Innovate to Elevate the Practice of Urology - Arie Belldegrun

October 1, 2019

Arie Belldegrun discusses innovation as a critical element in elevating the practice of urology.   He emphasizes that all urologists hold the potential for driving innovation in urology.

Biographies:

Arie Belldegrun, MD, FACS, Arie S. Belldegrun MD. FACS, is an Israeli-born American urologic oncologist, businessman, and investor. 

Read the Full Video Transcript

Arie Belldegrun: Well, I'll try to be a little bit more provocative today and tell you that we are heading to a place that it's great to have minimally invasive surgery, but how about not needing surgery? Let me try to, to do that. Some of my disclosures, so over a decade ago, you're all familiar with that, what physics was to the 20th century. The prediction was that biology will be to the 21st century and I can tell you that even the wildest imagination couldn't think of what it is in genetic engineering that will happen. So I think the society here shouldn't be only engineering should, if you add genetic engineering as well, believe me, this room, at least in the crowds that I'm surrounded would be a much larger room we need for that. So we talked about my days of a big surgeon, big incision, small incision, a big surgeon today. 

But I'll try to look at the new knife, which will be the targeted therapy and whether we will be able to avoid it. Well going back to my days as a fellow, with Steve Rosenberg, back at the National Cancer Institute starting with Dr. Marston Linehan and Rosenberg discussing immunotherapy, how you build your immune system to fight your own cancer. This was early on. We were always in a tiny home at any conference because immunotherapy was not something of discussing at all other than a few believers. 

I then moved to UCLA and obviously took the immunotherapy and combined it with the most sensitive tumor those days to immunotherapy, which was kidney cancer. I was recruited to UCLA to start a gene therapy and immunotherapy program. We did quite a lot clinical trials, NIH grants, but it was not easy to start cloning genes, which is you don't get money for, at least those days, for just cloning a gene and we needed to move and do it in a different pace.

So with that next to UCLA, we started our first venture, which was a company called Agensys, was focused on gene discovery and development of human monoclonal antibodies. Again, this was 20 years ago, monoclonal antibodies were not then what they are today, but we all believe that that will find its way. Incidentally, this company was eventually sold to Astellas, but, incidentally, just a few a month ago, the product that we have discovered then Enfortumab AGS-22 showed extremely good responses in patients with bladder cancer, with advanced bladder cancer, who failed PD1 and PD-L1, and we anticipate that in the next few months you will see a drug, a new drug in bladder cancer coming from Astellas. You will not see it from Agensys. That's kind of history, but Astellas will have some very interesting product. 

We then moved to found another company looking at Cougar Biotechnology by which are to help patients with advanced prostate cancer. At that time, there was nothing else other than LHRH agonists and we have developed abiraterone acetate or what's known today as Zytiga for metastatic prostate cancer. Obviously, Johnson and Johnson have done a fantastic job moving it early on the left in the disease and actually the sales of Zytiga last year, were about $3 billion. 

We then came back to, where we really believed at UCLA, to go back to the immunotherapy and this time there was something different because we called genetically engineered the human immune system. It's not anymore take t-cells, activate them and give it, but you can genetically engineer it and give it to the patient and then you have essentially a target that you attack cancer cells, sparing normal cells. I'm not going to all these details of Kite Pharma, but essentially this drug was approved by the FDA earlier last year and is today available for patients with non-Hodgkin's lymphoma and leukemia. 

Why is all that exciting? Because you can look at this patient here and receiving multiple chemotherapy regimens, essentially exhausted all treatments available, two to four months to live. He then, we took his cells, engineered it in the lab, gave it back to him, and you can see four weeks later all of the cancer has completely disappeared and he is now, but five years through the treatment with no evidence of disease. Obviously, this is the heart and as you know, kidney, but there's no evidence of any of the tumors. So you can genetically engineer and essentially introduce a GPS that identifies the cancer versus normal and that's kind of the general idea. 

What I would like to a little bit focused on two future directions that we have taken. One of them on the left, UroGen Pharma, the other one is Allogene, and I'm the chairman of UroGen, and I'm executive chairman of Allogene. So take it with a grain of salt of whatever I'm telling you right now. 

In any case, UroGen was a technology, it was developed based on a chemical that is a proprietary polymeric biocompatible reverse thermal gelation hydrogel. So essentially it's a gel. And we started looking at it some years ago. And since we are not experts in this gel, I asked one of our colleagues in Nobel Chemistry and a Nobel lawyer from Stanford, whether he would analyze for me these properties of the Gel. 

He took it to the lab for several months. He said it looks like a very interesting molecule. I think you should continue. I said we know as urologists what to do with it. All we needed to know, whether it's a real gel that has all the properties that we would like to use in urology. 

So I'll start with that. And then I move to something which is exciting. It's the future on how we developed for kidney cancer, a new targeted therapy for metastatic disease. The RTGel, you can see it's not rocket science here. There's no genetic engineering here. It's a great gel that when you put it in room temperature, it creates a gel form. However, when you cool it at low temperature on ice, it becomes completely liquid. So at that point, you can mix it with whatever you want. And then when you instill in low temperature to patients in any body cavity, in this particular case, bladder, it gels, it sticks to the wall and it will deliver the product that you have mixed with for about four to six hours. And you can see on your right-hand side when we did it originally with multiple pigs and you in infuse it up to the ureter and the renal pelvis, you can see that it sticks there for about four to five hours. And interesting, it does not block the urine, because this was the big question that the FDA was initially asking. What's the side effect? 

This has been then, moved to clinical trials. And you can see on your left-hand side a previously treated patient with endoscopic surgery, the last tumor. All the patient had is a retrograde infusion of the gel in repeated sessions. We did not want to change anything from what urologists are using once a week for six weeks. And therefore, the idea was to use the same instrument, the same everything that we are using in our practice. And you can see the clean post-op. 

I would not steal this presentation today at three o'clock from Seth Lerner, who is the PI at the late-breaker news. He will present the latest in the study. The submission to the FDA has already begun. So you'll hear today about the data. It's quite exciting data, I believe, compared to what we all, and the opinion leaders, thought that what will be a meaningful outcome to patients with advanced recurrent and inoperable disease. 

So the UGN-101 is a mitomycin gel for installation. It's used in low-grade upper tract TCC. It received an orphan drug legislation. Then breakthrough therapy from the FDA. And in NDA submission begun already and we hope by the end of the year to submit to the FDA the entire package with a potential approval in 2020. We hope that this will be the first drug ever approved in low-grade upper tract TCC. And we obviously moved to a system molecule, which is a gel, but with the different concentrations. UGN-102 for a currently ongoing clinical trial in bladder cancer. And again, there has not been a drug approved in more than 15 years for bladder cancer. And we hope that this will be in low-grade non-metastatic bladder cancer. Another model is the UroGen 201 which is a toll-like receptor and Immuno activating molecule in bladder cancer and another BotuGel which is mixing it with Botox and the clinical trial is taking place right now. 

Finally, in the last few slides, just to show you where is the future heading? We have the company Kite was all based on taking blood from patients, engineering it, giving it back to the patient. This is expensive. It's time-consuming. It's complicated. In the era of genetic engineering, gene editing, there is no reason why to do all this complexity. So we have come up with Allogene, a new company, that from a healthy volunteer. You take his blood, you gene edit it and you return and from this one patient, you can at least treat a hundred patients or so and get it as a potent cell to patient. This is currently in clinical trials. 

How do we do that? That's again, as I said, without going to all the gene editing, you edit a TCR Alpha receptor, you edit the CD52 so you create essentially a universal donor and then you put the chimeric antigen receptor on top of it. So you have now a universe of allogeneic off the shelf low-cost product that we hope that we advanced to kidney cancer. 

Currently it's in hematologic diseases. It's in the clinical trial in the lowest hanging fruit, which is lymphoma, leukemia. But here is CD70 renal cell carcinoma in this AACR, the American Association of Cancer Research, just last month we presented for the first time this construct that shows a very unique target on kidney cancer that we have identified, and this is in 80% to 100% of renal cell carcinoma. So essentially, if we construct a chimeric antigen receptor, what's called CAR for CD70 that will home directly to kidney cancer wherever the tumor is. And we hope to see some responses similar to what we have seen before in other diseases. It's easier said than done. 

Solid tumors are different than hematologic tumors, so there is some complexity in that story and therefore it has never been approved yet by the FDA and there is a challenge here, but we believe that we are on the right path to bring to patients metastatic kidney cancer patients who actually failed every other mode of therapy. 

Finally again to innovate is to elevate the practice of urology. I think that if urologists are not staying in the driver's seat with all innovation, we will lose. We already started losing and I don't have... It's not the place to say where we are losing in kidney and prostate and bladder cancer to other specialties, but innovation can come obviously in all forms. You can work with gene therapy and hottest topics today, but as I try to show you that UroGen has a potential to be kind of the first drug approved for common diseases in urology, but at the same time it's not rocket science. 

The future obviously will be in stages. It will be a combination of minimal disease with other modes of treatment with the PD1, PD-L1, with checkpoint inhibitors, but eventually, I believe that this will go into the mainstream urology where treatment will be based on engineered T-cell therapy. and I think that urology should understand the basic principles in order to bring it to combination treatment with currently existing therapies. Thank you very much for your attention.
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