Northwest Biotherapeutics – Linda Powers’ Speech Transcript at the Oppenheimer 25th Annual Health Conference on 12-10-14.
Thank you for taking time to listen to our webcast. Today I'm going to tell you a little bit about our company, particularly focusing on looking at what's been achieved this year, as we come toward drawing the year to a close; and I'm going to tell you a little bit of update information - new information from the DCVax Direct trial that I know we're all anxiously watching the progress of. So for those who are not already familiar our company has developed a platform immunotherapy for cancer. This immunotherapy uses dendritic cells as the active agent. The dendritic cells are the master cells of the immune system. The two key things about our technology, our type of immunotherapy that I want to really highlight is number one, that the dendritic cell mobilize the whole immune system. That means you have many active agents hitting the cancer. That includes the T cells that you're reading a lot about today and that are very exciting. But it also includes many other players: B cells, natural killer cells, macrophages, neutrophils, and so on; so many agents hitting the tumor. Secondly, very different from most other products is we hit the full set of targets on the tumor. We don't cherry pick one or a handful. And the products that do that, you know that the concept is to be highly targeted but being highly targeted means first of all that it's Russian roulette about whether that patient’s cancer does or does not express that target. And secondly, it means that it's easier for the tumor to escape. So we hit all the targets on the tumor - key characteristics. And that solves the patient-to-patient variability. You see a picture of our product in the lower left. We produce a full batch of three-to-five year worth of doses, in just one manufacture batch in eight days, and we freeze it into single doses, like you see in little vials, and from there on out, it’s off the shelf for that patient, making this a very practically product. A quick word about how this works, again the activation is the dendritic cell, the masters cell of the immune system. It plays such an important role that it was the subject of the Nobel Prize in 2011. What the dendritic cells do, they are not the ones that do hand-to-hand combat with the tumor. They pick up the biomarker information about anything bad in your body: bacteria, virus, tumor, etcetera. And secondly, they communicate that biomarker information to all of those other immune agents that you see there. And that's how the immune system gets mobilize. Key point is when the dendritic cells mobilize the immune system, they immobilize it with a huge multiplier effect. Each activated-educated dendritic cell mobilizes for example hundreds of T cells, the foot soldiers that engage with the tumor. Key point, we do it in the natural way. Nature designed your immune system for the dendritic cells to do this job. And one big difference between our product and some of the others that are very exciting, such as using T cells directly, is our product has had no toxicity in 10 years of clinical trials. Some of these other products are so toxic the patient end up in the ICU and a couple patients have died from the treatment. So again, there's a lot of excitement but this one has the benefit of being an excellent safety profile. Now this is the platform technology that I have explained. It is embodied into two key product lines, two major products. The first one that you see up there, DCVax-L, is for all types of operable tumors, and the second one is for all types of inoperable tumors. Both of the products use the same two key ingredients: that's the immune cell, the dendritic cells themselves, and the biomarkers of the tumor that we want the immune system to hit. The difference between the two products is just in how we get the biomarker ingredient. With the product for the operable tumors, when the tumor’s surgically removed in the operating room, they just drop the tissue in a kit and send the kit to us. It literally takes a couple minutes in the operating room. And then we process it and we get the biomarkers from that tumor tissue. Well for the inoperable tumors, we don't have the tumor tissue to get the biomarker, so instead we activate the dendritic cells in a little bit different way. We directly inject them into the tumor, in the body, and the dendritic cells pick up the biomarkers on-site, in the tumor, and from there on out they operate the same, to mobilize the immune system.
Now, I want to go through some of the highlights in each of those two programs. It's been a very busy year. We're proud of this year and had a lot of major milestones this year. But most importantly, besides those milestones in and of themselves is, those milestones position us for really exciting 2015. So our DCVax Phase III trial for brain cancer is our lead program. It underwent a major expansion across the U.S. and in Europe. We had a safety-only evaluation, of the, by the Data Safety Monitoring Committee. Very importantly, in the latter part of the year we had some regulatory enhancements to the trial, which allow us to add some factors to the statistical analysis at the end of this trial. Nothing changed about the eligibility for the trial. Nothing changed about the treatment in the trial. But by adding these factors at the end of the trial, counting more events, and adding factors, we were able to significantly de-risk the trial. For example, in order for it to be a successful trial, we need only to show, instead of showing a six-month difference in the time to tumor recurrence, in patients who receive DCVax and those who don’t, we only have to show four-month difference. That’s a big lowering of the threshold for success. We actually think we’re going to show a much bigger difference than that, because in our earlier stage trials we showed a year-and-half of difference, not six months, not four months. We tried to design this trial to be very conservative and to maximize the chances for success. We had to get separate regulatory approvals from the U.S. FDA the German regulator in the UK regulator - all three, in order to make these changes and we were really excited to achieve that.
Also very exciting in September we released information about 55 patients who had not been enrolled in the Phase III trial because they were too sick to meet the eligibility criteria. After they had surgery to remove the tumor tissue and six weeks of daily radiation and chemotherapy, already by then the tumor was re-growing or appearing to. That kind of a patient is, has such an aggressive form of cancer that normally they don't respond anything. But we had already made the product for those patients because we make it while they're going through the six weeks of radiation. So as a compassionate use, we allowed those patients to be treated with the same DCVax product as in the clinical trial, on the same treatment schedule, at the same clinical trial sites, in the same time period, with the data collected by the same CRO, as the trial and maintained. And that data when we released it, showed that these patients who normally wouldn't be expected to only have survival in the 7 to 10 month range had survival in the 18 -19 months range. So the patients who are even to sick to be in the trial really were getting a major benefit from the treatment. That was a very encouraging set of additional data this year.
A whole nother track of milestones this year have been coming to fruition in multiple early access programs. These are early commercialization programs. These are programs where we can now make the product available to the patients. We charge the patient for it. Yes, that means revenues. But the main focus that we have any programs is the validation of getting these early approvals, because these early approvals that were getting from the regulators have not been given to any other company or product. As well as the opportunity to practice for commercialization before we get to commercialization. There's a tremendous number of moving parts here. I know a lot of folks have felt that, that felt very impatient and anxious to see the program getting ramped up and we have been to. Just give you a sense of it, at every single medical center where we’re implementing these early commercialization programs; in Germany, for example, we have to separately negotiate at least three and often four separate contract. Business contracts: we have to negotiate an overall business contract with the hospital; a separate contract with the radiology department; a separate contract with the hematology department for the blood draw. And typically a separate contract with the hospital pharmacy to handle the product - additional to getting local regulatory approval. Additionally our manufacture has to negotiate their own separate two contract to collect the tumor tissue and to collect the blood draw. Six contracts per hospital, every single one of them different, with their different hot buttons. That's a daunting task. I actually didn't think any players on the planet had as many contacts as the United States but I now know that that's not the case. We've also gotten the eligibility approval for reimbursement and we have been in active negotiations. That process is a long process as well. It's not unusual to take a year. We’ve been working on it since we announced it in March. We are currently in active negotiations with four separate sickness funds in Germany - that's what they call their health insurance. Germany does not have a single payor system like the UK does. They have a national health system, but they have multiplicity of health insurers; and you, yes, have to negotiate with each of them separately. And we are going to. We are taking the more rigorous approach to make sure that we can get our desired price structure and price level with all of them before we come out of the closet with any of them. Right, so you can look for that in the, in the, hopefully coming months. Additionally in the UK we were approved, the first company approved for the early access to medicine scheme, stage one where they do a technology evaluation and our technology was the first to get promising innovative medicine designation. That has made us a priority project of the whole UK government at the minister level.
Okay and our other program DCVax Direct this is been a busy year in the Phase I trial. This is been as I'll show you because I'm going to mostly concentrate the rest of my remarks today on some, as I mentioned new information, from the DCVax Direct trial. And here you already see during the first few months of enrollment in the trial between last September and this year in March we had to proceed very slowly. The FDA only let us treat about one patient a month to make sure it was safe. By March they let us take the brakes off and we literally enrolled basically the whole trial between March and June. We were mobbed. We were flooded with patients. We had waiting list for slots in the clinical trial. Why? Because this clinical trial was for an immunotherapy for inoperable tumors. These are patients who have failed all conventional existing treatment. They have no other options left to them. They have multiple inoperable tumors and those tumors are actively progressing. That means that each doctor's visit they have more tumors or bigger tumors or both, then the last doctor's visit. It's a very-very late stage aggressive disease situation. These patients are basically on the doorstep of hospice. So having an immunotherapy that is expected to be non-toxic and offers a possible new treatment option, you can imagine why we were so flooded. We cover diverse cancers. As you see we treated, the enrollment again is finished. Patients are continuing through the treatment regimen right now, as we speak. We treated eight sarcoma patients, seven pancreatic, seven colorectal, six melanoma, four lung, as some others, including breast and ovarian. That is a very diverse range of cancers. And that again brings up one of the key values and competitive strengths of our technology. Our technology, both products, the one for the operable tumors and the one for the inoperable tumors can apply to any patient. We are not limited by tumor characteristics and we're not limited by patient characteristics. So we can treat with the same product, made the same way, all of these diverse cancers. That also means that from a regulatory pathway standpoint, after we get the first approval, in the first cancer, each additional cancer is just a label extension. You're not starting all over again with the whole clinical trial pathway.
Some of the key aspects I'm going to go over in the, in the, in the following slides. And we have been busily in preparation for a couple months now on the Phase II trial and we expect to be announcing something about that relatively soon. Again I've already explained the DCVax Direct is for inoperable tumors. We get the immune cells through a blood draw and we partially activate them in a special way and then directly inject them into the tumor in the body. The secret sauce of this product is partial activation. If the dendritic cells are immature they'll pick up the biomarker information but they won't communicate it effectively to the rest of the immune system like you saw is what needs to happen. If the dendritic cells are fully mature they won't pick up the biomarker information very well. They're good communicators but they won't pick it up very well. The key is for them to be partially activated and then the dendritic cells will do both steps very effectively and mobilize an immune response very effectively. What do we mean by an immune response? What are we looking for? As you can see on the table here we’re looking for three things. First, we're looking for local effect in the tumor that are injected, meaning effects, meaning tumor cell death by the dendritic cell secretes these factors called cytokines which actually kill tumor cells in the tumor where they're injected. Secondly, we're looking for systemic body-wide effect because again like you saw in the cartoon the dendritic cells mobilize the whole immune system and your whole immune system travels through your whole body. So we're looking for systemic effects in the tumors that have not been injected. And thirdly, we’ll be looking in the future for immune memory. In preclinical studies, animal studies, we saw both the local effect of systemic effect with the eradication of tumors in most of the animals.
So what have we been learning from ... Now comes the new information about the DCVax Direct trial. What have we been learning from the trial over the course of this calendar year? First of all let me remind you that this trial is still on-going. Most of the patients were enrolled between March and June. And, we actually over enrolled the trial. The trial exceeded its maximum. So we had some other patients enrolled in July and August. But once the patient enrolled it takes about a month for them to go through the blood draw, have the one week product manufacturing, and get scheduled for their injections to start. So call it a month of preparation, and then it's an eight month treatment regimen. Right, so you can do the math. The patients who were the last ones in, who came in June and July will be finishing their treatment regimen in March and April. So the finish, the finish point and the full set of data for this, will come, of course, after everybody's had all their treatment. So you know it would be around Q2 in the coming year. But this trial is not blinded and we’re seeing effects as we go along. We’d, we would like to be sharing more of that with you but there is very mixed views about whether that's a good idea or not. So are mostly waiting til' the end of the trial to provide most of the information. But in the meantime, a couple of points that I would emphasize is this trial has been designed to be very information rich. It is telling us a lot of information. And that's partly because of the FDA was so supportive in how they let us design the trial and that's kind of our cane. But suffice it to say with all this information listed here, it lets us accelerate the development of the product because it is given us a lot of information that sometimes you wouldn't get until you're even in a phase II trial. So we have treated more than seven different kinds of cancer in this trial. Normally and that's thanks FDA letting us be in all types of inoperable tumors, normally you have to do a separate trial for each cancer, even the early stage trials, so this saved us a lot time. We treated seven different cancers, more than seven different cancers. We’ve tested three different dose levels of the DCVax Direct. We've tested two different activations. Remember I told you the secret sauce is the partial activation. You don't want them to be immature. You don't want to be fully mature. You want to be teenagers, as it were. But within that zone, it's even sensitive. We’ve tested two different activations. We also tested the feasibility of the direct injection. Remember it's important to be able to reach anywhere in the body, if you want this to be able to treat any type of solid tumor. And we've designed this - everything we design is designed to try to fit as easily as possible into existing medical practice, right. So we designed this trial for example, so that the physician can use any type of imagine guidance that they like. They can use ultrasound; they can use CT; they can use MRI; whatever they like. Okay, well, it was a bit of an unknown about whether this diversity of approaches could all work. And, actually now we’ve shown that it can work beautifully. Also another way in which the trails been very information rich, is we've done quite a bit of imaging, MRI at most of the treatment visits and needle biopsies and correlated these with each other. That's actually done far less often than you would think. It's very logical to do it because it gives you an important correlation, particularly as to the issue of when the tumor looks like it's getting bigger on the imaging. Internally we kind of referred to this for shorthand as the ‘bulge’ issue. If the tumor bulges, is it a good bulge or a bad bulge? Is a tumor growing more tumor cells – a bad bulge; or is the tumor being infiltrated by lots of immune cells that are coming there and doing their job, in which case it’s a good bulge, right? Imaging alone cannot tell you the difference, right? So by doing the biopsies and comparing the needle biopsies we get a much richer information from this trial. We have also evaluated both local and systemic responses from the, both the tumors that are injected and those that are not injected. And, we’ve evaluated the end points, and the bulge issue, and, of course safety, that was very key. With the first product it's been a clinical trials for 10 years - DCVax-L, that has a long-established safety profile. We administered over 1000 treatment cycles to some 300 patients, and in all of that time we’ve had a grand total of three serious adverse events. And they were things like a seizure in a brain cancer patient. Well, unfortunately that is what happens with brain cancer. Right, so, we knew the first product was excellent safety profile, and we believed, because of the underlying biology, that DCVax Direct, direct injection, would likewise be very safe. But, of course, we had to find out. Well we now have about 15 months of clinical experience and it’s beautiful. All the patients get fevers. So far none of the fevers have lasted longer - after each treatment. So far none of the fever have lasted longer then two days; and none of them have been greater than 2 degrees centigrade. You ask a patient if that is okay with them. Yes, that’s okay with them. They are fine with that. We have nothing like a patient getting anywhere near an ICU. Okay, so that is the information that we’re getting from the trial.
What are some of the results we’re seeing on some of those measures? This is again is new information that we haven’t presented before. So first of all, one thing that is really striking right off the bat, is what I mentioned briefly before, how diverse the cancers are that are responding to DCVax Direct. Some of our particularly striking responses have been in the cancers listed: sarcoma; pancreatic - some of you may have seen the National Geographic video; colon; lung –one of the most difficult, I’m going to show you an example in a minute. Those are very diverse cancers and having now, seeing the actual responses in the clinic to these diverse cancers, from the same product treatment, is quite an encouraging observation. Secondly, I won’t go into yet, but stay tuned til' the end of the trial. But, we are seeing very encouraging survival. These are patients as we said are on the doorstep of hospice. Their expected survival is a very few short period, measured in months. And the patients that we’re seeing are very encouraging survival. Importantly, we’re seeing that the immunology responses, where we see the T cells infiltrating, and we see that from the biopsy and stuff, that is correlating with the clinical results that we see, which is a very nice reinforcement. Very importantly also, we’re seeing not only necrosis, tumor cell death, in tumors that are injected, we’re seeing shrinkage in tumors that are not injected. Also what has emerged is that the patient’s own report about their quality of life, their condition, all of that, is turning out to be a significant indicator as well. The patients come in saying “I’ve never felt better”, “My energy is back”, “I’m back to working”, and those type of things. And those patient conditions, quality of life factors, and turning out to correlate with what we’re seeing in the imaging and biopsy and so forth, as well. One conundrum is what I’ve already mentioned, we’re seeing actual or apparent bulge, tumor enlargement, which could either be a good bulge, immune response, or it can be a bad bulge, but followed by shrinkage. That’s a characteristic of immunotherapy. They take time to show up with their results. Okay. And that is not seen only with our immunotherapy but lots of type of immunotherapy that are out there, checkpoint inhibitor drugs, and so forth. In late stage disease we’re finding that the treatments that are earlier in the regimen which are just a one week apart, and then are followed by treatment that are spaced very far apart, as much as 2 months apart. Again to be conservative, this is the first in-man study. That is too far apart. No big surprise there. But you have to start out conservatively. And, I mentioned the safety, and I mentioned the feasibility of the tumor.
I just want to give you these two examples. These are two examples that have not been presented anywhere before today. These are not the case studies that we presented in our information in May and June. They are not the case studies that we presented in our poster at the SITC conference. These are additional case studies. Okay, the first one is another sarcoma patient. It is a different type of sarcoma that we mentioned in our May profile. This patient, like the other, has failed all conventional treatments, has five measurable tumors. And you see, this is a, this is a very typical example. This line graph, where you see first the tumors enlarging. And, then the immune response is catching up. And the immune response is starting to overtake the tumors, and the tumors are shrinking, and all five of them are shrinking in this patient. The time course, is seeing on the X-axis. This the all just in week 16 to 24. This patient has not even finished the treatment regimen yet. And remember, only one of those five tumors have been injected. This is a Phase I trial, it’s been very conservative. One tumor injected. Injections spaced far apart, and treatment regimen not even finished yet. The second example that I’m showing here, this is the first time we’ve mentioned anything publicly about lung cancer. Lung cancer is one of the most difficult cancers, as we all know. This is a 54 year old woman who was first diagnosed at stage IV. She had a tumor of 10 centimeters. That’s almost 5 inches. That’s the size of a grapefruit. This lady had a grapefruit sized tumor in her lung. That’s pretty bad. Um, she actually had not, she’s one of the few patients that had not had every treatment on the planet and failed every one of them. She actually had no prior treatment except radiation. She had no chemotherapy - nothing. She just was diagnosed at this stage. As you can imagine, with a grapefruit sized tumor in her lung, she had difficulty even breathing. She couldn’t really breathe when she came in to be treated. She's been, she too has not even yet finished the treatment regimen. Her tumor is shrinking meaningfully. And as you see, she’s now back to her full life. She’s swimming. She’s exercise swimming. And in email exchange with her physician, that personally I’m going to frame, like forever. Her physician wrote to us and said “she seems to have recovered”. We wrote back and said, well, um, "What do you mean recovered? Because she’s a stage IV lung patient with a grapefruit sized tumor, what do you mean by recovered?". “ Well she’s back to her full life and she’s swimming”. Again it’s just a case study. I have to caution you, we’re not finished the trial. The data could get better than this as we go along, it could get worse. But these are two more case studies, on top of the four that we already reported with sarcoma, pancreatic, ovarian and so forth, and they are very encouraging.
I’m really running out of time but I don’t think there is anybody after us, right? So, maybe we can run over just a couple of minutes. Okay, so this is what we’ve been measuring and this is what we’ve been learning and seeing from the Phase I trial. And I think we mentioned in prior presentations, our trial design with FDA allows us to go ahead and start with Phase II now. We don’t even need to finish until all the Phase I patients finish with their treatments. We are very grateful to the FDA for that, and I know the patients are grateful, it saves half a year, three-quarters of a year or more. Just, stayed tuned for announcements about this. But based on what we’ve learned so far, I can say now publicly, and this is the first time I’ve said it, in the Phase II trials we will be injecting multiple tumors, not just one tumor. We will also be on a treatment schedule, where the treatments are closer together – a couple of weeks apart, not a couple of months apart. We will continue to do extensive imaging and biopsies and correlate them. We will look even more at patient condition and quality of life, like this lung cancer patient. We announced that we will do two different trials, in two different cancers, in parallel in the coming year. And that’s in addition to the fact that our Phase III trial in our lead product is coming towards fruition over next year. That’s a lot of programs in parallel. And we will be significantly expanding the clinical trial sites for the Phase II trial, so stayed tuned.
I’m just going to spend one minute or two going through DCVax-L. I really pretty much covered it. And this is the Phase III trial. It’s blinded. Looking towards 2015, we expect to finish enrollment. I went over the 55 patients. We expect to finish enrollment, in the Phase III trial, hopefully in around September time frame, it depends a little bit on how fast, how many more of the European sites come on. But, we expect to finish about then. And we expect topline results to be about 3 to 5 months after full enrollment. So around the end of next year or slightly after, we expect to be reaching the finish line on that Phase III trial. I’ll skip over Ovarian and Prostate. I’ve already mentioned that the manufacturing is very practical. We want this technology to be able to become new standard of care. Not a last resort technology. Be the standard of care for diverse cancers. So it has to be practical. And, we’ve worked many years. It’s kind of a thankless job. You don’t get any jazzy press releases out of it generally. But today we have a very-very vigorous and very practical batch manufacturing, that produces the batch as I described earlier, in eight days, and from thereafter, it’s off the shelf. Our manufacturing, this is quite unusual for a small biotech company like ourselves. Over the last five years, both in the U.S. and in Europe. We are fully operational there. We have over 180 issued and pending patents, so a very large patent portfolio. The management team, and everybody on it, has at least 20 years’ experience in their area. And financially, to finish here, you probably saw just a few weeks ago, we’ve just raised another 35 million dollars: from the most, 25 of it in equity and 10 of it as a mortgage. The 25 from the most celebrated biotech investor, in the UK, Mr. Neil Woodford, so we’re very excited about that. That concludes our three and half minutes over, and thank you for the extra time.
