ZIOPHARM Oncology, Inc.
Q1 2017 Earnings Call Transcript

Published: 2 May 2017

[Operator:]

Good day, ladies and gentlemen. And welcome to the ZIOPHARM First Quarter 2017 Earnings Conference Call. All this time all participants are in a listen-only mode. Later we will conduct a question-and-answer session and instructions will follow at that time. [Operator Instructions] I would now like to turn the conference over to Amy Trevvett, Vice President of Corporate Communications and Investor Relations. You may begin.

[Amy Trevvett:]

Thank you very much, and thank you all for joining us today for ZIOPHARM's first quarter 2017 earnings conference call. Leading today's call will be Dr. Laurence Cooper, Chief Executive Officer. Also joining us on the call for the question and answer session is Dr. Francois Lebel, Chief Medical Officer; and Caesar Belbel, Executive Vice President, Chief Operating Officer, Chief Legal Officer and Secretary. Before we begin, as outlined on Slide 2, let me remind you that during today's conference call we'll be making forward-looking statements that represent the company's intentions, expectations or beliefs concerning future events. These forward-looking statements are qualified by important factors set forth in today's press release and the company's filing with the SEC, which could cause actual results to differ materially from those in such forward-looking statements. Information discussed on today's call is accurate as of today May 1, 2017 only. With that, I’d like to turn the call over to Dr. Laurence Cooper.

[Laurence Cooper:]

Thank you very much, Amy. Welcome everybody to our quarterly call. Slide 2, as Amy explained is our forward-looking statements and of course there is more details on ZIOPHARM's website if you are interested. Slide 3, so I would have said a few minutes review on this call talking about how ZIOPHARM has engineered for success indeed our competitive edge in cell-based therapy. So let's take a moment now on Slide 4 and look at the totality of technologies that needs to be embraced if wants to be successful in the CAR-T and indeed in the TCR, in other words, the space for the genetic engineering of therapeutic T-cells. But the first on the upper left, how does one manage cost? When seeing number in the late press, where these large numbers are associated with the cost of goods of generating generically modest by T-cells. The company that understands how to manage those costs will essentially trump the headwinds of payers and of hospitals that are having to negotiate essentially how to deliver on the expectation of patients. We at ZIOPHARM have made major headwinds in essentially managing the costs of the therapies I’ll share with you. On the upper right, you see the control after infusion. In other words, how is it that investigators and patients alike can control their T-cells after they’ve been infused? For instance, if T-cell is given to a patient with a lot of malignant T-cells, these T-cells are of course expressing CD-19, then those infused T-cells are synchronically activated and it becomes like a runaway engine. Those T-cells then takeoff, proliferate in an uncontrolled fashion. And while there has been dramatic anti-tumor sponsors including in our own work, those patients are at risk for toxicity. For instance, cytokine release syndrome. And we’ve seen some of the difficulties others have had managing that type of toxicity. So as I’ll go through this presentation. I’ll explain to you how ZIOPHARM is meeting the need of the community to be able to control T-cells after they’re infused. On the bottom left, addresses the major issue of what is the one can scale, one technology. In other words, from the CAR-T therapy space is anticipated to grow, is anticipated to be great demand for these products like CD-19, directed therapy and other directed therapies. How is it that proprieties such are ourselves are going to be able to scale for the future. Here again as I go through the slide deck you’ll see a solution. And then on the bottom right, how can we avoid lymphodepletion? As you know, chemotherapy is given to the recipient before the infusion of T-cells to prep that patient. So they are better receptacle for the infused T-cells. So why is it that in 2017 we are marrying state-of-the-art cell therapy with 1950s technology? ZIOPHARM has a solution for this, I’d like to explain. So let's look at these solution together on Slide 5. So in order to be able to manage cost, we have avoided essentially the expense and the complexity of viral based therapies. For advancing in the human, this non-viral approach to gene therapy. In other words, we use DNA plasmids to genetically program the T-cells to express a gene of interest for instance or cytokine or our chimeric antigen receptor. This DNA technology provides the major competitive advantage compared to using the viral based approach. It essentially allows us to move faster and cheaper than others. Again, we are addressing how does one manage cost? On the upper right hand side of the slide, you’ll see the RheoSwitch Therapeutic System or sometimes we shorten it to RTS. This is a system that we have employed successfully now in the clinic to be able to control on and off a gene of interest, for instance, IL12, as I’ll show you in a few minutes, but importantly, it’s not only the on and off switch that one needs in human biology but it’s to be able to alter essentially the amount of expression. And as I’ll share with you, we have robust data now in humans that definitively shows that we can use a small molecule which happens to be a drug called veledimix, that patient take by mouth and then the amount of veledimix they take essentially drive the relative level of IL12 or the gene of interest. So note the words, ZIOPHARM has a switch. And this is all important essentially for our ability to be able control T-cells after infusion. On the bottom left hand side, is our new technology that we are advancing around point-of-care, and this is a solution for manufacturing. And this is really the idea we have to be able to answer the all important question of how does one scale ones manufacturing approach. Some groups are investing in large dedicated infrastructure around centralized manufacturing. Others like ourselves, have embraced the idea that why would one want to grow T-cells outside of the body, when you can grow T-cells inside the body? Why does one have to take the time and expense therefore to propagate T-cells in large manufacturing facilities when a natural receptacle of T-cells is the human being? So we’ve cracked the code if you would for our ability now to do this point-of-care manufacturing, this very rapid production of T-cells using our scalable solution which we refer to, again, as point-of-care. On the bottom right is the answer for how all of these works to avoid lymphodepeletion. So lymphodepletion as I've alluded too and as actually we’ll look at it little bit of data in the slides to come. Lymphodepletion essentially is a preparative regimen that prepares that recipient for the infused T-cells. When that chemotherapy is given to the recipient, it essentially suppresses the natural T-cell mass in that patient. In other words, it lowers your count. It lowers your lymphocyte count. As a result, the IL15 that had been soaked up by the indigenous immune response is now liberated and free essentially so that the infused T-cells can be bathed in that pool of freed up IL15. So why would one want to do that when one can generate T-cells that have their own IL15? Because if you have your own 1L15, as we will demonstrate, one may not need to lymphodeplete the patient. In other words, you don’t have to take the patient through chemotherapy prior to the infusion of our current modified T-cells. So on Slide 6, we want to show you some high level of how we’ve actually achieved success. So this idea of managing cost through the Sleeping Beauty system has already had success in clinical trials. We’ve had a first generation technology that has demonstrated the ability for patients that have an anti-tumor response. It’s demonstrated the ability as the Sleeping Beauty modified T-cells to engraft and persists in patients. And then we’ve gone on in our second generation technology where we’ve shorten the manufacturing time. And again, we’ve shown success. So it’s no doubt that the Sleeping Beauty system is the most advanced non-viral approach in clinical trials, and it’s no doubt that it had success. On the upper right, the RTS system or the RheoSwitch system, this has also had success. As I’ll share with you, we’ve had a major move forward in our adenoviral program where we’re treating patients with recurring glioma. This is proof positive that that switch system works and is essentially is a platform by which we can lift the switch out of that particular vector system, that adenoviral vector system, and paste it into the T-cells using the sleeping beauty system. So now we can have control of T-cell biology. So there again, we’ve had success in clinical trials. Our point-of-care manufacturing solution is built on really a long period of work now in the laboratory, and we’ve been able to declare success in the laboratory science because we can definitely show in our mouse models that T-cells can be genetically modified using the Sleeping Beauty system to express this IL15 molecule and immediately go into mouse of leukemia. Again, this points essentially the way forward now for clinical trials. And our IL15 molecule which we refer to again as membrane-bound IL15 or [tablet] IL15, this idea that the T-cells themselves can bring their own IL15 to the war on cancer. This IL15 molecule again has shown success in pre-clinical studies as we’ve published several times in the last several months. So turning it now on Slide 7, one can wrap it up into what the solutions looks like for point-of-care. In other words, it’s very rapid manufacturing of T-cells for the purposes of infusing CAR and TCR modified T-cells into human. It hinges on the Sleeping Beauty system, the non-viral gene transfer to express the RTS. Under the control of the RTS, it’s the membrane-bound IL15. Also the Sleeping Beauty expresses the CAR or the TCR, for instance, for part of our neo-antigen program. So you can see now how all of this wraps up where ZIOPHARM has solutions to some of the major problems facing the CAR-T world. In other words, how does one get a handle on the cost, on the control of genetically modified T-cells? In Slide 8, I’ll provide a compare and contrast to where ZIOPHARM is on the right hand side using non-viral gene transfer to express our CAR, whereas other companies they are using viral based, lentivirus or retrovirus to genetically modify their T-cells to express their CAR. So let’s just look now 1, 2, 3 on the left hand side with the viral based approach. Where one uses a virus in the GMP setting to generate clinical bred T-cells, one has the cost essentially to make the virus, and then one has the cost associated with propagating those T-cells in the GMP facility. And that represents a substantial ongoing advancement for this particular tactic. On the second issue, the second headwind if you would for the viral based therapies, is that the infusion of these CAR-T has caused major toxicities due to the lack of real time control of T-cells after administration. Here again, I'm alluding to the cytokine release syndrome, the cytokine storm that happens when you have T-cells that are runaway in the humans. And the third is the current need for lymphodepletion and again this increases the cost and the risk due to the needs to free up the bodies own cytokines perhaps the most important one of the cytokines being IL-15. On the right hand side I have now in a one, two, three format essentially answered the concerns. So the first is that we’re using viral we’re using the non-viral system to put in a variety of genes like the CAR and the Membrane-Bound IL-15. And again this provides a solution for growing T-cells in the patient rather than having to build large manufacturing facilities to grow up the T-cells in centralized facility. On bullet two or point two the RTS is clinically proven now it’s a clinically proven switch that we have gone to work in the adenoviral system and now we adopting it to work in the T-cells so that we can regulate the behavior of the T-cells by dialing up and down the expression of Membrane-Bound IL-15 and to be able to control the level of IL-15 so we can customize essentially the T-cells that are being infused to that particular patient’s need. And in the third bullet point is because we are able to hard wire in Membrane-Bound IL-15 with the co-expression of the CAR we may be able to avoid the need for lymphodepletion. These technologies that are now encapsulated around the idea of point of care represent a generational events a major set forward essentially as ZIOPHARM moves it’s technologies forward for the infusion of CAR modified T-cells. Slide 9, reflects a little bit, this reflects back on the history now I have been in the CEO's chair for two years it will be by anniversary coming up mid May. And what are we’ve been doing over this last two years and now it’s essentially you can see the grand plan starting to come into focus. When I first took the helm we had an academic program and academic program which we called first generation CAR which T-cells are being made with our partners at M.D. Anderson but it was being made where the T-cells were generated on the feeder cells and it took a number of weeks to generate those technologies. Even so we were able to declare success even so many patients now are benefit from that first generation technology again the T-cells can be seen in the patients and the patients are in remission. But as we transition as I transition to the company I recognize that we needed to shorten to the manufacturing time and that we’ve done we’ve gone from the four weeks that are associated with the first generation CAR now to where we are approaching two weeks with a shorten manufacturing approach. Again it had success and I’ll show you for instance the patient who has benefited from the shortening manufacturing. So these two anchors if you would are the first generation and the second generation CAR demonstrates that we can do non-viral gene transfer and that if you would shorter is better the amount of time and culture that T-cells are being generated is better. We’ve also gone on and treated patients with the adenoviral Vector system AD on the top for adenoviral RTS there is a switch of course in IL-12 is the cytokine IL-12. In our glioma study we notice demonstrate that we can control the expression IL-12 with V, V for veledimex again this has success in humans. At the NCI we had published an important work in just the last few weeks demonstrating the biology of IL-15 this is something that we predicted at ZIOPHARM but in the NCI study they use lymphodepleting chemotherapy again to free up IL-15 in the patient. And they were able to show that IL-15 levels were biomarkers for success they herald in success. In other words elevated IL-15 levels as a result of lymphodepletion resulted in complete responses to patients who had CD-19 directed CAR modified T-cells so that again shows that IL-15 is a driver for complete response all of these now add up if you would to the third generation technology which we are launching. This third generation technologies is centered again around the point of care. Slide 10 looks at some of the data that underline our technologies again we’re focusing on CAR modified T-cells here directed towards CD-19 this is an excellent space to be working at because we know essentially the boundaries around CD-19 directed therapies. So the first generation technology completed published clearly show that we could have responses in patients indeed we have doubled the survival rates in these patients and clearly showed that the T-cells persisted in patients after they are being infused. Then we have gone on the right hand side to shorten the manufacturing, this actually is where the trial currently stands and patients are benefiting from this approach as we speak. Here on the left hand side of this PET scan is a patient unfortunately has a factor ALO this is patient whose disease persisted despite all available therapy. Then they got lymphodepleting chemotherapy and they got the sleeping beauty modified T-cells and as you can see on the PET scan on the right hand side by day 48 they had a complete response. So again this is like other peoples data in that it shows a complete response. It shows a dramatic anti-tumor response but unlike other people’s data this is done with a non-viral approach to gene transfer. And for us this is not the resting ground this is essentially the proof positive so that we have the line of sight to get to the next stage which is on Slide 11 which is where we further reduce the time and culture to under two days, this again is our point of care technology. So on the left hand side I schematize this for you so you can see that the patient for instance would come in and have a look free as products would be genetically modified using the non-viral system of sleeping beauty to express the CAR and the Membrane-Bound IL-15. Here the Membrane-Bound IL-15 is under control of the switch the RheoSwitch system and then the T-cells are rapidly infused into patients there is no need to propagate the cells in large facilities now. After they have been infused we can control their expansion by activating the switch activating the switch using veledimex. And this will allow us again to customize the amount of T-cells needed to that particular patient. So in the middle we have modeled this we have model this in these mice you can see little images that mice now in these boxes there is five of them in these groupings. For instance in the tumor mice tumor only section these mice that receive a leukemia, a human leukemia and the human leukemia has been genetically modified to emit light and you actually on your slide seeing light except it’s been full colored like a weather map if you would. In other words red is the most light coming out of the animal so as you can see by inspection these mice just receiving tumor of course die from rapidly progressing tumor when you put in the CAR you do have an effect but it doesn’t clear the tumor. But when you put in a CAR made by this point of care technology in other words the simple DNA introduction followed by the immediate infusion you can sweep mice clear of tumor. On the far right hand side at our technology where we have now taken the switch put it into the T-cells and allowed the T-cells now to be under the control of the RheoSwitch and we can use veledimex to turn on and turn off and turn back on again IL-15. And this will be the technology that when these T-cells go into the humans we can essentially control IL-15 levels using the clinically available molecule veledimex. So this puts our priorities in place on Slide 12 so as we go through the year we are focused wholly on decreasing the cost and the time of manufacturing. We are avoiding the complexities of generating T-cells using virus. We are using the clinically established switch technology to express Membrane-Bound IL-15. And then we’re going to be controlling T-cells after their infusion to mitigate any off target effects and we’re going to be testing the hypothesis so we can get ready of chemotherapy. We can simply electroplating the plasmas infuse the T-cells and not have to lymphodeplete that patient. And on the right hand side you can see how powerful that is because we can use the point care to target through CARs, we can target through TCRs for instance for our solid tumor program and we could put all of this under the umbrella of the RheoSwitch to control the expression of Membrane-Bound IL-15. On Slide 13 we let you know that one of our partners has also embraced our technology. The sleeping beauty non-viral system as well as the RTS switch system. Merck KGaA, Darmstadt are going to be using the sleeping beauty system for their prop program they are going to be co-expressing the RTX with RTS the Membrane-Bound IL-15. And this they are going to be using at least in this initial comment for their two CAR targets and we anticipate all of this essentially coming into the clinic plant in the next year 2018. Another partner on Slide 14 is our work with the NCI with Dr. Steven Rosenberg. Here Dr. Rosenberg is working with ZIOPHARM to be able to use the sleeping beauty system to personalize immunotherapy. The great advantage or one of the great advantage of using DNA versus virus is that we can readily make that DNA at a fraction of the cost that would take to make a virus also generically modified T-cells. Therefore we can begin to think about personalizing immunotherapy and that is the key. You have to essentially personalize immunotherapy because the T-cells receptors that are targeting solid tumor targeting neoantigens as to express within solid tumor. These are unique to each patient’s tumor there they are actually heal of those cancers. So once one can target them you can go after the vulnerability of the cancer itself, but you have to make one product for each patient and you can only do that with a non-viral approach to gene transfer. Because again the simplicity of the biology and cost savings of avoiding a virus open up this window and we have that window open to us. So we are working with the NCI as you can see two papers there in June and January from last year essentially provide the backbone of what we’re doing. And then the CRADA that we announced at the beginning of the year with our partner Intrexon. In addition to the work of the NCI we are also building our own program with respect to targeting neoantigens using the sleeping beauty modified T-cells and we’ll have more to say about that in the weeks and months to come. So that cell therapy program in the first 14 slides really emphasizes the cutting edge signs that we’ve now brought to the bedside to be able deliver on point of care therapy again I trust in the major issues of cost and control. These next few slides now pivot to our adenoviral program so on Slide 15 I’m going to essentially remind the audience that we are advancing to Phase III studies with this important asset. And we’ve been able to do so basically since May of 2015 to where we are today in two short years we’ve taken this program from Phase I to cusp of a pivotal trial. On Slide 16 I want to remind folks about IL-12 Interleukin-12 this is master regulator of the immune system IL-12 promotes immune responses by activating NK cells and T-cells it does so with the receptor you can see I carton this out as IL-12 as a little circle, yellow circle and buying in IL-12 receptor it then kicks off activation pathways within T-cells and NK cells. These activation pathways have a number of reports essentially through the biology of NK cells and T-cells. For instance they make NK cells and T-cells sticky. They up regulated adhesion molecule that’s very important for what for the T-cells and the NK cells are within the two micro environment because they can stay plus. For instance IL-12 also drives the differentiation of T-cells again making it angry making it a killer just like in NK cells so they can fight tumor. And on the right hand side you can see the flooding in now of these immune cells these T-cells and NK cells into the tumor micro environment to do tumor killing. So biologists have known for a long time the power of IL-12 that it could generate cytokine that are T-cells and NK cells proliferate T-cells and NK cells it will stop regulatory T-cells from getting in the way of these killer cells. This biology was known but was not know was to how to control IL-12. It was known until now because ZIOPHARM is the company and it’s been able to attain as if you would this master regulator of the immune response. So how do we do that? So on Slide 17 we set up a trial across North America enrolling some of the sickest patients in the United States. These patients who have not just brain tumor not just glioblastoma but have a current brain tumor or currently glioblastoma. We have been able to essentially work with some of the best in the United States across the United States you can see the hospitals there and the medical centers on the left hand side. When patients are involved in our study they have the desperate news that their brain tumor has come back. And for some of those patients they can go on have another resection this resection is not curative this resection is palliative basically there is a control some of the pacing of the disease to release some symptom but it allows us the window if we are able to give the neurosurgeon a syringe and in that syringe they inject just a 100 mg to 100 microliters of fluid basically the tip of your pencil and that is placed into the tumor and there is tumor still there despite resection. The patient is then take 14 days of veledimex the activator ligand to drive RheoSwitch systems and then we then and the patient all importantly takes advantage of the IL-12 biology all look what I showed you on this prior slide as ability for the T-cells and NK cells to get activated to kill half in these patients as a result of IL-12 being made in their tumor under the control of the RheoSwitch system. So to understand this biology we started a Phase I trial in which patients were signed to three cohorts and these cohorts they got 20 mg, 40 mg and then sort of a dose finding study of 30 mg of veledimex in other words high medium and lower levels veledimex. And this veledimex essentially we are asking the question could it activate IL-12 biology in the human and could it do in patients with brain tumor. So on Slide 18 the answer is yes so these are data that definitely show that the switch work the RheoSwitch works, So to help you understand these data I set up a little Rheo stat if you would on the left hand side it goes from off to on an actually than has a gradation in between because that’s exactly how it works it’s not a light switch it’s rheostat it is a RheoSwitch. So we have green 20, blue 30, 40 orange color dosing as veledimex. So the patient take the drug the veledimex by now and then it across as you can see in the lower left hand side into the plasma and announce of veledimex we not activate infection you would that we are measuring it’s proportional to the amount of drug the patient taking by now in other words it crosses from the gut into the bloodstream no major surprise but very satisfying that there is effect function I know that we can both lean high that it’s actually narrows the low medium high dosing of the veledimex. What was important and still is important is that we can measure veledimex in the brain tumor in other words the veledimex crosses from the blood across the blood brain barrier and again does it with proportionality patients take the lowest amount of veledimex 20 mg to the highest amount of veledimex 40 mg we can again find proportionality that step function from low medium and high and as the veledimex in the tumor. So these data are necessary but not sufficient on the right hand side is what happens then when the veledimex interacts with the RheoSwitch. The RheoSwitch has been deposited in the tumor by the injection of the adenovirus at the time neurosurgery so it’s sitting there it’s waiting ready its’ waiting essentially to be programmed to be activated by the veledimex. The patient takes 20 mg of veledimex another cohort 30 mg and another cohort 40 mg and let’s look and see what happens now to the IL-12 levels. Now as you can understand we can’t measures IL-12 level serially by measuring IL-12 and the brain tumor that would be too invasive for these patients but fortunately for us we are making so much IL-12 that’s coming essentially out of the brain tumor environment that we’re able to put a needle in the arm of these patients and draw blood from the patients and measure IL-12 that it’s peculating back out of the brain and we can sense it we can measure in the peripheral blood. So at the beginning as you can see on the upper right hand side there is no IL-12 circulating these patients once they begin to take veledimex you can see in the green, blue and the orange you again get low medium and high levels of spec function of IL-12 that drive essentially the biology and tumor response. So again you’re seeing now it’s goes from off to on and the on it’s proportional it’s a RheoSwitch once the patients stop taking the veledimex so the IL-12 levels stops and return to baseline. So this is we’re confidence IL-12 this is if you wouldn’t made from us ZIOPHARM adenovirus what happens when the body senses this IL-12 is it active absolutely it is active because it then kick off the body’s own generation of another cytokine for gamma interferon so baseline it’s very little to none expression of gamma to interferon then the patient takes veledimex low medium high levels of veledimex and kicks off IL-12 which again kicks off the proportionality of the gamma interferon the patient stops veledimex and the levels of gamma to interferon return to baseline. Again this is proof positive that the switch works as not only they will turn things on and off but as a transcriptional regulator to dial in graded doses of this all important drug IL-12. So on Slide 19 we’ve gone on this Phase 1 trial to follow these patients who are now steady cohorts and we’ve identified some very exciting biology with patients who receive the adenovirus to control the IL-12 who receive 20 mg of veledimex that’s in green at the top. And when we watch these patient we can see that there median overall survival is 12.7 months. Now, I would remind the audience that these patients have had multiple recurrences. And this is, we think, very encouraging data for these patients. And we think also encouraging data as we talk to the regulator. But let’s just put this in comparison now for what is available for instance to a patient. If you got a bit with how occurrence of your GDM, you walked into your doctor office. He or she would go through these data, right here in the blue lines, and they’d say to you, I’m sorry, the tumor came back. But this is the best that science has to offer. And I would caution also that in these studies, I show these studies because we think they are representative as the best studies in literature in the way they are randomized or they are multicenter. These studies often have patients. For instance, who only have one recurrence. Let's look at just one study for instance. The randomized multi-institution Phase-2 study comparing POLIMA versus Compazine, Compazine is a chemotherapy agent. So in this study, patients, just like our patients, went in and had another reflection because their tumor recurred. And then they were randomized to either get a wafer impregnated with Compazine or a wafer that was in nerves. In other words, it just had the polymer, the backing. And then the patients were followed. So you can see here that really unfortunately for the study, really not much happened when you added Gliadel. You added the Compazine, you can see those 110 patients can live about on average about seven months. But also similarly did the patients live who had that repeat surgery. So in other words, these are some of the data that if you’d control for surgery - again, our biology, our understanding of our median overall survival look very good when can stack it up against what’s really the best available therapy for humans. Thus we have an eye now towards proceeding with our pivotal trial. We’re starting to look forward to what the commercial landscape might look like. What does the totality of experience around the current glioma? What is the major unmet need? There’s 74,000 or so new cases annually worldwide. In Europe, there’s estimated about 13,000 patients each year was recurrent glioblastoma. In the US about 11,000 each with recurrent glioblastoma. And as you can see, because the recurrent rate is so high, this really represents essentially the initial diagnosis. 90% of patients unfortunately with their initial diagnosis of glioblastoma reoccur. So this is the major unmet need. On slide 21 is a reminder of our regulatory stands. We are currently in collaboration with investigators and regulators assessing the protocol design option of our pivotal trial. And I’d emphasize here, this includes the potential for a single arm study comparing the adenovirus delivery of IL12 and Veledimex to historical controls and a sub population of patients for the recurring GDM. And I know many of you want to hear about details of this trail, and we’ll give you details. But at the moment, we’re going to complete our discussions with our advisors and our regulators before we reveal further information. I’m summarizing the clinical data here. Currently the median overall survival stand at 12.7 months for the patients with receiving 20 milligrams of Veledimex, and we’re going to have an update for you at ASCO in June, basically next month. And then we also have an eye towards commercialization. That’s where undertaking the plan for this pivotal trial, we are also actively evaluating partnership opportunities with a goal for commercializing this Adenovirus and Veledimex asset. Like to now to move the conversation in the last few slides on how we do. Really to touch on some important other aspects of our program. Again, I think we’ve been very thoughtful about how we are rolling out new therapies that are really widespread untapped opportunities in the oncology arena. So on slide 23 gives you an update for two of these. On the left, they are both addressing acute myeloid leukemia. So acute myeloid leukemia for the most part doesn’t express CD-19. So it can’t be targeted with CD-19 directed therapies. So on the left hand side, is a new CAR-T program that we are launching where we’re targeting a molecule called CD-33. CD-33 is important because it’s on many acute myeloid leukemia. And we’re using a CAR to do this. Now because this is essentially an unproven target, we’re putting this on the backbone initially of our lentivirus program. And then as the data come in reassuring us about the target and as we move forward, which maybe even be its own commercial space. We are also adapting our technology to target CD-P3 with the point of care technology we’re trying to introduce with you earlier on. On the right hand side, is our NK or Natural Killer cell program. We've essentially figured out how to grow large numbers of primary NK cells. These are not in more flies or tumor NK cells, these are primary killer NK cells. And we've figured out how to identify universal donors and then to grow a very large numbers of those NK cells using a specialized seeder cell that expresses a molecule called IL-21. This is an important event because now we can make a large biobanks of these NK cells, and we can make them in advanced as the patient comes to the clinics. In other words, we can make them today put them in the freezer when the patient comes in the clinic we can infuse them on demand rather than when the NK cells are available. These NK cells have important biology because they lack the T-cell receptor. So in another words, we don't have to edit or genetically engineer a way or cut out the T-Cell receptor. So NK cells have a lot of good biology that are good cellular template to be used essentially for off the shelf therapeutics and we'll look at that together and indeed we are might advancing steadily towards clinical trial this really addresses our issue of cost. So, you again see some of the tenants here of control on the left hand side where we're targeting CD-33 but we also have a switch there in which we can blow up the T-Cells if we need to, it's a kill switch or an off switch. And then the issues of cost on the right hand side, where we are essentially making cells, using a inexpensive an appealing technology where they're made in advance of one's need. Slide 24, I want to turn to a summary of our financials and also looking ahead. So we have cash and equivalents of $66.4 million of express at present time. This has a cash runway through 4Q 2017. And this actually will allow us as you can see on Slide 25 to initiate the pivotal trial. We're in excellent share, as I've shared with you now to talking that we have terrific data and we have terrific assets and this opens up many opportunities to address our financial reserves and also add just in the past that we have money for MD Anderson in which we use for advancing our clinical programs on their campus. On Slide 26 really now summarizing our competitive advantages. We have this point-of-care technology there is very rapid manufacture that we're applying to CAR and TCR. This is based on the clinically validated Sleeping Beauty platform. This allows us to decrease cost and with the RTF system increase the control of the genetically modified T-Cells. The RTS now, we've demonstrated proof positive that we can control cytokines in the clinic. The adenovirus program with IL-12 of veledimex is proceeding to pivotal trial. We're harnessing RTS and T-cells so essentially we can customize IL-15 expression in the membrane round form using veledimex. The solid program now is gathering momentum as we target new antigens with personalized therapy using the Sleeping Beauty platform. And again, the off the shelf program built on our NK Cell approach. This is studying partnered with Intrexon who have just been terrific as well as clinical sites across the United States and I mentioned the NCI earlier. A milestones on Slide 27, for the RheoSwitch program delivering inter-tumor IL-12, in other words the adenovirus program, we're going to updated data for you in June at ASCO. We're going to initiate the pivotal clinical trial for current GDM. I haven't have enough time with you today, but I will just again emphasize that we're going to launch two other Phase 1 trail, the first is a combination trial where we're combining checkpoint blockade anti-PD-1, with the adenovirus controlling IL-12. This will be a very interesting study to do. And then we're also initiating a Phase 1 study again delivering adenovirus with the control generation of IL-12 for children with brain tumor, again a major opportunity for the program. The CAR-T program we're continuing our Phase 1 clinical trial where we're shorten the manufacturing time, I'll again share with you the anti-tumor response that patient had, and we're advancing our third generation technology where we're combining the controlled generation of IL-12 membrane of IL-12 towards this point of care approach. We're initiating the study with AML with our CAR-T with our CD-33 directed therapy, and we're advancing the program personalizing therapy against neoantigens which is our solid tumor program. Building on that solid tumor program is our work at the CRADA, we couldn't be more excited about this to see Rosenberg and his team, and we are also as I alluded to advancing our own technology to deliver personalized in modify T-cells targeting neoantigens and solid tumors. Also 2017, we are going to kick off the off-the-shelf and T-cell program specially useful for patients with eligibly AML. These patients unfortunately are not eligible for substandard chemotherapy so this represents a real hope for these patients. And our TVHT program, we are advancing steadily for - have more to say as this near clinical translation. Slide 28 is our last slide of our pipeline that put it all together. Rather than going through this, I have said this in words. I’ll leave this with you on the page and I’ll now end the conversation and we’ll pick it up again with Q&A. Thank you.

[Operator:]

[Operator Instructions] And our first question comes from Keith Markey from Griffin Securities. Your line is now open.

[Keith Markey:]

Thank you very much for taking my question. I was just wandering if there would be a simple way of describing the difference between what you call a point-of-care therapy and a cell that has been modified to express Membrane-Bound IL-15 and either a CAR or TCR receptor?

[Laurence Cooper:]

Sure, Keith, thank you so much. So the point-of-care technology builds on the IL-15 data. So another word, point-of-care harnesses the IL-15 biology because what IL-15 does, it is provide a growth signal for T-Cells. So that when you have IL-15 present, in other words when its balance of the membrane, those T-cells have a growth advantage or proliferator advantage over their neighbors that done express IL-15. So, this allows one under the point-of-care platform to take those T-cells that express IL-15 and say for instance CAR or TCR and put them immediately into the patient and grow the T-cells through IL-15 biology in the patient and that's the major advance compared to for instance growing the T-cells in bioreactors and then putting them into patients.

[Keith Markey:]

Thank you. And so would it be reasonable to consider the program that you are going to be initiating in the clinic next year with Merck KGaA as a point of care therapy?

[Laurence Cooper:]

Sure, that's a great question. So, we haven’t actually reviled that level of details but I would remind you and the audience that they are really behind our technology with respect to the CBD system and the Membrane-Bound IL-15 as the control of the Membrane-Bound IL-15 under the RTS.

[Keith Markey:]

Okay. Thank you.

[Operator:]

Thank you. And our next question comes from Reni Benjamin from Raymond James. Your line is now open.

[Reni Benjamin:]

Thanks for taking the questions and congratulations on the progress. Maybe just to start off, can you give us a little bit more color on the interactions that you had with the FDA which is recently announced and I guess what would you need to decide between historical single arm study versus a randomize study and can you brake it maybe a how large either those two studies might be?

[Laurence Cooper:]

Sure, so that's a great question. Thank you. So, our meetings with the regulators in America with FDA have now gone on and we have meetings in Europe with major regulators over there. As we essentially look at the totality of feedbacks that the regulators are getting us, we’ll have more to say about the protocol design and so we have to hold it there basically as we go through essentially that dialog.

[Reni Benjamin:]

Okay. And then just regarding the cash position in the exploration of partnership opportunities, have you started talking with partners, what’s the ideal partner sort of look like, is it one you might focus on ex-U.S. versus maybe worldwide. How should will you thinking about that?

[Laurence Cooper:]

Yes, so, we're open to whole of the above are enticing. Folks are now seeing the survival data and are recognizing especially in the background of the desperate need of these patients, so this could be a major advance. So we are in active discussions and we will have more to say as this solidifies.

[Reni Benjamin:]

Okay. And then just I guess one final one. What kind of trends - when we did the comparing contrast on the slides, clearly you talk about how much better the plasmid is over the viral but what kind of introduction efficiency do you see, because that would seem to be a importance. Right? And then also what is the half life of the Membrane-Bound IL-15 on the cell and how long does that stay even after you’ve get a cold shut off the switch?

[Laurence Cooper:]

Yes, sure. So in terms of the last part of the question first. The regulation and the up and down on and off the membrane of IL-15, we haven’t gone into those details yet but I had more to say is that biology start to transition to the clinical, so that stayed tuned if you would. If the transaction efficiency also I think is an important point. So I thank you for that. So, the non-viral system is able to stably introduce a gene whether of the Ad or the RTS expressing IL-15 or whether be a CAR that TCR. And once that cassette is hard wired into T-cells, it doesn’t matter whether that cassette came from a virus or came from a non-viral DNA plasmic. The T-cell than have to the bidding, if you would have to cassette. So the non-viral approach the great advantage of non-viral approach is that is able to insert these genes and particular able to insert the RTS system. So even if we have small starting numbers, I think we shows this - even we have small starting numbers, these T-cells then proliferate in the patient. And I think this is the real key now, because you are seeing us and you are seeing others recognize, so you don’t have to give large number of T-cells and we really want to challenge that further and say, what is essentially the fewest numbers of T-cells we can give, so we can use veledimex to drive the expansion in the patient.

[Reni Benjamin:]

Perfect, thank you very much and good luck going forward.

[Operator:]

Thank you. And our next question comes from Tony Butler from Guggenheim Securities. Your line is now open.

[Tony Butler:]

Thanks very much, Laurence two questions really. One is, with the amount of capital currently available and the notion of moving forward in the pivotal trial for GBM. Can you give us a flavor for how sites might think about the notion that will you actually be able to complete the trials with the current capital that is where they want to engage despite the fact there maybe some financial risks, they would have to in gender, that’s question one. I want to actually ask question two if I may, based on the last question, which I think you answer very adorably. If you have RTG and its - let’s say the efficiency is not great, but yet those cells can proliferate. Aren’t you going have variability by patient, because what you really do need is maybe some sort of critical math or so, having RTS in them something around tend to be a. How can you ensure those patients have that if you will that number of cells are enough replication has occurred and if I get one other - I am sorry - but it's really around Merck KGaA. Clearly a good partnership, I might have thought or I wondered, if in fact some of the discussions you had with them already did include the adenovirus cell 12 veledimex program and so if you like to speak about that. Thanks.

[Laurence Cooper:]

So thank you that. So in terms of the cash and the starting of the pivotal trial. So we’ve had no problem identifying patients per sites, but indeed we have a waiting list for our program. For instance, as we transition to a Phase 3 company, it’s hard for us to manage fill the Phase 1 trial because we have so much interest in it. So that really has not been a concern. Your second question around the efficiency being transferred really is really good. But it makes an assumption that the efficiency of Sleeping Beauty is limiting and is not because the simple fact is, if you can take a look at recent product an electroporation, the insprints and if you wanted to, you don’t have to, but if you wanted to you can just take the entire look of insprints products and electroporation. And then you have plenty of cells. But the great beauty if you would Sleeping Beauty, is that you don't have to do this. By the engineering of the switch controlling IL-15 with the CAR you can start from relatively small number, it's not a big threat if you would on the manufacturing facility to do this. And then the last question, just remind me again, I'm sorry I just - on that? The Merck question, so I getting it at last, thank you. So the question around Merck and their interest in adenovirus and IL-12, I would just say that's just probably it's a conversations between us and I don't want to really go forward at this point.

[Operator:]

[Operator Instructions] And our next question comes from Whitney Ijem from JP Morgan. Your line is now open.

[Whitney Ijem:]

A lot of my questions has been asked, so I'm going to ask a very forward-looking one. But as we look toward the point-of-care program, how do you guys think about it, or would could that look like from a GMP, kind of regulatory perspective and commercial perspective? What does that look like?

[Laurence Cooper:]

Sure, thanks Whitney. Obviously from a commercial side, you can see the major advantages. The simplicity of being able to generate the T-cells immediately infused into the patient. That technology we're managing very well in terms of our regulatory approach. And you see me do this now by having these generations if you would T-cells. The first generation was to firmly establish Sleeping Beauty system work, until I conceptualize this is never been done in humans before and now it has. The second part of this system is the second generation which is how does one shorten the manufacturing time and rolls in into that Whitney is a lot of the regulatory ideas I have will then smooth the transition from that second generation to the third generation. So in another words, we're working with the regulators now on the path forward, and we're not delivering point-of-care to them and saying here, look, swallow this whole idea, we're passing this slowly with them to make sure the patients are safe, to make sure the technologies are feasible, and then with the expectation this could will be essentially accepted. The other part of your question is as we kind of think forward in terms of how this disrupts the feels, I think you know is also equally we're managing carefully. We are given over to the idea and this is why we haven't built out large GMP facilities. We're given over to the idea these are just simply don't need them. And the costs that are encumbered by having large programs associated with GMP facilities that do viral transactions and large bioreactor facilities is just not scalable and it's just simply speaking, it’s just not going to be affordable. So we have to do better and I think this is a legitimate way forward about how we can improve on that science.

[Whitney Ijem:]

Got it. Thanks for taking the question.

[Operator:]

Thank you. And our next question comes from Jim Birchenough from Wells Fargo. Your line is now open.

[Unidentified Analyst:]

Hi, good afternoon. It’s Nick in for Jim, thanks for taking our questions. Lawrence, just firstly, obviously I know you don't want to go into any detail about potential pivotal trial designs for adenovirus. But can you comment on where you are in terms of manufacturing and do you have a commercial supply is when you start pivotal trial will be using commercial material and I have a follow up, thanks.

[Laurence Cooper:]

Sure, that's a great question Nick, so thank you. So at the moment this is completely on our radar screen and in our real house but we are not disclosing what the exact tactics are right now.

[Unidentified Analyst:]

Okay. And then my follow-up is, going back to the point-of-care, and obviously the one of the goals of CD-19 CAR-T manufacturing campaign because is self-sterilizing. And so when you get to this point of discussing, what is the potential for transuding - tumor cells that haven't to get caught any for instance for any leukemic blood that happened - you pen. How do you get over that barrier in such a quick turnaround?

[Laurence Cooper:]

Sure. So couple of things, one is that the, where patients have tumors in other words, say if I have CD-19 positive malignancy, the return of that tumor cell to them is not where the patients start it. Right? So in other words, I haven’t changed the bulk in that tumor as a result of aphereising them. The second part of that is, we also had developed kill switches , so if there is a problem associated with the return of leukemia that maybe a little bit more grafter or so called and so on, we will able to handle that with our kill switch biology.

[Operator:]

I’m showing no further questions at this moment. I’d like to turn the call back to Dr. Laurence Cooper for any further remarks.

[Laurence Cooper:]

Thank you very much, operator and thank you very much listeners. I wish you a good day.

[Operator:]

Ladies and gentlemen, thank you for participating in today's conference. This concludes today's program. You may all disconnect