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BIO Emerging Company Investor Forum
13 October 2004
Our final presenting company this afternoon is Geron Corporation of Menlo Park. Geron develops therapeutic and diagnostic products for cancer and cell based therapeutics using its embryonic stem cell technology. The company's lead product is in Phase II studies for the treatment of prostate cancer. Presenting for Geron Corporation, CEO Thomas Okarma.
DR. OKARMA: Thank you and good afternoon. Thanks for coming. Surprisingly, I too will be making forward looking statements, so we call your attention to our risk factors in our most recent SEC filings.
Well, let's start really with who we are and what the game plan is. Historically, both of our therapeutic platforms evolved from our original core competence – telomerase biology. In the case of cancer, telomerase is expressed by all cancers – it's a pan cancer target – so our oncology products are directed against telomerase. On the embryonic stem cell side, telomerase is normally expressed in these cells, enabling for the first time scalable production of cell therapy products.
Our strategy is first to build an oncology business by developing and commercializing our inhibitor drug and our vaccine and by licensing oncolytic virus and diagnostic rights to others such as Cell Genesys and Roche. On the cell therapy side, the strategy is to first achieve proof of principle with our stem cell program which is a year away from our IND filing and to then co-develop with partners other cell therapy products for heart failure, diabetes, neurologic and musculoskeletal diseases. So let's now lower the plane a bit and talk quickly about our oncology program based upon telomerase – still the best clinically validated, universal and specific cancer target. Telomerase achieves cellular immortality for cells by adding DNA back to the ends of chromosomes, called telomeres; so the enzyme is processive and continues to add T2AT3 repeats, thereby elongating the telomere and preventing the cell from reaching apoptosis.
Our first program is based upon a drug that specifically inhibits this enzyme. We have demonstrated it to be active in a wide variety of all major human types–cancer types, in vitro and in vivo. The original compound is called 163; it's a 13 mer that specifically inhibits telomerase and as I mentioned it's been active literally against all major cancers of man which express telomerase. The mechanism of action is straightforward: the drug blocks the active site, shutting down the enzyme. The clinical formulation is 163L, which has a lipid molecule covalently attached to one end. This lipid molecule makes enormous difference. Our GMP manufacturing has been scaled. We have GMP material in house for the Phase I/II which should start next year early. Now, why 163L? First, it's from 2 to 10 fold more potent than 163 in vitro in a wide variety of tumors. That increased potency is also expressed in vivo where a lesser dose of 163 is more powerful in inhibiting telomerase and resulting in telomere shortening. Bioavailability is dramatically improved – a 70 percent reduced dose of 163L is just as effective as a full dose of 163 whether you look at reduced tumor growth, reduced telomerase activity, decreased tumor cell proliferation. The kinetics of this drug are extraordinarily important – a single IV dose of this drug produces telomerase inhibition for more than a week in animals. We have finished now most of our pharmacokinetic work that shows a dramatic difference in the tissue half life of this drug; this has gone through monkey studies. It's enabled us to do modeling that strongly suggests a single IV dose of this drug will easily achieve therapeutic tissue levels. So going forward the milestones are, first, multiple publications over the next months on 163L as a single agent in new tumor types, extending the list of tumors that succumb to the drug. Second, multiple publications at ASH and AACR that describe combination use of 163L that does not extend the toxicity of the second drug – synergy with Taxol in ovarian cancer; Melfolan in myeloma and melanoma; and with Doxorubicin in liver cancer; and, most importantly, the filing of our IND in the first quarter of next year and the initiation of our Phase I/II in hematologic malignancy.
Our second program, in the clinic, is our telomerase vaccine which, like the drug, is demonstrating widespread use – activity against a long list of tumor types because of the ubiquity of telomerase in cancers. The Phase I/II completed at Duke was a randomized study testing two different doses in two different forms of the telomerase antigen. The first thing the protocol proved is that the manufacturing process is efficient and reliable – one blood draw provides enough cells for 12 to 15 vaccinations. The results of the study set a new bar for cancer vaccination. First, the telomerase antigen gave responses in T cells for all but one patient. And secondly, the altered form of telomerase using a signaling sequence not only gave us responses of CD 8 killer cells, but also dramatic responses in CD 4 help, which is required for a robust effect. The story got exciting in the high dose group – again, no adverse reactions but a dramatic increase in T cell anti telomerase levels. These are 4 of the 8 high dose patients whose CD 8 cells are between 1 and 2 percent of the total circulating T cell pool now directed against telomerase. Despite that high level of T cell immunity, absolutely no adverse reactions. Efficacy evidenced by two surrogate markers. First, of the 10 patients who had elevated levels of circulating prostate cancer cells in their blood, 9 of them lost those tumor cells; some of them with a decrease as much as a thousand fold. The cells stopped metastatic disease in its tracks. Secondly, in the high dose group we had a highly statistically significant prolongation of the PSA doubling time, from a pre vaccination value of 2.9 to a post vaccination value of over 100 months. That's essentially stable disease.
So, our milestones in the next few months: full length publication of this study in a very well known peer review journal which will set a new standard in the field of cancer vaccination. We're now transferring this process to Geron with the ultimate aim of selecting a CMO for the manufacturing of the cells. We're initiating several new small studies at Duke to optimize the process using modifications we've also licensed from Merix to make the vaccine more potent, reduce the ex vivo processing and testing, of course, the boost strategy to maintain the T cell levels for a longer period of time.
Quickly turning to the oncolytic virus. This is licensed now to Cell Genesys. We've recently published work in Cancer Gene Therapy that shows a single injection of this virus to be effective in an animal model of human prostate cancer and used in conjunction with Doxorubicin, virtually curative in a model of liver cancer. This product uses the telomerase promoter that restricts the virus replication only to telomerase positive tumor cells. Soon we will hear the decision by Cell Genesys to move this into clinical development.
Lastly, diagnostics partnered with Roche. They have done a 300 patient study in Europe demonstrating this assay has a positive predictive value of 84% in bladder cancer – that means 84 out of 100 people with telomerase in their urine have bladder cancer. The AUA recommends over 15 repeat cystoscopies over 3 years after the diagnosis of bladder cancer because it always recurs. We plan to substitute this assay for those procedures. If all goes well, this could be marketed in Europe in ‘06.
And of course intellectual property that protects the platform and all of these specific products.
Turning to the embryonic stem cell side, a different approach -- all based on perhaps the most marvelous stem cell ever discovered. We've made dramatic progress on this platform. We have two lines that are now fully qualified for human use and both of those lines produce now 8 different therapeutic cell types, each of which has a specific disease application.
Our first application will be in spinal cord injury and we are on track to file our first IND a year from now. These cells express high levels of telomerase without the genetic instability that characterizes cancer cells. So, in these cell types telomerase is an asset and it enables for the first time the generation of scalable manufacturing banks that enable us to make these cell types with scalable, multi dose production lots at enormously low cost of goods. This is like manufacturing a biological drug or a monoclonal antibody. The business model is, starting with the renewable source - embryonic stem cells - we have 8 discrete manufacturing recipes that have as their output frozen, functional cells that are shipped frozen and stored frozen for off the shelf use and we're actually doing this today with our investigators in our animal models of spinal cord injury.
So let's look at this spinal cord injury cell, it's called a glial progenitor, a cell that makes oligodendrocytes. We've shown lots of times the animal, movies which illustrate this fact. If we inject these human cells into the injury of an animal, we significantly improve the animal's function. The control animals drag their tails about the cage; they don't have use of their hind limbs. The animals that receive cells support weight on all four legs and their tail is erect. Why did this occur? When we sacrifice the animals we see two striking findings. First, right where the cells are injected there is exuberant new neural growth. The glial cells make trophic factors that enable the nerves to regrow. Secondly, there is exuberant myelination; we are reinsulating the nerve fibers in the injured spinal cord. This is highly significant. Most importantly, the tissue architecture shown in the cartoon where one oligodendrocyte can myelinate multiple neurons is exactly replicated in these animals. Here is the human glial cell with multiple axons being wrapped with myelin by these cells. So this makes the general point of what this platform can do: restore organ function in an injury or chronic disease by restoring tissue funciton. We have gone so far now as to begin to develop our clinical protocol.
[So this makes the general point of what this platform can do: restore organ function in an injury or chronic disease by restoring tissue function. We have gone so far now as to begin to develop our clinical protocol.]
Patients who get spinal cord injury all go to spinal stabilization surgery within a week and it's at that time that these cells will be injected. The protocol will be a standard dose escalating protocol first starting at thoracal lumbar injuries, then moving up to cervical injuries where the endpoint will be decreased time on a respirator. Milestones going forward is full length publication of the animal work and the progression of our IND enabling studies. Today we are making a GMP embryonic stem cell master bank from which this product will be manufactured. And the IND we expect to file Q4 next year.
Other cell types behind the glial cell. Cardiomyocytes which express all of the right markers showing them to be true human heart muscle cells; moreover, they respond in normal dose response fashion to cardiac drugs, illustrating the second principle of the platform – not only will the cells restore organ function, but they will also restore the organ function's response to drugs which, in the case of heart failure, is lost. These cells have normal electrical properties, predicting their normal function when transplanted. When we transplant them into animals they engraft exuberantly and they integrate with the animal's heart muscle cell, and as striking a result as the spinal cord injured rats – when we infarct an animal with a major left ventricular infarct and inject these human cells into the infarct, these cells a month later restore cardiac contractility back to normal.
Third cell type are the islets -- the big home run here. We know from the Edmonton Protocol that exogenous islets can cure the disease. Well, we have now produced islets. They make glucagon, they make somatotropin, and they make insulin in dose response fashion to glucose. Our first animal studies have demonstrated significant prolongation of life and human insulin in the plasma of the animals.
While you hear lots of talk about oh, these cells will be rejected immunologically – not true. First, we have published now that the embryonic stem cell is immune privileged. What does that mean? Normally when you mix cells of two different people, one person will react – it's called a mixed leukocyte reaction. They do not react to undifferentiated stem cells or cells differentiated from embryonic stem cells. Why? Because these cells have retained the immunosuppressive properties of the blastocyst. Pregnant women rarely immunologically reject an implanting embryo, which is an allograft – it has mother and father antigens. The reason is the embryo suppresses locally the immune response. So do embryonic stem cells. That tells us that we will need very low doses of immune suppression in our first clinical trials. We also now have evidence for a more permanent solution. One of the cell types we know how to make are hematopoetic cells and our collaborators in Canada have shown that the stem cell derived hematopoetic cells form stable chimeras in animals. That means that the animals have made, been made partly human in terms of their blood system. We know from bone marrow and organ transplant studies done in humans that that will tolerize the patient to the organ taken from the donor who gave the bone marrow; the same principle is applicable here. Because these cells are pluripotent, all of the 8 cell types are made from each line, we simply give the hematopoetic cells first to the patient which then tolerizes that patient to any functional cell made from the same line. So then we follow with the therapeutic cell to which that patient should be tolerant.
The last cell type on this side of the operation is the liver cell. This is a near term economic opportunity. These cells make inducible Phase I and Phase II drug metabolizing enzymes; they can therefore be used to rule out drugs early in development that are hepatotoxic, and more importantly, completely define hepatic metabolism of new drugs before they ever enter human clinical trials. We expect to beta test this cell type in pharma in ‘05.
Manufacturing. We mentioned we now have GMP pilot plans at Geron that are completely validated. The manufacturing of these products is truly scalable, which has never been achieved before in cell therapy. To give you an example: A 200 vial master cell bank. If it was all dedicated at today's efficiency to glial cells, the spinal cord product, we would have enough cells for 1.3 million glial doses – that is five times the prevalence of spinal cord injury in the United States.
Our IP is as broad on the stem cell side and deep as it is on the telomerase side. In addition to background IP, we have patents that cover not only how we make these cells, but the cells as composition of matter. Just as deep and broad as if these were single entity compounds.
So that's the Geron of today – a therapeutic product development company with its first product in the clinic, our vaccine; the second, the drug, to enter the clinic first quarter next year; and the surprise to most, the IND for the first embryonic stem cell product to be filed a year from now.
Thanks very much.
