España
http://www.rtve.es/noticias/20140212/camara-representantes-eeuu-aprueba-prorrogar-limite-deuda-hasta-marzo-2015/877120.shtml
Sietesoles que te parece el SEC Filling de
http://www.masttherapeutics.com/investors/secfilings/
Cada vez más largos 90% que cortos 10% ayer en este valor a pesar de la dilucion http://www.shortanalytics.com/getshortchart.php?tsymbol=MSTX
Entrada mental en KIPS en 0'68, AVEO en 1'75 y GTXI en 1'74. Esta última con riesgo de dilución. Que malo es esto de que el cash se acabe que ya hay que ir con juegos mentales. Las tres parece que quieren recuperar terrenos perdidos.
Pues ya podrían los republicanos quitarnos la incertidumbre de estar cada mes con la cantinela del fin del mundo. Es que no hay político bueno!!
ACTC
De la reunión privada no sabemos nada aún, pero mi lectura del mensaje del asistente es que no estaba demasiado emocionado. Yo tampoco por la transcripción de la conferencia (que pego a continuación). A falta de que lo analice el foro (que andan todos durmiendo), yo no leo nada nuevo. Efectivamente hablan de aparición de los datos preliminares de fase I pronto en un artículo especializado peer-to-peer, pero dicha fase no terminará hasta junio. Lo malo de esto es que, al menos yo, contaba con que el diseño de la fase II estaba bien avanzado (porque la comisión oftalmológica se reunió en octubre para iniciar su diseño), pero por lo visto no es así.
A falta de ver si la presentación de las diapositivas es clara, creo que la conferencia era demasiado complicada para un público oyente inversor. Por lo demás, todo está bien, pero no confío en que aguante la cotización a este nivel, la verdad. No obstante, he de decir que los 3 o 4 mensajes que han aparecido de comentarios en el foro son de gente contenta con los datos, el nuevo lenguaje más cauto de la empresa tras la dimisión del CEO y más optimistas que este análisis mío.
Transcript CEO Bio Conference, 2/11/14, NYC
I just want to remind you we're a publicly traded company, so there is the cautionary forward looking statement.
I'm not sure how many of you are aware of what our company does. I would characterize us principally as a regenerative medicine company. While we have technologies that relate to neuroprotective biologics, the vast majority of our clinical and pre-clinical pipeline relates to transplantable cell therapies. In particular we have been focused on allogeneic therapies, cells that can be transplanted from a single source into multiple different patients. In that context, we focused on being able to generate in large quantities transplantable cells from truly pluripotent stem cell sources, whether those be embryonic stem cells using a technique we have that allows us to generate embryonic stem cells without destroying embryos, or taking advantage of some of the more recent technologies like induced pluripotency, and some of the other pluripotent stem cell technologies that are currently in laboratories and making their way towards clinical platforms.
To give you a sense of kind of where things stand, I'm going to talk principally today about our clinical programs, but I wanted to give you a little bit of an idea of what we have in our pipeline. We have four principle areas of research and development. Most of our efforts have been focused in the ophthalmology space. Beyond the clinical trials that we have in macular degeneration, we're also generating photoreceptor progenitors that can be transplanted into patients with retinitis pigmentosa or patients with macular degeneration who have proceeded to a point where they have lost their own photoreceptors. We also have transplantable sources of ganglion progenitors that can be used in the treatment of diseases like glaucoma. In each of those instances, we have pretty extensive animal data that we've begun to build up as we make our way towards IND filings. We're also generating transplantable sources of corneal tissue.
Beyond the eye, we have been focused on generating mesenchymal stem cells from pluripotent stem cell sources. Rather than deriving them from adult tissue, we're able to make them from this infinitely renewable pluripotent stem cell source, and the focus there is on autoimmune and inflammatory diseases. We have a wonderful relationship with Tufts Vet School, which allows us to inexpensively test these cells in companion pets. We have a number of INADs that have been approved by the FDA that allow us to do this. Those are presently directed towards developing veterinary applications for these cells that have a very important secondary benefit of allowing us to test these human cells in spontaneous models of these diseases, which gives us a much more robust focus on those go, no-go decisions that we may reach, but also provides effectively data that could be used in human clinical INAD to IND files as well.
Based on where we are, we're starting to look at lupus as probably a lead indication that we can move towards human IND filing some time in the not too distant future.
We also have a blood component program where we're making big white blood cells and platelets, and then beyond that, because we control the stem cell source that we're making these tissues from, we're also looking at being able to engineer the cells and the platelets to be able to ultimately selectively deliver protein therapeutics, small molecules and nucleic acids, either in an activated way or in a passive way.
Again, most of our financing efforts and spend have been around our clinical programs. The R&D efforts we have here, our end goal ultimately is to move to proof of principle and move to IND filing, and then look for partnering and collaboration opportunities for the rest of our pipeline.
So, our three ongoing clinical programs relate to macular degeneration. Specifically, they relate to a transplantable tissue that's involved in the maintenance of the photoreceptor layer. I'm not sure how many of you are familiar with the anatomy of the back of the eye, but this is what it looks like. The nerve layers are actually arranged so that the light has to penetrate the nerve fiber and the bipolar ganglion cells, and then ultimately the photoreceptors form the terminal nerve layer in the back of the eye. Beyond that is a very specialized differentiated set of cells call the retinal pigmental epithelial cells. They form a monolayer that secretes what's called the Bruch's membrane. Now the Bruch's membrane is a natural anti-angiogenic barrier. It separates the choroidal blood flow from the very back of the retina from the neurosensory retina. The consequence to the Bruch's membrane is that the RPE layer actually becomes the conduit and provides many important functions that are required for the health and ultimately for the function of the photoreceptors. In particular, because the photoreceptor layer does not see blood directly, the RPE layer is required to bring water, ions and nutrients from the capillary bed to the photoreceptors. It also removes the metabolic waste from photoreceptors. When photoreceptors are active, they shed about 10% of their mass on a daily basis in what are called outer segments. Those outer segments that they build up in the back of the eye, they form drusen and other toxins. The RPE layer actually phagocytoses the drusen, or the outer segments, metabolizes those into a form that then can be secreted back into the blood.
Another critical feature that the RPE layer plays in the function of the photoreceptors. Photoreceptors require Vitamin A metabolite called 11-cis retinal in order to be excitable by light and to propagate a signal along the optic nerve. In that process, they convert that to all-trans retinal, the RPE layer that reconverts that back to 11-cis retinal to be used by the photoreceptors again, so it plays a role in maintenance and toxification, but also plays a very significant role in the excitability photoreceptors.
As it turns out, there are a variety of different macular degenerative disorders. The end stage is loss of photoreceptor function and ultimately photoreceptor death. Preceding that is actually loss of RPE layer function. Those range from orphan indications like Stargardt's disease, which is a juvenile onset form of macular degeneration that's caused by a genetic mutation, to myopic macular dystrophy, which is actually a structural issue in the eye. When the eye gets elongated, it can put stress on the RPE layer and cause the RPE layer to die. Then age-related macular degeneration, particularly dry AMD, which over the course of your lifetime you accumulate the damage such as from UV light that causes the RPE layer to die and ultimately atrophy and then death of the photoreceptor layer.
So dry AMD, I think as many of you are aware, is the leading cause of blindness in people over the age of 60 in this country, and one of the leading causes of blindness. It is a truly unmet medical need. Wet AMD represents 10% of all AMD patients, and you have Lucentis and Eyelea and drugs like that. The other 90% with dry AMD really have nothing available. It is down to Ocuvite and other vitamin supplements. There is nothing that's been approved in the clinic at this point for the treatment of dry AMD. And it's a problem that comes with age. You can look at just the perfect storm in some respects in terms of the convergence. The prevalence of the disease goes up dramatically as we get older. Combine that with the aging of our population and the increase in longevity and what you see as Dr. Comfort put is an epidemic on its way. When we look at the potential market for dry AMD in the States and in Europe, you know we've looked at about 30 million patients between North America and Europe that would be potentially able to take advantage of the therapies that we have been developing, and we see that growing to almost 50 million by 2025. I think we'll probably have to revise those numbers up. There's a recent Lancet article that came out the beginning of last month, in which by 2020 they're projecting worldwide almost 200 million AMD patients, and by 2040 almost 300 million.
Again, our focus has been to develop transplantable RPE cells. The goal was to create a suspension of cells that could be injected into that subretinal space and to replace the missing RPE cells that die as a consequence to one of these diseases. There are a number of reasons to look at this as a first allogeneic product coming from a pluripotent stem cell. These are relatively small doses we're talking about, at the most only a few hundred thousand cells. It's not hundreds of millions of cells. It's a very small number of cells, easy to manufacturer. Because it's an allogeneic product, we wanted to find a product opportunity where you could use allogenic cells without the risk of immune rejection. That portion in the back of the eye, the subretinal space, is considered to be immune privileged, which means that we can use either very light courses of immunosuppression or no immunosuppression at all. That is all explained in our clinical trials. We have a very light course of immunosuppression we start the patients on, but many of them are weaned within weeks after the surgery and some of them are out two-and-a-half years now with evidence that the cells have persisted for that period of time.
It's an easy site to access. Vitreal retinal surgeons routinely make injections into the subretinal space, so it didn't require the development of a brand new injector system, or any kind of specialized training. It is a very readily accessible site surgically. And then because the eye is transparent, and there are a number of noninvasive imaging techniques, it allowed us to be able to monitor the fate of these cells after they were injected.
So the first thing we did was set up a GMP process. We have as I said a non-destructive embryonic stem cell derivation process, which allowed us to create an embryonic stem cell line, which once you've created it, you never have to go back and make another one again if you don't want to. These lines will propagate indefinitely. Because this is allogeneic, it can be centrally manufactured in one setting. The cells can be easily cryopreserved. Again, you can make huge numbers of doses in relatively small spaces. I point out here a 6-well plate in our hands could make 50 to 100 doses. A 600 sq. foot clean room that we have, we can manufacture 50 to 100,000 doses a year running one shift a day. So it's imminently scalable when you start thinking about the size of the patient population out there and the doses that we want to sell.
The way that I pitch this when I talk to the pharma companies, is that if you're afraid of cell therapy, you shouldn't be afraid of this product. It manufactures, stores and ships and can be used at the surgical end much the same as an antibody or a protein therapeutic. It is really something that is that straightforward.
I'm going to show you just a little bit of the preclinical data that we have, only because I think it helps illustrate what these cells do. So what happens in this first slide, these are cross sections of mice eyes from a mouse model for Stargardt's disease called Elovl4 mouse. This mouse by about 30 days of age has lost about half of its native RPE layer. We inject these mice with the human RPE cells that we derived, and then we look at them in different periods of time over the course of their life, sacrifice animals, do the pathology on them, and when we stain the human cells with a green stain, what you can see in the lower magnification panel in the upper right hand corner, the cells actually incorporate into the existing monolayer and they continue to form the correct anatomical structure, that of a monolayer rather than a big clump of cells. So again, this is a solution of cells that's injected in the subretinal space that's capable of finding the gaps in the native RPE layer filling those back in and they are recapitulating the correct anatomical structure. When you look at higher magnification in the lower left hand panel, what you can see are two green cells. Those are human cells. In between though is actually a mouse RPE cell that was actually there when we did the cell injection. So these cells are truly finding the gaps in the monolayer filling them back in. They're capable of reforming the tight junctions with the existing RPE cells in the monolayer.
In this particular slide, this shows you data from a rat model for macular degeneration called the Royal College of Surgeons rat, the RCS rat. This is the gold standard for dry AMD models. In this case, again these animals begin to lose their RPE layer. By six months of age they've lost substantially all of their photoreceptors and in an optokinetic motor response test are blind. And what you see in the left hand panel, which will become more evident when I show you the right hand panel, is where there should be a photoreceptor layer in the untreated animal, there really is none. It's down to maybe one nuclei of photoreceptors here and there. In the animals that we treated with the human embryonic stem cells, not only do we see the correct anatomical structure being formed like you saw in the mice, but here we actually were able to also correlate that with the thickness of the photoreceptors. The photoreceptor layer in the treated animal at six months of age is about 5 to 7 cells thick, and what this animal let us do was then go further to correlate that with visual acuity. Using an optokinetic response, we're able to demonstrate that the treated animal retained the vision of 70 to 80% of the visual acuity of what would be expected in a normal wild type animal.
So that along with a lot of safety data went to the FDA. This was the initial trial design that was approved by the FDA for all three of the different clinical trials that we have approved in the US and for the Stargardt's trial in the UK. It is a 12 patient trial design, cohorts of 3 patients each, ascending dosage format. When we initially started the study, we had been approved to treat patients who were very end stage in each of these diseases. 20/800 was the best vision we could treat. From 20/800 it's counting fingers and hand motion to give you a sense of how far down the spectrum of visual loss we were at. Based on the data from the first cohort of patients, we went back to the FDA and to the MHRA and they allowed us to modify the inclusion criteria to move this up to patients as good as 20/400 halfway through the trial, based on the very good safety data that we had at that point. Both sets of patients in the US trials as well as those in the UK, and the fact that we were seeing improvements in visual acuity, we went back to the FDA. This time we asked them to allow us to continue with the 100,000 cells, which we had already crossed the safety profile for, but now to do it in a special cohort of patients with vision as good as 20/100. So in the US in both the Stargardt's and the dry AMD trial, we have the ability to test 4 patients in each of those studies at this better visual acuity. The goal was to head towards patients who represent intermediate AMD rather than very late stage AMD, or very late stage Stargardt's disease and to start to kind of tease out what the potency or efficacy of these cells might be as we think about a Phase II study. So that's where we are. I'll tell you in a minute where we are on the trials all together.
As a little company, we're very proud of who we have been able to attract into these studies. We've managed to pick up four of the top five eye hospitals in the US as clinical trial sites. The only one that is missing from that list is Wilmer Eye at Johns Hopkins, and they have a member of their surgical team who is actually part of our Data Safety Management Board, so all five are effectively represented within our clinical trial team, four of them as clinical trial sites. We also have Jim Bainbridge at Moorfields running the UK study and between Moorfields and Bascom Palmer, you can pick 1 and 1A, those are the two top eye hospitals in the world. So we have really managed to bring in some of the best knowledge leaders in this field, who actually participate very closely with us. We have a meeting every October, in which we bring all the surgeons together. Jim flies in from London and the folks at Jules Stein fly out as well, to sit down and go through the clinical data and work through, not only the design of Phase I, but now the design of what the Phase II studies will look like as well.
Procedure is really straightforward. It's actually done on an outpatient basis. It's done under sedation rather than anesthesia. It uses a standard off-the-shelf injection system, that is a needle that tapers down to a soft tip cannula. It's a vitrectomy followed by a PBD induction and then a subretinal injection of the fluid that contains the cells. So once you've gone past the vitrectomy, the rest of the process takes all of about 90 seconds.
As of today we have treated 33 patients across the three enrolling trials. We have completely finished Cohort 3 in both of the Stargardt's trials, the US and UK, as well as the US dry AMD study. We have treated 3 of the 4 patients in each of the two special cohorts that we have in the US.
The third trial, which I'll talk about in a minute, is for myopic macular dystrophy. We are actually working with Jules Stein hopefully looking to enroll the first patients in that study by the end of this quarter.
In January 2012 we actually published a paper in the Lancet on the first two patients that were in the US studies. It was one Stargardt's patient, one dry AMD patient and what I can tell you is what we reported in that paper actually continues to be true across the board in terms of the safety profile for the cells and for many patients, the observations we made with respect to changes in visual acuity, improvements in visual acuity, we've seen in many other patients in these studies. Those have been visual acuity improvements that could be measured on an eye chart, but we also do VQF testing, which allows us to test things like reading speed, low-light vision and color perception. This just again from the paper, the first Stargardt's patient we treated, when we started she was hand motion in both eyes. She couldn't even count fingers. At three months she was capable of not only counting fingers, but she was reading five letters on an eye chart, still hand motion in her fellow eye. She has now crossed through her two-year follow up and has maintained and actually had improvements in her visual acuity in her treated eye and yet remains hand motion only in her fellow eye. She has now gone through two years, three months. She has been off immunosuppression for over two years, so again, at this point we believe that these cells persist even in the absence of getting immunosuppression, which was our goal.
Going from Stargardt's and dry AMD, we also have been approved by the FDA for another disorder called myopic macular dystrophy. Again, like the other diseases, it is a disease that results in death of the RPE layer followed ultimately by atrophy and death of the photoreceptors. In people with myopia, their eyeball is elongated. That causes the focal point to be ahead of the retina. For some of those patients, that elongation can actually create stress on their RPE layer and the consequence is you get fissures that are created in the RPE layer resulting in RPE atrophy, death and then photoreceptor atrophy and death.
In the US, MMD is the seventh leading cause of blindness. Because of the prevalence of myopia in Asia, in mainland China and Japan, it's the second largest cause of blindness. Part of this is because it's an early adult onset disease and as people live longer, then you accumulate many, many patients who are ultimately blind from this disease. As I said earlier, the goal here is to start enrolling our first patients by the end of this quarter.
Beyond what you can do with the native RPE cells, there are 200 macular degenerative diseases that we can tackle together. We've also started looking at the ability for second generation products, where we're using the RPE cells to deliver other agents, which may have either cooperative or synergistic effects with the RPE cells that we're delivering, or could be used again to mitigate some of the damage that's already occurred, particularly in trying to prevent wet AMD from occurring in these patients. 90% of all wet AMD patients come through dry AMD. Our hope is that by resurfacing the back of the eye with fresh RPE cells, they will in turn lay down fresh Bruch's membrane, which will recreate that anti-angiogenic barrier, but we've looked at the ability to engineer these cells to express anti-angiogenic factors. There are various inflammatory components that have been implicated potentially in dry AMD. Complement Factor D, C5 and C3 inhibitors have been tested in the clinics. They are all largely antibody based, which means you could imagine or preceptor trap, that you could generate single chain antibodies or receptor trap constructs that could be secreted by transplanted RPE cells.
Finally, the intellectual property platform is robust for this company. One of the kind of interesting features to being an embryonic stem cell company just birthed before George Bush took office, was that when he came in and put a moratorium on all embryonic stem cell funding by the Federal Government, because we were not relying on Federal money, it meant that we had no competition in this space. So it meant that being the first mover and first into the clinic has actually given us a really broad first to file patent system. So our original filing is based on the derivation of these cells and the various pharmaceutical deployment of these cells, whether they be again in cell suspensions the way we deliver them, whether you deploy them on a solid supporter, or whether you just deliver them as a polarized layer, were all things that we thought to cover in these early filings. The language in our case was actually broader than embryonic stem cells, so it actually covers the type of pluripotent cells that iPS cells represent as well. Getting first into human patients meant we solved what I would call the vital mile problem, and that is we figured out some of the issues that were actually very significant to engraftment and functional performance of these cells, so while sometimes these may seem like only incremental changes, from a commercialization standpoint moving from for instance 25% viability to 95% viability is the difference between a commercial product and one that's not, and those are what are covered by some of our more recent filings, so I think we have a good life cycle management strategy around our patent filings that comes with this as well.
That leaves me one minute, so I will just end by saying again focusing on the eye. We're quite excited by the photoreceptor progenitor and ganglion progenitor programs that we have in animal models for various forms of blindness. We've been able to demonstrate that the human photoreceptor progenitors, when they're injected into the subretinal space as a suspension of cells, are actually able to migrate into the outer nucleated layer, differentiate the rest of the way into being rods and cones and integrate actually into the neurosensory retina in a way that you see functional enhancement of vision in those animals as well. I will end there.
If there are any questions I'll take one or two now and then I'll head out in the hallway so the next speaker can come up.
Question: When do you expect the AMD results?
Matt: I know Simon was going to ask that question as well. The end of Phase I is still a ways off. What we have been looking at is releasing through peer-review publications interim data that we have available to us now. So we've been working closely with all of the clinicians in the US for example on a co-authored manuscript that would provide a tremendous amount of detail around the safety studies, as well as some of the changes that we've seen in respect to visual acuity and the VQF measurements as well.
Question: So the Phase II might be what, 2015?
Matt: No, I think, again, there still is a long way to go between here and finalizing of Phase II study for both the Stargardt's and the dry AMD. Because the Stargardt's is Orphan, we actually think we could, in both cases we could overlap them at the end of Phase I and start Phase II with the doses that we've already demonstrated are safe from Phase I, in part because, again at this point, we have some patients with more than two years worth of data for them. And then amend the Phase II protocol later, but this is all speculative at this point, as to what the design will be. All I can tell you is we've got a tremendous amount of input from not only the thought leaders, but we have consultants who have been in CBER, who have been in the MHRA who are helping us work through the strategies, and then we're having direct discussions with both agencies about how to best streamline this process in a way that, you know we can in one case may produce a Pivotal Phase II study.
A second question is about patents, just in general. What is the patent for these cells?
Matt: I don't know if you follow what's been happening in Europe, but when the first embryonic stem cell patent got challenged there was a Dr. Rosfelt who was making neuromyal cells from embryonic stem cells. It got knocked out on the basis that he had used a cell line in which the embryo had been destroyed. Since then, and actually as of last week, there has been a confirmatory decision from the European Patent Board of Appeals. They said they reaffirmed that actually they will patent inventions where the invention was made using an embryonic stem cell that was made through a non-destructive technique, and they cite our papers as the example for making embryonic stem cells through a non-destructive technique. So I think from our perspective, we feel like we're on a pretty good trajectory, even in those jurisdictions where the underlying use of embryonic stem cells has had any impact on the patent system. That being said, we're also far enough into the RPE portfolio that we've had good outcomes in Europe, in the US and in other major jurisdictions, China for example; we've got very broad patents in Australia and Japan.
Question: What specifically do you have in the US?
Matt: In the US we have claims to methods of treatment using RPE cells generated from embryonic stem cell sources. We have methods of manufacturing those cells, and then we're working through additional claims based on the pharmaceutical preparations. These cells, because they represent a cell that you ordinarily wouldn't get from adult tissue, actually have properties that make them distinct. That gives you the ability to patent them as a composition of matter, particularly in the context of our pharmaceutical preparation.
«Después de nada, o después de todo/ supe que todo no era más que nada.»
ACTC
Nuevo e importante: están utilizando el sistema en combinación con otros agentes
La gente se ha emocionado con esta fase porque la lectura es que han pasado de un 25% de viabilidad al 95%. A mí ese "for instance" no me lo deja tan claro...
Getting first into human patients meant we solved what I would call the vital mile problem, and that is we figured out some of the issues that were actually very significant to engraftment and functional performance of these cells, so while sometimes these may seem like only incremental changes, from a commercialization standpoint ***moving from for instance 25% viability to 95% viability is the difference between a commercial product and one that's not, and those are what are covered by some of our more recent filings, so I think we have a good life cycle management strategy around our patent filings that comes with this as well.***
«Después de nada, o después de todo/ supe que todo no era más que nada.»
ACTC
Pues si parece que habrá oportunidades de entrar más adelante.
Fenomenallll trabajo compañera reportera.
Ostras!!! El fin del mundo!!!
http://www.marketwatch.com/story/scary-1929-market-chart-gains-traction-2014-02-11
ACTC
La presentación en diapositivas:
www.advancedcell.com/documents/0000/0479/2014-biotech-showcase-presentation,-january-13,-2014.pdf
«Después de nada, o después de todo/ supe que todo no era más que nada.»
