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Rodman & Renshaw 6th Annual Healthcare Conference
www.wall street webcasting.com/webcast/rrshq4/gern/
October 26, 2004
We have quite a few companies in the conference and the schedule is tight, so, so why don't we get started. As a reminder, speakers have 20 minutes followed by a breakout session. I implore speakers to keep to time as best as they can so that other companies' investors get an equal opportunity here.
The first speaker today is from Geron, Tom Okarma, CEO and President and Tom will be in the breakout room at 8:20 in the Gramercy Room. Tom.
DR. OKARMA: Thanks, David. Good morning. Thanks for coming. So like everyone today, I'll be making forward looking statements so we refer you to our SEC filings for our risk factors.
Let's start today with who we are and what the game plan is. Historically, it's important to know that both therapeutic platforms evolved from our original core competence which is telomerase biology. In oncology, telomerase is the pan cancer target against which all of our products are directed, while in embryonic stem cells, the normal expression of telomerase allows for the production of scalable cells for therapy. Our strategic plan is - in oncology - is to build an oncology business by developing and commercializing our telomerase inhibitor drugs and our telomerase vaccine and by licensing rights to the oncolytic virus and telomerase diagnostics to others, while on the stem cell side, our objective is to first demonstrate human proof of concept with the spinal cord injury product and then to co-develop with partners products for heart failure, diabetes, musculoskeletal and neurologic diseases. So today we are a therapeutics product development company with our first cancer product in the clinic - the vaccine - our second to enter early next year - the drug - and the year after that our first embryonic stem cell product for spinal cord injury. So let's now jump down first into the oncology portfolio to get a sense of where we are.
Now telomerase for cancer is still the only clinically validated, universal and specific cancer target; that's important to recognize. This is a model of the enzyme which interacts with the end of the chromosome in the following way: the chromosome end binds to the binding site and the enzyme is able to catalytically add the T2AG3 repeats thereby extending the 3 prime end of the telomere, which then recurs over and over again in a processive manner, or the enzyme dissociates to find another chromosome to begin the process again. Now our drugs are specific inhibitors of that enzyme and we have shown them to active against all of the major cancers in vitro and in a growing list of tumors in animal models. The parent compound is 163 which is a 13 mer oligonucleotide that uses a proprietary chemistry that affects the way the drug works. And here's the long list of tumor types – all of the major cancers in man – against which the drug is active and the growing list of models in animals, which again show activity, some of which I'll describe to you. And of course our issued IP protects the compound fully, including its use to treat cancer. The way the drug works is very simple. It binds tightly to the active site prohibiting the binding reaction of the drug–of the enzyme to the telomere. It has no antisense activity. Now the clinical version of the compound is 163L. It is lipidated covalently with a C16 molecule that as you will see in a moment has major impact on the utility of the drug. We have GMP material in-house for the Phase I/II; we're now doing fill and finish and we are in the last stages of our IND enabling studies. Now why did we choose 163L? Well, the following few slides make the point. First, if you look at the concentration required to inhibit the enzyme telomerase in various cancer cells, 163L is from 2 to 10 times more potent than its parent, 163. Moreover, if we move into animals, in a model of multiple myeloma, a lower dose of 163L is more potent than a higher dose of 163 in terms of inhibiting telomerase in the tumor cells in the animal and causing a reduction in telomere length, the object of the exercise. If you look more traditionally at the progression of tumors in animal models, here done for liver cancer, again we show that there's no significant difference here between a low dose of 163L versus a – I'm sorry, low dose of 163L versus a higher dose of 163, so a 70% reduction of the dose of 163L is as effective as 163 if you measure tumor growth reduction, telomerase inhibition, or decreased tumor cell proliferation. Moreover, we have significant inhibition of telomerase after a, for 7 days after a single IV dose of 163L, and again, enormous differences in potency. Great inhibition for 7 days after a single IV injection for a low dose of 163L which is superior in terms of enzyme inhibition to a much higher dose of 163. So I think we've made the point.
Now, the reason for this is the kinetics of the compounds are very, very different and there is a very–there is a lot of tissue accumulation of 163L in animals. This is data from rodents; we have moved up through monkeys which has enabled us to make the calculation that we can achieve therapeutic levels of the drug in man with a single IV injection once per week. So, in terms of news flow going forward: first, there'll be multiple presentations at AACR and ASH first on new tumor types that are susceptible to this drug; second, interesting studies on synergy between 163L and other chemotherapy agents: Taxol in ovarian cancer, Melfolan in myeloma and melanoma, and Doxirubicin in liver cancer and then most importantly, early next year we'll be filing our IND and beginning our Phase I/II trial in hematologic malignancies.
Now, the second program, a little more advanced than the drug, is the telomerase vaccine. And like the drug, multiple people are beginning to present, including us, data that shows broad spectrum activity of vaccination strategies designed against telomerase. And this is true we think for our platform as well. This is the schema for the trial design at Duke. These are metastatic prostate cancer patients who are hormone refractory. The protocol is quite simple. They are leukapherised once; this provides enough blood to make 12 to 18 vaccine doses. They have been randomized to either a telomerase RNA loaded platform or a LAMP telomerase loaded platform which I'll explain in a moment. And then these patients are either given 3 weekly doses of their DCs or 6 weekly doses. The last leukaphersis is only to collect blood for the immunologic monitoring; it has nothing to do with the therapy. And I would make the point that this process has not failed a single time. So the ability to make 12 to18 vaccine injections from a single blood collection seems quite robust. So, what do the results show? In the low dose group, first, 11 out of 12 patients responded immunologically and there were absolutely no adverse reactions. Many of these patients have been followed now for over 18 months. So if you look at the group that got telomerase as antigen, all but one responded with CD8 killer cells against telomerase, rather, when we look at CD4 cells, however, in the TERT group there was only one patient who actually had a measurable CD4 response. The situation was quite different when we used LAMP TERT. We maintained a uniform CD8 killer T cell response, but now we also induced helper CD4 cells which is critical for the anti tumor activity of the CD8s. So LAMP TERT is the formulation going forward. Now the story gets a little more interesting when we look at the high dose group, and the, as you'll see, the immune response increased dramatically after 6 vaccinations compared to 3, and again, all 8 patients, absolutely no adverse reactions. So what happens here, this is a very different scale now. After the, here are the 6 immunizations and you can see the profound level of CD8 T cells that are specific for telomerase that were engendered by the vaccine. This peak level is between 1 and 2 percent of the total T cell pool. These are the kinds of levels you get in infectious disease that results in clearing the infection; it hasn't been reported before in cancer vaccination. And once again, if you look at LAMP versus TERT, we see significant CD4 induction with LAMP and you don't see that with telomerase–with just TERT alone. The clinical impact of this is measured in two ways. First, there are 10 patients that had measurable circulating tumor cells in their blood before the vaccine and 9 out of 10 reduced or cleared them to zero. Here are two examples of two subjects whose circulating tumor cells were reduced a thousand fold concomitant with the induction of the T cells against telomerase. A more traditional measure of efficacy is PSA doubling time, the time it takes for the PSA level to double. In the low dose group, we saw no effect. But in the high dose group, we saw a statistically significant increase in the PSA doubling time to over 100 months, essentially a flat line suggesting no progression of disease during the time the T cells were present. So going forward now, there'll first be a full length publication of this Duke study. We are now initiating several new studies that use improvements that we licensed from Merix, now Argos. We are transferring the manufacturing process into Geron with the intention of picking a CRO–a CMO for the manufacturing, and of course this all will be leading up to our eventual filing of our own IND on the program.
The oncolytic virus. This is a technology that relies on the promoter of telomerase, the on/off switch. We have licensed this to Cell Genesys who is now developing the program. Recently, in Cancer Gene Therapy, there was a very good publication that shows, first, single dose efficacy in a model of human prostate cancer with one IV injection of the virus, shown here in green, and dramatic synergy of the virus - again, single injection - here in a model of liver cancer, showing synergy with doxirubicin – virus alone, doxirubicin alone, and both compounds together. This compound is being developed by Cell Genesys and going forward we expect over the next months a decision by them as to which formulation of our promoter to put into their virus for clinical development.
Lastly, we do have a diagnostic program. We commercialized 12 kits for the research market and have a relationship with Roche who has now developed our diagnostic into a format for bladder cancer which in a 300 patient study in Germany showed a positive predictive value of 84% – that means 84 out of 100 people who have telomerase in their urine have bladder cancer. This is being further developed by Roche now and we do expect if all things go well that this could be commercialized in Europe as early as ‘06. And of course we have a controlling intellectual property estate that covers all of these products broadly and deeply, as we've been into telomerase now for nearly 10 years. We were the first to clone the enzyme.
Turning now to the stem cell based portfolio. The headline here is that we've positioned this technology for clinical development, and these are some of the accomplishments. We've now learned how to make 8 different therapeutic cell types from our stem cell lines. All of them show normal biology and 6 of them are in preclinical animal testing. We have two embryonic lines that are fully qualified for human use. That's important. We are now in the process of, having validated our GMP plant, in making a master cell bank from these qualified lines. Because of the scaleability of the production of these products for the first time, we have a high margin, product based business model, as opposed to a service model, which has been the case before. And, like telomerase, because we were in this field first, we have a controlling intellectual property estate. Now I can't emphasize enough that because the embryonic stem cells express telomerase, they are immortal and they are stable. We've had these lines over 600 - 700 population doublings without losing their pluripotency or their ability to turn into useful therapeutic products. And that's what enables the manufacturing of banks from which the therapeutic products are made. So the process is just like a monoclonal antibody or a biological drug – for the first time in cell therapy. Let's jump into a couple of examples of the technology.
First, the glial cell, our product for spinal cord injury. You may have seen the movies I used to show of these animals who are given an injury under anaesthesia and, in red, have a deficit in their lower limbs and in their tail – they can't support weight in their lower limbs. Animals that receive human glial cells about a week after the injury show significantly improved locomotion. The animals support their weight on their hind limbs, they have – carry their tail erect in the air. More importantly, when the animals are sacrificed and we asked what caused the improvement, first you see a striking increase in new axon growth. The oligodendrocytes are providing factors which enable new nerve growth right at the site of the injury which is where the cells are, of course, injected. More obvious is the myelination that occurs. Here is the injured animal with very sparse myelin in the injured area. Here are the animals that received the cells. All these small circles are human myelin surrounding the rat's axon, which is why the animals recover. If you look at one of these circles under high power, it's really striking because the architecture in the animal treated with cells, cartoon here, where one oligodendrocyte simultaneously myelinates multiple axons is exactly what you see in the animal. Here is the oligodendrocyte, and here are multiple rat axons being myelinated by the same cell. So this illustrates the principle generally – that embryonic stem cell derived cells think they're making a new organ. So this is actual re-engineering of the injured tissue in the spinal cord. We are – proceeded now to begin designing the clinical trial protocol which will take patients with complete lesions in the lower thoracic region and during the time of normal spinal stabilization surgery which all patients undergo, these cells will be injected, much as they were injected in the animals and we will use validated instruments to demonstrate recovery of sensory and motor function. So going forward we'll -- there'll be several full length manuscripts describing the animal work done by our collaborator, Hans Kierstead at UC Irvine and we will be now beginning our master cell bank from which this product will be manufactured. We expect to file the IND here at the very beginning of ‘06 with a clinical trial to follow very shortly thereafter.
Another cell type that's moving along rapidly is the cardiomyocyte, heart muscle cells. Again, all the markers show these are unequivocally truly human cardiomyocytes. These cells respond to cardiac drugs normally, illustrating a second general principle. Not only will the cells restore organ function, but they will restore drug responsiveness in that organ. It's critical that when these cells are placed in a left ventricle that's been infarcted that that patient's response to cardiac drugs of the new cells is equal to that of the old cells, and that's what these data predict. The ventricular depolarization, the electrical characteristics of these cells, are absolutely normal for adult human ventricular myocytes. When these are, cells are engrafted, transplanted into animals, they exuberantly engraft and they induce new blood vessel formation. Their sarcomeric myosin lines up with that of the host cell, and in a model of infarction, in which we infarct the mouse, inject the human cells right into the infarct, sew the animal up, come back a month later and measure cardiac output, the embryonic stem cell group has actually restored the animal's cardiac output virtually to normal. And this is with a massive left ventricular infarct which the LAB has been completely tied off. Again, terrific animal model data indicative of progress. This story will be presented at the Cell Transplant Society meetings in November.
Thirdly are islets where we're also making progress. We have in fact now derived human islets from human embryonic stem cells. They make glucagon, somatotropin, and insulin. They secrete insulin in appropriate dose response fashion to glucose. We are in animal studies now at Edmonton where the Edmonton Protocol was invented and I'm happy to say that we now have some animal model proof of efficacy. We are significantly prolonging the animal's life, a diabetic animal, and we're now detecting human insulin in the blood of those animals – a giant step toward proof of concept.
Now there's been a lot of talk about immune suppression required for these kinds of therapies, so I want to clarify the situation here, and there are two take home points. First, embryonic stem cells are immune privileged, they have retained the capacity that is in the implanting blastocyst to prevent immune detection of those cells. I'll show you that in a moment. And secondly, we have a way to actually tolerize the patient specifically to the cells he or she would receive as a form of therapy. So. First, this is a mixed lymphocyte reaction – if I mixed my blood with yours, our blood would react to one another because we're not genetically identical. That's what you see here in a dose response fashion, the allo reaction, whereas if I mix my own blood with myself, there's no reaction. Surprisingly, when we put either undifferentiated human embryonic stem cells or even differentiated descendants of them, there is no mixed lymphocyte reaction. The blood cells of humans do not recognize these cells. Therefore, the amount of immune suppression we need is very low. More importantly, we have a way to completely tolerize patients to these cells. And that's because we now can make hematopoetic cells from embryonic stem cells and -- this'll be published later this year from our collaborators in Canada -- the stem cell derived hematopoetic cells form permanent engraftment in the gold standard animal of bone marrow transplantation. That means that we can give, in the following cartoon, hematopoetic cells made from embryonic stem cell line A to the patient prior to he or she getting the therapeutic cell and this dose of hematopoetic cells will tolerize that patient to any cell type made from the same cell line – that's been worked out in man in organ transplants and bone marrow transplantation. Now that's only possible with embryonic stem cells because each line is pluripotent. We can make all eight therapeutic cells from each of our undifferentiated lines.
Last cell type I'll mention quickly is not one for therapy, but it's one for a major problem in drug discovery, hepatic toxicity and drug metabolism. These are liver cells that we make from embryonic stem cells and they express inducible phase 1 and phase 2 drug metabolizing enzymes. This is a big problem for pharma – to identify early in the process drugs that are toxic and to really quantify before a human trial begins, what a human liver will do to the drug in terms of metabolism. That can all now be done in vitro. And we expect to beta test these cells in pharma in ‘05.
o lastly the manufacturing is extremely scalable and this is really critically important to understand for uniformity of the product, for tight product release specs, and for low cost of goods. So four passages of the undifferentiated cells in our system gives you a thousand fold amplification of the cell types. Again, we have a culture system that is completely defined, it's a defined medium with a single growth factor. The cells have been qualified, there's no serum. It's done in a way that's absolutely compatible with GMP processing. And to finally illustrate the scaleability, most of our master cell banks will have about 200 vials of embryonic stem cells in them. At today's efficiency if we were to convert all 200 vials of one of our master cell banks into glial cells, we'd have enough glial doses for 1.3 million patients – that's five times the prevalence of spinal cord injury in the United States.
We have a very broad and deep intellectual property portfolio that covers not only generic IP for how you grow the cells and transplant related IP, but each of the cell types that we make, as composition of matter, just as if it were a single entity compound.
So, I've run out of time. Here are the next steps that I've mentioned in passing today that illustrate the transition the company has now successfully made from a company that has pioneered the molecular biology of telomerase leading to first in class anti tumor treatments and for the first time we believe, scalable cell therapy products and the company is spending the majority of its resources on three INDs, the drug, the vaccine and the spinal cord injury product.
Thank you very much.
gruss meislo
www.wall street webcasting.com/webcast/rrshq4/gern/
October 26, 2004
We have quite a few companies in the conference and the schedule is tight, so, so why don't we get started. As a reminder, speakers have 20 minutes followed by a breakout session. I implore speakers to keep to time as best as they can so that other companies' investors get an equal opportunity here.
The first speaker today is from Geron, Tom Okarma, CEO and President and Tom will be in the breakout room at 8:20 in the Gramercy Room. Tom.
DR. OKARMA: Thanks, David. Good morning. Thanks for coming. So like everyone today, I'll be making forward looking statements so we refer you to our SEC filings for our risk factors.
Let's start today with who we are and what the game plan is. Historically, it's important to know that both therapeutic platforms evolved from our original core competence which is telomerase biology. In oncology, telomerase is the pan cancer target against which all of our products are directed, while in embryonic stem cells, the normal expression of telomerase allows for the production of scalable cells for therapy. Our strategic plan is - in oncology - is to build an oncology business by developing and commercializing our telomerase inhibitor drugs and our telomerase vaccine and by licensing rights to the oncolytic virus and telomerase diagnostics to others, while on the stem cell side, our objective is to first demonstrate human proof of concept with the spinal cord injury product and then to co-develop with partners products for heart failure, diabetes, musculoskeletal and neurologic diseases. So today we are a therapeutics product development company with our first cancer product in the clinic - the vaccine - our second to enter early next year - the drug - and the year after that our first embryonic stem cell product for spinal cord injury. So let's now jump down first into the oncology portfolio to get a sense of where we are.
Now telomerase for cancer is still the only clinically validated, universal and specific cancer target; that's important to recognize. This is a model of the enzyme which interacts with the end of the chromosome in the following way: the chromosome end binds to the binding site and the enzyme is able to catalytically add the T2AG3 repeats thereby extending the 3 prime end of the telomere, which then recurs over and over again in a processive manner, or the enzyme dissociates to find another chromosome to begin the process again. Now our drugs are specific inhibitors of that enzyme and we have shown them to active against all of the major cancers in vitro and in a growing list of tumors in animal models. The parent compound is 163 which is a 13 mer oligonucleotide that uses a proprietary chemistry that affects the way the drug works. And here's the long list of tumor types – all of the major cancers in man – against which the drug is active and the growing list of models in animals, which again show activity, some of which I'll describe to you. And of course our issued IP protects the compound fully, including its use to treat cancer. The way the drug works is very simple. It binds tightly to the active site prohibiting the binding reaction of the drug–of the enzyme to the telomere. It has no antisense activity. Now the clinical version of the compound is 163L. It is lipidated covalently with a C16 molecule that as you will see in a moment has major impact on the utility of the drug. We have GMP material in-house for the Phase I/II; we're now doing fill and finish and we are in the last stages of our IND enabling studies. Now why did we choose 163L? Well, the following few slides make the point. First, if you look at the concentration required to inhibit the enzyme telomerase in various cancer cells, 163L is from 2 to 10 times more potent than its parent, 163. Moreover, if we move into animals, in a model of multiple myeloma, a lower dose of 163L is more potent than a higher dose of 163 in terms of inhibiting telomerase in the tumor cells in the animal and causing a reduction in telomere length, the object of the exercise. If you look more traditionally at the progression of tumors in animal models, here done for liver cancer, again we show that there's no significant difference here between a low dose of 163L versus a – I'm sorry, low dose of 163L versus a higher dose of 163, so a 70% reduction of the dose of 163L is as effective as 163 if you measure tumor growth reduction, telomerase inhibition, or decreased tumor cell proliferation. Moreover, we have significant inhibition of telomerase after a, for 7 days after a single IV dose of 163L, and again, enormous differences in potency. Great inhibition for 7 days after a single IV injection for a low dose of 163L which is superior in terms of enzyme inhibition to a much higher dose of 163. So I think we've made the point.
Now, the reason for this is the kinetics of the compounds are very, very different and there is a very–there is a lot of tissue accumulation of 163L in animals. This is data from rodents; we have moved up through monkeys which has enabled us to make the calculation that we can achieve therapeutic levels of the drug in man with a single IV injection once per week. So, in terms of news flow going forward: first, there'll be multiple presentations at AACR and ASH first on new tumor types that are susceptible to this drug; second, interesting studies on synergy between 163L and other chemotherapy agents: Taxol in ovarian cancer, Melfolan in myeloma and melanoma, and Doxirubicin in liver cancer and then most importantly, early next year we'll be filing our IND and beginning our Phase I/II trial in hematologic malignancies.
Now, the second program, a little more advanced than the drug, is the telomerase vaccine. And like the drug, multiple people are beginning to present, including us, data that shows broad spectrum activity of vaccination strategies designed against telomerase. And this is true we think for our platform as well. This is the schema for the trial design at Duke. These are metastatic prostate cancer patients who are hormone refractory. The protocol is quite simple. They are leukapherised once; this provides enough blood to make 12 to 18 vaccine doses. They have been randomized to either a telomerase RNA loaded platform or a LAMP telomerase loaded platform which I'll explain in a moment. And then these patients are either given 3 weekly doses of their DCs or 6 weekly doses. The last leukaphersis is only to collect blood for the immunologic monitoring; it has nothing to do with the therapy. And I would make the point that this process has not failed a single time. So the ability to make 12 to18 vaccine injections from a single blood collection seems quite robust. So, what do the results show? In the low dose group, first, 11 out of 12 patients responded immunologically and there were absolutely no adverse reactions. Many of these patients have been followed now for over 18 months. So if you look at the group that got telomerase as antigen, all but one responded with CD8 killer cells against telomerase, rather, when we look at CD4 cells, however, in the TERT group there was only one patient who actually had a measurable CD4 response. The situation was quite different when we used LAMP TERT. We maintained a uniform CD8 killer T cell response, but now we also induced helper CD4 cells which is critical for the anti tumor activity of the CD8s. So LAMP TERT is the formulation going forward. Now the story gets a little more interesting when we look at the high dose group, and the, as you'll see, the immune response increased dramatically after 6 vaccinations compared to 3, and again, all 8 patients, absolutely no adverse reactions. So what happens here, this is a very different scale now. After the, here are the 6 immunizations and you can see the profound level of CD8 T cells that are specific for telomerase that were engendered by the vaccine. This peak level is between 1 and 2 percent of the total T cell pool. These are the kinds of levels you get in infectious disease that results in clearing the infection; it hasn't been reported before in cancer vaccination. And once again, if you look at LAMP versus TERT, we see significant CD4 induction with LAMP and you don't see that with telomerase–with just TERT alone. The clinical impact of this is measured in two ways. First, there are 10 patients that had measurable circulating tumor cells in their blood before the vaccine and 9 out of 10 reduced or cleared them to zero. Here are two examples of two subjects whose circulating tumor cells were reduced a thousand fold concomitant with the induction of the T cells against telomerase. A more traditional measure of efficacy is PSA doubling time, the time it takes for the PSA level to double. In the low dose group, we saw no effect. But in the high dose group, we saw a statistically significant increase in the PSA doubling time to over 100 months, essentially a flat line suggesting no progression of disease during the time the T cells were present. So going forward now, there'll first be a full length publication of this Duke study. We are now initiating several new studies that use improvements that we licensed from Merix, now Argos. We are transferring the manufacturing process into Geron with the intention of picking a CRO–a CMO for the manufacturing, and of course this all will be leading up to our eventual filing of our own IND on the program.
The oncolytic virus. This is a technology that relies on the promoter of telomerase, the on/off switch. We have licensed this to Cell Genesys who is now developing the program. Recently, in Cancer Gene Therapy, there was a very good publication that shows, first, single dose efficacy in a model of human prostate cancer with one IV injection of the virus, shown here in green, and dramatic synergy of the virus - again, single injection - here in a model of liver cancer, showing synergy with doxirubicin – virus alone, doxirubicin alone, and both compounds together. This compound is being developed by Cell Genesys and going forward we expect over the next months a decision by them as to which formulation of our promoter to put into their virus for clinical development.
Lastly, we do have a diagnostic program. We commercialized 12 kits for the research market and have a relationship with Roche who has now developed our diagnostic into a format for bladder cancer which in a 300 patient study in Germany showed a positive predictive value of 84% – that means 84 out of 100 people who have telomerase in their urine have bladder cancer. This is being further developed by Roche now and we do expect if all things go well that this could be commercialized in Europe as early as ‘06. And of course we have a controlling intellectual property estate that covers all of these products broadly and deeply, as we've been into telomerase now for nearly 10 years. We were the first to clone the enzyme.
Turning now to the stem cell based portfolio. The headline here is that we've positioned this technology for clinical development, and these are some of the accomplishments. We've now learned how to make 8 different therapeutic cell types from our stem cell lines. All of them show normal biology and 6 of them are in preclinical animal testing. We have two embryonic lines that are fully qualified for human use. That's important. We are now in the process of, having validated our GMP plant, in making a master cell bank from these qualified lines. Because of the scaleability of the production of these products for the first time, we have a high margin, product based business model, as opposed to a service model, which has been the case before. And, like telomerase, because we were in this field first, we have a controlling intellectual property estate. Now I can't emphasize enough that because the embryonic stem cells express telomerase, they are immortal and they are stable. We've had these lines over 600 - 700 population doublings without losing their pluripotency or their ability to turn into useful therapeutic products. And that's what enables the manufacturing of banks from which the therapeutic products are made. So the process is just like a monoclonal antibody or a biological drug – for the first time in cell therapy. Let's jump into a couple of examples of the technology.
First, the glial cell, our product for spinal cord injury. You may have seen the movies I used to show of these animals who are given an injury under anaesthesia and, in red, have a deficit in their lower limbs and in their tail – they can't support weight in their lower limbs. Animals that receive human glial cells about a week after the injury show significantly improved locomotion. The animals support their weight on their hind limbs, they have – carry their tail erect in the air. More importantly, when the animals are sacrificed and we asked what caused the improvement, first you see a striking increase in new axon growth. The oligodendrocytes are providing factors which enable new nerve growth right at the site of the injury which is where the cells are, of course, injected. More obvious is the myelination that occurs. Here is the injured animal with very sparse myelin in the injured area. Here are the animals that received the cells. All these small circles are human myelin surrounding the rat's axon, which is why the animals recover. If you look at one of these circles under high power, it's really striking because the architecture in the animal treated with cells, cartoon here, where one oligodendrocyte simultaneously myelinates multiple axons is exactly what you see in the animal. Here is the oligodendrocyte, and here are multiple rat axons being myelinated by the same cell. So this illustrates the principle generally – that embryonic stem cell derived cells think they're making a new organ. So this is actual re-engineering of the injured tissue in the spinal cord. We are – proceeded now to begin designing the clinical trial protocol which will take patients with complete lesions in the lower thoracic region and during the time of normal spinal stabilization surgery which all patients undergo, these cells will be injected, much as they were injected in the animals and we will use validated instruments to demonstrate recovery of sensory and motor function. So going forward we'll -- there'll be several full length manuscripts describing the animal work done by our collaborator, Hans Kierstead at UC Irvine and we will be now beginning our master cell bank from which this product will be manufactured. We expect to file the IND here at the very beginning of ‘06 with a clinical trial to follow very shortly thereafter.
Another cell type that's moving along rapidly is the cardiomyocyte, heart muscle cells. Again, all the markers show these are unequivocally truly human cardiomyocytes. These cells respond to cardiac drugs normally, illustrating a second general principle. Not only will the cells restore organ function, but they will restore drug responsiveness in that organ. It's critical that when these cells are placed in a left ventricle that's been infarcted that that patient's response to cardiac drugs of the new cells is equal to that of the old cells, and that's what these data predict. The ventricular depolarization, the electrical characteristics of these cells, are absolutely normal for adult human ventricular myocytes. When these are, cells are engrafted, transplanted into animals, they exuberantly engraft and they induce new blood vessel formation. Their sarcomeric myosin lines up with that of the host cell, and in a model of infarction, in which we infarct the mouse, inject the human cells right into the infarct, sew the animal up, come back a month later and measure cardiac output, the embryonic stem cell group has actually restored the animal's cardiac output virtually to normal. And this is with a massive left ventricular infarct which the LAB has been completely tied off. Again, terrific animal model data indicative of progress. This story will be presented at the Cell Transplant Society meetings in November.
Thirdly are islets where we're also making progress. We have in fact now derived human islets from human embryonic stem cells. They make glucagon, somatotropin, and insulin. They secrete insulin in appropriate dose response fashion to glucose. We are in animal studies now at Edmonton where the Edmonton Protocol was invented and I'm happy to say that we now have some animal model proof of efficacy. We are significantly prolonging the animal's life, a diabetic animal, and we're now detecting human insulin in the blood of those animals – a giant step toward proof of concept.
Now there's been a lot of talk about immune suppression required for these kinds of therapies, so I want to clarify the situation here, and there are two take home points. First, embryonic stem cells are immune privileged, they have retained the capacity that is in the implanting blastocyst to prevent immune detection of those cells. I'll show you that in a moment. And secondly, we have a way to actually tolerize the patient specifically to the cells he or she would receive as a form of therapy. So. First, this is a mixed lymphocyte reaction – if I mixed my blood with yours, our blood would react to one another because we're not genetically identical. That's what you see here in a dose response fashion, the allo reaction, whereas if I mix my own blood with myself, there's no reaction. Surprisingly, when we put either undifferentiated human embryonic stem cells or even differentiated descendants of them, there is no mixed lymphocyte reaction. The blood cells of humans do not recognize these cells. Therefore, the amount of immune suppression we need is very low. More importantly, we have a way to completely tolerize patients to these cells. And that's because we now can make hematopoetic cells from embryonic stem cells and -- this'll be published later this year from our collaborators in Canada -- the stem cell derived hematopoetic cells form permanent engraftment in the gold standard animal of bone marrow transplantation. That means that we can give, in the following cartoon, hematopoetic cells made from embryonic stem cell line A to the patient prior to he or she getting the therapeutic cell and this dose of hematopoetic cells will tolerize that patient to any cell type made from the same cell line – that's been worked out in man in organ transplants and bone marrow transplantation. Now that's only possible with embryonic stem cells because each line is pluripotent. We can make all eight therapeutic cells from each of our undifferentiated lines.
Last cell type I'll mention quickly is not one for therapy, but it's one for a major problem in drug discovery, hepatic toxicity and drug metabolism. These are liver cells that we make from embryonic stem cells and they express inducible phase 1 and phase 2 drug metabolizing enzymes. This is a big problem for pharma – to identify early in the process drugs that are toxic and to really quantify before a human trial begins, what a human liver will do to the drug in terms of metabolism. That can all now be done in vitro. And we expect to beta test these cells in pharma in ‘05.
o lastly the manufacturing is extremely scalable and this is really critically important to understand for uniformity of the product, for tight product release specs, and for low cost of goods. So four passages of the undifferentiated cells in our system gives you a thousand fold amplification of the cell types. Again, we have a culture system that is completely defined, it's a defined medium with a single growth factor. The cells have been qualified, there's no serum. It's done in a way that's absolutely compatible with GMP processing. And to finally illustrate the scaleability, most of our master cell banks will have about 200 vials of embryonic stem cells in them. At today's efficiency if we were to convert all 200 vials of one of our master cell banks into glial cells, we'd have enough glial doses for 1.3 million patients – that's five times the prevalence of spinal cord injury in the United States.
We have a very broad and deep intellectual property portfolio that covers not only generic IP for how you grow the cells and transplant related IP, but each of the cell types that we make, as composition of matter, just as if it were a single entity compound.
So, I've run out of time. Here are the next steps that I've mentioned in passing today that illustrate the transition the company has now successfully made from a company that has pioneered the molecular biology of telomerase leading to first in class anti tumor treatments and for the first time we believe, scalable cell therapy products and the company is spending the majority of its resources on three INDs, the drug, the vaccine and the spinal cord injury product.
Thank you very much.
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