Kommt nun die Stammzellentherapie ? GERON - 500 Beiträge pro Seite

[meislo]

Kommt nun die Stammzellentherapie ?
Geron – Das Unternehmen des Tages



Bisher war die Stammzellentherapie wohl eher Zukunftsmusik und von einer Anwendung noch meilenweit entfernt, doch das Biotechunternehmen Geron konnte nun zwei wichtige Meilensteine erringen, die eine Stammzellentherapie in greifbarere Nähe rücken lassen.

Auch Geron gehört zu den Unternehmen, deren Produkte noch ein ganzes Stück von einer ersten Anwendung am Menschen entfernt sich, dennoch ließen es sich die Investoren nicht nehmen, die gute Nachricht vom Erhalt eines wichtigen Patents, mit einem überschwänglichen Kursgewinn zu belohnen.



Bereits in der Vorbörse war die Aktie von Geron um mehr als 30 Prozent gestiegen und obwohl im regulären Handel die Verkäufer in der Überzahl waren, blieb Geron zum Börsenschluss noch ein Plus von 19 Prozent. Bei mehr als 10 Millionen gehandelten Aktien, das sind etwa fünfmal mehr als an einem ganz normalen Handelstag, konnte Geron sein 52-Wochenhoch, das bei 7,40 Dollar liegt, mit Leichtigkeit knacken. Zeitweise notierte die Aktie bei bis zu 9,75 Dollar.



Vor wenigen Wochen erst war es Geron gelungen, ein Differenzierungsmedium zu entwickeln, dass ohne den Zusatz von speziellen Zellen, den sogenannten Feeder-Zellen, auskommt. Mit dieser Entwicklung war der erste Schritt zu einer erfolgreichen Stammzellentherapie getan. Mit Hilfe dieses speziellen Mediums lassen sich Stammzellen nun möglicherweise erstmals im Großmaßstab herstellen. Diese Massenproduktion von Stammzellen war bis vor kurzem einer der limitierenden Faktoren einer erfolgreichen Stammzellentherapie.



Das neue Patent löst nun einen zweiten limitierenden Faktor, nämlich den der Reinheit einer Stammzellenpopulation. Werden Stammzellen in einen bestimmten Zelltyp differenziert, so bleiben immer auch undifferenzierte Zellen zurück. Leider war es bisher nicht möglich, diese, den Therapieerfolg beeinträchtigenden, Zellen abzutrennen. Dies ist Geron nun mit einer genetischen Veränderung der hES (humane embryonale Stammzellen) gelungen. Eine Methode, die gestern mit einem entsprechenden Patent belohnt wurde und auch viele Investoren zu wahren Begeisterungsstürmen hinrieß.



Die unter Patentschutz gestellten hES-Zellen tragen eine bestimmte Gensequenz, die nur dann ausgeprägt wird, also in ein Protein übersetzt wird, wenn die Stammzellen den Differenzierungsprozess nicht abgeschlossen haben. Durch den Nachweis dieses Proteins kann Geron dann die undifferenzierten Zellen von den therapeutisch wirksamen differenzierten Zellen unterscheiden und in einem nachfolgenden Schritt abtrennen.



Unabhängig vom gestrigen Kursanstieg zählt Geron zu den führenden Unternehmen im Bereich der Stammzellenforschung. Sein Spezialgebiet sind zellbasierte Therapien gegen Herzkrankheiten, Wirbelsäulenverletzungen, Diabetes, Parkinson und andere degenerative Erkrankungen. Die von Geron benutzten hES-Zellen sind insofern einzigartig, dass sie über das Potenzial verfügen sich in jeden gewünschten Zelltyp des Körpers zu entwickeln.



Gegenwärtig testet Geron aus hES-Zellen differenzierte Herzmuskelzellen, dopaminproduzierende Nervenzellen zur Therapie von Parkinson, sowie Vorläuferzellen der Blutbildung am Tier. Weltweit besitzt Geron mehr als 100 Patente und schwebende Patentverfahren im Hinblick auf die Nutzung seiner Stammzellen als potenzielle Therapeutika




Darüber hinaus ist Geron noch auf vielen anderen Geschäftsfeldern tätig Eine Aktie die in jedes Spekulative
Biotechdepot gehört

gruss meislo

[meislo]

Hier Informationen einer Biokonferenz aus erster Hand durch CEO OKARMA

Konferenz vom 5.6.2003


We`re going to go ahead and get started, slot here, our next presenting company is a company out of the West Coast, my name is Carlos Saltzenberg by the way, I`m representing Needham & Company`s West Coast biotech team, and Geron is a company that`s, that`s had quite a bit of exciting news over the course of the first five months of this year and here to tell us about it is Dr. Tom Okarma.

Thanks, Carlos, and welcome to you here and welcome to those following the talk on the webcast. Like everybody else in Manhattan today, I`ll be making some forward looking statements, so we call your attention to our risk factors in our most recent quarterly report.

What I`ll do first is talk about the half of our company dedicated to regenerative medicine and the theme I`d like to develop with you today is that the company is really positioning ourselves for the clinical development of human embryonic stem cell based therapies and that we`re doing this faster and more broadly than even we had anticipated. So the headlines to develop this theme are as some of you may know this is truly a new paradigm for medical therapeutics in that what we are proposing to do in chronic disease cannot be done by pharmacology and has never been done before. Unlike other forms of cell therapy, this is not a service business, it is a high margin, low cost of goods, product based business model and we`ll come back to that a little bit later
We now have scalable methods to produce seven different differentiated cells types made from human embryonic stem cells which I`ll quantify for you later. Four of them are now in preclinical animal testing in models of human disease. Two of our lines, each derived from a different IVF produced embryo, have now passed all of the tests required for them to be used for human use. Based on the data today, we think that the spinal cord injury opportunity will be the first cell type to enter clinical testing. And we do have a controlling intellectual property estate both from our exclusive commercial licenses from Wisconsin and our own patent estates which we are filing as composition of matter on the cell types, two of which in the U.S. have issued on our liver cells.

Now, what is this story about, what is the promise of regenerative medicine? You`ve all seen these kinds of cartoons that individual embryos can be used as a source for pluripotent human embryonic stem cells, that perhaps someday with complex procedures could be changed into therapeutic cell types to replace portions of the organs damaged by chronic disease. So what progress have we made against that promise? Well, the first step was to in vitro demonstrate and reproduce what takes place spontaneously in the animals, namely the differentiation of the single undifferentiated cell type into multiple different progenitor cells. Where are we now? We have now furthered that into progenitor cells or specific differentiated cells that are in animal testing in animal models of a number of these chronic clinical conditions of man. So let`s go beyond the cartoons and talk about what we`ve accomplished.
First let`s talk about cardiomyocytes, human heart muscle cells. Shown here, they spontaneously contract, they, it makes it easy for us to find them. We`ve reported before, and published in peer review literature on the process to derive them. If they are of normal shape and contractility at the molecular level, they make the appropriate gene products which designate them as human cardiomyocytes. We`ve demonstrated dose responses of these cells to cardiac drugs which is important, because when these cells are transplanted into human hearts, they need to respond to cardiac drugs the same way as the patient`s own host heart tissue does. We`ve demonstrated that for a wide variety of cardioactive agents. We know how to enrich these and are doing that and we are now supplying both our own research internally and two external groups – University of Washington and Stanford University -- who are doing our animal experiments that I`ll now share with you. So right out of the bat we have early data that these cells when transplanted into immune compromised animals in fact engraft. So here are some of the first pictures of these animal studies.

With human cardiomyocytes shown in the center engrafting in the embedded area of the host animal. In addition, we see blood vessels beginning to form in the engrafted tissue. These cells make human sarcomeric myocin in situ, so they are morphing in situ into the appropriate kind of cell to produce improvements in contractile force. We know that they are human cardiomyocytes because they stain positively for the human Y chromosome, this particular line being of male origin. We have electron micrographic evidence that these are forming the appropriate kinds of structures to electrically and mechanically integrate into the host tissue. These studies are early, they are done in animals without infarctions. The next step is to experimentally induce an infarct in the animal and demonstrate that the injection of these human cells improves cardiac output. Stay tuned.
Another cell type we`ve talked about are human dopaminergic neurons, shown here on the right side, expressing tyrosine hydroxylase, the rate limiting step to make dopamine. We`ve published and presented on how we derived them scalably, that these cells make appropriate synapses in vitro and in vivo. They make and respond to appropriate neurotransmitters. Like cardiomyocytes, they express the right genes to unequivocally identify them as dopaminergic neurons. Their electrophysiology is normal, normal membrane potential, normal sodium and potassium flux when depolarized and of course they make human tyrosine hydroxylase. We`ve recently learned now how to scalably make these cells and to prepare them for animal transplantation, which is a major improvement over the work we`ve reported on earlier. So the animal model has a one-sided lesion that resembles loss of dopaminergic neurons in the disease of Parkinson`s. We transplant into that lesion human dopaminergic cells that we make from embryonic stem cells and this is the kind of robust engraftment we are now getting. Outgrowths of human dopaminergic neurons making connections at multiple levels. This is a high bar. Parkinson`s Disease has major needs for brain structural remodeling by these cells, so it`s not just replacing a tiny portion of dopaminergic neurons, we need to demonstrate that these cells are making connections including to those neurons in the cortex. And that`s what we are beginning to see in these animal studies. So stay tuned as we have about 80 animals now carrying these grafts that will later be examined for behavioral improvement which is one of the outcomes of these animal studies.

Our most advanced type, oligodendrocytes. These are cells that we are developing with an external collaborator, Hans Keirstad at UC Irvine. Again, we have published on the derivation, their markers, their morphology, their purity, and the fact that these cells do make myelin in vivo. What I`m about to show you is the first time that we`ve presented these data in the United States, some very exciting news in the animal model of human spinal cord injury. First, the data in summary form. These are animals who under anesthesia are given a specific lesion on one side of the spinal cord, resulting as you can see in red in a permanent loss of function in one of the lower hind limbs and in the ability of the animal to carry its tail erect, as you`ll see in a moment. The animals are given either cells or a control treatment about a week or two after the injury, so this is an acute model. The injury is not allowed to gliose which is a second chronic model that we`ve, studies on which we`ve now begun. And what the data here show, and this has been repeated now three times in three separate groups of animals, is that animals that receive the cells, shown in blue, have a statistically significant improvement in their ability to walk and to carry their tail. This is a log scale on this axis. Now to illustrate the drama of the response to these animals, I`m now going to show you two movies. The first film demonstrates the control animal which is about 9 weeks after its injury. This is not the best or the worst animal, this is a typical animal that will illustrate the permanent loss of function the injury induces. I will then show you a film of one of the animals in the treatment group to visibly share with you how much better these animals are.

Here is the animal in the control group. Left lower extremity does not work. The animal walks by dragging that hind limb and it drags its tail along the bottom of the cage. This is the best the animals ever get. This is 9 weeks after injury. In contrast, the animal that gets cells has almost full function of the left lower extremity and the tail is held erect off of the floor of the cage, almost normal ambulation.

Now, what`s the mechanism of this? Is this anecdotal or is this true spinal cord injury tissue re-engineering? Well, let`s look into the spinal cord of these injured animals. First, under low power, you can see the degree of the injury. It is substantial. This is the entire dimension of the spinal cord. Under high power using a special technique, we demonstrate that only in the animals that received the cells there are new axons growing across the lesion. This is one of the reasons the animals recover. Moreover, when we do cross sectional analysis in the site of the injury, again, only in the animals that receive cells, we see new mylenation around the existing axons which is the purpose of injecting these oligodendrocytes into the spinal cord in the first place. So stay tuned for the publication of this and for the follow on studies in the chronic model which more accurately represents the market segment of humans with spinal cord injury.

Other cell types in animal studies. Hematopoietic cells, bone marrow cells, which we can now derive in a collaborator`s lab in Canada with as much efficiency as deriving hematopoietic cells from cord blood or from peripheral blood or bone marrow. These cells are just like your CD34 cells or mine. They make all the lines of blood. They are now in animal studies and our early results are they are engrafting creating permanent chimerism of human cells in the animal models. A little bit later we`ll be presenting the clinical, excuse me, the published evidence of deriving osteoblasts, bone forming cells, by our colleagues at Geron Bio Med in Edinburgh and the publication will demonstrate that the electron defraction studies of the bone material these cells make is spot on normal human hydroxyapetite. The hematopoietic cells have application in bone marrow transplantation and in one of the ways to achieve tolerance to transplanted functional cells. This is borrowed from the bone marrow transplantation world. When we first introduce the hematopoietic cells from a particular stem cell line, that tolerizes the patient to any cell type derived from the same stem cell line. So we`re leveraging the pluripotentiality of human embryonic stem cells. Osteoblasts have obvious clinical potential for nonunion fractures and for the larger opportunity of osteoporosis.

We`ve successfully now derived insulin secreting cells for the treatment of diabetes, shown up here, as well as glucagon producing cells. These cells have not yet reached the scaleability point where we can begin studying them in animals. We expect to do that in the next few months. Now, unlike other clinical applications of these cells, there is no tissue re-engineering required for the clinical utility of these cells, demonstrated by the Edmonton Protocol, using cataveric islets transplanted into the livers of Type 1 diabetics, reducing or eliminating their need for insulin. So once these are ready for animal studies, that`s exactly what we`ll do with them – inject them into the livers of diabetic animals and demonstrate that they take up permanent residence in the liver and can sense blood glucose and appropriately respond by secreting insulin

A more near term cell for commercial purposes are hepatocytes. These cells, like the other cells you`ve heard me describe, are spot on normal. They make all of the same markers that adult human hepatocytes make and importantly for their near term application, Phase I and Phase II drug metabolizing enzymes. So now, for the first time, pharma can eliminate early in drug discovery drugs that are hepatotoxic. For the first time they can now quantify the human metabolic pattern of new drugs in development, alone or in combination with the other drugs the intended population will likely have on board. A new paradigm for drug discovery.

I`ve mentioned that two of our lines are now qualified for human use [H1 and H7] and here is the list of tests given to us by the FDA that two separate lines now have completely passed. So the challenge now is for us to do the same sort of validation on the differentiated cells ...the actual therapeutic product, but because they are made from these two starting material lines, we don`t expect that to be a difficult burden.

We talked about how this is a product based business model, low cost of goods, high margins. It is unlike the traditional individualized cell therapy production procedures that you have heard about in the past where there are more people required to produce the product than there are actual patients who will use them. It`s a very inefficient process which is why many attempts to do this with adult stem cells have failed. The difference with embryonic stem cells is their scalability These cells have the same kind of scalability as the monoclonal antibody or a biological drug. They are suitable for closed system, automated production which can be housed in these kinds of units which give, again, low cost and high scalability. Just how highly scalable are these cells? Well, here`s the arithmetic. It takes 4 cell factories, one of those red stacks, to make a master cell bank of the starting material, the undifferentiated stem cells. One of those vials of the stem cells makes 600 vials of neural progenitors which we can turn into dopaminergic neurons or oligodendrocytes. One vial of those neural progenitors makes 100 to 125 patient doses of the dopaminergic cells for Parkinson`s. So if you do the arithmetic working back, 1 master cell bank of 200 vials yields enough cells to dose 10 million patients with Parkinson`s. That`s the scalability of a drug or of a monoclonal.

Let`s turn now to the second half of the company, cancer, oncology.
And the theme I want to develop here is that we now believe we have clinically validated the telomerase target. So the headlines are, as you know, telomerase is the only known universal cancer target – expressed in all cancers, obligatory for the progression of all human cancers. The validation of the target is based on our early results in the Duke/Geron telomerase vaccine trial where we`ve demonstrated in advanced prostate cancer patients that generating specific immunity to telomerase significantly reduces circulating cancer cells without toxicity, so when you target telomerase, you get efficacy and no toxicity. Our partner Roche on the bladder cancer diagnostic program, we now have results that show that measuring telomerase in the urine of bladder cancer patients has a positive predictive value of 84%, meaning 84 out of 100 people who test positive for telomerase in their urine do in fact have bladder cancer. Our partners GTI and Novartis who are presenting as we speak at the gene therapy trials in Washington have advanced the oncolytic virus program which uses the telomerase promoter. They now have multiple animal studies that not only show safety and anti-tumor efficacy, but now synergy with multiple chemotherapeutic agents in multiple different kinds of cancer. Our home run, our telomerase inhibitors GRN 163 and 719 in vitro are active against virtually all major human cancers. We`ll show you that in a moment. They are now, been demonstrated to be active in five different tumors in animal models: brain cancer, prostate cancer, lymphoma, myeloma and cervical cancers, and, like in the regenerative medicine side of our company, we have a dominant and controlling intellectual property estate on the infrastructure of the technology platform, as well as all the specific embodiments I`m about to run through with you.

Let`s start with the cancer immunotherapy trial at Duke. This is a Phase I/II trial in advanced metastatic prostate cancer patients with hormone refractory disease. This is an ex vivo program in which we incubate dendritic cells that are harvested by a pheresis procedure with the RNA coding for telomerase. One pheresis produces enough cells for up to 12 vaccinations. We either use telomerase alone or a LAMP sequence which helps to induce CD4 helper cells in the vaccine process. We reported last month on the low dose half of the study. Patients who get only three weekly vaccines; we`re now beginning to enroll patients in the high dose which is six vaccines. The endpoints of the study are of course safety and efficacy, and efficacy is monitored by both immunologic responses and a effector mechanism that gives us a loss of circulating tumor cells. So what do the data look like? First, this is data for 8 of the 12 patients. 11 out of 8 subjects responded to the vaccine with very high titre – going from the green bars to the red bars -- T cells specific for telomerase which are cytotoxic. That`s what this assay shows. There is the one patient who didn`t respond; we don`t yet know why that occurred. So advanced cancer patients respond vigorously to the vaccine with T cells. Does that do them any good? Of the 7 patients out of the first 12 who had high circulating levels of prostate cancer cells in their blood, all 7 showed a dramatic and prolonged loss of those tumor cells in their blood. These are the two highest patients whose levels of circulating prostate cancer cells were reduced by three logs, one thousand fold, during the duration of the vaccination. We know it`s caused by the vaccination because here in these subjects when we follow them for a long time, as the T cell effect wanes, the tumor cells are once again found in the bloodstream, so this clearly correlates with and is caused by the circulating T cells. So our next step is to finish the enrollment in the high dose group and follow those patients out, and whom we expect to demonstrate the same kind of effect with a much longer duration. So the object of the exercise is not to treat the primary tumor but to prevent completely metastatic disease.

Our Roche bladder cancer pilot study. We`ve studied now a lot of patients, 175 patients with bladder cancer, nearly 200 patients with benign or normal urologic systems. The simple results are measuring telomerase or the telomerase RNA gives you a positive predictive value of about 79 to 84%. That compares to a positive predictive value of 21% for the widely used cancer surrogate marker PSA. The next step is to tweak the assay just a little to increase its sensitivity and then following that we will initiate the pivotal trial for approval funded by Roche.

The oncolytic virus. Here, this is an engineered adenovirus that incorporates the telomerase promoter, the on/off switch that will drive a structural gene in the virus, rendering the virus ... only in telomerase expressing tumor cells. We`ve licensed this nonexclusively to GTI/Novartis who we believe have the best intellectual property position in oncolytic viruses. And this is a typical experiment in which you see for lung cancer in an animal, a xenograft model where the tumor volume is shown on the Y axis, a very dramatic expression of this tumor as it grows in the control group contrasted with virtual complete clearing of the tumor cells in the animals that get the oncolytic virus and in multiple different tumors -- the GTI folks are presenting in Washington -- synergy with a number of chemotherapeutic agents in multiple tumor types. Another example of the specificity, safety and efficacy of targeting telomerase.

Finally on the oncology side our drugs, the inhibitors, 163 and 719. There are over 200 publications that link cancer progression with telomerase. Our compounds are potent, specific and nontoxic inhibitors of telomerase. The challenge to the company was to create compounds whose specificity mirrors that of the enzyme telomerase in cancer having a toxic or a nonspecific inhibitor to telomerase really wouldn`t cut it. So 163 is active against a long list shown here of human cancer types in vitro and a shorter but important list of animals bearing human cancers in their bodies and in all of these animal studies GRN 163 is both effective and nontoxic. 163 is a 13 mer oligonucleotide, meaning 13 building blocks glued together. It`s a competitive inhibitor of telomerase. It is not an antisense molecule. It is active in vivo, both in intratumorally and parenterally We are now in our GLP tox studies that will be IND enabling for this compound. We have multiple manufacturing contracts in place, IP protection for the compound, its chemistry which is novel, and allows this drug to behave as if it were a true small molecule, as well as for the clinical use of these compounds in cancer patients. And our next step will of course be filing the IND and initiating our Phase I trials. The data in brain cancer are shown here, dramatic cures of this tumor in the brains of animals, 5 out of 7 animals are alive at day 116 when they are sacrificed for histology in the brain and 5 of the 7 of them are completely cured of the tumor compared to the control animals, all of which are dead by Day 43.

We have new data now in multiple myeloma from two sites -- here in Sloan Kettering and at the Dana Farber Center. This drug gets into myeloma cells, both [...] and patients` primary cells. It is highly potent inhibition of telomerase that leads to measurable telomere shortening and necrotosis confirming the mechanism of action. If we treat, pretreat myeloma with 163, we enhance the sensitivity to the standard myeloma drugs and there is systemic efficacy that is equivalent with this drug to the standard myeloma chemotherapies but without the accompanying toxicity. So the take home message for these compounds is that they are active as single agents, they are nontoxic, therefore synergistic with other chemotherapy approaches, as well as radiation therapy, without adding to the toxicity profile.

Our second line compound, 719 is a lipidated version of 163 which has ... enhanced bioavailability and potentcy, has certain manufacturing advantages, lower costs and it is of course ideal for systemic administration.

So our patent position continues to evolve, both in terms of numbers, but more importantly in terms of depth and breadth of claims that are not restricted but are well exemplified in the body of the patent, so these are dominant and controlling estates in the three arenas of the company.

So the theme of positioning for clinical development in regen med is supported by the headlines: multiple subtypes, two qualified lines for human use, spinal cord injury will be first to the clinic and multi dose production lots enable for the first time in cell therapy a product based business model.

In cancer, clinical validation of the target evidenced by the Geron/Duke trials, the Roche results in bladder cancer diagnostics, the GTI/Novartis results in the oncolytic virus, and most importantly to us, the early preclinical data on GRN 163 broadly against cancer. We have controlling intellectual property estates for both platforms and a balance sheet and a cash burn rate that are now enable us to be a sustainable enterprise for the next several years for the continued product development of these mega brands,

Thanks very much. I`ll see you in the breakout.

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