Geron at BIO CEO & Investor Conference 2007
Monday, February 12, 2007
1:15 p.m. ET
corporate-ir.net.
Hello everyone. We're going to get started with our next presentation. If everyone could take their seats. Thank you.
Our next presenting company is Geron Corporation from Menlo Park, California. Presenting for Geron is the President and CEO, Dr. Thomas Okarma. Thank you very much.
DR. OKARMA: Thank you, Brian, and thank you all for coming today. I will be making forward-looking statements in my comments, so we refer you to the various risk factors in our SEC documents. So today we're going to be talking about two groups of products, one group based upon our telomerase technology – two products addressing the cancer marketplace and a new telomerase activator drug dealing with HIV/AIDS; we'll then talk about three of the lead products from our human embryonic stem cell platform – one for spinal cord injury, second for heart failure, and a third for diabetes.
Now the first program, 163L, is our telomerase inhibitor drug which targets the enzyme telomerase, a universal, specific and very critical cancer target. All cancer cells obligatorily depend upon continued expression of telomerase. The drug has a very dramatic preclinical dossier – literally all tumors types succumb to treatment with the drug. It has excellent PK and biodistribution properties. We give the drug intravenously once a week. It has a very long half life. So we're now in two phase I/II studies, one in CLL and one in solid tumors and next quarter we'll begin a third indication in multiple myeloma and in third quarter, lung cancer. And the first new point I'd like to make is new data showing that this drug is active against cancer stem cells.
Cancer stem cells are the cause of clinical relapse. They are chemotherapy resistant and they're found in most tumors in which they've now been sought for. Our drug is absolutely active against the cancer stem cell. First, here in myeloma lines, showing both the mature and the stem cell from myeloma lines, are progressively inhibited by weeks of contact with the drug. More relevant, however, are patient samples, shown here. The mismatched control has no effect on the myeloma stem cell. The 163L with as little as 3 days of incubation knocks the tumor stem cell down by 50 percent. This is from myeloma patients' bone marrow. For this reason and for the synergy we've demonstrated between 163L and Velcade, myeloma - the next indication - may become our registration pathway.
So we are currently in a Phase I/II trial in CLL, chronic lymphocytic leukemia, and the purpose here is to do elegant PK/PD correlations because the CLL cell circulates in the bloodstream so we can actually measure telomerase inhibition and telomere length in the targeted tumor cell. Otherwise the endpoints of this study are fairly traditional for a phase I/II study and we are now enrolling the so-called therapeutic dose cohorts – doses at which we expect to see inhibition of the target.
We're also in a separate Phase I trial in solid tumors. Here the protocol is a little bit different. We still give two 4 week cycles of once a week IV infusion, but in this study the infusion duration is a short two hours, possibly moving even to one hour, and the dose escalation is a little more rapid. Same sorts of endpoints, and, like CLL, we're now enrolling the therapeutic dose cohorts.
So what we presented last December are the results from the so-called sub therapeutic cohorts, so well over 80 doses as of then were administered with absolutely no serious adverse events or dose limiting toxicities and, importantly, the PK results are that which we predicted from our preclinical animal modeling. So the first and second CLL cohort shows the appropriate increase in Cmax as the dose is elevated with no change in either the alpha or the beta half life. Appropriately, in the solid tumor cohorts, shorter infusion of the same dose between CLL and solid tumors gives the higher expected Cmax with no change in T one-half. And here in Cohort 3 of the solid tumor trial, this demonstrates we are now hitting the therapeutic range which is somewhere between 5 and 10 micrograms per mil with a single IV infusion. We've also demonstrated, as predicted, that the telomere lengths in the tumor target cell in CLL, the mononuclear cells, are shorter on average than the telomere lengths in the nonmalignant white cell fraction in blood. That's in CLL. As expected, you do not see that disparity between lymphocytes and polys in the patients with solid tumors, again reinforcing that the target is ready for inhibition in the target cell.
So what we've learned is that there are no safety issues in our early studies. The PK is linear over the range tested so far. All of the PK behavior is as predicted from our preclinical work and, again, telomere length at baseline is predictably shorter in the target cell than in normal tissue in blood. The next steps, obviously, are to collect the data currently undergoing on the therapeutic dose cohorts and we expect to have that story ready for public display about the middle of this coming year. So we want to complete this analysis and achieve the recommended dose for our phase II studies, expand our clinical trial site participation, add multiple myeloma and lung cancer this year, breast cancer perhaps early next year, and continue our manufacturing process development to continue lowering the cost of goods.
Turning now to the telomerase vaccine. This product also targets telomerase, but in a different way. Now we're looking at attacking the telomerase fragments on the surface of the tumor cell, whereas the drug inhibits the enzyme in the cell nucleus. Now in order to maintain the broad applicability across all tumors we had to develop a platform that was HLA independent and we've done that. So we use RNA loaded dendritic cells as the immunizing cell type. Under an investigator IND we have experience now with over 45 vaccinated cancer patients which actually created the safety package for our own IND which we submitted late last year, and I'm happy to announce today we now have FDA concurrence to proceed with our vaccine trial in AML which I'll discuss in a moment. How we got here.
Well, we demonstrated in metastatic hormone refractory prostate cancer very dramatic anti telomerase immune responses to the vaccine. Because of the way the vaccine's configured, we get both CD4 and CD8 specific anti telomerase T cells induced. Despite the overwhelming immune reaction, absolutely no adverse reactions and significant impact on circulating cancer cells as well as PSA doubling time. So all of the patients in this Duke study responded this way. After 6 initial immunizations you see the robust CD8 and CD4 anti telomerase T cell response which, in a dose dependent fashion, resulted in highly statistically significant increases in the PSA doubling time. Pre-vaccine these patients doubled their PSA at an average of 2.9 months. Classic for this kind of patient. After vaccination it was essentially flatline - over a hundred months. We also at Duke optimized the boost strategy. So here you're going to see now three patients primed and then boosted up to 45 weeks after the last prime, and you will see the anamnestic response, a rapid return to peak after the boost. So, first, the typical patient who peaks a few weeks after the sixth injection, but here the boost - made of the same material - gives an immune response much faster. Another patient, and almost superimposable with the prime peak, here, very rapid recall. Thirdly, same kind of response to prime, and now, 45 weeks after the prime, you get a very rapid recall. This is real immunology, never before shown in cancer patients. Moreover, we continue to see the same kind of flatline PSA that we saw in the prior studies. So we learned from the Duke study that we induced both CD4 and CD8 immunity. The vaccine was extremely well tolerated, it responded in a dose dependent fashion. We have excellent recall now with the boost strategy and we saw anti tumor effects based on surrogate markers in a common solid tumor.
So our next step is now to initiate our trial in acute myelogenous leukemia - at high risk for relapse. The dose will be 6 weekly intradermal injections followed by a month rest and then 6 boosts every other week until we run out of the vaccine. We'll begin at two initial sites and expand to two to four additional sites after enrollment begins. We'll be vaccinating patients at the completion of the consolidation chemotherapy and the endpoints here, in addition to immunology, will be objective impact on disease, both residual disease burden as measured by PCR and bone marrow, as well as clinical remission and event free survival. If we get the signal we anticipate we will then roll into a randomized Phase II/III for our registration trial. As I mentioned, we have IND concurrence from the FDA to begin this study.
The Geron/Merck telomerase vaccine, was actually--collaboration--was actually driven by our publication of the Duke studies in ‘05. This is a collaboration agreement to potentially combine our platform with Merck's, as well as a license to Merck with a telomerase target for their nondendritic vaccine. We also have a joint development committee where we're looking at mixing and matching their platform with ours. This is going extremely well; we're doing the animal studies in Europe now to mix and match our dendritic cells with their adenovirus and we expect them to file their IND this year in prostate cancer.
Turning to the new entry, the telomerase activator drug. We've made the comment that the opportunity for telomerase activation may be as large as the inhibitor opportunity in cancer. That's because there are a wide range of diseases in which telomere loss is pathophysiologic – it causes the disease. The simplest example of this is actually HIV/AIDS, where we show that the progression of the disease from asymptomatic carrier status to being sick with the illness is caused by one telomere event - the loss of CD8 anti HIV T cells. We've published that transducing the gene for telomerase into those cells restores anti HIV activity. We've done that in a number of cell systems. So that caused us to look then for actual small molecules that would upregulate telomerase, and we actually found several in a traditional Chinese medicine from a screening program we had in Hong Kong. We formed a joint venture with a group in Hong Kong – they provided the money that got us this far and we provided the intellectual property. So the kind of data we're generating is shown here. This is a culture system in which we test our drug's ability to enable the weakening CD8 cells to repress autologous viral expression. So viral expression in the untreated state is up here at 1. When we add the telomerase activator, viral expression significantly declines. These are all n's of three patients. Even at very low effector to target ratios. Interestingly, if we add back to that culture 163L, the telomerase inhibitor, you abrogate or lose that activating effect, proving the mechanism of action.
So we're now in our IND enabling studies. We have a contract manufacturer for GMP material in China. We are–this is an orally available drug and thus far the PK and the toxicity testing are very benign. We are developing now the clinical protocol for HIV/AIDS and we expect to file the IND at the end of this year or very early next year.
Segueing to human embryonic stem cells, the second main platform for the company. The first and most advanced product is for spinal cord injury, so-called OPC1, glial cells that remyelinate the axon. Before we talk about the biology which of course excites all of us, there's an important point to understand from the business perspective. These cells are scalable and they can be made with the same sort of precision and scalability as any biological. So to cut to the chase, we have a master cell bank of a fully qualified embryonic stem cell line that is sufficient to generate enough glial cells to treat the entire spinal cord injury marketplace for the next 22 years – that's over 250,000 patients from one embryo from one embryonic line. So this is the proof of concept, for the first time ever in cell therapy for a product-based business model as opposed to a service-based business model like bone marrow transplantation or most of the other so-called adult stem cell therapies.
So the first product is these cells here. They're oligodendrocyte progenitors. They're taken in manufacturing to almost full differentiation. They are injected in, in this case animals that are given an acute spinal cord injury about two weeks after the injury, and the injection of the cells transforms the animal from one which is permanently hemi-paralyzed, its tail drags on the cage floor, it cannot place its hind limbs and it's incontinent, to an animal that has normal paw placement, full weight bearing and its tail is off the cage floor. How do we do that? It's because these cells remyelinate or insulate the injured axons. So the axons of the rat spinal cord are coming out of the screen at you and all those tiny circles are human myelin reinsulating those damaged axons, not seen in the control group. We repeated this with the cryopreserved formulation, the one that's going into the clinic, in a different animal model and under electron microscopy you see normal human myelin, compact myelin formed in the animal. Even the cellular architecture, where one glial cell can myelinate multiple axons in its vicinity is maintained in this animal model. Here's the stained cell, human, that is simultaneously myelinating multiple axons. So we've gone pretty far along now in devising our clinical protocol. This will be a unblinded but randomized study, we'll have at least 6 to 8 study sites - we have identified 20 that want to participate. It's primarily a safety, but we are looking for approvable endpoints. We'll be starting with patients who have complete thoracic lesions, for safety reasons. If there is any tox, it'll be manifested in an upward migration, which is not significant for a thoracic injured patient. Once we demonstrate safety in the thoracic lesion, then we move to the more common cervical lesions. Now, what we're trying to accomplish in complete spinal cord injury isn't necessarily restoration of full recovery, that would be a lot to ask, but if we simply move the ball from complete loss of bladder and bowel control to having some, we've reduced the impact of infections. If we move the ball from total anaesthesia below the point of injury, we move the ball by increasing some sensation which reduces the likelihood of decubitus ulcers, which was the–a common mode of mortality in these patients. And lastly, if we restore some locomotor activity, we've frame shifted their outcome from one that is bound to a wheelchair for life to another one which can respond to standard physical therapy. All those endpoints we think would be approvable.
So we're fairly far along now on the path to clinically developing this product. So we have full agreement with the FDA on the scope and content of the IND, we're in the midst now of our IND enabling studies in animals and thus far show complete safety, no teratomas, absolutely normal biodistribution and we've demonstrated in the animals that these cells are alive and functional for as long as 12 months after injection. So we plan to complete these IND studies this year and file our IND in the fourth quarter of this year, which will be the world's first human embryonic stem cell clinical trial.
The second cell type behind glial cells are cardiomyocytes to treat heart failure. Now this is not bone marrow into your heart, this is bona fide human ventricular cardiac muscle. It has absolutely normal ventricular electrophysiology at the cellular level. These cells respond normally to cardiac drugs. They can be cryopreserved, just like the spinal cord injury cell, and we are now scaleably producing these cells to begin our large animal studies which are really important to document not only efficacy in a large animal, but also to optimize the catheter system by which we'll be injecting these cells into human patients. So, again, unlike the bone marrow story, we show human ES produced cardiomyocytes surviving in the infarct of the animal for at least 4 weeks after the cells are injected. Our older data demonstrates that the cells after 4 weeks of injection in an infarcted animal show decreased end-systolic and end-diastolic diameters, evidence that we have prevented the swelling of the heart that occurs in heart failure. New data that's now under review will be as important for cardiology as the spinal cord injured paper of two years ago was for our neurology application. Here we're studying the rodents with MRI and what you can see first in the control, diastole and systole, here is the animal's heart versus infarcted animals that get cells, shown here. We have a statistically significant increase in the injection--ejection fraction – in fact here we show that the animals that receive cells, their ejection fraction is almost the same as the non infarcted control. More dramatic is the increase in systolic thickening. You can see here in systole the thicker wall in the cells–in the heart that has cells versus the one that does not. And here the increases are really quite dramatic – hard animal evidence that these cells prevent the progression of the heart attack into heart failure, the object of the exercise.
Thirdly, islet cells for diabetes. This product of course has the precursor of the Edmonton Protocol where cadaveric islets have been injected into the livers of Type I diabetics and this has actually been shown to work, short term. We now have the cell. So these human embryonic stem cell produced islets make insulin, glucagon and somatotropin. This is not a human islet, this is an islet cluster produced by us from embryonic stem cells. We have a scalable production method now and these cells do respond to changing glucose concentration. So here's the amount of human insulin secreted in low glucose. When we up the glucose concentration, you see a very dramatic increase in the secretion of insulin, showing that these cells functionally respond to changing glucose concentrations in their environment. We've already shown that these cells compared to fibroblasts dramatically extend the survival of diabetic animals and that's because we can pick up in the animal's bloodstream human insulin produced by the cells we've injected. We're now taking these cells which are much more potent than the cells used in these experiments into animals in our collaborators in Edmonton, Canada.
Our patent estate, as you've heard me describe before, is robust. So we have literally hundreds of allowed and issued patents protecting the whole telomerase estate both in terms of the background IP or technology as well as very specific product formats you've heard me describe. The IP estate for human embryonic stem cells is also growing rather rapidly, both our exclusive licenses from Wisconsin as well as our own IP that we have submitted to cover our–the advances that we've made in learning how to make differentiated therapeutic cells. Nuclear transfer as well is heavily protected, and as I'll mention in a moment, we put all of our Dolly the Sheep IP into a joint venture called stART Licensing; it's a joint venture with Exeter. And you may recall that the FDA has announced their intention to put milk and meat from cloned animals into the food supply this year, and that will obviously begin the licensing from that joint venture which is, again, based upon that IP estate.
So, you've heard me quickly give you a summary of where our six main products are at this point in time: two for cancer, one for AIDS - based on telomerase; and three different differentiated cells each scalably made and in animal proof of concept based upon human embryonic stem cells. In addition to these products - I mentioned the animal cloning joint venture - we have a wholly owned operating subsidiary in the UK called Geron Bio-Med in which we're developing hepatocytes for liver failure and ADME tox, osteoblasts for osteoporosis and chondrocytes for arthritis. That whole operation is now at the University of Edinburgh and is enjoying funding from the UK. This is the joint venture with Hong Kong that is funding the development of the telomerase activator drug, and lastly, our Merck collaboration on the vaccine which I mentioned. Roche is our partner for diagnostics, they're developing an assay for detecting bladder cancer recurrence in urine and Cell Genesys acquired our license originally given to GTI for the oncolytic virus promoter. So this is how Geron today has leveraged our three core competencies into products that we think will change the face of medicine. We have a robust balance sheet; we ended the year last year with over $200,000 million in cash with no debt; we are hiring people, particularly on the cancer side who have significant experience in commercializing oncology products, including, most recently, Alan Colowick who came to us indirectly from Amgen of Aranesp fame. So the company is maturing, and this is the year, ‘07, in which we will fully complete our transition from a science company to a product company. By this time next year we'll have four products in the clinic: the inhibitor drug, the telomerase vaccine, the activator drug, and the world's first embryonic stem cell therapy for acute spinal cord injury.
Thanks very much and I'm happy to take your questions.
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