Dr. Kamat Speaks with ImmunityBio's Dr. Soon-ShiongIn this 3 part interview, posted yesterday, Dr. Kamat speaks with Dr. Soon-Shiong about ImmunityBio's newly FDA approved treatment for BCG-unresponsive NMIBC with CIS, with or without papillary disease.
In part 1 Dr Soon-Shiong notes that to win the battle against cancer you need to get a response, but to win the war against cancer you need a durable response. The duration of response is what really matters.
Anktiva plus BCG obtained a 24 month complete response rate of 25%. By the end of May Theralase should know the
24 month CRR of 39 patients. I beleve this number will be much higher than 25%
In part 3 Dr Soon-Shiong deals with the BCG shortage.
Part 1 - The Triangle Offense: Harnessing NK Cells, T-Cells, and Memory Cells in Bladder Cancer - Patrick Soon-Shiong Part 2 - New Bladder Cancer Treatment: Mechanisms, Clinical Findings, and Implications - Patrick Soon-Shiong Part 3 - Addressing BCG Supply Shortages, Workflow, and Enhancing Bladder Cancer Treatment through Strategic Partnerships - Patrick Soon-Shiong Transcript Part 1
Ashish Kamat: Hello everyone and welcome to UroToday's Bladder Cancer Center of Excellence. Today it's my pleasure to introduce to you, to all, a special guest who has been on UroToday before, but today Dr. Patrick Soon-Shiong, who's Chairman of ImmunityBio, a surgeon scientist, a deep thinker, someone who's truly involved in wanting to do and has now actually gotten approval for a drug that will do great things for our bladder cancer patients here with us in the studio. Patrick, welcome.
Patrick Soon-Shiong: Thank you so much, Ashish.
Ashish Kamat: Patrick, very exciting news, and we're going to break this down in a few easy-to-digest snippets for the community that's listening, the educational value, and the urologists at large. First off, if you could share with us your journey. What made you think of bladder cancer, IL-15? What got you involved in this field and how did it evolve?
Patrick Soon-Shiong: What got me really involved is I was doing cancer surgery at UCLA for pancreatic cancer, and also doing pancreatic transplants at UCLA. I trained under Dr. Donald Morton who was using BCG for the treatment of melanoma. By 1990 I wrote the first paper on natural killer cells, and it became very apparent to me that the parent cell that either kills the transplant when you do transplant rejection or has an opportunity to kill the cancer is this natural killer cell, which is 500 million years old. That began the quest while I was at UCLA and it says we have to find a way to activate your immune system to fight the cancer.
Ashish Kamat: It's amazing. Your background as a transplant surgeon and a transplant immunologist is what led to this stimulus. Take us through the journey of how you moved from there with the mechanism and the IL-15 into bladder cancer. Just briefly, because everyone's interested in this.
Patrick Soon-Shiong: Everybody uses chemotherapy and even everybody uses BCG, and now as it evolved, everybody uses checkpoint inhibitors for all tumor types. It became very apparent to me that we were winning the battle. We see a response rate. We were winning the battle even more when you talk about progression-free survival, but we weren't winning the war. The war is a cancer-free overall survival with the duration of response. The complexity of this immune system, the more I studied it, the deeper I got. It was like getting into an astrophysics room looking for God's particle and it just got more and more and more complex and became really clear that there were cell-to-cell discussions between T-cells and K-cells, IL-15 discussions about proliferation.
I needed to not only sort it out but actually derive a product that clinicians like myself and like yourself could use in everyday life that is safe and active and would synergize BCG, which is an amazingly good stimulant, to activate your immune system. That's how I started this journey, 2010, it's now '24, across first developing Abraxane, now Anktiva, and it's soon the next generation of another molecule. But I think this is a slow walk towards changing and transforming bladder sparing in the community of urologists.
Ashish Kamat: We'll clearly talk about the drug and its approval and indications in a segment shortly, but if you could take a little bit of a deeper dive into the mechanism for those in the audience that are truly interested in the whole hot/cold tumor, the NK cells, how the B-cells, T-cells interact, the whole memory effect, that would really be enlightening.
Patrick Soon-Shiong: I will share with you and maybe we'll give you a slide that you could put on that I drew in 2016 when I shared this with the White House to say we want to launch this cancer moonshot and this is how I think the body's cancer cells work. It's a crazy drawing that I presented in Toronto.
But to boil that down to the essence, it turns out that all the therapies that we use—chemotherapy, radiation, BCG, checkpoints—cause what we call a Darwinian progression to a clonal selection of a cell that hides from the T-cell. I call that an MHC-1 negative T-cell, a cold tumor. We all recognize the cold tumor.
We all recognize the T-cells, like checkpoint inhibitors and CAR-T can treat all tumor types as shown by Merck and Bristol-Myers. But all of them get to a point where the tumor has selected the cell regardless of cancer and bladder cancer, prostate cancer, or kidney cancer, that is cold. If it's cold, the T-cell can't recognize it. And guess what God has given us? God has given us where if any cell is MHC negative, you and I have in our body a natural killer cell that looks for that cell and kills it. That was the key to actually activate this natural killer cell to kill this clonal selected cell and not only kill it, but then stimulate a thing called gamma interferon. You may know about interferon way back in the urology space. What gamma interferon does is it reactivates the receptor to the T-cells. Now you rescue the T-cells. Now, when you have a combination of the natural killer cell and the killer T-cell, you now kill the tumor and you get the complete response. But that's not enough because it is the duration of this complete response that really matters.
In order to get the duration, you need to stimulate the memory T-cell. Once you have these two cells working, the memory T-cells come on with the gamma interferon and the natural killer cell, and that's the mechanism. I call that the triangle offense of the natural killer cell, the memory T-cell, and the killer T-cell. With one molecule, we can actually activate that and that's the Anktiva molecule. It's taken me eight years to get it through the system, develop it, demonstrate it, and now get it approved.
I see that as the next generation immunotherapy for bladder cancer, soon hopefully for kidney and prostate cancer, lung cancer, but that's how it works. Converting a cold tumor to a hot tumor with an Anktiva cycle in which we use BCG within the same workflow as BCG and synergize with BCG.
Ashish Kamat: It's a perfect segue into the whole study and the approval and so on and so forth that we'll come to in the next segment. Thank you for taking the time to explain the mechanism to our audience. There are some that clearly just want to know if the drug works and there are many that actually want to do this deep dive. Hopefully, we'll be able to get that slide, put it up, and have it for everybody to look at on this UroToday podcast.
Patrick Soon-Shiong: Thank you for having me, and you're right, we'll talk about the what, which is, what does it do? This is about the why or the how. As you know, I love talking about the why and the how, but soon we'll talk about the what. I appreciate the time. Thank you so much, Ashish.
Transcript Part 2 Ashish Kamat: So everyone, welcome to part two of this discussion that we're having with Dr. Patrick Soon-Shiong, who again has taken the time to come here to the UroToday Studio, share his knowledge, and his experience with our audience. In part one, we talked about your journey, how you went from identifying the problem, figuring out the immunological questions that needed to be addressed, and then going through your different iterations and multiple different organ types, but coming down to bladder, and then coming up with the drug that is now approved as of just this week. So in this part, if you could focus a little bit on those who want to understand better the genesis, the phase one, phase two studies, the design of the trial, and what led to the approval of the drug? If you could share that with us.
Patrick Soon-Shiong: Well, thank you again for having me. I think here it is really not only the journey of the science but the journey of how to get a drug through the FDA and, more importantly, validate all this information. So the first thing was we started two studies, in BCG-naive patients where we did a randomized double-blind control, which is still going on, comparing BCG alone versus BCG plus Anktiva. Not only would that give us insight into the combination, but it also gives us insight into the contribution of effect, and we'll get to that. Then the second study was a single-arm study in which patients were facing cystectomy and you couldn't randomize against a cystectomy. So that was in BCG-unresponsive CIS and papillary disease, which we published in the New England Journal of Medicine. To get through the stages of the FDA, we did the first approval in the CIS arm, which is CIS with a visible papillary disease.
Let me talk about what's approved in the label, first. The most important thing in these patients, and as you know in your practice, these patients will do anything to preserve their bladder, the quality of life of having a bladder removed. And so the concept from our perspective as a surgeon is to move the treatment into the hands of the surgeon, away from actually having to do that horrific surgery, which has a 4% mortality by itself and high morbidity and high cost. So the single-arm study was asking the question, can we get a complete remission in the patients who failed BCG, but continue giving them BCG? Now that doesn't make any sense, but unfortunately, you have to go to part one to explain why you give more BCG plus add to Anktiva. What we found was a high rate of complete remission in the New England Journal of Medicine, which was 72% of 82 patients.
The agency took some of those patients and said, even though they had complete remission, because you didn't do upper stage urethrogram, et cetera, from a diagnostic perspective, we'll evaluate the 77 patients. We are now up to a hundred patients and that will come out soon. So if you look at the complete remission rate, it's high, it's fantastically high. But really that's not the story for us and for you. It's really how long does that stay? How long can you preserve that bladder? So the FDA said to us, what was important is this duration of response. And as you know, Ashish, your paper and the IBCG in which the guidelines were set, that if you got 30% at 12 months, that would be a bar. And in fact, in your paper you said, that's an unrealistic goal. We had 58% at 12 months and it almost doubled that, quasi-unrealistic goal, and it was so incredibly pleasing.
So that's in the label. What was amazing, however, in this label is that this complete response rate is still ongoing. So the agency said to us, look, we're going to put in the label, 47 plus. So you'll see the word "plus," and you see in the label an asterisk. That plus means ongoing complete response, which means we have yet to determine, until we get to the end, what the median complete response would be. Dr. Reddy will be presenting some data at this meeting, which we estimate it'll be over three years, a median of over three years. And by Kaplan-Meier plot, it could go even four. The FDA also said to us in the label, you can give this drug up to 37 months and follow the patient up in our protocol, now for five years. The safety, as you could hear, is no different than that of BCG.
It's very exciting and there's no difference in the workflow to BCG. There's no difference in ordering to BCG. There's no difference in the follow-up as with BCG. So we've actually now from the label addressed exactly what we do. We've taken the powerful stimulant of BCG, now activated the memory to the BCG-infected cell. So there's this concept of trained immunity, which you and I probably talked about a year ago. We have now activated that trained T-cell, that memory T-cell. What's exciting is that the FDA gave us in the label activation of NK cells, CD-4 T-cells, CD-8 T-cells, and memory T-cells without stimulating the immunosuppressive T-reg cells. That's a mouthful. But what that means is that your patients now can get a treatment that is no different from what you're giving with BCG, and having it available right now with data showing a durable complete response.
We will present data also on Sunday on our naive study. In the naive study, the FDA, in a very unusual manner, asked us to unblind the interim analysis of the naive data that we had to date in October 2019 to confirm that the contribution of effect was Anktiva. We did so and we had 81-85%, I forget the numbers, I think it was 81% complete response by nine months. And you'll see that data on Sunday. We reached statistical difference in the duration response between BCG alone versus our combination. So it's consistent, the immunology is consistent and I'm pleased to say that the availability of this drug is so important. We recognize that. So we plan for that. By this Monday, we will release the news that we have 175,000 doses available with the stability of up to three years. And we just announced our partnership with the Serum Institute of India, in which we are going to bring BCG to the world through the Serum Institute of India, which is a magnificent institute that's built BCG for the world. And this is a recombinant BCG, which will be combined with Anktiva to address this issue of BCG shortage.
Ashish Kamat: Well, that's great, and in fact, we'll talk a little bit more about that in detail in part three. I want to focus the audience's attention again on a point that you mentioned because you are absolutely right. When we see a patient in the clinic, he or she doesn't really care what's going to happen at three months. They want to know what happens at 12 months and beyond, right? Because you could get a response at three months with almost any drug, but then that tapers off fairly rapidly. And what you showed in the publication, and again what you have publicly disclosed with the FDA, is that that tail, that duration of response is extremely prolonged with this combination therapy. How would you, and I know you don't yourself treat bladder cancer patients, but with your knowledge of the immunology, if a patient says, why is this combination better than any other immunotherapy? How would you explain it to a layperson?
Patrick Soon-Shiong: Right.
Ashish Kamat: As to why they should go on this treatment?
Patrick Soon-Shiong: I would explain to the layperson that we've been relying, and rightly so, on T-cells. And you know you have T-cells in your body. This is the first time now that the drug is approved to rely on the cell that's on top of this T-cell called the natural killer cell. When you have these two cells talking to each other, they release yet a third cell that's in your body called the memory T-cell. So now you have this triangle offense and I'm a Laker fan. And you release this memory T-cell, and that's what matters. So time matters, duration matters, memory T-cells matter. Your body has been trained already to this cancer.
Through this memory T-cell, the tumor has actually put that memory T-cell to sleep. We awaken it and Anktiva awakens it. And that's why we get this long tail, and we keep boosting that, and that's why we can treat you up to 37 months. And this is why we have the duration response ongoing and the median is yet to be determined. So I would tell a patient that, look, God's given us this natural killer cell, for the first time we have now a molecule that can activate it and proliferate it. And it's your body's ability to fight this cancer without chemotherapy.
Ashish Kamat: Yeah, no, that's great. And again, thank you so much for explaining that. In summary, to close this section, if you could just, again, for the folks listening, remind the audience. Anktiva is approved for patients with BCG-unresponsive disease with CIS plus or minus papillary, and it's fully available at this point.
Patrick Soon-Shiong: That's correct. I think what we've done to make sure that the doctors and the nurses in the ordering, we've created a hub at Anktiva.com. By going to Anktiva.com, you have this drug available through this hub, through every one of these distributors: AmeriSourceBergen, Cardinal, and McKesson, that covers 99% of the United States. So yes, this drug is completely available now. In fact, it's already been shipped.
Ashish Kamat: Great. Thank you so much and stay tuned for part three.
Patrick Soon-Shiong: Thank you.
Transcript Part 3
Ashish Kamat: Hello everyone, and welcome to part three of this chat we're having with Dr. Soon-Shiong, eminent surgeon scientist. In part one, we talked about the mechanism and how you got to your journey from discovering the idea and bringing it to bladder cancer. In part two, we talked about the official label and the indications for bladder cancer patients. In part three, I'd like to revisit a little bit of what you did with the AUA at the forum yesterday here in San Antonio. Questions that people have: where is this drug now? Is it fully available? The partnership with the Serum Institute in India, the label indication, etc., etc. So let me ask you first, the drug has to be given with BCG and people always have this question, "Well, if I have to give this drug with BCG, where is the BCG supply shortage in this country going to go?" And I know you've taken steps to address that. So if you could share with the audience, where your thoughts are and where we're heading.
Patrick Soon-Shiong: Even during the trial, we had trouble because of the BCG shortage, as we're post-COVID and Merck has tried very hard. As you know, they are the only manufacturers, currently, of BCG. We recognize that if this drug gets approved, we have to address it on behalf of the United States and the world. And we didn't have that capacity, but the Serum Institute of India certainly had that capacity. Not only did they have that capacity, it's a magnificent organization with GMP manufacturing facilities that produced this for 20 countries in the world already, not only for TB but for bladder cancer. So we approached that institute and happily we signed an exclusive agreement, not only to bring back BCG to the United States, but to bring this next generation BCG that they're already doing phase one and two in Europe called recombinant BCG.
So we will be launching, together with the Serum Institute, the availability in the trial format of Anktiva plus BCG, and obviously the label allows Anktiva plus BCG for any BCG. But the label currently, the standard of care today in the United States is Tice BCG. We need to get the Serum Institute BCG approved through the FDA to replace or be on terms with Tice BCG. So that trial will be opening as soon as we can get that through the trial mechanism of the agency. That molecule is available to be shipped today. That BCG is available in the hundreds of thousands of doses at Serum Institute. Our Anktiva, as I shared with you in the last episode, we have over 170,000 doses if that's needed. So supply is not going to be an issue, and we plan for that. It took us many years, two years, to plan and produce and invest for that because we want to invest for success if this drug got approved.
In order to have the logistics of that easy for the urology practices, which is really difficult, we want to ensure that there's no difference in ordering, change, or workflow with that of BCG because it's mixed with BCG in real time. So we've also accomplished that, and that is really in motion. I'm happy to share with you that the first hub ordering has gone through successfully with the software, and that's at anktiva.com. If you just press that, you'll get through the logistics availability of that ordering.
Ashish Kamat: That's a very important point you bring up because the urologists, the academic centers that only may deal with bladder cancer, have that workflow set up, but we have a lot of colleagues in the community and a lot of our patients in North America actually get their care in the community. So it's very important for the community practice urologists not to have to disrupt their whole day or workflow. Could you again, educate the audience a little bit on exactly what you said, what was done in the trial, how it's mixed with the BCG, what's the actual workflow for those that are listening in and thinking, "Should I get this at my practice?"
Patrick Soon-Shiong: So the workflow for BCG, I think everybody understands the workflow for BCG, in which you actually take the BCG vial and if you look at the Tice label, you actually reconstitute it into 50 cc's and you pull it out and put it into the syringe and inject it into the Foley inject. Nothing changes, absolutely nothing changes. That's the workflow. The only difference is that as you add the BCG, you also add the Anktiva. So it's as simple as that, which is quite remarkable. So again, just to repeat, you take out the BCG and you take out the Anktiva from the fridge. If the patient doesn't show, you put it back in the fridge and it's fine and stable for 24 months. So there's no danger of thawing or re-thawing this. It's not frozen. You then reconstitute, like you normally do, you reconstitute BCG and you just add the Anktiva into that same 50 cc reconstituted volume and you put it into your syringe and inject it.
So from the nurse and from the pharmacy workflow, nothing changes. From the urology workflow, nothing changes. You put it into the bladder, you hold it there for two hours, and you send the patient home. So that's what was exciting because what we are really doing is activating the immune system inside that bladder. By the way, what's also exciting, our PK shows it doesn't go through the bladder wall. So there's no systemic absorption, meaning it's a completely local effect. And that's why the adverse events are no different from that of BCG. Some may say it even alleviates some of the BCG adverse events, but that's not what we've said in the label. So the grade three, four adverse events are 0% to 3.4%. 0% grade three with all the urinary frequency, etc. That's in the label. And for a practicing urologist in the community, we've not changed anything.
Ashish Kamat: And that's very important. And also what you mentioned about the fact that if you thaw it and it doesn't get used, you can put it back and it's stable because some of the practices will always be thinking about cost and how to save precious healthcare dollars. So that's a very important point you brought up.
Patrick Soon-Shiong: Well, it's not frozen, so it doesn't need to be thawed. So this is exciting. You just pull it out of the fridge, if the patient doesn't show, you leave it back in the fridge or you needn't take it out and it's stable there for 24 months.
Ashish Kamat: Exactly, exactly. The other point I wanted to ask you about, and it has something to do with the whole issue nowadays, there's a BCG shortage in the country. And I know this wasn't part of the label, but from a mechanistic standpoint, if a urologist were to want to use a reduced dose of BCG with the drug, do you have any sense as to whether that's okay for them to do to save the BCG?
Patrick Soon-Shiong: Yeah, it's not in the label, but I can tell you some of the science, and we did a planned subgroup analysis in terms of how much BCG the patient received, less than 12 and greater than 12, and published in the New England Journal of Medicine. And again, I want to emphasize it's not in the label, but it was a planned subgroup analysis of that subgroup. There was no difference in either CR or duration response. So that's the good news because it's an immunological stimulant. What I'm really excited about is the potential that the Serum Institute's next generation recombinant BCG is even more potent, more immunogenic, and even, according to them from the phase two data in Europe, safer than the current BCG. So yes, I think the combination of the synergistic effect of the BCG giving you the CD4, CD8 T cells, and then our Anktiva proliferating that as well as giving NK cells, is really, really exciting as this next immunotherapy generation for bladder cancer.
Ashish Kamat: Yeah, and the recombinant BCG that they've had, we've seen the phase one, phase two studies coming out of Europe and everyone's been anxiously awaiting some way for them to be able to hopefully come in and get studied here. So that's a big push and a big benefit for our patients. It's appropriate that this is May, this is Bladder Cancer Awareness Month, and there's so much activity going on, not just with the approval of the drug, but also with your efforts to get more BCG into the US approved by the FDA. In closing, I would love for you to share with me and our audience your thoughts on where this or the company is going next in urology.
Patrick Soon-Shiong: Well, I think, as you could see, you understand that T cell is used for all tumor types. So within the bladder world, we are going to muscle invasive next. We are looking at a bladder sparing opportunity, trying to transform truly bladder sparing. If we can capture patients in muscle invasive before they metastasize and create a complete response there, then we're going to go into metastatic disease, which is the same. All within the bladder world. Within the prostate world, to me, that's one of the most exciting areas that we're going to go right now because one of the areas is basically active surveillance and patients who, let's say, had a prostatectomy, they can get radiation if their PSA goes up. We don't know where the cell is, but this is exactly where we can activate that natural killer cell. And then thirdly, the BCG, getting the recombinant BCG.
What I've learned, and I didn't know this, is that all the current Pasteur strains, Connaught strains, Danish strains of BCG sit inside the cell and really stimulate mainly CD4 T cells, and a little bit of CD8. What this recombinant has done, they've taught this BCG to not only make CD4s but actually get out within that cell to make high doses of CD8 T cells. Now, that to me, was why the biological basis of increased immuno stimulation. So to me, I think hopefully at the next AUA, this recombinant BCG, we will study it, show it. Hopefully at the next AUA, we'll actually have some data on the muscle invasive bladder cancer and hopefully we will actually show some data on prostate cancer.
Ashish Kamat: Excellent. Looking forward to it. Thank you so much for taking the time, Doctor.
Patrick Soon-Shiong: Thank you for having me.