Ladies and gentlemen, thank you for standing by and welcome to Geron's Key Opinion Leader 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 will need to press star one on your telephone keypad. Thank you. I would now like to hand the conference over to your moderator for today, Suzanne Messere, Head of Investor Relations. Ms. Messere, please go ahead.
Thanks, Jack. Welcome to Geron's KOL event to discuss recent data presented at the virtual edition of the 25th Annual European Hematology Annual Congress. I am joined today by Geron's Chief Medical Officer, Dr. Aleksandra Rizo, Dr. Valeria Santini, Dr. John Mascarenhas, Dr. Rami Komrokji, and Geron's Chairman and CEO, Dr. John Scarlett. 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. These include, without limitation, those regarding that imetelstat has potential disease-modifying activity and that Geron has a plan to open for enrollment a phase III clinical trial in Intermediate-2 or high-risk myelofibrosis in the first quarter of 2021. These 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, risks and uncertainties related to whether the COVID-19 pandemic slows or prohibits the company's ability to open for enrollment the planned phase III clinical trial in Intermediate-2 or high-risk MF in the first quarter of 2021, whether regulatory authorities permit the further development of imetelstat on a timely basis or at all without any clinical hold, and whether imetelstat demonstrates disease-modifying activity in clinical trials. 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 Geron's quarterly report on Form 10-Q for the quarter ended March 31st, 2020, filed with the SEC.
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 would like to hand the call over to Aleksandra, who will review today's agenda and get us started with our first introduction. Aleksandra?
Sure. Thanks, Suzanne. Thank you all for joining us today. We're so glad we could connect with you in our new virtual format. As we've announced, we have four abstracts accepted for presentation at this year's EHA conference. The data from the abstracts suggest potential disease-modifying activity of imetelstat in the two indications that are our current focus: low-risk MDS and myelofibrosis. The recent data from the phase II part of IMerge, which continues to show meaningful and durable transfusion independence, will be presented first. Of particular note, we're reporting a one-year TI or transfusion independence rate for the first time. Three separate analyses from IMbark will be presented. Of utmost importance, the updated overall survival analysis will show correlation of the potential improvement in overall survival with other clinical benefits, such as fibrosis.
We expect these results to drive further interest of investigators, which will promote enrollment for the ongoing phase III clinical trial in low-risk MDS and the planned phase III study in refractory myelofibrosis. After each speaker, as already mentioned, we will have a Q&A session, and we encourage the invited analysts to participate. To close out today's event, I will provide an overview of the trial design for our planned phase III trial in refractory MF, and then Chip, our CEO, will provide closing remarks. Now, I'd like to start by introducing our first speaker. Dr. Santini will be reprising the MDS presentation, and I'm sure a lot of you will know her. She's one of the most prominent and renowned investigators in the MDS field. She's currently an Associate Professor of Hematology at the University of Florence in Italy.
Dr. Santini has hands-on experience with imetelstat and even continued to enroll patients through the COVID pandemic period nowadays. I've worked with Dr. Santini for the past 10 years or so, and it has been nothing but pleasure to hear her advices, discuss patients, and continue to brainstorm on protocols. With that, Dr. Santini, would you like to start?
Yes. Thank you, Aleksandra, for the very nice introduction. I think I'm going for the first slide, and I will introduce what was presented at EHA, the virtual EHA 25th meeting. Now, MDS is a very different and heterogeneous group of disease dominated by the presence of anemia in the majority of cases. This anemia can be extremely severe but can be treated in the beginning with the use of erythropoiesis-stimulating agents, the problem being that the majority of patients become transfusion dependent because they lose response to ESAs. Now, what we need to have for this increasing population, that is the majority of MDS patients, is a treatment that avoids transfusion and increases transfusion independence with a durable, of course, duration of response.
We also want to have agents that target both ringed sideroblast positive and ringed sideroblast negative, being these two the characteristics indicated by WHO classification as a different type of low-risk MDS patients. Of course, our goal would be to get disease-modifying therapy to prolong survival. I'm sorry, I don't see the slides any longer. I don't know what happened. Next slide, please. This is the study that I'm going to present. Next slide. That was an international study in which imetelstat was used for low-risk MDS patients. You see, imetelstat is a first-in-class telomerase inhibitor and blocks telomerase activity, which normally is increased in MDS in myelodysplastic cells and progenitors. Next slide.
What I'm going to talk about is the phase II study that is completed, and that is a single-arm open-label study, as I mentioned, for relapsed refractory low-risk MDS that received treatment with ESA or were not suitable for treatment, eligible for treatment with ESA. Imetelstat was given 7.5 mg/ kg IV every month, and 38 patients were treated in this study. The patients had to be, as I mentioned, ESA refractory or not eligible because of endogenous EPO greater than 500 units/liter, but they also should not have received treatment with HMA or lenalidomide. On top of that, they need to have a transfusion dependency measured in the 16 weeks before screening, and the transfusion need had to be higher than four units. The primary endpoint being the achievement of eight-week transfusion independence.
As a key secondary endpoint, we had a 24-week transfusion independence, duration of this transfusion independence, and hematological improvement. I will talk at the end about the phase III currently ongoing and enrolling. Next slide. This is a study that has been conceived with a very long median follow-up. As you may see, there are two years of follow-up. The median duration of treatment for all patients was 8.5 months, and the number of cycles was nine. This 30—next slide—these 38 patients were elderly. Median age was 71.5 years. The striking thing is that the patients enrolled in this study had a very high transfusion burden with a median of eight units of red blood cells in eight weeks. As you may see, the majority of them, 84%, had more than six units in the eight weeks at baseline.
That means that this was a group of patients with a quite important burden of disease and high burden of transfusion. The majority of patients, as it happens very frequently in the study with ESA-resistant patients, was formed by refractory—sorry, of course, refractory to ESA—but ringed sideroblast MDS patients. And almost all of them received ESA, and very—well, one-third had higher endogenous EPO level, higher than 500 units. Next slide. The patients are still ongoing treated, nine out of 38. 76% stopped treatment for several reasons, some for lack of efficacy, some for the adverse event. The median follow-up, of course, it's the reason why we see so many stopping treatment. Next one. Now, the results are, in my opinion, extremely interesting because the eight-week transfusion independence was achieved and reached for 42% of these patients.
The duration of transfusion independence is remarkably long, with 88 weeks of response, with a rise in more than one-third of the patients higher than 3 grams/dL of hemoglobin. The duration of response indicates the stability and the depth of these responses. At 24 weeks, transfusion-independent patients were still 32%, and there was almost 30%—29%—of patients who were still transfusion-independent after one year of treatment, with a longest transfusion independence of 2.7 years. Next slide. Now, when the hematological improvement, which is certainly another very important point, that is the decrease of transfusion burden measured always in eight weeks, we see that according to IWG 2006, hematological improvement was present in 68% of the patients. The duration of this hematological improvement, erythroid, was 92.7 weeks, so extremely long as well.
When we measured with a more stringent criteria of response, the ones of the IWG 2018 group criteria, you see that major response was achieved for 16-week transfusion independence. As I mentioned, very stringent, 37% of the patients achieved this response, and more than half of the patients had a decrease in transfusion higher than 50% in 16 weeks. These are data that are really very promising and very intriguing. Next slide. Now, when we look at the duration of response, as I mentioned before, you see that in this 29% of the patients are still transfusion-free at one year. As I mentioned, many of these patients have been treated for a very long period with one transfusion-free period of 2.7 years. What is very striking is also that the great majority of the responders had a substantial rise in hemoglobin, 3 g/dL.
As you may see in this dark green bar, these are the patients who had achieved and maintained response in terms of transfusion independence longer than one year. Next slide. Now, if you look across the different patient subgroups according to WHO category or IPSS-R, you see that there are not so many differences in the rate of response to imetelstat. What is to be noted is both ring sideroblast positive and negative patients do respond. The interesting factor is that the patients who had a very high transfusion burden, so once again, the median was eight, but here it is more than six units, you see that these patients do respond as well as the ones who have a lower transfusion burden. IPSS low Int-2 needed does not really matter as well as the level of endogenous serum EPO. Very, very active all across the subtypes of MDS.
Next slide. Now, the adverse events observed during imetelstat treatment were mainly due to hematological adverse events, a little bit of myelosuppression, thrombocytopenia, neutropenia were reversible. Here you see that some of them were grade three, four in around half of the patients. There are some patients who also presented anemia. Just to remind, these are all the patients, responsive and non-responsive ones. Anemia is, of course, the characteristic of the patients undergoing therapy with imetelstat. That means that the patients not responding will have anemia as grade three or four as the majority of them. Now, as I mentioned, all the cytopenias were reversible. You see in light blue, 10% of the patients will not recover from grade three, four cytopenias within the four weeks.
That means that they resolve the cytopenias after four weeks or they have been observed for a shorter time than four weeks. Next slide. Now, the non-hematological adverse events were really not significant and not very frequent. I want to stress the fact that the liver toxicity was very mild, only very few grade three, four adverse events regarding liver hepatic function. Next one. Now, the activity of imetelstat, as I mentioned in the beginning, is due to the inhibition of telomerase. On-target activity was demonstrated for several patients. The 50% reduction in telomerase activity was seen in a good proportion of patients. The reduction of hTERT expression correlates with the response.
The patients who responded were the ones who had the higher reduction in hTERT expression, meaning that the on-target activity of imetelstat is the one that is really determining response in terms of increase of hemoglobin. Next one. To note, imetelstat has a very important effect on the variant allele frequency of some mutation present in this patient. Now, as you noticed, the majority of patients included in the study were ringed sideroblast positive ones, meaning that the majority of them bear the SF3B1 mutation. Now, the 11 patients who responded and were mutated had a reduction in the variant allele frequency of SF3B1. The greater the reduction of the mutated clone, the longer was the transfusion independence. This is something extremely significant, in my opinion, because that means that the drug is acting directly on the dysplastic clone, decreasing the burden of the clone itself.
This is something that it's not common in active drugs, but I would say almost exclusive of this imetelstat study. Next slide. I would like to conclude just by stressing and reminding the data. The data indicated 42% of the patients treated with imetelstat achieved an eight-week transfusion independence rate, and 68 of them had a hematological improvement erythroid. The duration of both transfusion independence and hematological improvement erythroid was almost 20 months and 21 months. All the patients with MDS included in the study seemed to be responsive to this treatment, especially the ones—to stress the ones with high transfusion burden and very high transfusion burden. Finally, the data showing on-target activity, reduction on SF3B1 mutation by treatment, and the length of the response, it's indicating a potential disease-modifying activity of imetelstat. Evaluating adverse event, there were no new safety signals.
The cytopenias induced by imetelstat were reversible, and they were the most frequent adverse event. There is a trial that is ongoing. It's a phase III double-blind randomization 2:1. Next slide. With this currently enrolling study, we will be able to consolidate the data I just showed you. We have been busy, and we are busy, including patients that are a population similar to the previous one, so non-del(5q), lower risk MDS with transfusion dependency, more than four units in eight weeks, and HMA and lenalidomide naive. Here as well, the primary endpoint is eight-week transfusion independence, and the secondary, again, 24-week transfusion independence. Now, I think that we learned a lot from the phase II study, and we are very eager to see the final results of the current phase III study.
With this, I wish to go to the last slide and thank all the people who cooperated, the patients. My patients are very collaborative, and they are very eager to participate in these studies, and all the collaborators around the world. I thank you for your attention.
Thank you, Dr. Santini, for that nice presentation and overview. Suzanne, we will have some Q&As now, I believe, right?
If you have a question for Dr. Santini, please press star one. Chad Messer with Needham, your line is open.
Great. Thanks. Good morning, at least for me here. Very interesting that there's a nice subset of patients that are responding so well and for so long. Maybe two questions on that. One, can you put into context other treatments and things that are used for like luspatercept, for example? Are patients responding that long to other treatments?
It was also very interesting that there was some correlation with hTERT reduction. Did you look at baseline hTERT? In other words, is that a possible prognostic indicator for who may respond to this?
To answer your first question, of course, there are many studies focusing on this subtype of patients. The big unmet need of these patients, the low-risk patients with transfusion dependence, is they live longer, which is nice, but they need to find something that relieves them from transfusion. As far as my knowledge, there are not many studies, and I would say no studies that have shown such a long duration of transfusion independence. Sporadic long responders are found in many studies. I led a study with lenalidomide several years ago, and there are sporadic patients with long transfusion independence that can be seen as well as, for instance, in the luspatercept trial.
In this case, there is a good proportion of patients that do respond for a very long time. I mean, 30%, one-third of the patients are still responsive at one year. This is something quite indicative of the activity of the drug. Your second question was the on-target evaluation. Now, as far as I know, but this maybe it's more preclinical, there have not been prospective studies evaluating hTERT before treatment and then using it as a biomarker of response. Certainly, the signal we receive here with the 50% reduction of hTERT in the patients who do respond is quite interesting. I think a next step would be the one you suggested, to use it as a possible biomarker of response to the drug.
Great. Thank you very much.
If I may add to Valeria, since I already do both have of MDS and then myelofibrosis, the first question, I think as clinicians, we consider a transfusion independence of six months meaningful for the patient, like the duration. That is probably the bar that we look at for drug approval. For your question, for example, with all the current available therapies after ESA, with lenalidomide and non-del(5q), typically it comes to somewhere around 48 weeks transfusion independence. With the luspatercept, the median was like 30 weeks. Even with hypomethylating agents, all of them are really in the less than one year. So 88 weeks really looks very interesting and exciting.
Yeah. Yeah.
As I mentioned, it's sporadic, and then we are used to have something below, well, below six months usually, which is what we consider, as Rami just said, we consider significant because if you get a few weeks of transfusion independence for the patient, it's really not relevant.
Tom Shrader with BTIG, your line is open.
Good morning. Thank you for the update. I'm a little curious about your thoughts in the real world. How do you use a drug like this? If you look at slide 16, there are a couple of patients there that had a huge number of transfusions and then got pretty remarkable benefit from the drug. How do you decide who to keep on? Is it clear patients that are deriving nothing? It's really an interesting curve that they were almost a year with looks like no benefit, and then the drug started to work.
How would you use it in the real world?
It is also very much up to the patient. What I learned over the years is that with MDS, you don't have to be in a hurry. Very often, with several drugs, several types of drugs, you need to wait to see a response. Now, clearly, if the patient is progressing or is increasing transfusion needs, of course, that's another story. When patients do maintain a stable transfusion dependency, and then you may keep them with a drug that is not giving so many adverse events, I think that's the way to go and wait. When is a different story. When is a critical question, I would say. I have a patient just now. I can tell you that it's slightly borderline responsive, and he wanted to keep on being treated.
This is what we will do because probably it's a late responder. It's a little bit the same story also for ESAs. Some patients do respond very late. We, at present, don't know exactly why this is happening, but I suppose that it's something that we should elaborate on. In real life, what I would do is that I would surely stop the patients who either have increased transfusion need or absolutely no effect at all or even adverse events. For the other ones, I would keep, if possible, and if the circumstances allow it, for at least four to six months treatment.
The drug is benign enough that you think most patients would be okay with that, waiting half a year?
In my experience, I didn't get many important adverse events. Now, this is a trial, so it's a little bit different situation.
In real life, patients, it's difficult to say, but some patients will be okay if they know that the drug can give them an advantage in a substantial proportion of cases. If you explain in the beginning to the patient that they should come once a month to get this IV infusion because 50% or 60% of patients have had an advantage with a median, as you see, with a median time that is so that is not immediate, I suppose they will stay for it.
Okay. Great. Thank you very much for the color.
If I may add again, sorry. I think if you look at the median time to response was eight weeks.
Yes, there are some late responders, but in reality, most of the time on a clinical trial or real life, we'll probably be seeing some clinical benefit that there's some reduction that will make you continue the treatment. The other thing to keep in mind, anytime we are applying a disease-modifying agent, technically, or from examples of lenalidomide or hypomethylating agents, we always see worsening of the cytopenias actually in the first few cycles and then the improvement. In deletion 5q, where lenalidomide is the standard of care, actually cytopenia on therapy upfront predicts response. Upfront, you expect sometimes if there is a drug that's disease-modifying to have some cytopenia. To a lesser extent we see that with ESAs, for example. I would say the median time of eight weeks is very reasonable.
Probably what we do is at four or six months, if those patients who are starting to see some reduction in the transfusions, we continue. That is why you see some patients became transfusion independent completely almost at a 40-week.
Okay. Thanks.
And again, this is true for all the drugs for MDS, almost all of them.
If you'd like to ask a question, please press star one. Stephen Willey with Stifel, your line is open.
Yeah. Good morning and thanks for the update.
Maybe just a follow-up to Tom's question, and hopefully it doesn't sound like the same question, but just curious as to how you think about the difference between achieving transfusion independence and this notion of "clinical benefit." I guess when you treat these patients clinically, are you treating with the intention of achieving transfusion independence, or is a reduction in transfusion burden and some kind of erythroid response sufficient enough for some patients? I guess I ask the question because I know in the luspatercept data set, they showed very low transfusion independence rates in patients who had very high transfusion burdens. I believe when they updated their longer-term data, they showed a much higher proportion of "clinical benefit" occurring in these higher transfusion burden patients at baseline.
I guess I'm just trying to figure out to what extent either of those things matters more importantly to you as a clinician.
These patients here had the patients in the imetelstat trial had really a high transfusion burden, as you saw. Eight units in eight weeks means that this patient had one transfusion weekly, which is a lot. With the imetelstat, therefore, you have a severely transfused, I would say, patient group who gets a transfusion independence in 40%-42%. That is really an achievement. Now, is this clinically significant for the patient? Indeed, it is. Because if you talk to patients who are transfused weekly, their dream is to get rid of the transfusion and be free for a substantial period of time. Here, they had almost two years of transfusion independence.
That means that heavily transfused ones stopped coming to the hospital to be transfused. To me, this is really meaningful. Now, going back to the hematological improvement that here is nearly 70%, again, these patients may delay their transfusion, so they may delay their dependency on the hospital care and on transfusion. They would feel, I suppose, much better. At least this is what I hear from my patients, that instead of coming once a week, they come every two weeks, so once a month. That would be extremely significant for them. What is important is to talk to the patients and hear to them. Once again, to echo what was said before, t o me, it's indicating disease-modifying activity if I see that the duration of response is substantially long.
These patients have a decrease in the, I would say, in the burden of the disease, indeed. That is something I would call clinically significant. Talking also from the point of view of the patients. For me, from a more scientific and biological point of view, it is quite meaningful for the patients for practical reason and for their well-being and quality of life.
Okay. That is helpful. I guess if we see a replication of these results in the phase III and you have a patient who presents to you in the clinic with a high baseline transfusional burden, they are RS positive, do you start them on this drug or do you start them on luspatercept?
That is a difficult question to answer, but I would say that if the patient has, as usually it is, high platelets and no neutropenia, I would probably try to start with imetelstat.
Luspatercept is a very good drug. I would rather have luspatercept for patients who have lower transfusion burden, and for very high transfusion burden, would go for imetelstat. If these results are like that, you see the median transfusion burden for the luspatercept trial was five units, and here is eight. There is a bit of difference. I would go for lower burden for luspatercept and for higher burden imetelstat with normal count or near normal counts.
That's very helpful. Thank you. Maybe just one question for the company. You disclosed median duration of therapy from this phase II, but I'm assuming just given the long duration of responses here that something like mean duration of therapy is probably a more important statistic. Is that information that you have at all?
Yeah. That's from Aleksandra here. We've not disclosed that yet, but it's a good suggestion.
I think it's something we can certainly update. At other points, we were discussing even today with Dr. Santini, where just like the median duration of treatment just for the responders as well. These are a couple of things that we will be updating shortly and shared. It will be of interest. We understand that.
Great. Thanks for taking my questions.
There are no further questions at this time.
Okay. I would like to thank Dr. Santini so much for taking the questions as well. I would like now to move to our next speaker. That will be Dr. Mascarenhas, a prominent myelofibrosis expert for whom I actually don't know his introduction is needed. He is currently an Associate Professor of Internal Medicine at the Icahn School of Medicine at Mount Sinai in New York.
He has been involved in the development of imetelstat from the inception, I believe, from the phase II IMbark study. Most recently, over the past year or so, we have been working closely with him to evaluate all of our myelofibrosis data and discuss the design of the phase III trial in myelofibrosis that we expect to start next year. He will have two presentations today, and his first one will be on the biomarker analysis from the phase II IMbark portion of the study. John, would you like to take it from here?
Thanks, Aleksandra. I hope everyone can hear me clearly. My name is John Mascarenhas. I think I've met some of you previously when I've had the opportunity to present, and I'm honored to be able to come back again, and I've really enjoyed working with the folks at Geron.
I hope I convey my excitement on behalf of our co-investigators of the development of imetelstat for myelofibrosis because I really think this is the potential to be a game changer. I am saying that as an investigator, obviously not as a Geron employee. Please understand what I am trying to convey to you is sincere excitement about this drug. I was excited to hear Dr. Santini present in MDS, and it makes obvious sense because there is so much biologic and clinical overlap in MDS that you would see potential for disease course modification and improvement in important endpoint like anemia in low-risk patients. What I am going to show you today is in a related myeloid malignancy, myelofibrosis, the potential impact for a very urgent unmet need, which is survival, which we have talked about previously.
What I'm hoping to do is show you the link to biomarkers and on-target activity that makes this even more tangible and even more exciting, and I think brings it even closer to moving this forward. If you can give me the next slide, please. For those of you who just want to refresh, myelofibrosis is a clonal hematopoietic and progenitor stem cell malignancy. It is very closely linked to mutations that you see across myeloid malignancies, including MDS and AML. It involves malignant megakaryocytes that elaborate cytokines that induce fibrosis and scarring in the bone marrow and ultimately impair hematopoiesis. Anemia and thrombocytopenia can be prominent features of advanced myelofibrosis, as well as splenomegaly and other areas of organomegaly due to extramedullary hematopoiesis from inappropriate trafficking of hematopoietic stem cells that leave the protective bone marrow niche and set up hematopoiesis in other organs.
This is often a major manifestation and issue related to myelofibrosis, in which JAK inhibitors have been very successful in addressing spleen and symptoms which are thought to be related to cytokine overproduction by the malignant clone. This includes fevers, weight loss, night sweats, and a myriad of other symptoms. There have been many attempts to address the fibrosis, and the name of the diagnosis is myelofibrosis. Trying to address the phenomena of bone marrow failure that's related to the fibrosis has also been a translational focus of research. For patients with Intermediate-2 and high-risk myelofibrosis, in the U.S., we have two options that are available commercially: ruxolitinib and fedratinib. ruxolitinib since 2011, fedratinib since August of 2019. Both are excellent drugs. They address spleen and symptoms, but I would argue that, unfortunately, that's somewhat limited in what they do.
They do not really change the clonal nature of the disease. There really is very limited data that would suggest they change the natural history of the disease. The painful truth is that by three years, about half the patients have discontinued therapy, and by five years, over 75% of patients are off therapy. The effect of JAK inhibitors that we have right now, whether they are commercially approved or in clinical testing, is often limited in duration of therapy. When patients fail ruxolitinib, and multiple groups have shown this in analyses, the outcome is quite dismal, with a mean survival of approximately a year to a year and a half. Right now, there is really no approved therapy that effectively changes that. Let me restate that. There is no approved therapy. There is no experimental therapy that improves that.
That is why this drug, in its indication, is really quite exciting. Again, I'm hoping I'm conveying that to you effectively. There is unmet need. Therapies that can improve survival in patients who fail JAK inhibitors is really what we're looking for in the clinic because although improving spleen and symptom is important, when you fail a JAK inhibitor, many of the patients I have want to live longer. That is the primary goal. They do not want to die from the disease. Many of them may not be able to go to transplant, which is definitive therapy. Even those that want to go to transplant often need to be debulked of their disease process because there is a concept that patients that go into transplant with less disease are more likely to enjoy the benefits of transplant on the back end.
There is clear need for disease-modifying therapy, and I think that that speaks to the fact that we need a non-JAK inhibitor mechanism of action therapy, such as telomerase inhibition. You can see the stats on this slide. I think they're underestimated because I don't think we capture the actual incidence and prevalence of myelofibrosis well, but the estimations are that over 35,000 patients in the world have Intermediate-2 high-risk myelofibrosis by the International Prognostic Scoring System. In the U.S. alone, there's probably over 12,500 patients with an incidence of approximately 2,000 patients diagnosed a year in this high-risk category. Next slide. I know everyone on this call is familiar with the IMbark study, which was evaluating imetelstat in patients with intermediate or high-risk myelofibrosis who had failed ruxolitinib previously. This is the study schema for that study.
Patients were randomized to the study drug either at the high end of the dosing schedule at 9.4 milligrams per kilogram every three weeks or the low dose, 4.7 milligrams per kilogram every three weeks. The co-primary endpoint was spleen and symptom. The secondary endpoints were IWG responses and overall survival, and exploratory endpoints were cytogenetic and molecular responses. Of course, just to be clear, relapse refractory patients were defined as patients who had been on a JAK inhibitor previously, had worsening splenomegaly related abdominal pain at any time after the start of the inhibitor, and either no reduction in spleen volume after 12 weeks or worsening splenomegaly at any time after the start of JAK inhibitor therapy, documented either by nadir and then increased by 25% by imaging or, often more commonly in the community, increase in palpable spleen on exam. Next slide.
I think it's not needed for me to explain to you now what imetelstat is. Everyone here knows what it is. We are looking, and you'll see in these presentations, and I think it will speak to a question that was asked previously in MDS about perhaps biomarkers that show we're hitting the target and biomarkers that could actually have the potential to predict response. Those biomarkers of interest are going to be telomerase activity itself, hTERT expression level, and then particularly to MF would be driver mutation allele burden changes, for example, JAK2 V617F, as this is a marker, a surrogate marker for disease burden since we don't have imaging-like RECIST criteria for solid tumors. Short telomere length, high level of telomerase activity, and high expression of TERT levels correlates with higher risk and disease progression and shorter overall survival in patients with myeloid malignancies.
Cells with short telomeres, high levels of telomerase activity, and high levels of hTERT expression represent the best target for treatment with a telomerase inhibitor like imetelstat. The optimal pharmacodynamic effect of imetelstat has been defined as greater than 50% or greater reduction in the telomerase activity or hTERT level from baseline and is correlated with anti-tumor activity in preclinical PK/PD studies. The objectives of this study is to evaluate the on-target PD effect of the drug in relationship to dose, as well as exposure in MF patients treated on study, to assess the correlation of the optimal PD effect with symptom or spleen response, in my opinion, more importantly, with overall survival, and explore the association between baseline telomere length, hTERT expression level, and clinical benefits, as well as evaluate the change in allele burden, again, as a surrogate marker for changing the disease activity.
Next slide. Here, we're first looking at dose-dependent and exposure-dependent PD effects. If you concentrate first on the left-hand slide, what we're showing here is the % of patients who achieved at least a 50% reduction either in telomerase activity, which is the area on the left, the two bars on the left, or hTERT level reduction on the right. You can see it's color-coded. Blue is for the low dose and yellow is for the high dose, 9.4 mg per kg. As you recall, that's the active dose that we were going to move forward into the phase III study. In both cases, for both pharmacodynamic on-target activity, the high-dose arm achieved the PD effect of both telomerase activity reduction and hTERT level in a greater proportion of patients. That was statistically significant in both cases.
If you look to the right, we're looking at exposure-dependent pharmacodynamic effects. Again, this is the % of patients who have at least a 50% reduction in hTERT levels. The first two bars are looking at cycle one area under the curve, and it's stratified by low exposure versus high exposure. To the right, cycle one Cmax. Basically, what we're showing here is that a higher proportion of patients that had high exposure rates achieved higher PD effect in terms of hTERT attenuation. To me, this was very important to show because this shows that we are hitting the intended target and that it is directly related to the amount of exposure of the drug, very importantly. Next slide. Okay, how does that correlate to clinical response? What we're showing here is that if you look first, concentrate please on the left.
We're looking at the spleen and symptom improvement. Again, this is the % of patients who achieve optimal PD effect. PD effect, again, is defined as in the responders by spleen on the left and then symptom on the right. The patients who had a spleen response, so that's 35% spleen volume reduction, 100% of those patients achieved the PD effect versus 76% of the patients who did not. Nearly 100%, 91% of patients who had symptom response, that's a 50% symptom improvement by the TSS, also achieved an optimal PD effect. Again, suggesting that there's a correlation between hitting the target and getting those two responses. What I think is much more important, which I want you to look at on the right, is the survival curve. This is the patients who achieved optimal PD effect had a better overall survival.
That is shown with these two curves. If you look at the survival of those patients who achieved the PD effect, it was 27.2 months versus those who did not, it was 18.3 months with a hazard ratio of 0.54. This was, to me, in this presentation, probably the most important and most telling slide because here we are showing that it is not by chance, and it is not random that imetelstat was associated with an improved overall survival because it is hitting the target, and those patients that are hitting the target are more likely to enjoy that survival benefit. Next slide. Does it affect the disease in a meaningful way? This is an attempt to show by correlation with varying allele fraction of the driver mutations.
What I want you to look at in the table, and it is really showing the same thing, but look at the table first. What you will see is if you look at those patients who achieved a 25% or greater decrease in a driver mutation, this covers about 90% of patients with myelofibrosis that have driver mutations and are used as a marker for disease modification, that in each case, the higher dose arm had a greater proportion of patients that achieved it. These are very small numbers. If you scan down and say, "Of any driver mutation, what was the differential in effect?" you can see that 42% of patients who had any driver mutation achieved at least a 25% decrease in allele burden versus only 5.6%, one patient in the low dose arm.
Correlating dose with effect on the malignant clone, reduction in the malignant clone. If you recall back from the original paper in New England Journal of Medicine by Dr. Tefferi and his colleagues, there were even cases where he treated them perhaps more intensively with this drug of complete molecular responses. We do not see that with any therapy other than transplant in myelofibrosis where you can actually induce a molecular response of that nature. To me, this still speaks to the fact that we are modulating and we're hitting the malignant clone, not just killing off late progenitors. The graph on the right just graphically shows you what I'm also telling you. Next slide, please. What about patients if you segregate them by telomere length? Since it is a telomerase inhibitor, can this be a predictor of response?
This came up in the discussion previously with MDS. On the left, looking at the % of patients who achieved the response and then segregated by having either a shorter telomere length or a longer telomere length. Again, it is color-coded by dose. I would ask you to pay attention to the 9.4 mg per kg bars, that is the active dose. A higher proportion of patients achieved a response with shorter telomeres, and that is true for spleen as well as symptom. If you look at the right, if you look at baseline hTERT level, a higher proportion of patients achieved a response both in spleen and symptom if they had higher hTERT levels. Again, suggesting that there is a baseline biomarker that also can predict or associate with response in terms of these clinical endpoints. Next slide.
I would still argue, spleen and symptom is nice, but we're interested in overall survival in these patients who are unfortunately doomed to do poorly. This is really where imetelstat stands apart from the other therapies that you can see presented at the EHA meeting. Here, I would ask you to focus in on the right at the 9.4 milligram per kilogram arm. This is segregated by baseline telomere length in which the survival, although perhaps not statistically significant, is longer, and that curve sits apart from the patients who had longer telomere lengths at baseline. Again, trying to associate a biomarker for a mechanism of action of this drug with an important endpoint such as survival. Next slide.
In conclusion, imetelstat, here the data shows achieved dose and exposure-dependent reduction of telomerase activity and hTERT expression level, thus demonstrating on-target mechanism of action, very important, particularly for those, and I do not mean anyone on this call, but those naysayers who may say, "Well, this was a study initially that did not hit its endpoints of spleen and symptom, and the survival benefit could have been random." I would argue it is not random. It is not random at all because we are showing you that there is on-target activity. Achieving optimal PD effect as measured either by a greater than 50% reduction in telomerase activity or hTERT level in patients treated with imetelstat is correlated with clinical responses and longer overall survival. This really validates the preclinical PD findings.
That is, to me, very satisfying. Significant dose-dependent reduction in the granulocyte fractions of JAK2, CALR, and MPL mutations were observed.
This would indicate that imetelstat is actually modifying the disease at the basis, at the stem and progenitor cell level, very important because I believe that's why you see the survival benefit. I believe that's why even if you don't continue the drug indefinitely and you have a median exposure of eight months, 32 weeks, you get a survival that approaches almost 30 months. Treatment with the 9.4 mg per kg imetelstat dose improved clinical outcomes in patients with short telomeres and high TERT expression levels. That to me is very important because that, again, suggests that we're hitting what we should be hitting. The results are consistent with telomere biology in cancer cells. This really provides very important evidence for on-target mechanism of action through telomerase inhibition.
This is the first clinical report to systematically evaluate the mechanism of action based on PD effect of imetelstat and its relationship to exposure and clinical benefits. In my humble opinion, a very biased humble opinion, I was really surprised this did not get an oral abstract. If you look at the oral abstracts in the myelofibrosis studies, I think that they were modest, in my opinion, and this was much more exciting and addressed an unmet need that was unfortunately ignored by the symposium leaders that decided on who was going to present. That is just my opinion. I think that is it for me.
Thanks so much, John. Just as we moved through that Q&A session, now I'm sure there will be a couple of questions for Dr. Mascarenhas as well.
If you have a question for Dr. Mascarenhas, please press star one. Tom Schrader with BTIG, your line is open.
Thank you again. I have only one question. How do you use the drug? What I'm getting at is of the patients on JAK inhibitors, how many of them are on JAK inhibitors simply because there's nothing else to put them on? Are they all getting benefit kind of till the end? Would a drug like this increase your rate of taking people off a drug like ruxolitinib to get them the survival benefit? As a slight follow-up, does fedratinib fit anywhere in that equation?
Thank you. I think that's a really important question. Aleksandra and I, who spent a lot of time discussing this and planning the phase III and sort of thinking this through, have touched on these important points. Right now, patients almost across the board with Intermediate-2 and high risk, and even Intermediate-1 and some lower risk patients are getting JAK inhibitors, mainly driven by spleen and symptom, but in some cases, because they have the diagnosis and there are no other approved therapies, and in the community, that just might be prescribed because it's prescribed, because it's available.
I think the reality is when you do not have other available options, you tend to leave patients on that therapy as long as possible until they have "failed it." That definition is very different for different patients depending on the clinical context and the treating physician's perception and the patient's perception. In a clinical trial, obviously, you have to be quite rigorous and uniform in how you define things. In clinical practice, I would venture to believe that if, for example, the phase III study, which I am very optimistic will be a positive study, and if this drug is then available clinically, I do not think that the thought process for many patients or physicians for that matter would be to wait for patients to really fall apart, which is what happens eventually.
For example, I saw a patient yesterday who's been on ruxolitinib now for six years, and he really had a terrific response for four and a half of those six years. His spleen is progressing, his symptoms are progressing, his counts are declining, I can see blasts circulating. His disease is getting worse. He's either going to go to transplant or he's going to go on a clinical trial. If imetelstat was available, it would undoubtedly be my choice. Even if he was going to go to a transplant, it would be a bridge to transplant. Even in the absence of a transplant, it would be the drug.
If I saw a patient starting to fail, if I had a commercially available drug, I wouldn't wait for them to fail worse because we know in this disease, the longer you wait, the harder it is to salvage the situation and improve the outcome. I think the clinical use would be likely broader than the clinical trial criteria. I hope that answers the question.
Does fedratinib matter? Do you believe there's treatment data?
Yeah. I think fedratinib matters in the sense that at least in the U.S. right now, it is available agent. The data really from JAKARTA-2 supports the use of giving fedratinib as a second-line JAK inhibitor treatment for patients who are losing a response to ruxolitinib. I think it is a drug. My feeling is fedratinib is a good drug. Perhaps if fedratinib got out before ruxolitinib, fedratinib would be first and ruxolitinib may be second. There are differences in tolerability. There is more GI toxicity with fedratinib, so that has to be considered when giving it to a patient. I think the decision-making is going to be one of what is the treatment goal in any individual patient.
If I had an 85-year-old patient where the treatment goal was to address maybe discomfort in the left upper quadrant from splenomegaly and early satiety, that may be a fedratinib patient to use. If I had, for example, the guy I saw yesterday, a pretty robust 63-year-old, and now as I get older, I do not see 63 as old, I would treat that patient with imetelstat because the goal there is to try to have a more profound effect on the disease. One could always use or leave fedratinib for a later time point. I think that was one of the interesting things that we saw from the IMbark study was you do not need to necessarily get imetelstat endlessly. For example, and Dr.
Santini will appreciate this as well as Rami, when you give azacitidine for MDS, you continue to treat through the response to maintain the response. I'm not convinced you need to do that with imetelstat in myelofibrosis, at least for the endpoint of survival. One could imagine that, for example, if cytopenias became an issue, and I think they're manageable with imetelstat, and if anyone's going to ask me the question, I'm going to answer it now, it is a drug that can be delivered in the community because these are therapies that community hematologists would be comfortable with on a three-week to four-week basis and manage the cytopenias.
Let's say cytopenias were to become problematic for any given individual, one could imagine then going on to fedratinib, an oral drug after that, potentially enjoying the benefit of the survival benefit and disease course modification benefit, but then go on to get imetelstat, to go on to get fedratinib. I think fedratinib would be used in certain situations, but I think for many of the patients where survival is really the focus of ruxolitinib failure, I think imetelstat would be the choice.
Yeah. Great. Thank you.
Charles Duncan with Cantor Fitzgerald, your line is open.
Hey. Good morning. Thanks for taking our questions. I had a couple of questions for Dr. Mascarenhas. Very interesting data for target engagement that supports differentiated mechanistic rationale for the activity of imetelstat. I'm wondering if you would see these biomarkers as useful in the clinic in the future for predicting response, or is that even needed in the two different patient cohorts that you outlined that may be best used or exposed to imetelstat, those being patients who failed JAK inhibitors or those in which you're trying to debulk before transplant? Is this data that you'd like to see translated into, say, a prognostic indicator?
That's an interesting question. I think to me, the data is most important because it supports the idea that the drug is hitting the target of interest and that we're correlating that with outcome measures. I think if I were to see this drug approved and commercially used, I'm not actually sure I would want to advocate for biomarker-driven use of the drug because my fear would be you may miss the opportunity to actually have a beneficial effect in patients that may not "have the biomarker of interest" because although the association seems to be more robust with short telomeres or high TERT expression, there is still the potential to have benefit from this drug even if you don't have those clear biomarkers.
I think it's great in the context of developing the drug and proving a point, but I think a lot more work would have to be done in feeling comfortable as a commercial assay to drive use of the drug. Again, to make a parallel, perhaps unfairly in MDS, we don't really use methylation status to determine whether we're going to treat with azacitidine. We don't use DNMT3A mutation status. We treat irrespective of that. I don't think it would be incorporated in a commercial setting, but I think the phase III study would also give us a lot more information, confidence, and insight in the use or utility of those. I don't think—sorry, I didn't answer the last part.
If I were to segregate the patients who were simply trying to improve outcome versus a bridge, I don't necessarily think there would be a difference or utility in incorporating biomarkers in those two settings.
It seems like pretty provocative data has been shown thus far in IMbark and with a differentiated mechanism and now this biomarker data that suggests that it's clearly the result of the drug. I guess I'm wondering why you think it wasn't selected for an oral presentation. Is there any bias against the mechanism or anything?
No. No. I don't think there's any bias. I would venture to guess it's the same reason for any meeting, for any abstract, in which politics and friendships and global politics perhaps play a role. I don't think it's anything personal against Geron or the drug. Perhaps the selection committee was overwhelmed by COVID at the time. It's too bad for them that it wasn't an oral abstract. Most importantly, I'm forward-looking into getting the phase III out there because I think that's where it's going to go. I can tell you that there's true excitement regardless of whether it was an oral abstract. I've gotten a lot of phone calls and emails from physicians who are following this, actually even patients in the community that go online. Actually, it's interesting, I presume the MDS community is the same.
There's a lot of patient engagement, patient advocacy. There is a lot of excitement in the patient community, in the physician community, obviously in the investor community to see this move forward. Despite the snub, which we will not take personally, I think that the abstract was well received.
Okay. The debate, it seems like in the community regarding the value of the clinical outcome being improved survival versus symptom improvement is not really the driver in this case.
No. I do not think so. Just to emphasize, we had a meeting, a patient-driven meeting with the FDA. I think it was either September or October of last year where stakeholders from pharmaceutical companies, clinical investigators, patients, and the FDA were present. A lot of the discussion revolved around what is meaningful to patients and what should be meaningful outcomes, particularly as it relates to JAK inhibitor failure. If you go back to the transcripts of that meeting, what is really important to take away is that although spleen and symptom are important, they were endpoints that were created years ago, and I remember well because it was created during the development of the registration study for COMFORT, and it stuck. For JAK inhibitor-based therapy, it makes sense.
If you are now failing a JAK inhibitor, spleen does not always tell the whole picture for any given individual or even symptom burden for that matter. Survival is important, and patients will tell you that. Physicians obviously want their patients to live longer. To me, the debate, it really is not much of a debate. I think patients want to live longer. Just to lastly reemphasize is that I do not mean to—I do not mean to underestimate the benefit to spleen and symptom by imetelstat because 30% of patients hit that endpoint, actually, of 50% improvement. That is not shabby second line, even for a JAK inhibitor. Although 10% of patients hit the 35% spleen volume reduction, I think 25% or more hit 10% or more reduction. We now know that there is nothing magical about 35%.
Even if you reduce the spleen by a small amount, patients feel benefit from that. There is spleen and symptom benefit, but it's a survival benefit to me that's much more exciting.
That's helpful. Thank you for taking my questions, Dr. Mascarenhas.
Sure.
Andrew D'Silva with B. Riley, your line is open.
Yeah. Thank you for taking my question. I just have one. Just really curious if you thought the enrollment criteria for IMbark favored patients with a shorter baseline TL, or is there a way to stratify the phase III population anyway or have a patient population that more heavily favors a shorter-length patient population? I was also just curious, was there any correlation with triple-negative patients and them having a shorter baseline TL?
I think that what's really important to look at for the population that went on to IMbark was these were truly ill patients. This was not a cherry-picked population. These were patients who had, majority of which had a high molecular risk mutation, who were anemic, who had high DIPSS scores. These are the patients who don't do well. I think that they went on the study because, particularly at that point, there was a lot of excitement that this was a non-JAK inhibitor-based therapy and that the results of the original pilot study were very fresh in people's minds. There was really a lot of interest in taking these patients that were very ill after Ruxolitinib failure and putting them on drug. Now, whether that by itself selects for patients that are going to be enriched for short telomeres, I don't know.
I don't know the answer to that. I'm not sure. I won't even guess at that. I'll leave it to Aleksandra or other folks to speak about the association of telomere length and triple-negative. The triple-negative patients, if you recall, were really—they're the bad players. We knew that before the study started. They have a median survival of about three years. They particularly do poorly. They were also enriched in this study. I think they were enriched only because those are the patients who do poorly and come off ruxolitinib more frequently and come off doing very poorly. Those patients did particularly well with this drug, in which we have no therapies necessarily for JAK2, for JAK2 wild type, MPL wild type, calreticulin wild type patients.
That triple-negative population is also an area of interest that Aleksandra may want to speak about in terms of further clinical evaluation and development and perhaps the association with telomere length.
Yeah. Thanks, Dr. Mascarenhas. I would suggest that maybe we defer the triple-negative question and the length of telomeres after the presentation from Dr. Komrokji, if that's okay.
Yeah. No, that works for me. Thank you very much.
I think that will be okay. Okay. Sure. Thank you.
Stephen Willey with Stifel, your line is open.
Yeah. Thanks for taking the question. Just a quick follow-up. I guess, Dr. Mascarenhas, what's your thought on this notion of treating suboptimal RUX responders with add-on therapy, right? You gave the example of the patient who came in and they started to deteriorate after four and a half years. Is that the kind of patient that you would think about add-on therapy to RUX to try to salvage, or do you think that that patient is just too far along in his course of disease to be salvaged? Is this notion of suboptimal response something that you see playing out in the clinic within a year post-RUX initiation? Is that for early salvage patients or late, like I asked before? Thanks.
Yeah, we do see suboptimal. Suboptimal really means you're not hitting the "endpoints" that were regulatory endpoints. It's a continuum. You have some patients that are truly suboptimal. They still have a significant symptom burden. They still have a large spleen. It's very unsatisfying for the patient and the physician. Those are patients in which I would say would fall in the camp of either switching therapy or adding on therapy to see if you can salvage the response. Adding on, one could envision, and one would have to obviously do a study to justify this, one could envision adding imetelstat to ruxolitinib and considering that there may be overlapping myelosuppression, but that would be a very interesting combination.
Right now, there are a number of different trials with either PI3 kinase inhibitors, BET inhibitors, and BCL2 inhibitors trying to capitalize on patients who may not meet the regulatory endpoints. Within those types of patients, there are definitely patients you see, and you see them within six months that have a totally inadequate response to ruxolitinib. Those are the patients where I'm seeing them, I start to already discuss and prep them and set expectations that if we're not having success, usually by three months, but definitely by six months with RUX, we have to decide for that patient if it's a quick move to transplant, if they're transplant eligible, if it's a quick move to an add-on strategy with an experimental drug or even a commercial drug, typically experimental, or if this study allowed, it would be a quick move to imetelstat.
I think it would be patient-specific. It would be context-dependent in terms of what's actually driving the patient's suboptimal response. You do see those patients. For a point of clarification, I think Aleksandra is going to speak to this when she discusses the phase III study. We are looking forward-looking. We're looking at patients who are refractory, who are truly refractory. Those patients we think are not really going to benefit from another JAK inhibitor. We could debate that.
I think that the idea is that we're taking the worst of the worst, the patients who don't really have benefit from a JAK inhibitor, saying, rather than trying to add something to it or rather than trying to switch them for another JAK inhibitor in which the expectations would be low for a JAK inhibitor refractory patient, we are going to try to give them a non-JAK inhibitor-based therapy because these patients are destined to do poorly. That's very helpful. Thank you.
Chad Messer, your line is open.
Great. Thanks for taking my question. Thank you, Dr. Mascarenhas, for your presentation and insights. Rest assured that your enthusiasm for imetelstat and MS is coming through loud and clear. I think we're asking the right clinical question and focusing on JAK failures with this drug right now. Just wondering about your thoughts on the prospect, given that we have a differentiated mechanism of action that's disease-modifying, whether ultimately, some point out in the future, you would see a use for imetelstat in earlier-line patients, perhaps in combination with the JAK inhibitor, or JAK inhibitors do work very well for a lot of patients. Do you think they're too entrenched for that to ever happen?
No. I think there could be a world in which, let's say if the phase III study is a positive study, the drug is available commercially, even in the absence—not that I'm advocating for it—but even in the absence of the label, I would bet that in certain patients, you're going to see imetelstat used even earlier in the disease course, particularly in patients where the physician—and I know, for example, Rami sees a lot of MDS and MF patients—where there's comfort level and understanding of the potential for imetelstat to address anemia and MDS. To me, there's a significant overlap in biology and even clinical features of the two diseases. Although there are clear distinct differences, there is similarity.
One could imagine evaluating this drug, and I would advocate for evaluating it formally in a clinical trial earlier on in the disease course because anemia in MF is also an unmet need in which luspatercept is also being explored and has phase II data for 30% anemia responses in combination with ruxolitinib. The majority of the patients do not get that response. Many of the patients lose the response eventually. Luspatercept does not affect the disease probably beyond erythropoiesis maturation. I could see this drug being used earlier on. For example, patients who present, maybe 25% of them present for therapy and they are JAK inhibitor naive. In those patients, although there is data that ruxolitinib can afford those patients spleen and symptom benefit, we know often that the anemia gets worse.
One could envision a situation where the drug could be introduced earlier in the disease process.
Thank you. Very helpful.
There are no further questions for Dr. Mascarenhas at this time.
Thank you, Dr. Mascarenhas, for now. We'll come back to you again with the last presentation that we have planned for today. I suggest that we now move to our third speaker, who is yet another renowned expert in hematologic myeloid malignancies. You may remember Dr. Komrokji from last year's KOL event, just like Dr. Mascarenhas from the one in 2018. Dr. Komrokji was presenting the collaboration project on the RWD analysis from the IMbark study last year. He is the Section Head of Leukemia and MDS at the Moffitt Cancer Center as one of the leading cancer centers in the United States. We continue to work with him on multiple avenues in both myelofibrosis and myelodysplastic syndromes. He will be presenting the triple-negative abstract that we have for EHA here. Rami, would you like to take over?
Sure. Good morning. Thank you for the kind introduction. I'm glad to be back again. I was hoping it would be a New York live, but this is actually working nice. I'm going to focus particularly on the triple-negative. This question already came. At this abstract in EHA, the goal was to look at the subset of patients that are triple-negative. This is from the same study, from the study looking at patients with triple-negative disease. Next, please. I think Dr. Mascarenhas set the stage very nicely about the disease background, the imetelstat. What I'd like to cover is really a little bit more about that triple-negative patient. That's a term we currently use for patients that lack evidence of any phenotype driver mutation, the JAK2, the CALR, the MPL. We call them triple-negative.
That subset of patients have a worse outcome, unfortunately, with median overall survival reported in the range of two and a half to three years in our database, 30-month survival from time of diagnosis, actually, for those patients. There is a little bit of challenge in making the diagnosis in those patients. Sometimes they are missed. Sometimes patients with MDS with fibrosis or MDS/ MPN, there is a lot of overlap. That group is really challenging in terms of diagnosis and management. As discussed also, allogeneic stem cell transplant is the only potentially curative option. However, it seems also that those patients that are triple-negative have worse outcome with transplant. This is clearly a group with unmet need in terms of improving the overall survival for those patients as well as the response. Also, scarce data from JAK2 inhibitors. They do not do well with the JAK2 inhibitors.
The responses could be less. The duration of response could be less as well. In this abstract, we tried to focus on the triple-negative patients to look at the responses with imetelstat among that group. Next, please. This is the study design already discussed. The only thing I would like to highlight or add probably is that many of the studies you look at have included patients that are intolerant to JAK2 inhibitors, which in my mind, sometimes you see higher responses in those groups because that intolerance a little bit is more subjective. Those were truly relapse or refractory patients. That goes back to the question that was just asked. I think of patients into groups of primary refractory, no clinical benefit at all, loss of response, or secondary failure, or intolerant. Those studies with imetelstat were really including patients that were either primary refractory or relapse.
Every time you included patients that are intolerant, you diluted or the responses would probably look higher. Probably those are the ones that can be sometimes with suboptimal response. Next. When you look at the study here, if you look at all the patients included, around 25% of the patients or 26 patients out of the 105 patients were what we call triple-negative. They lack a JAK2, CALR, or MPL mutation. Obviously, this is a little bit higher than what is reported in general in myelofibrosis. That reflects the point Dr. Mascarenhas brought, that the study was enriched by patients actually that are higher risk and not doing well in general. Next, please.
If you look at the response rates and to focus on the 9.4 milligram per kg dosing, if you look at the spleen response among patients that were triple-negative, it was around 19% compared actually to 7% in the non-triple-negative. The symptom improvement was seen in half of those patients with triple-negative. Again, there were more clinical activity, spleen, and symptom response in patients with triple-negative disease. Next. What's very interesting to me is looking at the survival among those patients with triple-negative. If you focus again on the 9.4 milligram dosing, the median overall survival for those patients with triple-negative after JAK2 failure was 36 months. That was statistically better than the non-triple-negative, which was 24.6 months. Just to remind you again that even in the non-triple-negative, this is an improvement.
The benchmark we are looking at is really somewhere around 14-18 months survival after JAK2 failure. The non-triple-negative seems better. What's interesting is that also the triple-negative is more. As I just mentioned to you, typically we expect two to three years survival with the triple-negative from time of diagnosis, not JAK2 failure. In our database, it's around 30 months survival from time of diagnosis. This, to me, looks interesting that the triple-negative even did better than the non-triple-negative, keeping in mind again that the non-triple-negative did better than the historical outcome after JAK2 failure. Next, please. In line to what was mentioned, we think of fibrosis as a surrogate marker for the underlying biology of the disease. There have not been many agents that change the fibrosis on the bone marrow.
Some of the new models, like the MIPSS70+ , incorporate the degree of the fibrosis as part of a prognostic factor. When you look at those patients that have triple-negative disease, you can see that the grade 3, which is the most severe or extensive grade of fibrosis, the rate was higher at baseline, 94% versus 66%. When you look at the improvement, which is defined in the study as a grade or more, 50% of the patients in the triple-negative compared to 39% had a grade or more improvement in the fibrosis. Again, we rarely see fibrosis improvement anecdotally with the JAK2 or in a small subset with the JAK2 inhibitors after very long follow-up. You see some improvement.
We tend to think of it as a surrogate marker for changing the underlying natural history of the disease or the surrogate marker of biological response for the treatment. Next, please. This was covered. When you look particularly at patients that are triple-negative, you do observe that those patients had shorter telomere length at baseline, 79% versus 46%, as well as higher level of the hTERT at baseline. Maybe explaining a little bit more why we are seeing higher responses or better overall survival. As Dr. Mascarenhas just nicely showed us, there is correlation with the PD effect with the overall survival in those patients. Next, please. I think in conclusion, that we see in this study that the patients that were triple-negative did much better than we expect after JAK2 inhibitors with imetelstat.
The study included around 24% of patients that were triple-negative. We see a survival signal of 36 months again compared to two or three years from baseline of diagnosis. This is after JAK2 inhibitors. We see higher responses among patients that were triple-negative, correlation with some higher grade of fibrosis, shorter telomere length, and higher baseline, and some improvement in the fibrosis among those patients. Definitely, it's worth for the patient looking at that subset of patients that probably may be driving less benefit from the JAK2 inhibitors from the get-going. I'll stop here and I'd be happy to take any questions.
At this time, if you'd like to ask a question, please press star one. Andrew D'Silva with B. Riley. Y ou're line is open.
Yeah. Thank you very much. You did answer my last question there at the end. I'm actually just curious. In IMbark, it was noted that it was a little bit more heavily weighted to the triple-negative patients than necessarily the typical MF population would be. As you look at the enrollment criteria now for the phase III trial, it is slightly different than IMbark. Could you maybe discuss your thoughts on that and if you think it would more heavily favor triple-negative patients than IMbark would have?
Right. I think there will be first discussion of the phase III design. It is not going to be, obviously, exclusive for the triple-negative, but it will include those patients. In general, if you look at all myelofibrosis patients, the triple-negative patients are around 10% of the primary fibrosis. The study was 24%. Partly, as we mentioned, because probably those patients do not do well on JAK2 inhibitors. There is really not much data on the responses with the JAK2 inhibitor in those patients or the duration of the response. As I mentioned, the benchmark, the survival for those patients is somewhere around two to three years from time of diagnosis. I can tell you in our database that the responses to those patients with JAK2 inhibitors are less than the non-triple-negative. The duration of response also could be less.
I think naturally, anytime we're going to look at refractory or relapse JAK2 population, we are going to see some enrichment. I don't think we should restrict the study to that group particularly because I think there will be a survival benefit probably also in the non-triple-negative, and that's the majority of the patients. I do think that the triple-negative could be an opportunity to think, answering an earlier question, moving this earlier even in the course of the disease. This is a group that has only two years survival advantage. You could think in the future of looking at those patients upfront, particularly if the responses to the JAK2 inhibitors are low. In my experience, those patients also tend to have more cytopenias that sometimes preclude use of JAK2 inhibitors.
I would envision down the road a study in triple-negative patients as an upfront strategy for JAK2 inhibitors. I think we covered a little bit more of the design of the phase III. By nature, there will always be some more investment than the baseline 10% in those studies because those patients do not do well with the current standard of study at all.
That's very fascinating. Thank you very much.
I was just wondering, John, because he'll be the PI of the study and also has been working very closely with us in the design. John, you have anything to add to this question, maybe?
I mean, I absolutely agree with Rami. I just want to stress the point that what was, at least for me, somewhat unexpected finding was that this really poor prognostic molecularly defined group actually did well with this therapy. Not to suggest, as Rami pointed out, that the non-triple-negative patients did not. The phase III study will take refractory patients in which my assumption, as Rami put out, is it will incorporate or include triple-negative patients. The benefit of this drug, I think, is irrespective of the mutational status of the patient. Encouragingly, in the worst of the worst, you get responses that are totally unexpected and without any other obvious therapy. I would look forward to seeing what that subset that gets enrolled in the phase III study does in terms of their survival outcome.
I'm looking forward to enrolling patients regardless of their mutational status that meet that refractory definition that Aleksandra will go over at the end of this discussion because it's really those patients that really are this unmet need that are probably the worst players and are probably most likely to see the benefit, particularly in a randomized fashion, of this study drug.
Again, if you'd like to ask a question, please press star one. Stephen Willey, your line is open.
Yeah. Thanks for taking the question. Maybe just to follow up or clarify, and I apologize if I missed this. The triple-negative genetic signature that was shown in the presentation and the correlation to shorter telomeres and higher hTERT expression, is that a consequence? Is that a fundamental consequence of mutational burden in these patients? Or is that just a consequence of the fact that there was a small number of these patients in the phase II?
I don't think we know exactly. I think what we know is that, obviously, those patients lack a phenotypic driver mutation. They tend to have worse outcome. It seems that there are some clinical features for them. They tend to be more cytopenic, more anemias, more leukocytosis. They do have more severe fibrosis on the bone marrow. In this study, I think this is the first time that actually people have looked at the baseline telomere length and telomerase activity, to my knowledge, in that subset. It seems that they do have shorter telomere length, higher hTERT activity. That correlates with the data that Dr. Mascarenhas presented, showing that there is some good correlation between hitting the target PD and the overall survival.
It makes sense that this population will drive more survival advantage because it seems that maybe the telomere length and the hTERT activity is one of the main biologic derivatives of the disease in the triple-negative. To be honest, in my mind, that group is sometimes very difficult to diagnose. That will mean that the implication for this, for me, could extend beyond this because we have a large group of patients we call MDS with fibrosis that really share a lot of features of this triple-negative. Actually, some people think that triple-negative should be a separate entity by itself. There is a group of patients that have MDS MPN with some fibrosis. I think it would be important that we go and start looking at those patients, MDS with fibrosis, see, look at the telomere activity and the hTERT.
That may open the door for a group that also has unmet need for treatment, MDS MPN the same. For me, that is the interesting part. That category is evolving. Now we are starting to see that there could be different biology there. At least on this study, when you look at the baseline mutations other than the phenotype driver mutation, there was no difference in the triple-negative versus the non-triple-negative. There is not much there. We are trying to look at that actually as we speak.
Okay. That's helpful. Lastly, do you have information on the duration of prior RUX therapy in these triple-negative patients prior to enrolling into IMbark?
I have to call the number, but it was the same probably. There was no difference in the baseline characteristics between the triple-negative and the non. I do not remember the exact duration, but it would probably be somewhere two years, something plus. Aleksandra can correct me. There was no difference between triple-negative and non-triple-negative in the duration of exposure.
Right. It was approximately 23 months for both triple-negative and the non-triple-negative patients on the study. Yeah, Rami, you're right.
Great. I think that helps to put some of the OS data you're seeing in perspective as well. Thank you.
Valeria, you're trying to add something. I don't think we heard you. I think the voice is gone.
Dr. Santini, are you on mute maybe? We cannot hear you. Maybe the moderator is. You can unmute, Dr. Santini. No. I do not hear you.
Hello? Do you hear me?
There you go. Yes.
Okay. Okay. No, it's just that I agreed completely with what Rami just said. We have an urgent need and a very unmet need in MDS with fibrosis. These patients are more than we thought about. These patients share a lot of features with MF, as it has just been said. We do not have any therapy really active in this subtype of patients. HMAs are not really active when you have a high degree of fibrosis. We are left with almost nothing. Therefore, it matters that, especially for the data we just saw, it's highly suggestive of working in MDS with fibrosis as well. I would be really happy to use in these patients and see how the burden of disease and how the clonality goes down in these very, very, very difficult subtypes of patients. Very well, think about it, really .
It's really something we do not have any trial going for. Thanks.
Thank you, Dr. Santini, for that commentary as well.
Charles Duncan with Cantor Fitzgerald, your line is open.
Hi. Thanks for taking my question. This question may be for Aleksandra or going back to Dr. Mascarenhas as PI for the phase III trial. I guess I'm wondering if you would look for, in the conduct of the study or statistical analysis plan, there to be at least a secondary analysis that would pull out the triple-negative patients from the overall cohort. And then what percentage of the patients in the sample would you anticipate to be triple-negative? I imagine it's consistent with population generally, but what would that be?
Yeah. I think the.
I think the.
Sorry. I think the percentage of the triple-negative is going to be the same, probably 25% or so or 30%, which will also still allow us probably to look at the survival among that group. As I mentioned, as baseline, upfront newly diagnosed patients is 10%. Any study after JAK2, it will be higher.
I can just add to that that we will definitely pre-specify that analysis in the statistical analysis plan for the studies to look specifically for the triple-negative patients within the overall study population of refractory MF.
Okay. That's helpful. Thank you. Dr. Mascarenhas, you assume that it's post-JAK inhibitor. It may be around 25% or so.
Yeah. I agree with Rami. I think we're going to see similar numbers in the phase III study because these are the patients that unfortunately don't fully enjoy the benefit of JAK inhibition or are more likely to "fail" or be refractory and are in need of a disease-modifying therapy. My guess is it will be very similar. Just to reemphasize, when we enrolled to IMbark , we weren't enrolling based on molecular features. That was really just what came through the door. I suspect it'll be the same population going into the phase III.
Okay. Thanks.
There are no further questions at this time.
All righty. Thank you. John, I'll hand it back to you again to give an update on the overall survival data and the correlations with other clinical benefits from IMbark—sorry, from IMbark. I apologize—from the MF study.
Thanks, Aleksandra. I am aware of time, so I'll keep this moving. Here, we're going to talk about favorable overall survival that correlates with other clinical benefits, which I tried to allude to in the discussion previously. Next slide. Everyone here knows the study schema. There's really nothing more to say about the study schema. Next slide. Everyone knows the drug is imetelstat, and we're excited that we seem to be hitting the target that seems to correlate with the disease outcomes that are important, like spleen, symptom, and overall survival. We know that patients do poorly when they fail ruxolitinib. We know that the improvement in overall survival is seen with the 9.4 mg per kg on, and it is clearly better than what you would see from real-world data controls from multiple studies, including Dr. Komrokji's study.
Here, we're going to evaluate the association between overall survival and spleen volume reduction at week 24 as well as total symptom score reduction and fibrosis improvement. Next slide. Here, we're showing the overall survival at the active dose, 9.4 mg per kg. This is the updated analysis. You can see that the mean overall survival, when you compare the two arms in the low dose, is 19.9. I still think that's better than what you would see normally with patients who come off ruxolitinib versus 28.1 months in patients who got the active 9.4 mg per kg arm. If you look at landmark time points, like 12 months, the survival difference is 78.6% versus 84%. Perhaps even more impressively, at two years, it's 42% in the low arm versus 57.9%.
If you were to censor—and we did this in the initial analysis—if we were to censor for patients who went on to get transplants or other subsequent therapies, including JAK inhibitors, or patients who were on the low dose who had the opportunity to dose escalate to 9.4 milligrams per kilogram, it did not change the fact that the survival benefit was different, was improved with patients who got the high dose. Next slide. Here, we are pairing up everything. The point of this slide is to show, to impress upon you that there is benefit across the board when looking at any one of these rows in the high dose versus the low dose. If you are looking at survival, again, 19.9 versus 28.1 months. If you are looking at symptom response, 6.3% versus 32% symptom improvement.
I will just reiterate, the 32% TSS 50% reduction is quite good, actually, for second line, even for a JAK inhibitor. That is not to be minimized. Spleen responses, we are not there at the low dose on, but in 10% of the patients, they had a 35% spleen volume response. The progression-free survival was also better, 14.8 months versus 20.7 months. If you were to use strict IWG criteria for clinical improvement, which includes symptom, anemia, and spleen, it was 16.7% versus 25.4%. If you look at transfusion independence, not the primary endpoint or goal in this study in myelofibrosis of 12 weeks or longer, it was 14.3% versus 25%. Reduction in bone marrow fibrosis, which was done centrally, is at least one-grade reduction was seen in 20% versus 43% in the high dose.
Importantly, and I stressed in the previous presentation, allele burden reduction of 42% in the high dose versus 5% in the low dose. In every aspect, no matter how you cut, slice, or dice the data, there seemed to be a dose-dependent benefit in the high dose. Next slide. If you look at overall survival and you look at the effect of degree of fibrosis improvement, going from having at least one-grade reduction in fibrosis versus a worsening of fibrosis, there was an improvement in survival and reduction in hazard ratio for death. That was statistically significant. Although not statistically significant, still, there was a trend to improve survival in those patients who had stability in fibrosis versus worsening of fibrosis.
Again, making the point and what Rami has shown that affecting fibrosis as a biomarker just like affecting JAK2 mutation allele burden also correlates with improved outcome of overall survival. Next slide. If you look at symptom improvement on the top, if you have a 50% or greater symptom improvement, again, appears to correlate with improvement in survival. That also makes sense to me because symptoms is also mediated by cytokine expression. Patients who feel better tend to do better overall. Whether you have a spleen improvement, and here, it's broken down by degree of spleen improvement. You can see there's a stepwise correlation, improvement correlation with survival.
If you have a 35% versus not versus a 20% versus not versus even a 10% versus not, you have the plot on the left side of one, which would suggest that there's a survival benefit in all these cases. Next slide. If you look at clinical variables that we know are associated with poor prognosis, for example, having a higher risk score, having a higher baseline neutrophil count, having anemia versus not having anemia, having a lower platelet count versus a higher platelet count, being transfusion dependent versus not being transfusion dependent, what kind of response you had to a JAK inhibitor prior to imetelstat, across the board, it favors you have a survival benefit irrespective of those clinical variables that are associated with poor outcome. It was not like it was one patient characteristic that was driving the response with imetelstat.
It was seen nicely throughout all the different clinical variables. I think that slide is a very important one to consider because it gives me confidence going forward in the phase III study that we're not missing some subset of patients that the phase III will exclude for some unknown reason, that this is going to be this should be a benefit that you're going to see no matter how you look at the patients or how you divide them by risk. Next slide. In conclusion, imetelstat shows dose-related improvement in survival in patients who are relapsed or refractory to JAK inhibitor. That survival benefit is observed and is supported by trends of correlations with other clinical benefits like spleen and symptom, like allele burden reduction and fibrosis reduction.
With a median follow-up of 41.7 months, the median overall survival is 28.1 months in the 9.4 milligram per kilogram arm versus 19.9 months for the 4.7. I'll just remind you again, 12-14 months in multiple historical controls, so much better. Among 57 patients across both treatment arms that had matching bone marrow samples, 20 patients, which is 35%, had one degree or better bone marrow fibrosis improvement while on study and had a significantly longer overall survival than those who had worsening. Again, correlating biomarker with an important outcome like survival. A similar trend was seen in patients who had stable disease versus worsening fibrosis. Patients who achieved symptom and spleen response at 24 weeks also showed a trend for longer overall survival compared to patients who did not.
Pretreatment DIPSS score, ECOG performance status, transfusion dependence, response to the last JAK inhibitor, baseline neutrophil count, lower hemoglobin, and platelet values, all poor prognostic variables, correlated with increased risk of death but did not drive—not one of these particularly drove—the outcomes that were seen across the board. That is the end of this presentation. Thanks.
Do we have any questions for Dr. Mascarenhas?
Again, if you'd like to ask a question, please press star one. Tom Schrader with BTIG, your line is open.
Thanks again. You made a comment that kind of piqued my interest. Do you value more data at the lower dose so you have some confidence if you have to back off the dose in a patient?
I think if you look at spleen, symptom, and survival, the high dose wins on all three endpoints. What has never escaped me, as you're seeing, is that even at the low dose, you are going to get some on-target activity engagement. There does seem to be a survival benefit that is better than what you see with anything else or patients who historically come off ruxolitinib. It would suggest that if you run into cytopenias, if you have to dose modify, it gives me some degree of confidence that there's still activity that could be obtained. We have data that patients who started on the low dose can go up to the high dose and enjoy benefit as well. I suspect that there's some degree of activity even with the low dose. Clearly, the 9.4 is the winning dose.
If one were to think of this as a controlled study where the control was the low dose, which I actually do not think is an inactive control, I always thought that one could almost look at IMbark as a randomized controlled study in some ways because the low dose could be the control arm. There was a clear difference in survival, but there was probably some survival benefit with the low dose. Yes, the answer to your question in my long-winded answer is yes.
Great. Thank you.
There are no further questions at this time.
Okay. Thank you then. I suggest we go once more through the planned phase III trial and the study design. I think that's also important. What you see here on this slide is the schema for the study, which will be led by Dr. John Mascarenhas, as discussed. We are also joining forces with Dr. Verstovsek, who will be also a co-PI on the study. It is a study that will be conducted in refractory myelofibrosis patients. These are defined as patients that have inadequate spleen or symptom response after being treated with a JAK inhibitor for at least six months. Within these six months, they have had treatment with an optimal dose of a JAK inhibitor. The patients will be randomized to receive either imetelstat at 9.4 milligrams per kilogram on a three-week basis.
This is the dose that John and actually Rami were talking that we are taking forward based on the data we have from the phase II study. The control arm will be best available therapy, which will have to be predefined prior to the study entry for each of the patients. It is important that we will be excluding JAK inhibitors. The importance of this is the fact that we will be able to hopefully closely match to the historical data or, for example, the data that we have from the RWD analysis where the expected outcome for patients in this setting that have discontinued a JAK inhibitor is between, I know, it's approximately 14 months. The study is designed such that it will have an interim analysis and then, obviously, a final analysis for a primary endpoint of overall survival.
Both the interim and the final analysis will be looking at an overall survival. They are event-driven, obviously, so it is at the times that you're seeing here in terms of readouts are estimated timings. With the assumptions that we've put forward, right, for the overall survival, we expect to have approximately 320 patients involved. John, anything that you would like to add maybe from your point for the study design?
The only thing I would add is that this was really, I think, really well thought out. I think the patient population is the right patient population. I think the control arm is the right control arm. This was discussed with the FDA. I was really happy to see that they totally agreed with this because this is a patient population that is refractory to JAK inhibitor. Although one could imagine maybe getting a JAK inhibitor after imetelstat at some point, I would much rather try to treat them with a non-JAK inhibitor-based therapy. I think the dose we're going with is the right dose because what maybe I didn't stress before is it was the more active dose that won on all three endpoints, spleen, symptom, and survival. Also, there wasn't really more toxicity that led to worsening clinical events with it.
From an efficacy and safety perspective, this is the dose. I think I'm excited with the study design because I think it's the right study design. It's the first study we've seen where survival is the endpoint, which is really the unmet need.
Thank you for that. Are there any questions?
We have a question from Charles Duncan with Cantor Fitzgerald. Your line is open.
Hi. Thanks for taking the question. Quick one on the conduct of the study and then on the interim analysis. First of all, with regard to the study conduct, do you accommodate any dose holidays or how will you accommodate any dose holidays or reductions during the course of the drug exposure?
There will be a—I guess that this is a question for me, Aleksandra. We will have a clearly defined dose modification scheme, which will be—I would say it is driven from the knowledge and experience that we have from the IMbark study. Obviously, we will try to—or we are taking into account and trying to have patients on treatment as long as they can tolerate and they see efficacy from or benefit from the trial treatment.
Yeah. I guess what I'm saying is over the course of the administration, would you ever anticipate patients being exposed to the lower dose as kind of referenced in the previous presentation?
I understand now your question. Actually, in the myelofibrosis study, the starting dose is 9.4. We will allow two dose reductions. The lowest dose that the patients will be receiving on the study is 6 milligrams per kilogram. Actually, patients will not need to go down to 4.7. We will clearly have a treatment with an active dose of the drug on the study.
Okay. That's helpful. With regard to the interim analysis, I think we've discussed this before, but I can't remember. That is, what is the approximate or the actual number of events that you're looking for to trigger that? Could you share with us either the specific number or kind of what you would look for out of the interim analysis in terms of superiority? I imagine since it's an interim analysis, it requires a very high bar in terms of the p-value. Can you give us some additional details?
Sure. I can do that. I mean, for the final analysis, right, and typical for a study with an overall survival as an endpoint, you would like to have more than 50% of the patients died on the study, right? You would like to have more than 50% of the events to occur when you perform the final analysis. Moving to the interim analysis, we want to make sure that we have enough of these events such that we have enough power to detect the difference. At the interim analysis, we plan to have approximately 70% of the events that are required for the final analysis. Still, a good number of events will be, right, needed for the interim analysis. Of course.
So.
Go ahead.
My math, 7 times 5, 36%, around 36%, 35 or so % of the total events that you'd expect.
Right.
Okay. Sorry, Diane.
Yeah. No, no, that's okay. That's okay. I mean, in terms of a hazard ratio, right, of a p-value, we would expect to have, again, what is important is to have statistically significant difference between the two arms. Again, we have taken the hazard ratio of 0.6 in terms of assumptions, right? It does not mean that we necessarily need to hit a hazard ratio of 0.6 to have a statistically significant difference between the treatment arms. That is to have an indication for a successful study.
Stephen Willey with Stifel, your line is open.
Yeah. Thanks for taking the question. Just curious with respect to the secondary endpoint of spleen response. Is that going to be pre-specified as an SBR 35? I know that there's some attempts here, I think, from a regulatory perspective to try to bring that threshold down to maybe an SBR 20 or maybe an SBR 10. Just curious how you're going to be pre-specifying that as a secondary. Thanks.
Sure. I mean, a spleen response, as we now know of, and it's for the IWG criteria, it's more than 35% spleen volume reduction. This will be a secondary endpoint. Needless to say, we have pre-specified analysis with different cutoffs of 20% as well as 10% because we believe that's very important, especially in the refractory setting, as John was alluding for. I mean, we did have 37% of the patients who had the 10% reduction in SBR. We are definitely looking in different cutoffs.
Okay. That's helpful. Thank you.
I will now turn the call back over to Dr. John Scarlett for final remarks.
Thanks, everyone. As we close this event on behalf of the company and all of our employees, I'd like to sincerely thank Dr. Santini, Dr. Mascarenhas, and Dr. Komrokji for their presentations of what at least we found to be extremely exciting data coming out of the CCI. All three of these really outstanding clinicians and investigators have made significant contributions to the development of imetelstat. We look forward very much to working closely with each of them and their colleagues in the future. Needless to say, these data presented today continue to encourage us that imetelstat has the potential to be a very important treatment option for patients with the disorders described by our presenters. As the sponsor of the drug, we remain committed to developing imetelstat in myeloid heme malignancies. We now have really all the pieces in place to move forward.
We have a novel drug in the target. As described today, it's shown very meaningful clinical activity and indications where there are significant unmet needs. We have two phase III trials: one that's ongoing in low-risk MDS and one in the refractory MF, which will be in the startup phase. We hope to begin enrollment in the first quarter of 2021. Finally, I have to say we have a very experienced team who can collaborate with these outstanding clinicians in executing all aspects of our drug development. We have, as well, the financial resources to reach significant value inflection points for patients, investigators, and stockholders. We really look forward eagerly to the coming year. I want to thank everyone again for participating in this event. I hope everyone has a great day. Thank you.
This concludes the call for today. We thank you for your participation. You may now disconnect.