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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.