, we've improved on the assay. And now, again, in a limited number of patients, I guess that's still a caveat, but in a limited number of patients that had For a paired analysis, it is the first time that we are able to introduce some correlation between the TL, the telomere length, and the outcome. Do you think it will be a biomarker? Is that something that kind of has you excited, or is it still very exploratory?

47:57 I think we look at all of the three PD parameters, if you will, right? The telomere length, the telomerase activity, and the H3 expression, right? We look equally at them. I don't think we're thinking of any biomarker at the moment, but it is really good to have them as PD, pharmacodynamic markers, in order to confirm the on-target mechanism of action of hematosis. All right, and then one quick, maybe slightly annoying question, because the horse is out of the barn, but in the eMERGE trial, you have such a different drug profile where three-quarters of the patients that get an eight-week transfusion get a year.

48:46 Are you sorry you chose such a short endpoint, which that would be much noisier, or do you think that... You're confident that eight weeks is long enough so that the placebo rate is going to be very low. Maybe I can just comment that the eight-week, Alexandra, I'm sure we'll have a few other comments, but you know, Tom, the eight-week RBCTI is kind of the accepted or approved regulatory outcome or regulatory endpoint. And so it's really common in virtually all of these studies in lower risk MDS to use that as the primary outcome measure. I think we have a very robust, in the phase two, we saw a very robust outcome measure.

49:35 And even in the metallists, when you got into the higher transfusion burdened patients, such as we will have in our study, in our phase three, and as we had in our phase two, You know, the noise really goes down much lower. You're bringing up a really interesting point. So, for example, with the METALYST study, which I just use METALYST in this case not to harp on anything with regard to luspatercept, but because it is a study with a wide variety of patients in the baseline transfusion burden. So when you looked at the patients, just at the placebo rates, because that's what you're actually kind of getting at, right? So when you looked at the patient's placebo outcomes in their study as a whole, which included, remember, from two units transfusion burden up to actually 20, their placebo response rate was 16%. And I have to say, when we looked at that, we went, oh, holy cow, what was that? But the reality is that when you knock out the patients who had the less than four units per eight-week transfusion burden, so the two and three patients, okay? That placebo rate comes down to 7%.

50:50 In the MDS005 study, which Celgene did a couple of years ago and was reported, well, yeah, a couple of years ago at ASH, that was Revlimid versus placebo. The placebo rate, as I recall, was 4% or 5%. So I think we don't see a signal-to-noise ratio here as long as you have a sufficiently high Transfusion Burden. And if memory serves me correct, if you then flip the analysis and you look at the patients in the loose petriceps study that had only two units or three units per eight weeks and just that subgroup alone, their placebo response rate was extremely high. So I think it's really defined by the baseline transfusion burden and that signal-to-noise ratio in the patients that we'll be studying I think is more than adequately high. The additional durability is the icing on the cake, right? And I think everyone will pay a great deal of attention to the durability because we would expect an exceptionally low, I expect a very low placebo response rate there. And I think that will not be an issue at all in signal-to-noise ratio.

52:25 There are no further questions at this time. I'll now turn the call back over to John Scarlett for closing remarks. Well, I'd just like to thank everybody for participating in this conference call. We're exceptionally pleased by the progress that we've been able to make. I think that we have A really great opportunity to now drive forward with two phase three studies, not companies get this far. We thank all of our investors, our longtime investors who have been with the company and supported us, our new investors who we're excited to have, and also just simply want to thank all the patients and the investigators who have helped us get to this level.

53:10 We still have a lot of wood to chop, as they say, but I feel really, really good going into the next several years where we have some exciting times to come. So thank you all very much, and we look forward to taking the journey with all of you. I think that concludes our call, operator. This concludes today's conference call. You may now disconnect. Okay, thanks very much.