UBS Global Life Sciences Conference
Tuesday, September 25, 2007
events.streamx.us
COORDINATOR: The next presenter is Thomas Okarma, President and CEO of Geron Corporation, and just a reminder that there is a breakout session after the presentation in the Carnegie Room.
DR. OKARMA: Thank you and good morning. Thanks for coming to our presentation this morning. I'll be making forward looking statements today, and of course we refer you to our various SEC filings for our risk factors.
Well, those of you that know the company are familiar with this first slide. We are the world leader in embryonic stem cell and telomerase technologies, with two broad spectrum cancer products currently in the clinic and the world's first embryonic stem cell product scheduled for clinical introduction early next year.
Our intellectual property position is of course quite dominant. We have a strong balance sheet. We ended the second quarter this year with $217 million in cash without debt and have a very experienced management team which I'll turn to next.
So the original core group has been at Geron now for 10 years. During the last year we added some significant experience in clinical oncology led by Alan Colowick and Fabio Benedetti. And in the aggregate, our entire oncology team at Geron now has in their experience portfolio 27 successful cancer INDs and 17–or 16 successful cancer NDA or BLA applications. So we have the horsepower now to develop our oncology portfolio.
So today I'm going to focus on that cancer portfolio: our two programs in the clinic – 163L our telomerase inhibitor drug, and VAC1, our telomerase vaccine, and I'll also focus on our most advanced embryonic stem cell product for acute spinal cord injury.
Now the take home message for today's status of 163L which is a homegrown, proprietary oligonucleotide that's lipidated and made with Geron-owned chemistry, is that we're now recruiting for four trials in 15 centers in the United States, the multiple myeloma program to begin imminently. This is a drug that targets telomerase, an extremely broad and important cancer target, and therefore has the opportunity to be useful in most of the major cancer types. It's quite potent and specific. Thus far its safety profile is quite good, with excellent PK and biodistribution properties, even though it is in fact a short chain oligonucleotide. And I'll emphasize a very novel mechanism of action in terms of myeloma stem cells a little bit later.
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Now the breadth of the activity of the drug is of course underpinned by a series – now all of which have now been published – of animal experiments demonstrating the activity of the drug as both a single agent - in myeloma, in non small cell lung , ovarian and other tumors - as well as in combination with standard of care in a similarly growing list of tumor types. Now these observations plus a few others that I'll mention cancer type by cancer type underpin the pretty aggressive program for the clinical development of this drug. Now in July we had an analyst day here in New York and we spent 3 hours going through this program, so I'll only at this moment give you the highlights. So, we are currently enrolling in two Phase I trials, one in CLL and one in solid tumors, and the outcome of those studies by end of this year will determine our single agent Phase II dose. We have recently introduced the first combination study of 163L with standard of care carboplatinum-Taxol in non small cell lung cancer. Once we have optimized the dose and dosing interval in that combination study, that triggers two events: a randomized Phase II non small cell lung cancer of–in combination, as well as a randomized Phase II in ovarian cancer with the same combination, and both of those randomized Phase II are scheduled to occur at the end of ‘08, assuming success in this trial. The most important part of this schema, though, is the potential registration pathway for the drug in multiple myeloma.
So imminently we will initiate a Phase I/II single agent trial in myeloma and if that is successful, that should lead to a pivotal trial in ‘08 of a single agent 163L in myeloma. It will also trigger a combination study that will occur in next year in the same disease indication. So, a very aggressive program, the most rapid pathway to registration we think today will be in multiple myeloma for reasons that I'll explain in a moment.
Let's look at a little more detail in those four programs. So the two Phase I trials – CLL and solid tumors – have a little bit, are different from one another in terms of the infusion duration, 6 hours in CLL and 2 hours in solid tumors. We are learning from the kinetic analysis of these data that the two hour infusion is a much better way to deliver this drug, and we will ultimately convert all of our trials to that 2 hour infusion. We're now enrolling in the 5th dose cohort, which is roughly 5 mgs per kilo, in both of these studies.
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So in the CLL study, that's a standard three plus three per cohort, Phase I design. There are now five centers recruiting for this study and we expect to finish this program early next year, and as I mentioned, are currently enrolling in the 5th cohort. We presented in the summer some interim results from the first four cohorts. We had one subject with stable disease and another subject that had tumor lysis syndrome; we weren't able to document significant telomerase inhibition, so the etiology of these possible responses is unclear, but most importantly was the PK data that is dose proportional and that led us to conclude we could continue to dose escalate, which, as I mentioned, is now happening in the Cohort Number 5.
Solid tumor study was added onto this, to really, to look at the toxicity profile in a solid tumor as opposed to a hematologic malignancy like CLL. We have now two centers recruiting patients here and we're also in Cohort 5, roughly 5 mgs per kilo, once a week by intravenous infusion and when we get to the maximal tolerated dose, we'll elucidate PK-PD relationships in an extended cohort.
The new study we've begun recently is in non small cell lung cancer. Why? First, there is well established, published evidence that the higher the telomerase activity in the tumor cell in non small cell lung, the worse is your overall survival or event free survival -- there are multiple studies that show this. And there are plenty of tumors that have this same sort of rationale. So the more telomerase you have in your tumor, the worse is your prognosis.
Secondly, there's pretty profound animal model evidence of 163L in an animal model of non small cell lung as a single agent. The fluorescence here indicates tumor burden, and there is a dose response effect in this animal model, actually resulting in some animals that have no evidence of disease after a single course of this drug.
So the combination study is a Phase I trial of 163L in combination with standard dose, standard of care of non small cell lung carboplatinum and paclitaxel. We give the standard of care every 3 weeks: three weeks on, one week off and currently a 2 hour infusion every week of 163L. We're starting at a dose of the–of our drug equivalent to that of the 4th cohort in the previously described solid tumor trial. These are patients that are sort of early in their treatment, and we're able to do that because of the combination here with standard of care and the endpoints are of course, most importantly, establishing dose and dosing interval in a combination with standard of care.
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Now the important program for us in terms of registration is multiple myeloma. Same sort of rationale. Again, your outcome is inversely proportional to the amount of telomerase in your tumor: the more tumor the worse is your overall survival or likelihood of relapse. We've also demonstrated in an animal model additivity between 163L and Velcade, shown here on the bottom line, in a long term study of an animal model of disseminated myeloma. Perhaps most importantly is the evidence that this drug, and this drug alone, impacts not only the mature myeloma cell, but also the myeloma stem cell. And on the left are data from myeloma lines; on the right are data from myeloma human patients that show a profound activity at low doses, very early in incubation, of our drug on the myeloma stem cell. And this will be actually presented at a public oncology meeting later this year. So, for those reasons, we plan a important study of single agent 163L in refractile and advanced myeloma patients who've had more than two prior therapies. And again it's a standard design, three plus three. We will also begin at the 4th cohort dose of our two Phase Is, so we don't have to repeat all of the low dose work and there are four centers that will be recruiting to this study, all of which are major referral centers for this disease. And as I mentioned, this is about to initiate, imminently.
So that's our oncology program in the telomerase inhibitor drug arena.
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I want to segue now to our vaccine, which is also based upon telomerase and therefore in theory has the same upside potential in terms of broad utility in most major cancers, all of which express telomerase – in this case, on the surface of the tumor cell. So, we have completed as you know, a Phase I trial in prostate cancer which led to our agreement with Merck which I will talk about in a moment, and unlike all other dendritic cell cancer immunotherapies, our immune responses are robust and consistent across groups, and I'll show you that data, and we have now initiated a second Phase I/II in AML with disease endpoints. You've seen this data before. It's been published in JI. It's the results of our first trial with the vaccine in prostate cancer and it illustrates a few fundamental points. After 6 prime injections in the skin once a week we generate in all of the subjects very high titred CD8 and CD4 telomerase restricted T cells that kill tumors, and this occurs in all of the subjects. This is about 1 to 2 percent of the total T cell pool in these subjects which is therefore an extraordinarily high degree of anti tumor immunity generated in the context of hormone refractory, metastatic prostate cancer. In addition to demonstrating that these cells cleared tumor cells circulating in the bloodstream, we had a highly significant prolongation of PSA doubling time, a surrogate marker for disease progression, but certainly not an approvable endpoint. What we did subsequent to those studies was optimize a prime and boost strategy using the same cell administered over a longer period of time and we demonstrated an anamnestic response in the boost. In other words, in–even after 9 months of no therapy, the first injection of the boost immediately gave a peak of CD8 and CD4 cells after the first boost injection, confirming what we had published here, that in the prime we are generating memory, central memory T cells. So this is real immunology.
We've moving now into a Phase I/II trial in acute myelogenous leukemia, and these are subjects at intermediate or high risk for relapse. And the protocol is following standard consolidation chemotherapy we prepare the cells and give them 6 weekly intradermal injections for the prime, just as we had done in prostate cancer. There's then a month's rest and then we give 6 or more boost injections every other week. And depending upon the efficiency of the harvest, we will have enough boost injections probably for more than 6. Therefore we are able to we think sustain high level anti telomerase T cell immunity. There'll be five sites recruiting to this trial and in addition to the obvious safety and immunological endpoints, we're really looking hard now on residual disease burden and clinical endpoints like remission, duration of remission and event free survival. So one of our hopes is that some of these subjects, particularly in the elderly high risk group, will have positive PCR signals in their bone marrow of residual AML cells post consolidation chemotherapy and those subjects we'll look at very carefully to see if vaccination takes them to PCR negativity, which is of course an approvable endpoint.
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Now the prostate cancer data and the boost data that I talked to you about led us to an agreement with our vaccine collaborator, Merck, and there's been a lot of news and progress that I want to announce today in this relationship. So, first, under our license to Merck for the telomerase target for their platform, they have now decided to file their IND under our license in the fourth quarter of this year, not in ‘08 as we had said in the July, August–July analyst meeting. So that's an important milestone. It's a milestone payment to Geron and it indicates seriousness of purpose and good progress on our partner's part.
Now there's also a combination–excuse me, a collaboration arrangement in this existing agreement which has made substantial progress. So under Merck's guidance we have been combining our platform with theirs in an animal model, and we have shown pretty dramatic synergy between dendritic cells and their platform which is adenovirus and plasmid. So both companies are now motivated to look seriously at extending their option to our VAC1 program. That option formally expired in July of this year; we have granted them a 6 month extension til end of year while we negotiate a renewal of that option.
Also important in that context is progress we've made at Geron on the second generation vaccine, which is dendritic cells that are made from human embryonic stem cells. We've now shown that these ES DCs have all the bells and whistles of the dendritic cells we harvest from peripheral blood with the obvious advantage of multi dose production lots, greatly reduced cost of goods and absence of variability of the DC's activity from patient to patient. So we are hopeful that this renegotiation will include an option to the second generation, so-called VAC2 based on human embryonic stem cells.
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I won't say much about TAT2, our telomerase activator drug, other than to remind you that we changed the relationship of the joint venture - it's now 75/25 in favor of Geron, so we are in control of this relationship in Hong Kong and we're in the final stages of our preclinical ADME tox with this compound, and we'll have more to say about that a little bit later in the year.
So in the remaining time let me talk mostly about the spinal cord injury program and a little bit about heart failure and diabetes and I'll close with our milestones for the coming two years.
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Now it's important to understand that all of these embryonic stem cell based therapies are scalable and we have a very standard manufacturing schema based upon master and working cell banks which have been in use in the biotech industry for 20 years for, for example, monoclonal antibodies, that enables us to produce differentiated, functional therapeutic cells in a biological commodity fashion. So to illustrate that, our current master cell bank, if we were to convert every cell in that existing master cell bank to glial cells, the first cell type, for acute spinal cord injury, we would have enough doses to treat the entire US acute spinal cord injury market for 22 years. So this is like manufacturing a drug with the appropriate economics, low cost of goods, that are enjoyed in any product based business model in biotech and pharma. So the first therapy that we expect to begin human clinical trials in the beginning of next year are oligodendral glial progenitors for acute spinal cord injury. We've published now the proof of concept and mechanism of action in the Journal of Neurosciences in a spinal cord injured rat model these cells injected within two weeks of the injury remyelinate the injured nerves and secrete neurotrophins that enable a reconnection of the damaged axons. It's profound and it's durable. In our IND enabling studies -- which are nearly complete now -- we've followed some of these animals for as long as 9 months and the cells are still there and quite viable. So the scope and content of our IND has been agreed upon and is now finalized. Most of the in-life studies to enable this IND are done. We're now just waiting for the last few reports to come in. So we're in the process now of writing this IND, and so we're on track to submit by end of year as previously noted. Now we'll be only announcing the milestone here connected with clinical trial initiation; I need to tell you that this is an enormous application. It's both an IND and an IDE because we had to invent a delivery device that's computer controlled to allow precise placement of the needle to inject these cells in the OR into the spinal cord as the patients get standard stabilization therapy after their injury. This will be an IND that has over two thousand animal studies – there are animals in various studies – as well as over twenty thousand pages of information. So it'll be a major review task for the agency. So you've seen this slide before; it demonstrates that the control group are animals that are permanently paralytic, they cannot place their hind paws, they drag their tail on the bottom of the cage and many of them are incontinent; in contrast, animals that get the cells have almost normal weight bearing and paw placement and carry their tail above the cage floor.
So the clinical protocol is now virtually complete in collaboration with our clinical advisory panel, and it's really driven by a very conservative risk/benefit calculus. So the initial patients that will receive these cells are complete thoracic injuries. These are patients with no sensation or mobility below the thoracic lesion. Now these are rare today because of automobile airbags. The most common complete lesions are cervical. But the reason we're starting at the thoracic level is for safety. If there is a problem with these cells and you go from a, say a T4 to a T3 lesion, there's really no significant impact on the patient's longterm care. But if we started at the cervical region and went from a C3 to a C2, we could compromise respiratory drive. So we'll be starting with thoracic completes, then once safety's demonstrated, move to cervical completes, and then move lastly to incompletes, which is of course the full spectrum of acute spinal cord injured patients.
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We've made a lot of progress on our second cell type, cardiomyocytes for heart failure and there is a landmark study that just was published in the September issue of Nature Biotechnology that I really refer you to. And this is the first time that anyone has demonstrated mature cardiomyocytes generated from any stem cell, in this case embryonic, that are surviving in an infarct zone. That was not an easy accomplishment to achieve and it required our development of a pro survival cocktail that enables these cells to survive longterm in the hostile environment of a myocardial scar. In addition to the improvement in structure and function that I'll show you in the next slide, a very striking finding documented in the paper is that the cells induce host angiogenesis. So we're not adding angiogenic cells of human origin, but the stimulus of these human cardiomyocytes turns the animals' response on to generate new blood vessels that infiltrate the tumor which in fact is part of the therapeutic response. So these are the data taken from the Nature Biotech paper. This shows the human cells surviving for at least four weeks in the body of the transmural left ventricular infarct. This is a major insult of both ischemia and reprofusion and the cells are injected 4 days after the infarction. And the significant results are a significant improvement in the ejection fraction in animals that receive cells, and no impact on animals that receive only the factors alone and highly significant improvements in contractile function and systolic thickening that you can easily visually see on the MRIs that all the animals receive. So this is a highly important validation of our second cell type. We are now in large animal studies, so we have scaled the production. These are now in sheep studies which will be taking place in two centers in the United States. And the purpose of the large animal study is to validate the notion that we are not creating arrhythmias in an animal whose heart rate is slow enough to be able to measure that. Obviously these animals have a heart rate of about 300 beats per minute so you can't be sure that we're not generating arrhythmias, and also, because these are human cells which can only beat at 180 beats per minute, the impact on function is minimized. So, every other animal heart beat is aided by the human cells in the ventricle. So we're very excited by these data.
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And lastly the islet cells for diabetes. We really think we have the cell. It's taken us a long time to get there, but we now have cells that produce and secrete insulin in a glucose responsive fashion, as well as glucagon and somatostatin, the typical hormones of the pancreas. We have a scalable production method - as we do for all of our cell types - and we have early animal proof of concept in a diabetic animal. So this is actually the immunocytic chemistry to show that our ES derived islets make insulin - this is a precusor of insulin. Glucagon. Somatostatin. And that all of those hormone producing cells are in each of our produced islets in the merged image. This shows that the secretion of insulin is in fact glucose responsive, as it should be, and we have all the right secretory vessels in the cells. All of this has been published this year. We extend dramatically the survival of the diabetic animal, and can in fact pick up human insulin in the bloodstream of the animal that receives cells.
So to support this, we obviously have a very robust intellectual property platform. Geron is the fundamental adventurer and developer of both disruptive technologies - embryonic stem cells and the whole telomerase story in cancer and normal cells - so we have a broad portfolio of pioneering IP, as well as an expanding issue of impending portfolio on both sides of the house that cover specific product formulations that emanate from these disruptive technologies. And we are constantly operating and engaging in the world's patent literature to maintain our freedom to operate.
So the last slide in the last few seconds are our driving–value driving milestones. So, the two Phase I studies in 163L will come to a conclusion early next year and they will determine together the single agent dose for our Phase II programs. The non small cell lung program has initiated in combination and we expect to have results from that at the end of 2008. We are about to initiate our single agent Phase I/II in myeloma and we will later in next year initiate a combination Phase I/II that hopefully will lead to our pivotal study.
Under VAC1, we're–we have initiated the AML study and, not on this slide, is of course the Merck milestones of IND filing and by end of year hopefully the renewal of our–their option agreement.
Embryonic stem cells. Now the important milestone to focus on is the initiation of the spinal cord trial early next year and we do hope to have some interim safety data by end of year, again depending on enrollment kinetics and when this actually begins. We hope to have large animal proof of concept for cardiomyocytes from our large animal trials by end of the year, and that triggers the generation of our master cell bank and the IND filing which could occur in 2009. And final proof of concept for the islet cell in the middle of next year in terms of stably reducing hypoglycemia in diabetic animals.
So thanks very much. That's our program, maturing product portfolio in oncology, an emerging product portfolio in embryonic stem cells based upon Geron owned and developed disruptive technologies in telomerase and embryonic stem cells. Thank you very much.
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