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Geron Corporation (NASDAQ:GERN)

ASH 2013 Analyst and Investor Conference

December 09, 2013 7:30 pm ET

Executives

John A. Scarlett - Chief Executive Officer, President and Director

Xiaolin Wang

Analysts

Cory William Kasimov - JP Morgan Chase & Co, Research Division

Brian Klein - Stifel, Nicolaus & Co., Inc., Research Division

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

Graig C. Suvannavejh - MLV & Co LLC, Research Division

Chad J. Messer - Needham & Company, LLC, Research Division

John A. Scarlett

Well, thanks to everyone who has come here to the Hilton at ASH to hear a presentation that will take about 45 minutes, probably maybe a little bit less. It's very data intensive. And at the same time, we will also be offering these slides to people who are listening in via webcast to the -- we are offering those. They should go live on our website very shortly, so you should be able to follow through in that manner. We're going to close the back doors so that we can keep the room reasonably quiet so that everybody on the webcast can hear. Up on the desk with me are a number of my colleagues; Olivia Bloom, who is our Chief Financial Officer; Craig Parker, who is our were Senior Vice President of Corporate Development; Xiaolin Wang, who is our Vice President for Biometrics and Clinical Operations; and Bart Barrington [ph], who is our Head of Data Management and Statistics. My sincere hope is that none of them have to answer any questions. Hopefully, because I know the material well enough.

So this is the ASH 2013 Analyst and Investor Event. We wanted to have this event for a couple of reasons. The first one was so that everyone would have an opportunity to see a little more fulsome data set that Dr. Tefferi have time to actually present. This also gives us an opportunity to make all of this Reg FD compliant. It also gives us an opportunity to take questions at the end. I would like to ask you to hold your questions. We've got a lot of material to get through, and I am -- fear that we wouldn't get through all of it, if we took questions in the middle.

I would like to read the forward-looking statements. Except for statements of historical fact, this presentation and question-and-answer session contain forward-looking statements made pursuant to the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995, including without limitation statements regarding expectations, regarding time lines for data reporting and clinical trial initiation, imetelstat clinical activity in the bone marrow and potential to be disease modifying, scope of patient patent protection, ability to manage myelosuppression through dose hold rules and dose modifications, prospects and plans for imetelstat and financial and operational expectations projections and requirements. These statements involve risks and uncertainties that can cause actual results to differ materially from those in such forward-looking statements. Information concerning factors that could cause actual results to differ materially from those in the forward-looking statements is contained in Geron's periodic reports filed with the SEC, primarily under the heading Risk Factors, including the quarterly report on Form 10-Q for the quarter ended September 30, 2013. Undue reliance should not be placed on Geron's forward-looking statements and Geron disclaims any obligation to update these forward-looking statements to reflect the future information, events or circumstances.

So today, our agenda is going to consist of a very brief sets of slides regarding the background of myelofibrosis and imetelstat. This is primarily for people who are a little bit newer to the story than many people here at least here in the room. We -- I would then like to present Geron's independent efficacy analysis of the first 22 myelofibrosis patients enrolled in Dr. Tefferi's investigator-sponsored study of the imetelstat in myelofibrosis that was just presented a short while ago. We will also then repeat Dr. Tefferi's findings related to the safety of their first 33 patients enrolled in the study, and then we will open to Q&A.

So I'd like to give you our top line observations that sort of formed the basis going forward here. We'll repeat these at the end, of course, and have a little bit more commentary on them and hopefully, we'll have a lot of commentary in between.

So the first is the Geron's independent review of the data of the first 22 patients in this study, certainly suggest that imetelstat have disease-modifying activity. We've seen as any of you who saw Dr. Tefferi's presentation, we saw unprecedented remissions, both CRs and PRs by IWG criteria. This is in 5 out of 22 patients. We saw a clinical improvement by the IWG criteria observed in another 4 out of 22 patients and the overall response rate was 40.9%, representing 9 out of 22 patients. And as we will comment on a numerous occasions, myelosuppression is the principal dose-limiting toxicity of this product. It is believed to be or certainly the hypothesis is that it's an on-target toxicity due to effects on progenitor cells and specifically hematopoietic progenitor cells. And we believe that this is manageable through those hold rules and dose modifications.

So I'd like to just give a very quick overview of myelofibrosis as the disease and, of course, this is a disease that originates in the bone marrow. The underlying source of this disease is a malignant progenitor cell clone or clones and that plus changes, many of these cells involved are megakaryocytic cleanage [ph] and this leads to bone marrow fibrosis and impaired hematopoiesis. The fibrosis itself is thought to be induced by cytokines that are actually being produced by the malignant progenitor cell clone. Obviously, impaired bone marrow hematopoiesis then shifts blood production to the spleen in the liver and this is what is responsible for the palpable splenomegaly that can be seen in up to 80% of patients with myelofibrosis.

Constitutional symptoms which include fever, weight loss, night sweats and pruritis are present in approximately 35% to 50% of patients and that -- those are also thought to be due to abnormal cytokine expression. For anyone who is not as familiar with this disease, unfortunately, it is a very serious and life-threatening illness. If you look on the lower right of this slide, you can see that patients with intermediate risk 2 and high-risk series [ph] by the DIPSS 2 criteria have on average only about 3 -- up to 3 years of survival. So it's a very serious disease. Probably the most feared complication of the disease on patients parts is leukemic transformation to AML, which we called blast-phase-MF. The problem with that is that most of the existing therapies don't work very well and most of these patients have a very short survival. The rest of the lack of survival is due to thrombohemorrhagic complications associated with dysfunctional hematopoiesis.

When we started developing this product for a variety of different hematologic malignancies, one of the things that immediately struck us was that there is a deep unmet medical need, and that need is to actually to be able to achieve remissions. The only treatment to date that consistently can give remissions in the disease is allogeneic hematopoietic stem cell transplantation. And this, unfortunately, due to the rigors of the actual treatment, the lack of suitable donors, the older age of most patients with myelofibrosis and certainly, the many co-morbidities that many of them have. This is generally limited to less than 10% of the myelofibrosis patients.

The other issue that, I think, everyone in this room is aware of is that there only have been rare and anecdotal reports of remissions with drug therapy. And the recent report of the first case of bone marrow fibrosis remission after 3 years on ruxolitinib, I think, reflects the rarity of such events. I would also comment that the interpretation of some literature reports have been confounded by the inclusion of low risk and intermediate-1 patients with intermediate-2 and high-risk patients. So the one question that we also ask ourselves or another question that we ask ourselves was, is it even possible to achieve rapid remission of bone marrow? If you did have an effective therapy, is this a sort of a disease in concrete or is this the concrete of fibrosis as it work to have a mixed metaphor or is it something that could actually change. The answer is that there have been very few allogeneic stem cell transplant papers that actually do sequential bone marrow investigation but the few that do certainly suggests that patients who have grade 2 or grade 3 fibrosis at baseline can show a mere or complete resolution by day 100 in about 70% of patients and a much higher percentage approaching the low 90s by the first year. I think even more impressive and I think those of you, again, who were at Dr. Tefferi's presentation heard him describe this, in the early days of Gleevec, I think one of the things that was dramatically remarked on in many papers and by many physicians was in patients who responded to Gleevec to imatinib, they often had bone marrow fibrosis. And certainly, a treatment with imatinib has been reported to result in rapid resolution of fibrosis and there are variety of different papers. But as early as 2 to 5 months, certainly in chronic phase and even in accelerated and blast-phase CML. So I don't think there's any question that if you have an effective therapy, you can achieve this, that is by the underlying biology of the bone marrow abnormalities.

So our drug that we started to develop for this a number of years ago is imetelstat. And imetelstat is, of course, a telomerase inhibitor. The telomerase enzyme is a really interesting enzyme. It's a reverse transcriptase. But as far as I know, it's the only enzyme that has an RNA template that is actually bound to and part of the enzyme and then it has a large protein catalytic subunit which we call hTERT. What happens is that the telomerase which are nucleotide repeats at the ends of chromosome as cells divide, they atrip, they become shorter and eventually if they become too short, I think the story is quite well-known and those cells [indiscernible]. So telomerase is clearly designed, if you will, by nature to either maintain or even add to the telomeres on the end and it does that by actually using the RNA template in order to -- as a template for adding on the appropriate complementary nucleotide repeats on the telomeric DNA.

What's really interesting about this enzyme is that it is not active generally in somatic cells. It's transiently upregulated in normal hematopoietic progenitor cells and that's to support a very controlled proliferation. However, in malignant progenitor cells, in malignant progenitor cell clones, this enzyme is highly upregulated and this is needed in order to have continued and uncontrolled proliferation, so this become a very important target. Now when these observations were first made, these and many, many others early in the -- late in the '80s, early in the '90s and throughout the '90s, there was a real effort to drug this target. Unfortunately, it failed to yield to small molecule inhibitors for a variety of reasons that we don't have time to go into tonight. However, Geron actually persisted and I think came up with a winning strategy which was to actually target the mRNA -- sorry, not mRNA, the RNA template and to bind a oligo to that as a competitive inhibitor. So the first and most important thing for those who knew the story is to realize that imetelstat is not -- it does not work by antisense and it is a proprietary 13-mer thio-phosphoramidate oligonucleotide that's complementary to the RNA template.

Now the other thing that Geron did was it put a lipid tail on it. This was to enhance cell permeability and tissue distribution. So today, we have a molecule that has what we believe to be a very long half-life and bone marrow, spleen and liver. It certainly distributes where because of the lipid to lipophilic areas. It is a potent competitive inhibitor of telomerase. The IC50 is between 0.5 and 10 nM and cell-free systems. And its target is indeed certainly in this indication the malignant progenitor cell proliferation. So with that as a background, I'd like to talk about the results of Dr. Tefferi's efforts at the Mayo Clinic.

So we went to Dr. Tefferi when we had the results of our essential thrombocytopenia data which were presented last year ASH and this year at EHA. And these results suggested that there might be disease-modifying activity. And as a consequence, he was very interested and he started a IST at the Mayo Clinic in Rochester, in which intermediate high-risk -- sorry, high-risk or intermediate-2 patients with myelofibrosis either primary myelofibrosis or secondary, meaning that its post-PV or post-ET. These patients were given single agent imetelstat. The drug is administered by a 2-hour infusion, so it's sort of a chemotherapeutic paradigm from an administration perspective. And he started with 2 cohorts. The first cohort was Cohort A, 11 patients and these patients received what is basically a standard starting dose for us in all of the studies that we've done of 9.4 milligrams per kilogram given every 3 weeks. This was a less intensive treatments regimen than the ET patients but these patients we presume to have less marrow reserve and would be at more risk for myelosuppression. Cohort A filled up sequentially, and this was an all-comers trial. So whether or not you've been prior -- previously exposed to a JAK inhibitor or not or so forth, if there was really as long as you were intermediate-2 or high-risk, you are pretty much eligible, of course, there's a long list of other eligibility criteria but those were the critical ones. Once cohort A was filled up, then immediately Cohort B sequentially filled. And this was designed to evaluate whether patients with this disease could tolerate and would benefit by a more intensive upfront dosing regimen. And so these were people who are getting 9.4 milligrams per kilogram weekly times 4 and then they would go to an every 3-week cycle. You'll see this over and over again as we go through this presentation. The endpoints were exactly what you would expect, CR, PR and CI rates with spleen response, anemia response and safety and tolerability as secondary endpoints.

Now a word about the data you're going to see. We've had I must say a very extraordinary collaboration with Dr. Tefferi and also with the Mayo Clinic and we have been able to obtain and review the updated data as of mid-October, roughly, and these included summary tables, patient listings, pathology reports, a wide variety of electronic and other data associated with this product. And right now, we only have the data associated with these first 22 patients and so we'll not be making commentary of our own on the additional 11 patients that Dr. Tefferi described in his presentation today is occurring afterwards. We'll have a few comments about that, so that we get that in the record. But our data is really associated with the first 22 patients. We subsequently did an on-site review of the patient charts in clinical data base and I must say just to be very reassuring, all of the results of our analyses which I'm going to present to you are very consistent with the analyses performed and presented earlier today by Dr. Tefferi.

Now the cornerstone today of any clinical study in myelofibrosis is the use of the revised IWG-MRT criteria as primary outcome criteria for response in this disorder. I'm sorry to tell you, we could spend an hour today just going through the nuances of this criteria, and I also have the tell you no other drug or for that matter really no other treatment has ever been subjected, if you will, or been put through the filter of the CR and PR criteria much less the CI improvements of this revised criteria because there hasn't been any other drug that gave CRs and PRs in a sufficiently high rate. So we're all kind of learning about this. And one of the things that we've learned is as follows. The clinical improvement as you see hear. This requires that you have either an anemia, a spleen or a symptom response and no progressive disease or increases severity of the other 1 or 2 that you didn't have a response in. The new criteria now also allow just a pure spleen response where stabilization of the other criteria are not required and anemia response or a symptom response. Then there is a great gulf in this disease between what these generally -- what these outcomes generally identify which are usually sort of single-system diseases or certain responses or certainly not terribly complex responses. And then there are PRs and CRs. I make a point to say this because both of us who have worked in other areas of oncology, a PR is often a, first of all, a partial response and it's often sort of just better than sort of stable disease. In myeloma, which I worked in previously, you certainly have a complete responses than VGPRs and then PRs and people even subdivide it more. That's not the case here. The IWG purposely established, obviously, that any remission -- this is remission, it's not response. Any remission was important and as I think you will see as we go through patient after patient, it's very hard to actually ring all of the bells to get to a CR even if you have a bone marrow CR just because you've got so many variables moving. But on the other hand, the other conclusion, I think, that we draw is that a PR is really important and it's a really big difference from a CI. So we'll talk more about that.

The patient demographics, I will breeze through a couple of these slides in the interest of time. The patient demographics are not a whole lot different than you would expect within an intermediate-2 and high-risk myelofibrosis patient population. Average ages in the late 60s. The majority patients are male. 80% have been previously treated. We'll talk about that in the next few slides. 42% -- 41% had primary myelofibrosis, the remainder had post-ET and post-PV. And you do see one interesting little situation, in Arm A, you have a more intermediate-2 risk patients and fewer high-risk, 7 versus 4; and then in Arm B, you have that dramatically reversed. We think that that's probably because as the word spread as it does whether we like it or not on patient blogs and at meetings of patient groups that there was something going on at the Mayo Clinic, I know Ayalew was really deluge with very, very ill patients who desperately want to be on this interesting new therapy that I suspect none of them can even pronounce the name of. So we think that's the reason for that. It doesn't really matter I don't think at the end. So we had approximately 60 patients with palpable splenomegaly and a few patients with palpable hepatomegaly and a relatively by percentage 68% with a constitutional symptoms, the usual night sweats, pruritus, unexplained fever and weight loss. We will make comments about this later.

So the prior therapies are sort of summarized here most had prior therapies. Hydroxyurea is a very common prior therapy. It's not just in the post-ET and post-PV patients. Many patients with primary myelofibrosis have received hydroxyurea. And the next most common were JAK inhibitors. Dr. Tefferi and his colleagues have studied most of the JAK inhibitors and then many patients came in having -- have been previously treated with a variety of these products. So about 45% were JAK2 inhibitor experienced. Pomalidomide was a study drug at the Mayo Clinic, so 3 of the patients were there and 2 patients have had splenectomies due to nonresponsiveness to any other therapies, I suppose.

Now I'd like to talk a little bit about the efficacy assessment. The study actually started in October in 2012. And obviously, how to use the 2006 IWG criteria because there were not 2013 criteria. And I must say Dr. Tefferi was extremely careful to not bend any of the rules, so we never saw the 2013 criteria before they actually published in blood. After they published in June, they were adopted by Dr. Tefferi officially in the protocol. But as a consequence of that, some of the procedures were not in place at baseline and precluded full adoption of the updated criteria and in particular, imaging studies were not performed for the assessment of the spleen response endpoint and spleen and liver assessments were by palpation only. No patient reported instrument was used to assess symptom response. Symptom data was captured on adverse event forms for symptom response analysis. And we'll come back and, if necessary, talk about -- we'll talk about PRs and CRs. And finally, Mayo Clinic standard procedures were used for investigator assessment to baseline symptoms and resolutions of symptoms for CR and PR themselves. So it is a little bit different. This I would remind you is the first-ever study in myelofibrosis and it was intended to be a signal-seeking setting.

So now let's talk about the disposition in the study. As of October 2013, these are the median durations: 7.6 on Arm A, 4.8 months on Arm B and overall, 5.3. We count the duration as the time between the date of the first dose and the date of the last contact in the clinical database that we have access to. So some of Dr. Tefferi's commentary may actually be more updated than that, but this is what we have.

I'd like to actually -- this is an important slide I'd like to walk through carefully. So there have been a number of people who have discontinued treatment and I think it's very important to talk about each one. So in Arm B, we have a patient who actually is the only patient who PD-ed, who actually progress by the usual progression criteria. That was the patient who was not a responder and whose spleen actually became palpable. They had a non-palpable spleen that became palpable. So we count them as disease progression.

So the -- there were 2 other patients in the other category that we should talk about. The first one was a patient who transformed on study to CMML and ultimately did have an off-study death to AML. And both of those events were considered unrelated to imetelstat by the investigator. Ironically, Ayalew had 2 patients with CMML that we're going to go into the study about the time that this patient developed CML and now we decided -- or he decided not to put them in but I think this is a pretty common transformation, unfortunately, in some of these patients.

The -- there was another patient in this Arm A other column who simply discontinue due to lack of response. I don't have any more data about that patient.

So now to the 2 death. One I think was a death that was certainly considered unlikely to be due or not due to imetelstat. It's a sort of unfortunate tragic story that goes along with this disease. Many patients with long-standing hepatomegaly develop portal hypertension and varices disease. And this patient had a pre-existing varices. The patient had, I believe, it was 39-day something like that into the study had a catastrophic variceal bleed, coagulation parameters were normal, the platelets counts were normal. So this patient was not considered to be a study or a trial -- an imetelstat-related death.

The other patient who was in Arm B actually tells us a lot and taught us a lot and we should talk about it. So this patient was an elderly gentleman with all -- almost all of the signs and symptoms of later-stage myelofibrosis. He came in and he was allocated, he was the 10th patient allocated to the Arm B which remember is 4 doses of imetelstat, 1 a week and then going to the Q3 weekly dosing. And as you'll see actually in some further slides, he -- at the time that he came in, he tolerated the first and second dose quite well. He had some myelosuppression on the third. At the time he came in for the fourth dose, he had a very steep fall in his neutrophils and in his platelets. By protocol at that time, we had a limit of about 30,000 platelets under which we would not treat or Dr. Tefferi would not treat -- or continue treatment. However, at the time there also was the hint that patients who had more myelosuppression might be getting a deeper response and so Dr. Tefferi thought about this. He and his colleagues thought about it and they wouldn't have been treated the patient. This patient became aplastic and subsequently died after severe -- obviously, complete myelosuppression. The patient was supported with platelets and growth factors unfortunately to no avail, the patient develops a febrile neutropenia. We assume the patient became infected and subsequently, had a CNS bleed and died. The platelet counts were very low, the white counts were very low. It was a very difficult moment for all of us. But we certainly learned that patients whose platelets were falling rapidly and also down to those levels really shouldn't be treated. This was followed by a patient who doesn't show up here but it was followed by the 22nd patient. And this was a woman who had massive hepatomegaly. Her liver was down into her pelvis. She had already had a splenectomy. She was a young women. She was dying of myelofibrosis. And she was treated and had a very a similar clinical course, a similar decision was taken because we haven't seen the effects or Dr. Tefferi hadn't seen the effects on the previous patient. And this time, however, very fortunately through I think very, very outstanding medicine, she did survive. And after prolonged myelosuppression, her platelet counts did come back, her neutrophils did come back. She eventually regained normal platelet and neutrophil counts. Her spleen shrunk up to basically a normal-size spleen or a very close to it and she has done very well. She continues on drug today. So I think that we learned that the rate of fall and also the absolute fall in particularly in platelets but also in neutrophils was a very important thing. You heard Dr. Tefferi say that this was a very potent drug and we completely agree with this. And I do think that we have used this opportunity -- unfortunate opportunity to learn about the drug and also to change a lot of the ways or some of the ways that we treat patients. I'll end up with some of those comments perhaps.

So by the primary endpoint, as you saw, we have 5 patients with CRs and PRs and additional 4 patients with CIs. I'm not going to give you verse in verbatim about the CI's, although we will see what they CI-ed with, but I would like to walk through the individual PRs and CRs. There's been a lot of confusion perhaps by some language written by an academic who was not perhaps as tuned into some of the nuances that help people outside of academic medicine. We look at all of this, so I would like to make sure that there are no -- there's no confusion.

So this is the first way we'll look at it. These are the response parameters, and I just tell you something, folks. When you try to dissect and actually operationalize the 2013 IWG criteria is a big task, and we spent many, many, many weeks trying to really put together all the little nuances. There are little aside [ph], there are a little -- there are more footnotes than there are lines in the tables. And so this is the outcome that we've come up with. We think it's pretty darn good, and I'll just sort of give you a very quick view because I'm going to go through each of these patients individually. So obviously, the key is the bone marrow response. We'll have much more to say about that. If you either have an anemia or actually have a transfusion dependence, you need to become transfusion independent or in order to PR, CR, you have to have your hemoglobin to 10 or above. If you have leukocytosis or thrombocytosis which some patients do to a very substantial degree, you need to have a response there. They need to become basically normalized. You need to get rid of leukoerythroblastosis. This is something that I've learned about myelofibrosis is that this disease pushes out immature cells to the periphery and that's a hallmark of this disease and many of the other myeloid hematologic malignancies. So leukoerythroblastosis refers to a smear that has very immature white tells, lots of blast. It has very immature red cells, very strange looking red cells, nucleated red cells, immature cells. That means to go away, if you're going to claim a PR or a CR. Obviously, if you have organomegaly, that needs to resolve. If you have symptoms, they need to go away. And so that's how you come up with the IWG response criteria and I haven't put up here all of the other peripheral count that have to come up to certain numbers and we'll see excellent example of that in the next 5 patients. So we have this one patient who is still pending a 12-week duration, patient that a PR criteria way back when and I'm going to show that patient and you'll see exactly why they're still waiting or still -- why it took so long, and I think you'll understand.

So this is the first patient who CR-ed. This is a 73-year old man with intermediate-2 primary myelofibrosis. This patient failed hydroxyurea pomalidomide, lenalidomide and prednisone. The patient was requiring red cell transfusions every 1 to 2 weeks. The patient had a palpable spleen tip and did not report any symptoms. As you can see, I'd like to tell you how to read this slide now. The lighter green part on the top is the range that you have to get into for these peripheral counts which you -- I realized it's hard to see. This is hemoglobin, platelets and ANCs. You have to get into the lighter green part in order to qualify for CR. And if you're in the darker green part, you can qualify for a PR. And down here, we have individual weeks and then the little dots or squares indicate the dosing that occurred. The individual -- and then, of course, there are some individual notations about when milestones were achieved. I'd like to also point out that only baseline and day 1 lab results of each cycle are presented here. So for example, we can infer and I can tell you exactly what happened here that in this patient, they were supposed to get a 9.4 milligram per kilogram dose on week 3. You don't see a little square there. And yet you don't see on this graph, graphical representation, you don't -- we just draw a line from the ANC -- from 0 to 6 weeks and the same with platelets. That's true because it just becomes impossible to present. But I can assure you that the reason for this was that this patient actually develop grade 3 neutropenia and thrombocytopenia and so the second dose, and so this would -- that they want down there, and so the second dose was delayed because of that. And then it was restarted at week 6 and the patient has been receiving, I'm sorry, it's hard to see them in the back. But if you're looking on line, they got a little dots here and that's 7.5 milligrams per kilo. So this patient then became red cell transfusion independent. That's what the TI means and a bone marrow at 15 weeks met the criteria for CR. A follow-up bone marrow was actually done at 28 weeks. We don't note it here but a bone marrow was done then, and the patient met continued criteria for CR.

So I'd like to show you these bone marrows. I am not going to make many comments about them except to say that this is a classic hyper cellular marrow. This is 95% cellularity. It should be closer to 40 or less. This is a normal cellularity. This is the 7-month bone marrow. This is a reticulin stain. It obviously stains the fibrotic material. You can see that it's just chock-a-block full of that and now you see very nice cells and this is a reticulin grade 0 to 1. So this is a bone marrow CR.

This is a higher powered look. This is a 400X in the H&E stain, and you -- the comment of the pathology report was that megakaryocytes was quantitatively and morphologically unremarkable with only rare abnormalities. So this is the real deal.

Let's go to patient 2. Patients 2 is a 72-year-old man who had intermediate-2 primary myelofibrosis. He had failed a erythropoiesis-stimulating agents, androgen preps [ph] and proatinib, a JAK inhibitor that was under investigation. He was also receiving red cell transfusions approximately every 4 weeks in this case. He also had a palpable spleen tip. He had weight loss and pruritus. He received pretty much on target with little deviation, 9.4 milligrams per kilo. Every 3 weeks. His spleen tip resolved after about 6 weeks LES, leukoerythroblastic, picture resolved. He had symptom resolution and he had no grade 3 or 4 myelosuppression or other treatment-related toxicity to date. The 18-week bone marrow which is right here -- the 18-week bone marrow met the bone marrow CR criteria. But unfortunately, at that point in time, he still did not meet the platelet requirements for CR. You see he's in the dark green band. He did meet the ANC and he didn't quite need the hemoglobin. He had a hemoglobin, as I remember, about -- I think it was 9.2, something like that. So he goes along. He obviously got great results. He's continuing to respond. And finally, finally, at the 36-week point, he actually -- his hemoglobin rises -- sorry, his platelets rise above 100 -- they're 106 and his hemoglobin is 12.3 clearly in the CR range. Hemoglobin has to be above 10. So he was declared a CR at this point and that's the reason for the double asterisks that we're waiting for pending confirmation. This is going to be a recurrent theme here that we've got a lot of situations where we've got patients just sort of waiting along for all of these many, many variables to kind of come together, but I don't think anyone could look at this and not say this man hasn't had tremendous benefit from whatever therapy he would have been on. This is his bone marrow, similar story to all the others.

Patient 3, and I'm going to hurry through this a little bit quicker. This is a 79 year-old man with high-risk post-ET myelofibrosis. He was previously treated with hydroxyurea and [indiscernible]. Notice that he has a very elevated white count at the start and quite an elevated platelet count. He also had a 7% circulating immature cells with leukoerythroblastosis. 3 weeks into therapy roughly, he had achieved complete resolution of leukocytosis and leukoerythroblastosis. He -- but however, he had grade 3 thrombocytopenia and neutropenia and therefore, subsequent treatment was delayed for 4 weeks. And when he restarted treatment, he had it at a reduced dose level of 7.5. After recovery from the thrombocytopenia and neutropenia, the patient rang the bell for PR but the 12-week bone marrow assessment met the criteria for CR. And therefore, he was declared a CR at this point. And what I can tell you is that a 6-month repeat marrow, I'll show you that in a second. This is the 3-month. So clearly, he meets the criteria. Well, I said clearly, but I can't say it's clearly but a hematologist and pathologist can say it's clearly. But the 6-month post-imetelstat therapy and note the -- the pathologist note is normal cellular bone marrow with normal trilineage hematopoiesis, and no bone marrow fibrosis.

Patient 4, this last 2 I'm not going to show any more bone marrow just in the interest of time but these last 2 patients do not CR, they PR, but they do it in very different ways. I hope everybody will appreciate it. So this patient is a 67-year-old man with intermediate-2 primary myelofibrosis previously treated with hydroxyurea and he has a whopping platelet count of over -- close to 2.5 million. And at 6 weeks, and he's on the Arm B, so he receives 4 weekly doses and then has received continuous average 3 weeks since then. You can see that his platelet count fell very nicely, actually, just about the same timeframe that we would have expected with the patient with ET. His hemoglobin started to come up and his ANCs fell, but remained above the lower limit of normal. He had a bone marrow done at week 12 and clearly, met the bone marrow CR criteria. However, at no single time has all of these little numbers ever quite line up. He's had platelets that are normal but not at exactly at the same time that his hemoglobin has been normal and vice versa and so forth. So at the last time, his platelet -- his hemoglobin count was 10.2, that's in the CR range, but his platelets were 477. You got to have 450 in order to be a CR. That's a little elevated and his ANCs are completely normal, thus no CR. That patient, I think, we'll all see plenty of these patients in the future. They just don't quite line up. That's a little bit different than the last patient who PR-ed. This is a 68-year-old man with high-risk primary myelofibrosis previously treated with hydroxyurea. He had a marked leukocytosis white count of 32,000. He had also a high platelet count, 76,000. He had night sweats, weight-loss, spleen was palpable at 8 centimeters below the left costal margin. He had weekly infusion, followed by once every 3-week dosing, no delays, no reductions. At 12 weeks, he had a bone marrow done at 12 weeks when he met the criteria for PR but in this case, he did not have a CR by bone marrow. And he had another follow-up bone marrow at 24 weeks. It's actually past this, at fairly recently, and we still did not meet the criteria for CR. So this patient has met that 2013 IWG criteria for PRs based on peripheral blood count resolutions of splenomegaly, resolution of leukoerythroblastosis, resolution of night sweats, weight-loss and constitutional symptom but without bone marrow remission. His platelet count remained stable with hemoglobin of 11.6, ANC of 3.9 and platelets of 326,000. He's doing very well, but he doesn't have a bone marrow. So I hope that, that gives you a real flavor for how this is going.

I'm going to now move pretty quickly because I do want to have time for questions. We had a total of 38% spleen responses by palpation and the anemia response was 33%. The symptom response of the caveats that we talked about at the beginning of this, we saw a symptom response in 77% of patients. I'm not going to linger on this slide. It's available on the deck. It just simply says that the benefit is not just limited to patients achieving CR, PR or CI. Patients with high numbers of circulating blast, all of these are very immature cells, they get better and this is a good harbinger. If you got myelofibrosis and you got marked leukocytosis or white count of over 25,000, you'd really like to get it down.

Now this is -- it looks like an eye chart that it's actually quite an instructive chart. This is every patient in Arm A. And what you can see here are these are 3-week intervals, so if you see the squares going out every 3 weeks, that means that they have the 9.4 milligrams per kilogram as per protocol every 3 weeks. This patient PR-ed here, finally, CR-ed out here. This patient PR-ed very early at 6 weeks. This is the patient you'll recall. I think this was actually labeled patient #1 who had a dose hold due to grade 3 neutropenia and thrombocytopenia. When the dosing was restarted, the patient was put on to 7.5 milligrams a kilogram. The folks back at the office indulge me and made the little round dots red this time for those of us with aging eyes. And so you can see that this patient has remained on drug. This patient is now past a year. CR-ed out here and it's now, we are purposely, not we, Dr. Tefferi is purposely lengthening the treatment interval to see how long he can maintain his CR and good health without getting quite so frequent infusions. This third patient CI-ed by spleen, not very much else to talk about.

Now there are couple of patients where you see dose intensification has occurred. This is per protocol, won't go into it at all. One patient after dose intensification got this spleen response, another patient did not, another patient did not so these are all stable disease patients. This is the patient who transform the CMML and left the study and this is the patient who also -- who PD-ed -- who left the study after PD. I'm sorry, that's not that patient. That was the GI bleed patient, sorry.

Okay, this is Arm B. Similar story. Now, you see most of these -- many of these patients, most did tolerate 4 weekly doses. We had 2 CIs. We had a liver response. This is the patient I told you about who had very low counts for a prolong period of time. You can see that and did not start to get retreated but she absolutely have this massive response and is now a CI by liver and is continuing on. This is the patient who died at the intracranial bleed and thrombo -- neutropenia and this is the patient who developed the spleen tip.

So I think that the message is that we have unprecedented remission. The real remission. There's bone marrow fibrosis in 4 out of the 5. There's resolution in splenomegaly in all 4 of the CR and PR patients who have splenomegaly prior to treatment and there's resolution of symptoms in all 3 CR, PR patients who had symptoms prior to treatment.

Clinical improvements were observed in another 4 out of 22 patients. Time does not permit us to go through them. You sort of got a flavor from that path. So we have overall response rate of 40.9%. Very importantly, as reported by Dr. Tefferi in his ASH presentation, no patients with CR, PR or CI have lost their response to date. And clearly, there are some degree of clinical benefit including resolution on circulating blast and leukocytosis and thrombocytosis in the majority of patients.

So let's move on to the -- let's move on quickly to the safety, the appropriate safety. So here, we wanted to make sure we were as up to date as possible as I told you. We don't have the data from the patient from 23 through 33. So we are going to just simply repeat Dr. Tefferi's slides because I think they're very well done and quite illustrative. So this is Cohort A and is equal to 11, Cohort B as before. Now what we are going to do as he described, we were going to do a Cohort C which is going to be weekly, but after seeing the myelosuppression that occurred after weekly dosing, this was not a difficult decision. Dr. Tefferi made it but we were in complete agreement that this was -- that these patients could not be treated weekly. And so these patients were reallocated to either Cohort A or Cohort B. The patients who got into Cohort A were patients that had mutations in particular splices on mutations that might have suggested that they would be more sensitive. I'm not sure if that's true or not but it was a theory at the time and these patients were thought not to be as sensitive.

You saw this. This is the patient disposition. There's really nothing new to talk about. It's collated to slightly different way, but there have been no additional deaths, no additional transformations. We're unaware of any other changes, a lack of response and this is more updated that you can't pick and tie, guys. This is a more recent data set because he has access to those data. These are all of the grade 3 for non-hematologic adverse event that he showed today. He commented that these were not attributable to the drug in his view and these are the treatment related myelosuppressive toxicities and it ticks up with the picture that we've seen over and over again. I will tell you right now most hematologists who treat these disorders do not worry too much about grade 3, but they do worry about grade 4. And I think this is the very important finding in this and is equal to 33. The patients in the B -- group B treatment paradigm have clearly a higher grade 4 thrombocytopenia and neutropenia than the patients in grade 1 where there was no grade 4 thrombocytopenia and no grade 4, only 1 patients with grade 4 neutropenia. So this has certainly given us these observations that myelosuppression is principal dose-limiting toxicity. We think it's a theory that it's on-target toxicity due to effects on progenitor cells. I think most of the academics believe that to be the case. It's clearly manageable through dose hold rules and dose modifications. And to mitigate against the risk of severe persistent cytopenias, the Mayo Clinic protocol has been amended to raise the hematologic thresholds for retreatment and include more stringent monitoring and dose adjustment criteria. And the non-hematologic adverse effects have been generally not very much to write home about. So this -- these are the conclusion. We just simply reiterate the efficacy and safety conclusions. And so I think that I will end there, and we will open the floor to questions.

Thank you very much for your attention during this kind of a long presentation. First question? Thank you. Thank you very much.

Question-and-Answer Session

John A. Scarlett

First question. Adam will give you a microphone, whoever it is.

Unknown Analyst

Naviv Sync [ph] from Goldman Sachs. What's the development path forward and is there an accelerated approval path?

John A. Scarlett

So we've said quite consistently and we'll continue to reiterate that our plan is to provide 2 things. One, we have said that we do plan to develop the drug obviously and myelofibrosis and that we expect to begin a clinical studies sometime in the first half of 2014. We've also said that we will come forth to the investment community and others in the first quarter and discuss all of those point, and I don't think we're quite in a position to do that so we're refraining from commentary today about that. Thank you for the question. Stay tuned.

Cory William Kasimov - JP Morgan Chase & Co, Research Division

Cory Kasimov with JPMorgan. A couple of questions for you. First of all, on the revised IWG criteria, I think there's some confusion about it with the footnote at the bottom referring to Tefferi. Is this -- who -- how was this revised from its source of the Mayo Clinic?

John A. Scarlett

No, not at all. If you look it up, Cory, this was a very large consortium of eminent hematologist. Ayalew had been described for the 2006 criteria but he's by no means the sole author. It's a long list of very impressive people and they sat in rooms over many different days and thought it out as to what they should be. So he simply, the reporter, not the author.

Cory William Kasimov - JP Morgan Chase & Co, Research Division

Okay. And then a follow-up question, Dr. Tefferi in his presentation mentioned a few patients with AML. Do you have any plan to take us forward in AML?

John A. Scarlett

Dr. Tefferi is his own man as you probably all figured out. We're not going to have any comments to make if his study and his patients, he chose to discuss that. It's -- we don't have -- we actually don't have that information. He gave us and in any event, we're not in a position to make any comment about that. Well, hopefully -- I don't know if we'll be able to make any comment about other indications. For sure, we'll try to make comments about where we're going to go, Cory, with myelofibrosis in the first quarter but we're not going to be able to make any comments about that. Yes?

Brian Klein - Stifel, Nicolaus & Co., Inc., Research Division

Brian Klein with Stifel. So you showed some impressive bone marrow responses. Did you show -- or did you see any patients that showed improvements that didn't quite need bone marrows in the other patients? And secondarily, did you ever demonstrate any improvement in bone marrow without showing constitutional improvement?

John A. Scarlett

I'm unaware of any patients who didn't have -- who showed improvements of this nature of this degree who didn't have symptomatic and/or spleen responses. I actually don't know. Xiaolin, do we -- we don't have any additional bone marrow data from non-responders. Is that correct? Can you just come close to the microphone.

Xiaolin Wang

For the bone marrow -- the bone marrows were conducted for baseline and for patients who have met CR, PR or CI. So we don't have it on everybody. We only have it on select patients and was only done clinically indicated.

John A. Scarlett

So we just don't have that data. I'm sure there are some who he was trying to get a CR or a PR, and they didn't make it. I mean, we showed you an example of that in the fifth patient, but we don't have any quantification of that front.

Other questions? Yes.

Brian Corey Abrahams - Wells Fargo Securities, LLC, Research Division

Brian Abrahams from Wells Fargo. Can you help us understand a little bit more specifically the criteria used to assess symptoms and describes symptom resolution in this study and how that overlaps with the IWG criteria? And then more broadly speaking, I'm wondering where you see this fitting into the MF treatment paradigm? May you explore certain subpopulations, for instance, with mutations Dr. Tefferi described the first or other high-risk populations?

John A. Scarlett

Both excellent questions. Thank you. So the first question related, I'll try to make sure I got it right. It related to the question of how do you assess symptom response in the IWG criteria. And this is a really misunderstood point and very, very important. To meet the criteria for symptom response for a PR or a CR, you just simply have to demonstrate that symptoms have actually resolved. That's the actual language. The -- looking for a little cheat sheet that I did here, given the -- oh, you got there. So the actual language in the PR, CR is resolution of disease symptoms. For CR and PR, you have to show that spleen and liver are not palpable. Now here's the twist, if you are going for a spleen respond that's not part of CR, PR, then they say that you have to have the usual greater than 35% spleen volume reduction by MRI or CT. We obviously didn't have that. We weren't able to use it. And you also on symptoms, you have to have a greater than 50% reduction in the aptly named MPN ASF TSS [ph] and we'll give a free bottle of -- or load to anybody who can realize what that is. I'll read it for you. It's the Myeloproliferative Neoplasms Symptom Assessment Form Total Symptom Score. This is a tool that has recently been adopted. And so if you really want to know if you've got symptomatic responses, you need to do it by that. But if you're counting for CRs and PRs, simply showing that you have a resolution of disease, symptoms is efficient. Now if you ask me, what's the criteria for resolution, nobody knows. It's never been -- it hasn't been adjudicated, right. How can it be adjudicated? There hasn't been drugs to do it. So they and they're -- I mean, it was -- it must have been a hell of a meeting to get all the stuff down that they did. But that hasn't really been worked out. I suspect this drug will probably work a lot of these stuff out as we go through.

Yes, sir? I'm sorry, we have one over here and then he'll give you the microphone. Graig?

Graig C. Suvannavejh - MLV & Co LLC, Research Division

Graig Suvannavejh, MLV & Co. Three questions if I could. One, can you just...

John A. Scarlett

I'm sorry, I didn't answer your question. I apologize. Excuse me. The question -- the second question related back to where do we see this in the MF treatment paradigm. Well, I don't think we really know -- I mean, we've seen lots of responses and it's a little hard to understand why we would want to go really willy-nilly into combination types of therapy. But honestly, we don't know the answer. This is the first study this ever shown on this. So I think that we need some time to really think that through and probably give some clinical data and understand it better. Now I'm sorry, Graig.

Graig C. Suvannavejh - MLV & Co LLC, Research Division

Sure. 3 questions. First, just give a little bit more background around the 9.4-milligram per kilogram dose and certainly there's differential activity based on the weekly dosing regimen but in terms of the dose itself, can you just give us some context how you got there? My second question has to do with just overall thoughts around potential combination use with perhaps the JAK inhibitors and then my third question would have to do with given that this was early, though, may be tantalizing data from a small study, how do you think about the next trial that you guys will run in terms of the numbers of patients thinking about that?

John A. Scarlett

The 9.4 milligram per kilogram dose, it was fairly square in the dose response curve for -- both on nonclinical and early cynical work. And we did know that in humans using surrogate tissues like hair follicles and the like that you could clearly inhibit telomerase. So that was in -- it kind of went from 6 to 11 and in the middle it was 9.4. We've used 9.4 as a starting dose from literally years, and we have 345 or 350...

Unknown Executive

374.

John A. Scarlett

374 patients who have been treated with this drug in Geron-sponsored study other than this was not 8 Geron-sponsored study so we have a lot of experience around this dosing. It just kind of come to be de facto starting dose at least for the moment. There's nothing super magic about it, but it does have a real -- a really -- a thoughtful consideration behind it. With regard to combination therapy and for that matter sort of what the next trial needs to do, I'm going to beg off the same way I did before. I think we really -- this is -- there's a lot to put together and present to you and we need some more thinking and talking with people before we're in a position to really make comments that we feel comfortable about. Yes, sir?

Unknown Analyst

So what was the response under this old criteria [indiscernible] and then second [indiscernible] I'm not sure I understand in terms of determining the part of the response, was it by MRI or is just by the doctor actually...

John A. Scarlett

[indiscernible] patient.

Unknown Analyst

[indiscernible]

John A. Scarlett

Okay. So the 2006 criteria, it would be a little beyond our ability to have a big discussion right here now about the differences. But the principal differences are that you have the ability to have a PR even if you didn't meet the bone marrow criteria for -- I'm sorry, if you did meet the bone marrow criteria for CR but you are not quite there on the peripheral count. So that's a new addition. The addition of a durability component is another important ones you have to have 3 months of durability.

Unknown Analyst

So what was the number [indiscernible]

John A. Scarlett

Oh, that's a good -- yes, we -- since the protocol now is running by the -- but effectively using the 2013 which everybody wants, we haven't actually calculated it as far as I know.

Xiaolin Wang

I wanted to response to your comments about the spleen -- I'd like to respond to your question about MRIs assessment for CR, PR, because there was no MRI definition of a normal spleen or liver, it was not feasible to use MRI to assess the CR -- the spleen component of the CR, PR. And if you look at a recent -- 2007 criteria and [indiscernible] criteria for NHL [ph], they also used palpation for liver and spleen for the CR assessment. I believe that was used in the recent improvement [ph] approval. So that all I can say is it's not possible and it's not required for that reason. MRI assessment is only required for spleen response as a secondary endpoint here that is not required for CR, PR because it's not feasible. Does that make sense?

Unknown Executive

It's not feasible for establishing normalization of spleen size. So a CR and a PR requires effectively normalization of spleen size. Only when a spleen is palpable is that considered pathological. For just measuring a change in spleen size which is a response, one can use MRI; but for measuring what's normal, the authors of the criteria decided that it's not palpable. By definition, it's normal.

John A. Scarlett

Can we move on?

Chad J. Messer - Needham & Company, LLC, Research Division

Chad Messer from Needham & Company. Just if you could go back to the dosing just for a moment, I believe in the past, you've mentioned that Dr. Tefferi continues to enroll patients and one of the things he's doing is testing some different dosing schedules. Is it possible for you to comment on what he maybe trying to accomplish there and then maybe just a little bit more globally, how confident are you that the 9.4 Q3 weeks is a reasonable kind of go-forward dose for the next trial?

John A. Scarlett

So there are 2 comments to that. The first one is that in MF, I'm unaware of him using anything other than what we've kind have seen. As I've commented, dose intensification is permitted of going back to sort of the few [ph] weekly after you've established that the patients are safe. And I would say if you want to think about this a little bit, it's pretty straightforward. We didn't see humongous differences in the response rate in the patients who got the dose intensification up front or I should say the more intensive dose schedule. But that doesn't mean that patients who are -- who haven't responded, they may indeed respond to a dose intensification. So I think, in general, what you'll probably see, probably, it's not up to us in its entirety but probably what you'll see is a dosing where what would make sense would be that you find out what happens at the Q3 week dosing. Remember, patients did really well with that. If they don't drop their counts and some patients did, right, if they don't drop their counts, that would be probably pretty good idea to then try the dose intensification if they haven't responded. If they're responding, I don't know why you would do that. So I think that the very simple principle is likely to roll forward. Beyond that, I probably can't comment anymore.

I think we are about 7 or 8 minutes beyond, and I'm sure people have a lot of things to do this evening. So I'd like to thank everyone for your attention and for coming with us tonight. Thank you, and thank you to those who listened in on the webcast.

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