Lazard Capital Markets
Third Annual Life Sciences Conference
November 29, 2006
wsw.com
1:30 p.m. EST on Wednesday, Nov. 29, 2006
MR. SENDEK: Okay. Good afternoon, everyone. Thanks for joining us. My name is Joel Sendek. I'm a biotech analyst at Lazard Capital Markets and this afternoon we have, at this time we have Geron presenting. The presenter will be Dr. Tom Okarma who's the Chief Executive Officer. Tom.
DR. OKARMA: Thanks, Joel, and thank you for coming. I'll be making some forward looking statements today, so I refer you to our various SEC filings that contain our risk factors.
So today we're going to talk about six products - two that are in the cancer field, and in the clinic are our telomerase inhibitor drug and our telomerase vaccine. Thirdly, a new program, a telomerase activator drug directed against HIV/AIDS. And then thirdly, fourthly and fifthly, three cell types derived from our human embryonic stem cells: glial cells for spinal cord injury, cardiomyocytes for heart failure and islets for diabetes.
So let's first start with our cancer drug, GRN163L. This drug targets telomerase which is a universal and specific and critical cancer target. All cancers critically depend upon continued expression of telomerase. This drug has an extraordinarily broad preclinical efficacy package. Literally it is effective in vitro or in vivo on virtually all human cancers. We've developed this drug as an oligonucleotide with unique proprietary chemistry. This is not an anti-sense approach; it is a direct enzyme inhibitor and because of the chemistry and the lipid that we attach covalently to the molecule, it penetrates tissues and the cell nucleus where the telomerase target resides. It has excellent pharmacokinetic and bio, bio distribution properties, some of which I'll show you in a moment, enabling us to administer the drug once per week intravenously. So we are in the clinic now in two studies currently, a Phase I/II in CLL and a Phase I in solid tumors, and in the coming year we plan to advance into two other programs, multiple myeloma and lung cancer.
Now the new and exciting news about this drug is that in addition to killing off the mature tumor cells, it also has activity against cancer stem cells. What are they? Well cancer stem cells are rare, self-renewing cells that are very resistant to chemotherapy. They've been identified in a wide range of malignancies and they are response for clinical relapse. So, with our collaborator at Johns Hopkins, we've been investigating our drug in myeloma. So first, in yellow bars, you see what happens when we expose the mature myeloma cells to our 163L telomerase inhibitor. Over three to four weeks we eliminate the mature tumor cells, but in red you see we show exactly the same effect with the separated myeloma stem cells, and to our knowledge, this is the only drug available that has this property. And you'll be hearing more about this in myeloma patients at the ASH symposium upcoming.
So our program in chronic lymphocytic leukemia is based on the simple fact that CLL cells circulate in plasma and they have very high levels of telomerase. It's a sequential cohort dose escalation design. Patients receive two four week cycles of once a week IV infusion, in this study, given over 6 hours. There are now four sites participating and the endpoints are standard for Phase I/IIs: safety, tolerability, adverse events, maximal tolerated dose, as well as the PK/PD correlations which are so critical for advancing into Phase II.
Our program in solid tumor malignancies has one site currently enrolling and it's a bit more aggressive. The cohorts are smaller. The rise through therapeutic doses is, is a little bit faster and we've reduced the infusion duration to two hours with a, an additional arm that, where we expect to reduce it further, to about one hour, and the endpoints are about the same. So at the Prague meetings we presented our first early results on the PK/PD parameters of the drug, a little bit of which I'll share with you now. So, first, we've given now over 82 doses in both trials, including two subjects who actually received extending doses of up to two additional cycles - that's a total exposure of four months continuously once a week and we've had absolutely no serious adverse events and no dose limiting toxicities. Now more important is the pharmacokinetics. Remember, this is an oligonucleotide and they are very difficult to control in terms of dose, dosing interval and plasma levels, but ours is different because of the chemistry.
So first you see the first cohort in the CLL studies. These patients received point 4 milligrams per kilo over a 6 hour infusion and you can see that their blood levels are actually quite similar to one another. The average Cmax, the peak concentration, is about 1.44 micrograms per mil and although not shown here, we can actually detect drug for over 18 hours after the end of infusion. So it's very predictable and consistent. Now in the lower panel we see the average in blue of these subjects and in red is superimposed the first patient in the second cohort that got twice the dose, and you can see his Cmax is about 2.7, exactly appropriate, and they both have similar half lives of about 4 hours. Not shown on the slide is our subjects who in, in the solid tumor trial who received the same doses over 2 hours, and their Cmax is yet again higher, appropriately, with the same T one-half alpha. So this means that the drug is behaving appropriately and we can accurately correlate dose, dosing interval with plasma level, which tells us that we'll be able to control the dose level–plasma level of drug to achieve telomerase inhibition even in the tumor cells that circulate without causing toxicity.
So we are now, with these data, enrolling subjects into the therapeutic cohorts, which is, of course, where the excitement is. And we expect to have data on PK and PD on those subjects by the spring in the AACR and ASCO meetings.
So obviously next step is to optimize all of the PK, infusion durations, finish our PK/PD analysis – remember we can measure telomerase inhibition in the CLL cells that we collect at the same time we're doing the PK analysis. We'll be presenting at ASH and we already presented, as I mentioned, at the EORTC meetings in Prague, and we'll be filing for additional indications in, next year, particularly myeloma because of the stem cell activity I showed you and in lung cancer because of animal studies that not only show activity against the primary lung tumor, but significant activity in preventing metastasis of the primary lung tumor. Clearly, to do this we have to expand our clinical trial site participations, and we're also now doing mixing and matching studies. Because of the stem cell activity of our drug, we may wind up using this drug in combination with other existing chemotherapy agents, so we're now optimizing those combinations.
Turning to the vaccine. This is also targeting telomerase, but the telomerase here is on the surface of the tumor cell. Because it uses the patient's own dendritic cells, it is therefore indifferent to the patient's HLA type, and because it's against telomerase, it's indifferent to the tumor type. Therefore, this is a potentially universal cancer vaccine.
We've got quite a bit of experience now with over 45 patients with prostate cancer studied at Duke which actually have served as the safety part of our own IND, and as I'll show you, we've optimized now the immunization protocol. Cambrex is our contract manufacturer. We're developing a closed system to reduce cost of goods, and we have now just filed our IND for AML which I'll come back to in a moment.
So, just to quickly to review what we've already described in prostate cancer. We have very dramatic anti telomerase T cell responses. The yellow line shows the peak response which occurs about a week or two after the 6th prime injection, and these levels are 1 to 2 percent of the patient's circulating T cells – that's a level that's never been seen before to our knowledge in any cancer vaccination trial. Despite those high levels of anti telomerase T cells, absolutely no adverse reactions and we've seen significant impact on both circulating tumor cells and a more traditional measure of activity in prostate cancer: PSA doubling time. So these are all hormone refractory and metastatic prostate cancer patients who are expected to double their PSA value every two to three months. And so here, prevaccination, that's exactly where they were, a PSA doubling time of 2.9 months. But after vaccination, the PSA doubling time rose to over 100 months, essentially flatline, implying activity of this approach to the disease progression. Now if we go back to the curves here, you can see that rather rapidly there's a diminution back to baseline of the anti telomerase T cells. So, can we fix that? Well, with each blood draw we have enough cells for 12 to 15 injections. So what we did, we went back to the same kinds of prostate cancer patients and we studied the impact of prime, and later, boosting.
So I'll go through one patient at a time. First, one patient here receives the same 6 weekly injections and again you see the peak T cell response, about a week or two after the 6th injection, which then wanes. So now, 25 weeks later after 1 or 2 injections, the patient's T cells are back up. That's an anamnestic response telling us that we in fact induced memory T cells in the first vaccination. Second patient in blue, same exact response to the prime and he also responded very quickly to the boost injection. Third patient exactly the same. Now this one was boosted 45 weeks after the prime, and exactly the same response, and, again, flatline PSA. So we learned a lot in prostate cancer and our own IND is, which has now been filed, is in acute myelogenous leukemia. Why? AML is a immune responsive tumor. We know that because younger patients who get allogeneic bone marrow transplants respond. There is a huge unmet need and, after consolidation chemotherapy, the tumor burden is relatively low like it is in prostate cancer. So the protocol is that we draw the blood and manufacture the vaccine during the conso–the first cycle of their chemotherapy. We let them go through consolidation, after which time we administer the vaccine. Now the patients at that point will be of one of two kinds: those that have residual tumor cells detected by an assay of WT1 and the endpoint for them will be ‘does the vaccine eliminate the residual tumor cells'; prima facie evidence of activity against the disease; the other patients will have had a complete elimination of their circu–of their tumor cells by the therapy, but the endpoint for them is the duration of their, how quickly they relapse, or, event free survival.
So we're going to use what we learned in prostate cancer in this AML setting. We will use 6 weekly intradermal injections, give them a month rest and then at least 6 boost injections every other week. And obviously, in a disease like AML which progresses rapidly and which always relapses, we will be able to have objective evidence of impact on the vaccine against the tumor much faster than we could had we continued in prostate cancer. So stay tuned for the initiation of that trial which we hope will be very early next year.
So obviously the next steps: we've gone through the RAC, we filed our IND, and once the IND's approved, we then get IRB approvals and initiate our clinical trial sites.
Lastly, I want to remind you that this product, we have a collaborator called Merck. We have both licensed them to our telomerase target for their vaccine approach which is adenovirus and plasmid and they have an option to take a separate license to our dendritic cell program in the future. We are also under a joint research committee now looking at mixing and matching our platform with theirs, and should we find synergy between the two platforms, that's what will trigger the negotiation for their licensing our dendritic cell approach. We have been very pleased with their progress and their diligence to date, and I can tell you that their preclinical data using adenovirus and plasmids against telomerase in animals is very striking, and their IND filing is really quite imminent. So this is a program where we have a number of options in terms of how to proceed to commercialization.
Let's turn to the flip side of telomerase, telomerase activation. We've told you that all tumor cells critically depend upon telomerase for continued division. But there are also normal cells in the body called stem cells - in skin, gut and blood - that require telomerase activity in order to self replicate and renew the tissues that turn over. And when those stem cells are stressed, you get into trouble with chronic disease, and there is a great example in HIV/AIDS which I'll come to in a, in a moment. So what we have done is discovered from a traditional Chinese medicine extract a single entity, small molecule telomerase activator that's extremely specific and potent in upregulating telomerase activity in telomerase competent cells. We formed a joint venture in Hong Kong which fully funds this operation, so this is essentially off of our balance sheet and the preclinical work that we've done in various chronic and infectious diseases tells us that the upside for this drug may be as large as what we see for our cancer program. So the HIV story is very simple. When HIV subjects progress to AIDS, it's because of one thing, their CD8 lymphocytes senesce because they're continually being driven to divide by the persistent infection. Once you lose those CD8 anti HIV cells, you progress to the disease AIDS. We have shown in vitro that this drug upregulates telomerase in those lymphocytes and restores their anti HIV activity. So the expectation is that we by an oral drug will be able to indefinitely postpone the conversion from HIV positivity to disease. So we're now obviously doing all of the pre IND studies to move this drug into the clinical environment. We expect to file the IND for HIV/AIDS in the second half of next year.
Turning now to embryonic stem cells. Our most advanced program is of course the glial cell for spinal cord injury. But before I get into that, I want to remind you that in addition to the exciting science, this platform is the only cell therapy platform that enables a product-based business model. We have a fully qualified for human use master cell bank - which, interestingly, is one of the Bush approved lines, quote unquote - and from that master cell bank, we make working cell banks, each of which is dedicated to the scalable production of one cell type or another. With regard to our glial cell production, each production run now makes enough cells for over 2500 spinal cord injured patients, so this is truly scalable. The cells at the end of production are aliquoted and frozen and they are shipped and stored in the frozen state, ready for off the shelf use. So this is the first time that cell therapy is actually manufactured, distributed and used like a pill.
So turning to the glial cells. It's a picture of them. They're a progenitor cells, they're not quite glial, they're not quite glial cells yet. They terminally differentiate when you inject them. We've told you about our GMP production and they are in fact not recognized by the immune system in vitro or in vivo. The impact of these cells when introduced into a spinal cord injured rat has been published before. So we take an animal that has a spinal cord injury and therefore has no weight bearing support in the hind limbs or tail to, after injection of the cells, an animal that bears weight on the hind limbs with an erect tail, and the reason for that improvement is that the cells exuberantly myelinate the animal's demyelinated axons which are demyelinated because of the injury. We've done this in multiple models, including the shiverer mouse, and show under electron microscopy that this is normal, human, compact myelin. Moreover, one glial cell in your body and mine is able to simultaneously myelinate multiple axons and that's exactly what happens in our rats - a labeled glial cell here myelinating multiple axons in its vicinity. So, we've now moved to generating the clinical protocol.
This will be a Phase I/II trial. It'll be randomized and unblinded. We'll have about 6 to 8 clinical trial sites and patients will be referred to the sites from local trauma centers. We'll be starting the study in patients with subacute, complete thoracic lesions – that's because of the safety issue. If there is any toxicity, we might go from a T-3 to a T-2 lesion, which is not clinically significant for the patient. Once we demonstrate safety in the thoracic lesions, we'll move to the more common cervical lesions. We'll be using escalating doses up to 2 times 10 to the 7th cells which are injected into the lesion, just like in the rats, when the subjects go to standard spinal stabilization surgery which occurs about a week after the injury and they will of course will be evaluated very carefully with standard and validated neuro instruments.
Now, we've gone quite a long ways toward developing this product and introducing it into the clinic, so we've gone through most of the preclinical steps. We've met with the FDA several times and have agreed upon the preclinical package. It's a high bar, but we're going to give the agency what they're interested in, so by the time this IND goes in in the third or fourth quarter of next year, we will have treated over 2500 spinal cord injured rats in various ways with our cells to assure us, the FDA, and our clinical collaborators that this is going to be safe and effective when put into people.
Our next cell – there are cardiomyocytes, ventricular heart muscle cells. We've learned how to make these scalably from our embryonic stem cell lines. They respond normally to heart drugs. They are–they have normal ventricular electrophysiology and we have now efficacy in an infarcted rat model. That paper is under review right now and when published, it will be as significant for the field of cell therapy in cardiology as the rat spinal cord injury was in neurology. We now know how to directly differentiate them without any co-culture or any isolation procedure, so it's now scalable and we'll be beginning our large animal studies in the first quarter of next year. So what we know now in the infarcted rat model is that these cells survive for at least a month or two - these are human cells living, in this case, one month after they were injected in the infarct zone of an infarcted rat. So they survive. And they engraft. And they function. What good do they do? They prevent the dilatation of the heart which is a, which is a marker for heart failure. So there is significant reduction in the left ventricular n diastolic diameter and the left ventricular n systolic diameter, which is the therapeutic effect preventing the onset of heart failure, which is precisely the object of the exercise. So what will we do in large animals is now injecting these cells via catheters much the way the folks doing autologous bone marrow injections have been doing, so they've paved the way for us in terms of injection technologies, and these will be injected directly into the infarct zone of large animals where we hope once again to demonstrate engraftment, safety and efficacy, and in the large animals in contrast to the rodents, we can also do the electrophysiology after injection to be sure that we're not causing any arrhythmias.
The last subtype we'll talk about today are our islet cells for insulin dependent diabetes. Now these cells have been the hardest for us to learn how to make, and that makes sense because in our normal embryonic development they're made by the combination of multiple germ layers that interact with one another, but I can tell you now that we have done it. And there's a paper also in review describing the details of this. So our islet-like clusters which actually come out as little buds, much like the normal endocrine pancreas is evolved, they express C peptide which is the progenitor of insulin, glucagon and somatostatin, so here is the merged image of each one of the islet clusters that makes exactly the right collection of hormones that your beta cells and mine are making at this very moment. In addition, the secretion of insulin by these cells is dose dependent upon glucose concentration which is appropriate. So they have the normal glucose sensing mechanisms that lets them upregulate the production and secretion of insulin and they also have normal insulin secretory granules which is another hallmark of the appropriateness of these cells. In earlier studies not using cells that are quite this pure, we have shown dramatic extension of survival in a diabetic rat model. Animals that are made diabetic and given fibroblasts all die within about a week, in contrast to the cells that receive our islets, which live to the end of the experiment, which is 50 days. The reason for this survival is that we're able to detect in their bloodstream human insulin produced by the cells we've injected. So our hope now in the current studies that are in life in Canada with our Edmonton collaborators is that these new cells which are much more potent will not only extend life, but will also render the animals normal glycemic.
All of these programs in cancer and in embryonic stem cells and our telomerase activators are covered by a pretty robust and pretty rigorous patent estate that you've heard me describe before. We've successfully defended oppositions as well as interferences and we take patents at Geron very seriously. The numbers aren't as important as the exemplification of the claims. They're strongly supported by the experimental data.
So you've heard me describe the 6 programs or products that we are developing in house, but we also have other programs that are under joint venture collaborators. So stART is the place where we put our nuclear transfer technology to clone animals. The FDA has recently announced that they're putting–going to allow milk and meat from cloned animals into the food supply; that kick starts that licensing joint venture. We have a wholly owned operation in UK called Geron Bio-Med which is dealing with our liver cells, our bone forming cells and our cartilage forming cells, and you'll hear some interesting news about that subsidiary soon. And, as I mentioned, TAT, which is our joint venture in Hong Kong, developing our telomerase activator. We talked about our Merck relationship on the cancer vaccine. Roche is our cancer diagnostic partner, and we've also licensed our oncolytic virus technology to Cell Genesys. So that's how we are developing products that we think will change the way medicine is practiced, alone or with others, all based upon our three proprietary disruptive technologies: telomerase biology, human embryonic stem cells and nuclear transfer.
I've run out of time, so thanks very much.
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