Rodman & Renshaw
8th Annual Healthcare Conference
November 8, 2006
wsw.com
DR. OKARMA: Thank you for coming and good morning. Today I'm accompanied from the company by David Greenwood, our Executive Vice President and Chief Financial Officer and Alex Barkas, our Chairman.
I will be making forward looking statements this morning, so we refer you of course routinely to our risk factors as enumerated in our various SEC filings.
As most of you know, we're dedicated to develop and commercialize products that address unmet needs in cancer and chronic degenerative diseases, and this morning I'll be focusing my comments on five major programs: our cancer program based on telomerase -- our cancer drug in the clinic and our cancer vaccine; as well as a new entry, the telomerase activation program which we believe may have as much upside in chronic disease as our cancer programs have in oncology; and then I'll briefly summarize the status of our three human embryonic stem cell based programs - glial cells for spinal cord injury, cardiomyocytes for heart failure and islet cells for diabetes.
So let's start with 163L, our cancer drug. This compound targets telomerase which is a critical and universal target in oncology. Virtually all human cancers depend upon the continued expression of telomerase to continue to divide and spread throughout the body. We have a very broad preclinical dossier with this drug demonstrating that this compound literally impacts in vitro or in vivo all major human cancers. It's a very potent and specific inhibitor with a nanomolar IC50 and an excellent safety profile. We've modified the oligo with some proprietary chemistry which provides it with excellent pharmacokinetic and biodistribution properties and a long duration of action, allowing us to inject this drug intravenously once per week and seeing continuous telomerase inhibition. So I'll briefly summarize where we are in our two independent clinical trials: our Phase I/II in chronic lymphocytic leukemia and a Phase I in solid tumor cancers. First though I want to call your attention to a new and important discovery: that this drug is the only drug we're aware of that actually targets the so-called cancer stem cell. What's that about?
We now know in most tumors there are quiescent cancer stem cells which are resistant to chemotherapy and are responsible for clinical relapse. Our drug, in the first example of multiple myeloma, first we can separate in myeloma the myeloma cells into mature – (interruption) – mature myeloma cells, shown in yellow, so that over a several weeks in vitro exposure to our drug destroys the ability of the mature myeloma cells to proliferate. What is new is that when we expose the myeloma stem cell to the same compound, we see exactly the same phenomenon. This is really important and also impacts a wide variety of human tumors and will inform the way we use this drug in combination chemotherapy.
So our first program is in CLL. Why CLL? Well, first, it's a monoclonal B cell malignancy. The tumor cells circulate in blood and they're relatively constant over the course of disease. Additionally, we can subset patients on the basis of telomerase activity and telomere length in the CLL cells, giving us a very relevant biomarker which is of course our target. These are all advanced patients who have failed or are in relapse from two prior chemotherapy cycles. It is a sequential dose escalation trial, each patient receiving two four-week cycles of once per week IV infusion. There are now four US sites participating and the endpoints are of course fairly standard: establishing safety and tolerability of the compound; establishing any DLTs if there are any and the maximally tolerated dose. Most importantly, we are establishing the PK profile at escalating doses and at different dosing intervals and correlating that PK data with pharmacodynamic properties, tumor apoptosis as well as telomerase inhibition in the tumor cells so that we have a really accurate understanding of how to use this drug as a single agent. We're also in parallel studying this compound in solid tumor malignancies. This is an all-comers study. The tumors are predominantly lung, breast and colon and we're studying solid tumors separately because here we have the opportunity to expose patients with various different co-morbidities to the compound so we'll learn how liver failure or renal failure impact PD and PK parameters. This has a bit of a different design, although the patients still receive two four-week cycles of once a week infusion, we've reduced the infusion duration to 2 hours and actually have a second arm where we've been looking at a one hour infusion. It's a rapid dose escalation design so although this program only began in March of this year, it's actually now neck and neck in enrollment with the CLL trial. We have a single US site currently enrolling patients and the endpoints are predominantly the same as the CLL program.
So where we are now is that we're in the process of optimizing the infusion duration and completing the PK/PD analysis to determine the recommended dose, dosing interval and frequency for our Phase II studies. Now at the, this week's EORTC meeting in Czechoslovakia we'll be presenting the first data on the Phase I trials in CLL and solid tumors. The studies are early, but they're quite positive and really position us now to move into what we believe will be the therapeutic higher dose cohorts.
At the ASH meeting later this year in December we'll also be presenting some additional data from our clinical trial, as well as some data from our collaborators at Johns Hopkins on the impact of our drug in patient myeloma stem cells.
We're in the process of amending our INDs for additional tumor types and we are planning to look at multiple myeloma and lung cancer – myeloma because, again, of the stem cell activity and our documented synergy with Velcade and lung cancer for other reasons that will become clearer a little bit later in the year. We're clearly expanding our clinical trial site participations. We're finishing our preclinical drug combination studies because both the myeloma and lung cancer trials will have combination arms and we continue to improve upon the cost of goods and the purity of the drug with our partner Dow, who is our manufacturer. Clearly, as we progress into more advanced programs we need to reduce the cost and improve upon the purity of the compound. So those studies are in process.
Let's turn now to the telomerase vaccine which is also our program to target telomerase, but this vaccine targets telomerase in a different way. We now know that all tumor cells that are telomerase positive express a telomerase signal on the surface, so what we do here is we educate patients' dendritic cells to generate T cells that are specific and active against telomerase positive cells with a telomerase signal on their surface. Because of the characteristics of the program, this is a vaccine that is indifferent to both HLA type and tumor type, therefore it has the potential to be a truly universal cancer vaccine. We've explored this approach in over 45 cancer patients in various malignancies at Duke under an investigator IND. As you'll see in a moment, we've optimized the immunization protocol to generate sustained immune responses against telomerase. Cambrex is our contract manufacturer for our own studies. We are developing a closed manufacturing system which will substantially reduce cost of goods and we're imminently about to file our own IND in acute myelogenous leukemia.
I first want to quickly review the data we published last year in prostate cancer which really set a new bar in the field of cancer vaccination. So what we demonstrated in advanced hormone refractory and metastatic prostate cancer patients are dramatic anti telomerase immune responses literally in all the subjects who received 6 weekly vaccinations. So shown here are two typical patients from the 6 injection group which shows that we achieved one to two percent of the total T cell pool to turn them into telomerase restricted CTLs; that's never been demonstrated inthe field of cancer vaccination. We also are able to generate CD4 anti telomerase T cells which is an important helper cell to augment the potency of the immune response. Despite these robust immune responses, absolutely no adverse reactions and we have significant impact in these patients on both circulating tumor cells in blood and a more traditional measure of clinical impact, PSA doubling times shown here. These are metastatic advanced patients whose PSA is expected to double every two to three months which you can see is exactly the PSA doubling time in the group before vaccination. After vaccination the PSA doubling time essentially flatlines to over 100 months, indirect evidence of impact of this immune response on the progression of the disease. Now you'll notice that despite the high levels of immune responsiveness, the immune response wanes rather rapidly as a matter of weeks after the last injection, so we studied hard how to optimize and sustain that immune response, which I'll show you next.
So here are another small group of the same kind of prostate cancer patients, and I'm going to show you sequentially the immune response in the prime portion of the response followed by subsequent boosting later on as long as 45 weeks after the end of the prime. So here is the first patient's initial response, just like the data shown on the prior slide, very high response which then rapidly wanes, and here is the patient's response in the boost – a more rapid sustain and a maintenance of the T cell response. Similarly, a second patient. Here's the prime response and here is the patient's boost response. A third patient, almost superimposable in terms of immune response to prime who enjoys a rapid and sustained telomerase T cell response that's rapidly induced after the first boost injection which is given 45 weeks after the prime. And like the first study, we once again see flatline PSAs. So this is the protocol that we're now taking into acute myelogenous leukemia. Why AML? Big unmet need and this is an immune responsive tumor, as evidenced by the response rates in younger patients who are [ready] to be treated with allogeneic transplantation. So the protocol is an open label study where we're looking at feasibility, safety and efficacy of the vaccine. Sorry, I keep pressing the wrong button. In patients in AML in remission. So the way the protocol works is that patients are induced into remission and then receive one to two to three cycles of consolidation chemotherapy and at the beginning of the consolidation chemotherapy is when the blood is drawn and the vaccine is manufactured. So we administer the vaccine after the completion of consolidation chemotherapy at which time their immune response should still be intact and the tumor burden should be low. The dosing will be based upon our work in prostate cancer: six weekly intradermal injections with a month rest and then six bi-weekly booster injections to maintain that T cell response. We'll have about two sites enrolling initially and then add two to four additional sites as the protocol moves forward. Endpoints are of course safety and feasibility, but here we'll be measuring residual tumor burden objectively in bone marrow by a PCR assay, so one of the things we hope to show is a reduction in tumor burden after the finish of consolidation therapy due to the vaccination which we--would be the first demonstration of a prime impact on disease burden of vaccination. We will also of course be following event-free survival in these subjects over time. So the next steps here are to get RAC approval; that was accomplished in the summer. We are literally within days of filing our IND for the AML protocol, and we expect to gain IRB approvals and begin enrolling patients very early next year.
Lastly on the telomerase front, I want to remind you of our collaboration and license agreement with Merck. This of course was generated by the data from our Phase I trial in prostate cancer. So it's a collaboration agreement to potentially combine our platform with that of Merck's, as well as a license agreement to Merck from Geron for non dendritic cell vaccines. Merck has an option to negotiate for a license of our own dendritic cell program which is of course a second deal that's yet unpriced. We are managing the collaboration through joint research and development committees and this work is going really well–not only Merck's own work on their platform, but the beginning of our collaboration in mixing and maxing the technologies. So Merck plans to file their IND on both their plasmid and virus in prostate cancer in the first quarter of next year, and they appear to be on target for that goal. So we'll then be able to compare head to head our dendritic cell platform in the same kinds of patients as Merck's study in prostate cancer.
Quickly turning to the HIV/AIDS program. Again, we are now believing that our opportunity in telomerase activation may actually be as large as our opportunity in cancer with telomerase inhibition. We have discovered a small, orally active drug that is a potent and specific upregulator of telomerase activity in cells critical for the progression of chronic disease. I'll exemplify this with our first target, HIV/AIDS. When AIDS patients progress to frank disease, it's because of one thing: a telomere mediated senescence of the anti HIV T cell pool which we've shown first by gene transfer is reversed by upregulating telomerase, and we've now published that the telomerase activator drug absolutely reproduces those effects. So by upregulating telomerase in those patient lymphocytes, we reawaken the patient's immune system's ability to keep the AIDS virus in check. So the potential for this drug in AIDS is to indefinitely postpone the conversion from infection to disease. So we're going really gangbusters here. We now are conducting our in vitro efficacy and adne PK testing of the compound. We're beginning our GLP tox studies in animals. We have a Asian GMP manufacturer and formulator, scale production is underway, as is the clinical protocol, and we expect to complete our IND enabling studies and file our IND in the second half of next year.
So I'll quickly in my remaining moments summarize where we are on our three most advanced programs based on human embryonic stem cells. And I'll start first with the glial cells for spinal cord injury.
Now, first, as important and exciting as the biology is here, it's equally important to recognize that this platform and this platform alone can be scalably manufactured according to existing GMP rules. So we have world's only master cell bank manufactured under GMP using a line that is fully qualified for human use, and the way this works is that for each specific, therapeutic product we create working cell banks that are dedicated to the production of that product. This is exactly how you make large scale biologicals or monoclonal antibodies. This positions us for, for the first time in cell therapy a true product-based model.
So the most advanced program is for acute spinal cord injury and we've demonstrated in animal models robust improvement in locomotion in spinal cord injured rats. So by injecting these human (interruption), by injecting these human glial cells directly into the lesion of the animal we demonstrate the transformation of the control animals from inability to support weight on their hind legs, incontinence and dragging their tail around the cage to animals that can fully support their weight and hold their tail erect. The reason for the improvement is quite clear. In the animals that receive cells there is complete reconstitution of myelin, the insulating factor that allows nerve transmission to recover. Moreover, in another model we've shown that this myelin is compact and absolutely normal in terms of its ultrahistology, as well as being formed by our final cryopreserve formulation which we'll use in the clinic. Moreover, we know that glial cells in the normal physiology are able to simultaneously myelinate multiple axons in its vicinity.
Using labeling studies in the same rat model, we see here a labeled human glial cell that's clearly simultaneously myelinating multiple axons, so we're absolutely delivering to the injury precisely the reparative functions required for healing. We've now interviewed over 20 neurotrauma sites in North America, all of whom want to participate in this trial, the protocol is really quite advanced. We'll be beginning with subacute, neurologically complete thoracic lesions, then moving to cervical lesions and then moving into incomplete lesions. We inject the cells one to two weeks after the injury during the routine stabilization surgery that all of these patients get. It'll be an escalating dose study up to about two times 10 to the 7th cells and we will cover the patients briefly with low dose cyclosporine, although once the lesion heals, the cells are once again within the central nervous system which is an immune privileged site.
We're quite far along with our IND enabling studies. We've met with the agency in May and have agreement now as to what the IND package will look like, so although they've asked us for more animals than we would like to deliver, we will give them what they want and although our filing has been delayed until the second half of next year, the likelihood of it being accepted is now quite high, given our agreement as to what that package should look like. So the regulatory pathway and the IND generating data are really quite clear.
Quickly on heart failure. There will be a seminal publication in a high impact journal in the first quarter of next year that will be as important to the field of cardiology as the prior publication on spinal cord was to neurodegenerative disease. Stated very simply, we achieve now a scalable production of absolutely normal human cardiomyocytes that respond to drugs, that have the normal electro physiology; they survive for at least four weeks in an infarcted rodent and they clearly prevent the onset of heart failure in these animals, which is the object of the exercise. And in this paper we will demonstrate not only by ECHO cardiography and histology but also by magnetic resonance imagery that we restore contractility to a major infarct in the rat by a single injection of these cells, and that that response is durable.
Lastly, diabetes. The take home message today is that we have the cell. These cells produce insulin, glucagon and somatotropin, all together in each of our islets that come out in our manufacturing process. The insulin secretion is responsive to glucose concentration. We are now in the process of creating a scalable production method, and these cells are now in our collaborators' in Edmonton diabetic animals, where we've already shown dramatic prolongation of life and the presence of human insulin in the diabetic animal's bloodstream. So stay tuned for more announcements on the impact of these cells to hopefully normalize hyperglycemia in this animal model.
Our patent estate is broad and powerful. You've heard me talk about that as–many times. And to make the final point, that in addition to our own programs developed at Geron, we are developing other products through joint ventures and subsidiaries and through partners through outlicensing. So the final take home message is that Geron by itself and through partners is positioned with patents, people and the balance sheet to develop these programs alone and with others that are based upon disruptive technologies of telomerase biology, human embryonic stem cells and nuclear transfer.
Thanks for coming and I'll be happy to answer questions in the breakout.
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