Well, good afternoon. I think we're going to start so that we can have as much time as we can have to have any questions at the end. So today there will be several announcements I'll be making and I'm going to pack a lot of information into this talk in which we'll talk about the role of IL-15. Obviously there's a bunch of disclosures I need to make with regard to my relationship to ImmunityBio and the forward-looking statements since IBRX is a publicly traded company. But as I said, there's a huge agenda that I want to take you through and there's a theme to this agenda which I'm going to try and walk you through.
The first element about this theme is this concept of lymphocytes, which I believe is one of the most important things we need to learn not only as urologists, oncologists, but frankly the entire medical community hasn't recognized for a long time the real value of NK and T cells. But in the field of urology, it's been known since 2001, almost decades ago, that how BCG works is by activating these cells, the NK cells and T cells, who act to kill the bladder cancer. So this concept of immunotherapy has been there. We just haven't figured out what does it mean. Well, I want to take you through what it means if we don't have it. And this is what I want to talk about: lymphopenia and really the consequences.
And one of the most disturbing papers that I've read recently is a paper written by JAMA in which they looked at the United States population and asked a very straightforward question: Are low lymphocyte levels associated with reduced survival? In other words, is it associated with longevity? If you don't have lymphocytes, do you die early from all causes, not just from cancer? And they examined the United States population and what they found based on these findings, those with low lymphocytes die early. And the hazard ratios, and we won't go into statistics, the hazard ratios is frightening.
Here's your lymphocyte count called the absolute lymphocyte count. Now, this concept of the absolute lymphocyte count is not foreign. It's in your CBC. So yeah, I spent decades of my life working on genomics, proteomics, sequencing, and you have a $10 test that can measure ALC. And if your ALC is below 2,000, your chances of dying early from all causes is 200 to 300%. Think about that. 52 million Americans suffer less than 1,500 if you have cancer. So, is this just a survey? Well, look at this. 2019, every cancer type that you can think about, P-values hugely significant across all cancers of early mortality if you have lymphopenia below 1,000. So, this is a real phenomenon. Lymphopenia is a disease. Diabetes is a disease. Cancer is a disease. But it turns out that the fundamental cause, the root cause of disease of cancer is actually the collapse of the immune system. And if you treat the immune system, recover the immune system, the immune system itself treats the cancer. That's turning this whole concept of what we've been doing for 30 to 40 years on its head.
So I want to say that this is not a phenomenon that we've just now learned about, but the question is we all use chemotherapy and I do understand that what's becoming vogue now is gemcitabine and docetaxel. And that became vogue because there was BCG shortage and I want us to understand the consequence of that. 1994, Forcieri et al. showed that the drop, and this gentleman in 2000, a single dose of docetaxel, the drop of T cells and NK cells to levels what you call lymphopenic, exactly the levels that show the increased mortality. Another paper in 2021, all cancers but for this audience, renal cancer, bladder cancer, if you have lymphopenia, look at what the hazard ratios are in the 2 to 3s, meaning 200 to 300% increased chance of dying earlier when you have a low lymphocyte count.
So I asked myself, why is this surprising? Well, why wouldn't it be surprising if we know that NK cells and T cells kill cancer? And if you don't have NK cells and T cells in your body, it's like saying, you know, without going into details, I was at a regulatory meeting with the FDA. And the response is, well, ALC is just a number. Well, pH is just a number. Do you need oxygen? Hemoglobin A1C is just a number. Blood sugar is just a number. And ALC is a number. If you're below 1,500, this is the issue. And look at the statistics. P.00001. It wasn't, it's not even in a question. But worse, if you're lymphopenic for both TA and T1 disease, look at the recurrence rate, look at the recurrence survival.
So, we've lived in this world. We've grown up together in the world in which we give chemo and then Amgen developed a drug called Neupogen. And the measurement is a CBC and the CBC is a hemoglobin and we give more Neupogen so we can give more chemo. Well, the patient gets more chemo and the patient gets infected and you have a thing called neutropenia. So now there's an anemia and there's a neutropenia and now we have Neupagen and the count is ANC. Oncology friends and I've been in this world for over 30 years in which I used to do Whipples and pancreatic cancer and I speak to my oncologist and said, have you looked at patients' ALC? And they said, what's that? You mean? I said, no, no, no. I mean ALC, the absolute lymphocyte count, and there's nothing. So, we've addressed anemia, we address neutropenia. We've never addressed lymphopenia. And ironically, these is to really mitigate chemo and radiation. Ironically, chemo and radiation causes lymphopenia. Now, you begin to see the frustration and the madness of what we are doing.
Now, I know I'm going against the tide. I know there's a lot of chemo and radiation in the world, and maybe that's why you've not won the war on cancer. What could this be? Well, maybe it's the IL-15 and the power of IL-15. And have you even thought about that? Well, guess what? The National Cancer Institute in 2007 pulled NIH, FDA, AACR, ASH, every thought leader in the country. And I only discovered this booklet a month ago, a 50 plus page booklet, and they ranked out of all the 104 cytokines, the number one that could address cancer is IL-15. I spoke about this on the Sean Spicer show and I got a warning letter about talking about a nice NCI document and I talked, responded back to the FDA, look, I'm only repeating guess what what Maca wrote. And this is the title of the paper in 2008. It is Maca's paper that says 12 immunotherapy drugs that could cure cancer. He said that could cure cancer. Guess what's number one? IL-15. So I think we've known this now for over two decades.
What we've done is trying to find a way to actually evolve this so that we can get beyond this question mark. And the way we've done that is recognizing that the natural killer cell, the T cell, and then the dendritic cell, which results in memory T cells, all have IL-15 receptors. If they have IL-15 receptors, that's why you have a T cell growth factor. You happen to have an NK cell growth factor. You happen to have the memory T cell growth factor. And guess what? If you can figure out a way to activate these growth factors either through intravenously or subcutaneously, look at the proliferation that would happen. If that proliferation happens, the NK cell that recognizes the tumor independent of the T cell, independent of the T cell, has a separate receptor called NKG2D, goes into the tumor and literally melted through this thing called perforin and granzyme. And what has been elusive has been this identification of a molecule that you've been have a two week half-life, three week half-life given subcutaneously or intravenously, and that's this drug called Anktiva. Well, I now mention Anktiva which then says that was number one ranked by NCI and checkpoint inhibitors ranked number two and this entire industry rightly so went after checkpoint inhibitors and over 40 approvals across all tumor types by whether Merck, by Bristol-Myers Squibb, etc. But interestingly were done in single arm trials and I repeat that single arm trials with microsatellite stable tumors was enabled the ability for checkpoints to get approved for all tumor types.
This has now been 20 years in the making. And because I mentioned Anktiva, I want to now take you through what the clinical evidence is. Well, let me just digress a little bit. Our first trial was in BCG failures. I just showed you that BCG works by activating the NK cell and T cell. So why does it fail? Well, it has, now we're getting a little technical, but I'll be very quick about that. The T cell has a receptor and the tumor has the binder called MHC1. So, you give a checkpoint, the T cell is accelerated and it works. But the moment that happens and this is a point of checkpoint failures and the entire industry is now in trouble because we have multiple patients across 40 tumor types with checkpoint failures. And why? Because the tumor is smart enough to pull in this receptor called MHC1. And it's now called MHC1 loss. And all of a sudden you have a cold tumor. You can give as many checkpoints as you want. It won't work because there's nothing for it to bind. You can give LAG-3, TIGIT, CTLA-4, it won't work. And here it is, tumor escape published in 2021 because with BCG.
But what's exciting as soon as you have this MHC1 lost cell called a missing self, it is exactly the target of natural killer cells. That is how natural killer cells work. That is how natural killer cells protect all of us from cancer. Because all our normal cells have MHC1. As soon as you have a cell that is MHC1 negative, the natural killer cell turns on, activates the T cell and all of a sudden goes back. And now guess what? If you had activation of this IL-15 receptor together with a checkpoint, things would change. And that was the basis, the fundamental basis why the FDA allowed us to have in our package insert this mechanism of action. So I worked desperately hard to ensure section 12.1 has this fundamental statement that I am not aware of any medicine in the history of medicine having this fundamental statement that binding of this long word, noikan called N-803 which is Anktiva, to the receptor stimulates NK cells, T cells, and memory T cells without upregulating the suppressor cells. That is a fundamental change that treats lymphopenia because this is lymphocytes and we just went through the consequences of lymphopenia regardless of the tumor type.
Well, when we add that to BCG and this is published in New England Journal of Medicine for CIS and papillary disease in non-muscle invasive bladder cancer, or you add it to BCG in papillary without CIS, the results are equivalent and we'll come back to the question is CIS and papillary disease versus papillary disease without CIS the same disease. On Monday the FDA is about to hold a workshop and I'll address that to ask this exact question. So if we approve for this indication but yet not approve for this other indication for which now the NCCN has granted us unanimous vote. 30 members of the cancer community voted category 2A meaning that it is both based on the concept of CIS and papillary the same disease and that these based on the data we have now in NCCN guidelines category 2A. So on that basis we are at this position and here the data for the FDA approved and I must express clearly our supplemental BLA has been submitted. The 60 days have passed. We've not yet heard anything from the FDA. We're awaiting some response. I'm hopeful based on the NCCN guidelines where basically it's equivalent of an ODAC when 30 comprehensive cancer members independently vote and I don't even know who the members are a category 2A that this is not held up on behalf of patients. But we have no control over the FDA. So, we'll hope to see what happens as our BLA gets reviewed.
Obviously and in response to my speaking about warning letters I have to put up very clearly so there's no misconception about Anktiva and the safety information. But let's move on to talk about this idea. And this is the first time I'm announcing and presenting some of this data because the people said, well, does Anktiva really increase the ALC? How would you test that? Well, we would test that in a randomized trial and I'm going to show you data for the first time, a randomized trial that I shared with the Saudi Arabian FDA in which Quilt 2023 was in first line lung cancer. And we gave the patients Keytruda alone or Keytruda plus Anktiva. And they all had the same baseline. So there's no starting point. There's no difference. And as expected, and we've seen this in healthy volunteers, the ALC count in the patients receiving Anktiva in this clinical trial, statistically P.065 over the course of 27 weeks had a statistically difference to those receiving Keytruda and there's even a trend of checkpoints dropping the ALC. So this is the first demonstration now that I've made very publicly. There's a randomized comparison to show that indeed Anktiva is a T cell and NK cell growth factor. I don't need to actually have said that because it's actually in the package insert as I said in section 12.1. But the question is if that happens is there rather than correlative is there causative effect if in fact the ALC goes up does it change the outcome. Well here in this very small sample that we had of those that had a TPS score greater than 50% in that trial 7.5 month progression free survival versus 2.2 months and a P-value of 0.02. So clearly there's early indication that the causal relationship has now been shown in this randomized.
There's been huge amount of data as I just showed you before which then says if that's the case we've now addressed this concept of lymphopenia. We've addressed that IL-15 in the form of now Anktiva stimulates NK and T cells. We've addressed statistically in randomized trial that it works. We've addressed a correlative relationship to outcomes. Well, what's our experience as we speak today of the durable responses in bladder cancer? Because this is where we are in this symposium. Well, the first question is, is CIS and papillary do they arise from the same clonal disease? That's obviously an important question and this is a question that the FDA asked us when we were there four, five, six months ago. And clearly New England Journal of Medicine, bladder tumors arise from an uncontrolled split of a single transformed cell. It's a single clone. And the phenotypic change of whether it becomes flat like CIS or phenotypic change where it becomes grape-like like papillary. Well, it's just not one paper. The next one, it's the same disease. The next one, it's the same disease. It's the same disease, the next one. So there's compelling evidence that this is the same disease.
So my struggle has been if it's approved for CIS and papillary and we've got data for papillary without CIS. If the answer is I have to compare that to chemo and I know chemo is lymphopenic and a randomized trial, how do I ethically ask a patient, look, you got to go into this trial and you may go into this one arm that I've now published with the NCCN 2A category that says you've got long-term progression-free survival and or you may go into this chemo trial which I have to share with you the day that it just come out now with a drug of gemcitabine. It's just been approved by FDA and I'll show you the toxicity of 1.2% fatality and maybe 24% lymphopenia. I don't know how I'm going to recruit that kind of patients but yes I'll do that trial but in the meantime this is the safety. This is a safety now that we have now so far in trials not in real world of 379 patients where the results is no different when you have Anktiva than that of BCG alone. And I'm very grateful for the NCCN to with 30 independent members basically a scientific ODAC to give a category 2A. A category 2A in my understanding and I'm not an NCCN member but by reading it is a unanimous vote. A category 2A is actually saying to CMS by statute, you're okay to reimburse this. But it would be really far better that the FDA follows the NCCN. But we have a meeting on Monday. We'll find out how this workshop ends up with regard to is CIS and papillary equal disease.
Let me take you a little bit beyond bladder if I may because I wanted to have this opportunity to talk a little bit about all tumor types and that's real other issue. And if you look at lung cancer second and third line lung cancer so you will ask yourself the question that why did Saudi FDA approve us for now for lung cancer. They looked at 2023 and they looked at this data in 3055 and these are patients who failed checkpoint inhibitors. They failed radiation and failed chemo. They failed checkpoint inhibitors. Now think about this. They were progressing their cancer on the checkpoint inhibitor and it therefore would be madness to give them the same checkpoint inhibitor while they're progressing. Well, that's exactly what we did. And why? Because if we then add Anktiva to that the NK cell would rescue that T cell at MHC1 and they would act synergistically and then if you have an ALC that goes above 1.2, 17.4 months median progression. Now you all know about the trial with lung cancer where you have docetaxel and it's seven months and there's trial after trial after trial. If they don't respond, it's a little more than seven months here, but nine months. So clearly that synergistically the biology works. Without NK cells you have lymphopenia. With lymphopenia you have early mortality.
Well what happens with all tumor types this 149 patient study with all tumor types the results are the same hazard ratio 0.52. What was amazing when I looked into the Merck package insert for checkpoint inhibitors in 2018 they got it for all tumor types single arm trial MSI high 149 patients. So when the previous heads of the FDA, it was Dr. Pazdur and Dr. McClellan said, we need to do randomized clinical trials and no trial has ever been approved for single arm. That's not true. We know it's not true because Merck got it approved for single arm trial for 149 patients for all tumor types. Well, this is what's happening here. So the Saudis approved it for lung and we are now working with the rest of the world to get this through that system.
So now let me talk about the BCG naive data. Well this is a randomized trial. So in this randomized clinical trial, the patient gets BCG alone or BCG plus Anktiva or N-803. And in 2019 during the BLA review, the FDA asked us to unblind whatever we had, which was a surprising request, but it was okay. And what we showed a very big difference. By 2026 is fully accrued by 2025. I pick up 2026 in March. The independent review committee looked at the data that's fully blinded still obviously and concluded we do not need to accrue any more patients because the data was sufficient to determine the difference of power which puts us in position now to file the BLA of this randomized trial for BCG naive. Excitingly the data of the toxicity consistently is the same which then says where are we going to go in urology.
So we have been applying since clearly our podcast with Tucker Carlson we literally have 15,000 requests to our clinic. And so what we do, we file for what we call single patient INDs for every patient. I know that sounds an impossible task. But what we have now is this patient with biochemical recurrence prostate cancer that want to not have ADT. So the patient has very high risk prostate cancer and we filed with the FDA the single patient IND and gave the patient Anktiva or N-803 plus our adeno-PSA. This is now beginning of the beginning of a vaccine. The patient then got radiation and got another shot of Anktiva during radiation and the radiation oncologist was amazed without ADT. The PSA was undetectable and is still today undetectable which demonstrates that one can now take a biochemical recurrence patient with prostate cancer and maybe avoid ADT and this is a clinical trial and we put up this QR code for any investigator that may want be interested in participating in a trial because ADT is a very severe issue for patients and for men with prostate cancer. But there's a huge opportunity for us to go after prostate cancer where we could combine the adeno-PSA where we can combine our IL-15 receptor where we can look at radiation modulation where we can actually do even ex vivo NK cell therapy off the shelf and now we've actually started to work on the TROP2 targeted CAR-T therapy and lutetium. So this opportunity to truly change the concept of immunotherapy and prostate cancer is in front of us.
Okay. So I think I've spent the time I don't know how much time I have here but I think I have. Let me now change courses. We've had a 14-year unaddressed issue of BCG shortage. 84,000 patients can receive this affected 57% of urologists could not treat patients because of BCG constraints. Merck is the only manufacturer in the entire country. Well, part of the Monday meeting by the way the question the FDA asks is does this shortage really affect you? I don't think it's a question that needs to be asked. I think the answer is staring us in the face. But more disturbingly, the question is also being asked, can we use chemo? Now, I get it that you want to use gemcitabine docetaxel, but I've just showed you what gemcitabine docetaxel does to your lymphocytes. So, the question is who's going to take on the task of bringing back BCG? So we brought back recombinant BCG and there's a opportunity now where 800 patients and the country is now thank god through the expanded access have access to BCG, recombinant BCG and so far the experience has been wonderful based on what I hear but more importantly I'm making an announcement today. I am really proud of SWOG having completed this 9-year study of a randomized clinical trial between TICE and Tokyo strain BCG and showing an equivalence basically non-inferiority equivalence to the Tokyo strain of which Japan BCG Institute has been manufacturing for 70 years and for the last 30 years all Japanese have a full supply of BCG. So, my CEO, Rich Adcock, and I got on the plane, flew straight to Japan, and I'm pleased to announce we now have the exclusive rights and supply to Tokyo Strain BCG so that we can address.
I like that response because it just shows somebody has to take on this question of this multi-source expanded supply. So very briefly in closing, I just want to address what I know is going to be asked at this meeting coming up and it's a pivotal meeting. It actually all the questions that's coming up is exactly the question we posed to the FDA group that's reviewing our BLA 6 months ago. Is CIS and papillary are the same disease with shared clonal origin? The answer is yes. And we've got that data where I showed you. By the way, the answers to all these questions are supported by peer-reviewed scientific evidence. Peer-reviewed scientific evidence. It's not a company trying to make a pitch. Number one, it's yes. CIS and papillary is approved. Papillary and CIS. CIS is pending. The results are concordant. Both trials cohort A and concordant and that's consistent with the fact it's the same disease. The BCG and that has now received for papillary without CIS a category 2A endorsement. It's bigger than an ODAC, it's 30 independent comprehensive cancer center directors collectively making it an independent vote unanimously saying that this is should be available to the nation for reimbursement.
The question is well you just want CIS and papillary if you only don't have CIS. Well the opportunity to misdiagnose CIS because of with a white light one of the urologist in the meeting with the FDA says when we do a papillary biopsy there's blood all over the place and there's no chance of finding the CIS. So I think that question is also being posed. The next question is, should we use chemotherapy instead of BCG? Well, why don't you solve the BCG shortage? And if you do use chemotherapy, you do know that you're going to be faced with lymphopenia. And this 14-year shortage, it's now finally some company has taken on the task of saying, we have TICE recombinant BCG and now the Tokyo strain. And it's now up to the FDA to say this Tokyo strain it is SWOG that did a 9-year study to show that the Tokyo strain in a randomized trial is equal to TICE. So without going to details I'll be showing this details. This is all the science about number one. This is all the science about number two and three and this is all the science about number four. This is all science number five. And this is the question I want to dwell on. It's not about a competitive issue. It's about a patient issue. This is in the package insert. This is not my slide that when you give gemcitabine a 1.2% fatality, a 24% decrease in lymphocytes and 8% progression within 94 days of recurrence. Why would you want to replace BCG with chemo? Why not address the root cause?
And here is the announcement. ImmunityBio now announces exclusive supply of Tokyo 172. This is obviously a mockup box of this thing called Immunity Bladder or Immune Bladder. By the way, that's a trademark in Japan that they've allowed us now to use. And you could see this is a SWOG data, a 9-year randomized trial showing no difference between strains. So finally, we will solve what I call a multi-source supply from our approval. And our approval just says any BCG doesn't say TICE. We tried then with recombinant BCG. And I invite everybody to currently enroll and get access immediately and then this trial has already been done and I'm now going to submit this to the FDA for approval and hopefully we then solve this problem and hopefully we now begin to understand that maybe we've actually closed the missing link.
So with that I think I want to thank you for your attention. If there's any, if I can go back one slide. If I can go back one slide. I want to thank you for your attention. If there's any questions I'm happy to take questions. But I think we really have a paradigm change that this has been the consequence of chemo and this has mitigated the chemo. What has the chemo done? It's not just knocked out the red blood cells and your neutropenia but it's knocked out the NK cells and T cells. So for the first time we can address lymphopenia. And if we in fact address lymphopenia doesn't mean we don't use chemo. We can use low-dose chemo doesn't mean we don't use radiation. We can use low-dose radiation. And that combination of addressing the patient's own immune system using the tumor in the patient itself as the vaccine is a real paradigm change that we can do for all of cancer medicine and in fact for sepsis and infectious disease because this is unnecessary for that. So I leave you with that thought. I will continue to try to educate the world that we now have an opportunity to rethink how we treat patients with cancer. And I really thank you for your attention.
Are there any questions? Yes. Could you just come up and there's no mic but maybe I can hear you. There's a mic. There's comes a mic.
