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Oliver Sartor: Hi. I am Dr. Oliver Sartor, and I'm with UroToday and have a special guest, John Valliant. John Valliant is the Founder and CEO of Fusion Pharmaceuticals, recently acquired by AstraZeneca, and has provided leadership to that group for what, about eight years now, John? Is that about right?

John Valliant: Yeah. That's right.

Oliver Sartor: Good. Anything else you'd like to say in terms of introduction? Anything about yourself that you think the listeners would enjoy hearing?

John Valliant: Well, I have a background in chemistry. Started my life as a chemistry professor, and I've been in the radiopharmaceutical field for what is now a shocking, almost 31 years, so excited to see the evolution of this field over that time.

Oliver Sartor: Amazing. I'm going to start off with what may be a softball question, and I'm going to ask you about targeted therapy and radiopharmaceuticals, but we have antibody-drug conjugates, we have CAR T-cells, we have bispecifics, we have radiopharmaceuticals. Why radiopharmaceuticals? Why have you spent 31 years thinking about this particular treatment modality for cancer?

John Valliant: Oliver, you mentioned the incredible evolution that we're seeing in precision medicines in the chemotherapy side of the field and the immuno-oncology side of the field, and I think the potential that always existed to evolve external beam radiation therapy in the same way from sort of an effective cell-killing modality that was very effective for limited numbers of tumors, but may have had limitations with metastatic disease. The opportunity to use targeted radiation therapy using radiopharmaceuticals to bring that radiation to each individual cancer cell, for me, was always an incredible opportunity. And the other side of this field that I think is incredibly exciting and something I think you and I have talked about for years. The ability to use nuclear medicine imaging to select patients that goes hand in hand with the therapy, I think, differentiates this therapy from most other modalities that maybe use tissue biopsies where you're getting a sample of the tumor. In this field, you get the opportunity to look at the entire field of view of the patient, the whole body, look at the distribution, and get the right drug for the right patient at the right time. And when you combine that with the power of radiation, I'm so excited to see that radiopharmaceuticals are really starting to be realized as one of those rapidly emerging therapies that I think is going to change how we treat patients.

Oliver Sartor: John, you raised an interesting point about the ability to image. I'm actually shocked that the other targeted therapies, whether or not they be ADCs or CAR Ts or whatever, don't utilize the power of molecular imaging to select their patients better. I'm just actually shocked that these modalities are marching forward based on immunohistochemistry and the like. It's just crazy to me.

John Valliant: I agree. I mean, just the sampling error associated with doing a biopsy is something that's been well known for a long period of time. I think one of the reasons that it's become so commonplace in the radiopharmaceutical field is the therapeutic side evolved a lot from the imaging side of our field. And the technology lends itself to take the same molecule that you're using for therapy, and all you have to do is switch the isotope, and now you have the imaging form. So it's really, I definitely don't want to say it's easy, but it's convenient to be able to create the diagnostic pair with the therapeutic pair, probably more so than the other therapeutic modalities, but there's no reason why those others shouldn't be using this type of technology.

Oliver Sartor: Interesting. You have particularly focused as a company on Actinium-225, and it's a rare isotope, and we're unfortunately becoming even more aware of how rare it is. But I wonder if you might be able to discuss why Actinium for Fusion, and are there other isotopes that are in strong consideration in your pipeline?

John Valliant: When we started Fusion, the approach we decided to take is very scientific. We were taking a targeting molecule that we were interested in, and we would attach to it a wide range of isotopes, not just alpha emitters like Actinium, but widely used beta emitters like Lutetium or iodine. Yttrium-90 was a big one. And in fact, betas at the time we started were much more widely used than alphas like Actinium. But in every preclinical experiment we did, the Actinium showed greater efficacy at a lower radiation dose.

And so we just kept on seeing this pattern over and over and decided to use and focus on alpha emitters. The thing that emerged later on about Actinium was that patients who were treated with a Lutetium radiopharmaceutical, and this is something obviously, Oliver, you've been incredibly involved in, is when they would not respond to a beta emitter, which are small electrons. They cause single-strand DNA breaks. You need lots of them to create double-strand DNA breaks. You could take the same drug, put in Actinium, and some of those patients would start to see responses. So by going from a beta emitter to an alpha emitter, which causes direct double-strand DNA breaks, you could start to see responses.

So we made a decision strategically, we're going to focus on Actinium, and in addition to the science, the clinical data, its half-life is 10 days. So it allows for centralized manufacturing, distribution to the clinical sites in a convenient way, which has really been the successful model that's emerging from the radiopharmaceutical field from a commercial standpoint and a drug accessibility standpoint. So that's really why we focused. And one of the other areas, which I think is a huge opportunity, is in combination therapies, and we think the nature of the radiation from Actinium really positions these drugs well for combining with other therapies.

Oliver Sartor: Interesting. I wonder if you might elaborate a little more on that. Do you have some particularly favorite combinations that you're thinking about at Fusion? Any things that you'll be combining these alphas with to get a little more punch?

John Valliant: Maybe two examples. I mean, I think there's so much white space when it comes to combining radiopharmaceuticals more broadly. I think the one that we got interested in very early on, which is the obvious one, is the synthetic lethality space and the DNA damage response inhibitors like PARP inhibitors. The PARP inhibitors were really developed with the idea that if you have a mutation in your tumor that causes the buildup of single-strand DNA breaks, the PARP inhibitors, DDRIs, whether it's single-strand or double-strand breaks, they'll prevent the repair, cancer cell dies, but you have to have the mutation. We cause DNA damage. So the automatic combination of those two therapies would allow PARPs to work in a more broad patient population, was our thesis, but also allow us to use less radiation. And so that, to me, was an incredible opportunity.

The second area that was probably less obvious, but I think has a lot of excitement around it, is combining with checkpoint inhibitors. So the power of radiation, and particularly alphas, with the ability to stimulate the immune system, I think, is an incredible untapped opportunity. Radiation creating things that the immune system can recognize, so tumor neoantigens, and then the checkpoint effectively turning on the immune system to attack the cancer cell. I think those are things which you're going to see drive radiopharmaceuticals into more broader use and actually even earlier lines as well.

Oliver Sartor: Interesting. I wonder if you might be able to comment in a non-proprietary way, not trying to get any confidential information, about targets that you're assessing and why. And obviously, PSMA has been one of your lead targets, but I wonder if you might be able to talk about anything beyond PSMA as a target that Fusion is interested in.

John Valliant: So Fusion right now, we have four clinical programs, and as you mentioned, the PSMA in prostate cancer is our lead program. But our company was actually originally founded to take radiopharmaceuticals beyond its large focus in prostate and neuroendocrine cancers, because if they're that effective in prostate and neuroendocrine, in our opinion, we should be able to actually use this in breast and colorectal and pancreatic cancers. So two targets that we're currently working on in the clinic, one is called neurotensin receptor 1, NTSR1. It's a target that actually there were a number of academic studies showing uptake in a number of different tumors, including pancreatic, which I thought was a huge unmet need and an opportunity. The other target is one that we originally developed in collaboration with AstraZeneca. It's actually two targets, EGFR-cMet. So using an antibody that can bind both targets. So a bispecific approach.

These two targets have been well validated. There are approved drugs against them, but the opportunity to go after and use basically the two arms of an antibody to drive uptake in selectivity was really exciting and move the field into other tumor types like lung and colorectal. So those are two we're working on. But I would also say that one of the exciting parts for me about the acquisition by AstraZeneca is combining their precision medicine, their antibody-drug conjugate expertise, the ability to develop therapies against emerging targets with our expertise and how we attach the Actinium to the drugs. Really, again, that provides the opportunity to build a really deep pipeline of novel therapies.

Oliver Sartor: Well, interesting that AZ collaboration, which has turned now into an acquisition, I think does provide you some unique synergies because they've been looking at antibodies and targets for a long time and you have the ability to help deliver the radiopharmaceuticals.

John Valliant: Yeah.

Oliver Sartor: So John, when we are thinking about this, I'm going to ask you for a brief moment to kind of look in your crystal ball, if you will, and think about the next five years and what do you think the field will have accomplished in the next five years that we've not accomplished today? So it's a little bit of a forward-looking question about where you see the field going and what accomplishments you anticipate during the next five years.

John Valliant: So I'm going to build off the theme that we were talking about. I really think, Oliver, you're going to start to see successes in tumors outside of prostate and neuroendocrine, where obviously there's lots of programs going on in those spaces. So what we see the success in the antibody-drug conjugate space, which has now obviously had transformative results in breast cancer and bladder cancers. I think you're going to start to see that in the radiopharmaceutical field in other areas outside of prostate. In prostate cancer, my crystal ball tells me you're going to see these drugs move to earlier and earlier lines and be able to treat. Typically, radiopharmaceuticals have been used for late, late-line patients, and I think through the development of superior therapies, as well as the combinations that we're talking about, you're going to see them used earlier than just late-stage metastatic patients.

So for me, earlier lines, combinations, and moving outside of the sort of current focal areas that we've had is really where this field is going to go. And I think the use is going to continue to grow like we're seeing it. And the interest from people who have not traditionally looked at radiopharmaceuticals from the clinician side, I think, is going to continue to grow.

Oliver Sartor: Interesting. I'm going to ask a question that maybe is a little more on a personal front, but I'm curious, and if you're not comfortable answering, we can certainly divert on to other issues, but a lot of biotech companies like Fusion that have been sold end up having the CEO move on, and you've publicly announced that you want to stay with Fusion and AZ and develop these compounds. Help me understand a little bit, if you're comfortable, about that decision to follow through where you started rather than jump to another company.

John Valliant: So the reason for starting Fusion in the first place, it was really driven by the excitement around using radiopharmaceuticals and the science that we had. And this is, I think, a collective vision for the company to have a real transformative impact on patients. And from my perspective, the job's not done. I think the opportunity is there. I think investors, current, and past employees, collaborators, made an enormous commitment and effort to get Fusion to where it was when it was acquired. And I don't think the job is done, and I think the opportunity is enormous. I had the great fortune of collaborating with AstraZeneca over a number of years. They have incredible people, vision, and as you said, the opportunity to combine their expertise both on targeting molecules, but also in the combination therapy space, they're obviously one of the leaders in DDRIs. For someone who has a scientific background, it was an incredibly exciting opportunity. So really, when you make a commitment to a company and the teams to really grow things, I felt like it was an incredible opportunity to really deliver on that vision ultimately.

Oliver Sartor: Right. Well, thank you. John, we're coming to a close now, and I just wonder if you might have any last sort of parting comments for our audience today?

John Valliant: I think maybe one of the parting comments would be this field is growing rapidly. There's lots of information out there, but there's also lots of science that needs to be done. So this field was made possible by a tremendous number of academic innovators over the years, but also it was based on a lot of small studies. And I think people need to realize that we're still learning every day in this field. There's an opportunity to transform the field and medicine, and a great opportunity to learn about it. So certainly, I think increasingly as you see more companies form, more drugs getting approved, education is an important part of this field, and approaching it with a very open scientific mind. But the future is incredibly bright, and I'm looking forward to seeing how things evolve over the next 5, 10, 15 years.

Oliver Sartor: Right. Thank you, John. Pleasure to have John Valliant, Founder and CEO of Fusion, with us today on UroToday. Thank you, John, for being here.

John Valliant: Thank you, Oliver.