Latest / CareTalk: Healthcare. Unfiltered. / How Targeted Radiotherapy Is Changing Cancer Care w/ John Babich, President, CSO, Ratio Therapeutics

Transcript

How Targeted Radiotherapy Is Changing Cancer Care w/ John Babich, President, CSO, Ratio Therapeutics · CareTalk: Healthcare. Unfiltered.

• 0:00
  David: Cancer treatment has long rested on three pillars: surgery, chemotherapy, and external beam radiation.
• 0:07
  David: A fourth is now taking shape.
• 0:08
  David: Targeted radiotherapeutics pair a tumor-seeking molecule with a radioactive payload, delivering radiation directly to cancer cells while largely sparing healthy tissue.
• 0:18
  David: Since Novartis' Pluvicto cleared the FDA for prostate cancer, the field has drawn billions of dollars in investment and a wave of acquisitions.
• 0:26
  David: But it's a big challenge to source the isotopes and build scale manufacturing.
• 0:37
  David: Hi, everyone.
• 0:38
  David: I'm David Williams, president of strategy consulting firm Health Business Group, and host of the Health Biz podcast, where I interview top healthcare leaders about their lives and careers.
• 0:47
  David: My guest today is John Babich.
• 0:49
  David: He's president and chief scientific officer of Ratio Therapeutics.
• 0:53
  David: He's a longtime pioneer of the radiopharmaceutical field, and, uh, he's leading Ratio as it builds an integrated platform for next generation targeted radiotherapies, anchored by its Trillium targeting technology, macrochelation chemistry, strategic isotope partnerships, and a new manufacturing footprint in Utah.
• 1:12
  David: John, welcome to the Health Biz podcast.
• 1:15
  John: Thank you, David.
• 1:15
  John: It's nice to be here.
• 1:17
  David: Now, you spent decades in this field of radiopharmaceuticals, and I'm wondering what drew you to it originally, and what's different about where we are right now?
• 1:26
  John: So earl- early on, I, my undergraduate degree was in pharmacy, and pharmacy was a very, education-wise, was very exciting in, in regards to its implications in medicine and chemistry, pharmacology, a- and, and so on.
• 1:40
  John: And, and, uh But, but the practice of community pharmacy wasn't as attractive to me as the research aspects of pharmacy.
• 1:48
  John: And I got introduced to nuclear medicine at a very early stage in my career by the good, a good friend of mine who was a physicist.
• 1:56
  John: And as I saw what was possible in nuclear medicine, the research aspects of it became very attractive to me, and I thought, you know, this is something you can do research-wise in real time.
• 2:08
  John: So again, very naively taking that, that leap that something that I could imagine being very exciting from a research, it actually turned into, you know, a, a 30-plus-year career where, you know, I was, uh, fortunate enough to work at fantastic institutions with fantastic people and really have my fingers on things that were very cutting edge.
• 2:31
  John: So I, I, uh… It was the sort of I was heading towards the right, in the right direction not knowing what was in front of me, but that was how I, I, I jumped into the research side of nuclear medicine.
• 2:41
  John: And nuclear medicine is a big field.
• 2:43
  John: It's been around for many, many decades as well, and, uh, out, uh, it's older than I am.
• 2:48
  John: And so, uh, it's been, it's been interesting to see, particularly in the last 30 years, the advent of molecular imaging, uh, the expansion of PET imaging, uh, the, and then the, of course, the, as you ear- earlier mentioned, you know, the transition from a mostly, mostly imaging modality of function to molecular imaging and now to targeted radiotherapeutics and, and, and have been at the forefront of that with colleagues and on both continents of the US and, and Europe and, and, uh, in many institutions.
• 3:20
  John: So I've been very fortunate to have the a- in, the interaction and the experience, uh, to be where I am right now, Horatio.
• 3:28
  David: That's typ- that's, that, that really sounds great.
• 3:30
  David: It almost sounds like, like a Reese's, you know, like Reese, how the Reese's Peanut Butter Cup come together, like community pharmacy and physics, you know?
• 3:37
  David: Who, who would've thought?
• 3:37
  David: But, you know, the collision and it makes, it makes great sense.
• 3:40
  David: Okay.
• 3:40
  David: So let's you've, you've, you've thrown off a few, uh, a few terms there.
• 3:44
  David: So what is a targeted radiotherapeutic?
• 3:47
  David: And, you know, Pluvicto, which people have heard about, why, why is that considered so important?
• 3:53
  John: So as you earlier mentioned, you have three real pillars of, of cancer therapy, right?
• 3:57
  John: It's the, the best, the best way to find, you know, to treat cancer is to find it super early and ex- and extract it from your body, right?
• 4:05
  John: So I mean, like early, you know, a lumpectomy in someone who's got early-stage breast cancer or prostatectomy in someone who's got early-stage prostate cancer typically is, is curative, right?
• 4:15
  John: It's over.
• 4:16
  John: Uh, that disease is, is gone.
• 4:18
  John: Um, when things get a little less, um, let's say well sur- or s- you know, s- well, w- uh, they start to spread, you, you, you run into issues, right?
• 4:28
  John: And, and even if you have non-spread but you have difficulty in a surgical, uh, solution, you could come in with radiation therapy, and many people get treated with ra-- ex- as you said, external beam radiotherapy, where radiation beams are directed at the tumor and try to avoid structures wherever the tumor may be sitting.
• 4:49
  John: So, you know, you, you try to make sure that you hit the target from multiple angles and then, you know, avoid, uh, normal tissue damage.
• 4:56
  John: But if things get a little bit further out of, um, let's say out of, out, out of a, a simple solution, a localized solution, then you wind up with, uh, systemic therapies and, you know, w- the best known are chemotherapeutics.
• 5:09
  John: And now, you know, now it's immuno-oncology and, you know, these are all i- in drugs that are most, most of them are given by intravenous infusion.
• 5:19
  John: They need to circulate around the whole body in order f- to, um, find the tumors and kill the tumors, right?
• 5:25
  John: And so if you think about radiation therapy from the machine perspective, it really isn't applicable to, to use if you have metastatic disease all over or throughout your body.
• 5:38
  John: It's, it's really not a, a, a reasonable way to approach things.
• 5:42
  John: And so there is the possibility of actually putting radioactive elements onto drugs or-- and those drugs could be anything from a small molecule, uh, you know, maybe the size of an aspirin molecule, to peptides, you know, like somatostatin peptides for neuroendocrine tumors or other, other type size molecules, 1,000 daltons or less, that can carry isotopes and, and o- obviously as big as antibodies Those, those allow you to then inject intravenously a radioactive drug which then can find and bind to met- metastatic disease anywhere in the body, theoretically.
• 6:23
  John: And what the, the whole concept there is that there is a protein on the surface of the cell that's our target, and that we, we pick those targets because we have some information about that their expression is high, and so we can-- we will, we'll get binding, and that their expression is more selective to the cancer than it is to normal tissue because then you want essentially a ratio, hence the name of my company, you know, that we have a, a ratio in favor of, of irradiating the tumor at, in multiples, uh, of what we irradiate normal tissue.
• 6:58
  John: So we wanna make sure that we have a, a good therapeutic index, right?
• 7:02
  John: And so you, you generate a molecule, uh, we can get into the details of that, and that would then bind to that target.
• 7:09
  John: You have to attach most radioactive, uh, elements that are used for therapy are metals, radioactive metals, and you have to have what's known as a chelator, and that chelator is a little molecular basket that basically will hold onto that metal.
• 7:24
  John: And think of the metal as a ball bearing.
• 7:26
  John: It goes into the little pocket.
• 7:28
  John: It's, it, it, it, it gets clamped onto, literally chelate means claw, uh, from the Greek, and it basically will hold onto that metal and, and bring it to the tumor.
• 7:39
  John: And then, of course, when it's on the sitting in or on the tumor, the radiation given off by the element will destroy the tumor.
• 7:46
  John: That sometimes it punches holes in the membrane, other times it destroys DNA, and the idea that you have enough of it being delivered into the tumor to cause the tumor to die and then to shrink and then to go away, and that you don't irradiate the rest of the normal organ systems, or the little bit that you do irradiate them is tolerable to the patient, tolerable to the function of the patient.
• 8:07
  John: So that's, that's the essence of the, the, the approach
• 8:12
  David: And Pluvicto, you mentioned prostate cancer before, and I think Pluvicto- Right … is, is for that.
• 8:17
  David: Is that considered a big deal in the industry?
• 8:19
  David: What has that done?
• 8:20
  John: That is, that is an, an enormous deal in the industry, and I think, you know, for, for a couple reasons.
• 8:24
  John: And, uh, I had-- I was involved very early on in development of agents like Pluvicto, and we did the first therapy with our colleagues in Heidelberg many years ago now.
• 8:34
  John: And, um, what, what it, what it did was, I think two- twofold.
• 8:39
  John: One is it really focused on a, a cancer that was a mainstream cancer, and not, not to, to make, uh, light of any other cancer.
• 8:50
  John: But when it comes to a lot of the previous nuclear medicine therapies, they were in sort of niche cancers.
• 8:58
  John: They were in, you know, endocrine, endocrine-based, right?
• 9:00
  John: So nuclear medicine really is on some level from a therapy perspective all started with the treatment of thyroid cancer.
• 9:07
  John: And so, you know, you, you, you hear of iodized salt on your, on your dinner table, and you know, it-- we all need some iodine in, in our diets in order for our thyroid gland to function properly.
• 9:19
  John: And the, and the thyroid is very efficient at finding iodine floating around as a salt in your bloodstream and just sucking it up and then, you know, making hormones for your thyroid to function.
• 9:30
  John: And in the, in the terms of thyroid cancers, they still have that ability to scavenge iodine.
• 9:36
  John: And so it turned out very early on that people that were studying this understood that iodine would be taken up by the normal thyroid, but would also be taken up in huge quantities by thyroid cancers, and that really is the beginning of, of, of thyroid-- uh, of really nuclear medicine therapies.
• 9:52
  John: They all started with thyroid cancers.
• 9:54
  John: But a lot of that, uh, early applications were endocrine-based, you know, uh, um, therapies for neuroblastoma, which is a neuroendocrine tumor in children, for pheochromocytoma, which is a typically affects adults, uh, uh, tumors of the adrenal gland.
• 10:11
  John: And then there were other things that were being looked at at the time for the cortical piece of the adrenal gland.
• 10:17
  John: And then of course the, um, neuroendocrine tumors that affect the gut, such as carcinoid and, and pancreatic neuroendocrine tumors.
• 10:24
  John: And so that whole field was really in this very orphan space until applications hit for prostate cancer.
• 10:32
  John: And then prostate cancer, which is um, the most common ca-cancer in men, right?
• 10:37
  John: And, and similar numbers of women have breast cancer than men have prostate cancer.
• 10:42
  John: These are very interesting stats that anyone can look up on the NCI's websites.
• 10:47
  John: And you'll, you'll see that there's a-- at the time, it was very little therapies.
• 10:51
  John: The first therapies that came out post-castration type therapies, you know, medical castration were the taxanes chemotherapeutics, which were quite, you know, quite nasty.
• 11:01
  John: And, and this was a breakthrough from the point of view of, um It was very specific for prostate cancer, yet very good therapeutic index to go back to the comments I made earlier.
• 11:12
  John: A very high expression of something called prostate specific membrane antigen, not to be confused with PSA, which is prostate specific antigen.
• 11:23
  John: So not very creative names there, but, uh, there is a big difference, right?
• 11:26
  John: And so PSMA sits on the, on the, on the, on the surface of prostate cancer cells, and we have… You know, we know a lot more about what that th- that, that protein is now.
• 11:38
  John: It's really a glutamate carboxypeptidase II, so it's a, it's an enzyme that looks and, and, and, and seeks out glutamate-containing peptide sequences, and it clips off the glutamate, right?
• 11:50
  John: So if you then make a glutamate analog that can't get clipped, the enzyme will grab it, and the PSMA, the drugs like Pluvicto and many other things that have been out in the literature and, and tested, uh, in the clinic, have a glutamate mo- uh, motif on them that is recognized by the enzyme and pulled in.
• 12:11
  John: It turns out that enzyme also gets internalized, and so it, it basically will grab it.
• 12:15
  John: If it can't clip it, it kinda gets stuck in its mitt, and then it gets pulled into the cell, and you internalize a radioisotope.
• 12:22
  John: And so it's a-- it's, it's from a medicine perspective, it was a, you know, the first time there was a, a, I would say, a really robust radiotherapeutic for a very large cancer, and I think it also attracted the medical oncology community.
• 12:38
  John: Prior to that, it was really an endocrine nuclear medicine specialty, and now it became something much more mainstream.
• 12:45
  John: And in fact, if you're ever sitting watching a football game d- during the winter on the, on the weekend TV, you'll hear commercials for Pluvicto all the time.
• 12:54
  John: And, you know, the first time I heard that I was kinda blown away.
• 12:56
  John: Like, you know, we've, we've been doing this now for fifteen years, and now it's finally on mainstream TV being advertised.
• 13:02
  John: Yeah.
• 13:02
  David: You finally mean something to, uh, to your friends and family.
• 13:05
  David: Well, for those in the business audience that have trouble following the science piece, the main thing I, I always, uh, advise clients if they have an indication for prostate cancer to follow it because most of the investors are, you know, middle-aged men.
• 13:16
  David: And, uh, when you start talking about, you know, castration, and of course medical castration, but it does not sound good one way or the other.
• 13:23
  David: So, uh, a, a promising treatment for prostate cancer is, uh, usually will get people's attention.
• 13:28
  John: Yeah, and I think that there's a, there's also a, a I, I would think that, and the audience would, I think, benefit from understanding this, the side effects from that are very mild.
• 13:38
  John: So if, if you, you know, and I've talked… So l- let me go back a minute.
• 13:42
  John: So medical oncologists that are in the prostate cancer space have embraced Pluvicto, right?
• 13:47
  John: They've emblaced- embraced the, the, the targeted radiotherapeutics.
• 13:51
  John: And some of the, some of the, you know, key people then that were in the, in the development program, such as Dr.
• 13:56
  John: Oliver Sartor, um, from, from, uh, Tulane and then Mayo, and, uh, he, he He said to me early on, he goes,"I would have a bl-- uh, if, if I could give this therapy to, to men prior to castration therapy," right?
• 14:11
  John: Medical castration is basically shutting off your hormone, uh, production.
• 14:16
  John: They would be lined up around the block, right?
• 14:18
  John: So of course, you, you don't go too early with these types of therapies.
• 14:22
  John: You start in the later populations.
• 14:24
  John: So now we avoid chemotherapy potentially.
• 14:27
  John: So this is seems to be as good as chemotherapy in, in s- the studies that are coming out, but it has a hell of a lot less side effect profile than, than chemotherapy.
• 14:37
  John: It's not that it's not without some side effects, but they are much more tolerable, uh, than chemotherapy.
• 14:43
  John: They're much less, uh, draining, I would say, and, and, you know, more su- less severe.
• 14:48
  John: And that, that's been shown over and over again with different studies that have been published.
• 14:52
  John: L-
• 14:53
  David: let's, let's talk about the Trillium targeting technology- Sure I had mentioned again in the intro.
• 14:58
  David: And what does that do?
• 15:00
  David: There've been targeting approaches before, but so h- how is Trillium different?
• 15:02
  David: What can it do that others cannot?
• 15:04
  John: So one, one thing that you should, um, and no one would necessarily know this, and even, even maybe people in the field don't know so clearly, is that, you know, the maximal opportunity for treating the cancer is really in the vial that gets delivered to the hospital, of which the contents are gonna be injected into a patient's vein, right?
• 15:26
  John: And so all that radioactivity i- is really the potential of, of, you know, the radiation dose to the tumor.
• 15:32
  John: That's what you want.
• 15:33
  John: You wanna optimize radiation dose to the tumor.
• 15:36
  John: But of course, when you inject something into the bloodstream, lots of things happen.
• 15:39
  John: If people have taken lots of vitamins, they'll see that their urine turns bright yellow sometimes, right?
• 15:44
  John: Fairly quickly.
• 15:46
  John: Things are moving out.
• 15:46
  John: Your, your body doesn't want things that it can't make use of, and it will dive- you know, direct them to different organs to more s- more or less get rid of them, right?
• 15:55
  John: So you have enough of something, the excess gets peed out or you excrete it some other way.
• 16:01
  John: In the case of a, of, of a drug, you, you, you, you have lots of systems in your body that this is a foreign substance, and so we'll go through excretion, we'll go to metabolism, and we'll try to get rid of that.
• 16:12
  John: So of course, there's a fight now, right?
• 16:15
  John: So you have-- you're j- injecting this material and most of the drugs, P- Pluvicto included, Lutathera, Xedera is another drug.
• 16:23
  John: You know, a lot of things get excreted.
• 16:24
  John: A, a big portion of that drug gets excreted in the urine within, within the first forty-eight hours.
• 16:31
  John: So, you know, a lot of that potential goes by the by The other thing that's happening is that your t- tumors are not always highly perfused, so they, they, they're not taking a big percentage of the cardiac output.
• 16:44
  John: So every time your heart beats, a certain percent of their, you know, 10% goes to your brain and 10% goes to the heart muscle itself and other, other, you know, it gets dispersed is according to demand.
• 16:55
  John: And so you, you don't always have the chance if something is getting eliminated very quickly to get that all in front of the tumor to have the tumor suck it up more or less, right, or stick to the tumor.
• 17:07
  John: So Trillium, you know, this came from lots of observational work that we had done in a previous company called Molecular Insight that, you know, we were looking at compounds and trying to understand what we needed to do for an optimal diagnostic for prostate cancer.
• 17:22
  John: And in doing that, we brought several compounds into the clinic under the ex-- IND, um, uh Something called an exploratory IND, where you take more than one compound into a patient, do some very, um, preliminary imaging, uh, ex- ex-, um, scans, and then you can do the same patient again with a, a second compound so that you could make… Instead of having a mouse decide what's the best compound, because a lot of times the, the mice are not telling us everything we need to know.
• 17:53
  John: You could do a, um, a scan in a patient, then re-scan them again with another analog of the same type of compound, and then make your best decision based on the preliminary imaging data.
• 18:04
  John: This is not a therapy study.
• 18:06
  John: And so then you get this information, you say, "Okay, wow, this is a better diagnostic theoretically." And then but this other compound, this actually happened, this other compound became much more attractive from a therapy perspective.
• 18:18
  John: It didn't, it didn't show you what you wanted to see within the first two hours, but by twenty-four hours it was incredible.
• 18:25
  John: And so now we, now we see that the, you know, we, we have the ability to understand that if you change the pharmacokinetics, the PK, the blood curve, and this is what we, we were observing, you could actually get more and more into the tumor.
• 18:40
  John: So Trillium was a… We started playing with this just with very small PSMA molecules in my lab when I was at Cornell Medical College, and we couldn't manipulate the molecule enough as it… when it was too small, because you would change too many parameters at the same time.
• 18:55
  John: The, the tail was wagging the dog.
• 18:58
  John: And so we decided, so let's break this molecule into its component pieces.
• 19:02
  John: We had therefore the, it was a trifunctional compound, and we came up with the word Trillium based on the flower.
• 19:08
  John: And so it was a something that bound to the tumor that was linked to a core hub, and that was then would have a, a payload.
• 19:16
  John: So you, you'd have a chelator, as I mentioned earlier, this molecular basket we put the radioactive compounds in so that we could actually use it as an imaging agent or therapeutic.
• 19:25
  John: And then the third piece to that was something that would reversibly bind albumin, and we could fine-tune the structure of that, so we could generate for the same affinity for tumor and the same payload, we could keep changing the affinity for the blood For, for albumin in particular.
• 19:42
  John: So the blood curve would change, and we can manipulate that so we could try to optimize how much of what got injected into an animal or a human being would wind up in the tumor.
• 19:52
  John: And so we did that for the PSMA, uh, target, uh, targeted molecules.
• 19:57
  John: That became quite obvious that this was the way to go in terms of optimizing what is administered.
• 20:04
  John: And, uh, that's, so the Trillium, the Trillium scaffold itself, the Trillium concept is to have one targeted, a, you know, one, one part of the molecule targeted to the tumor, the other one targeted to another protein, in this case albumin, and then the third piece carrying the warhead or an imaging agent or whatever it might be.
• 20:23
  John: So it's, it turned out to be very efficient.
• 20:26
  John: Uh, that comp- those early compounds eventually got acquired, uh, by Biopharmaceuticals, and now we're in, uh, heading into phase three from what we understand.
• 20:35
  John: We've, we've developed a FAP diagnostic using the same concept where we fine-tuned a PK.
• 20:41
  John: Again, not, not for therapeutic applications, but for imaging applications.
• 20:45
  John: That was licensed to Lantheus.
• 20:47
  John: And we have an, a yet another compound for FAP as a therapeutic, which again is another unique structure, u- again, based on Trillium, and that's in our phase one ATLAS study, which is in soft tissue sarcoma.
• 21:00
  John: So we really, you know, we, the, the, the PK is critical to get right because it enhances tumor uptake.
• 21:07
  John: That enhanced tumor uptake, if you have good clearance from normal tissue, gives you that therapeutic index, and you wanna drive that therapeutic index as, as high as you can, that, that ratio of dose to-
• 21:19
  David: So that's Trillium, which I think I have more got that.
• 21:21
  David: Yeah.
• 21:21
  David: Now, now let's switch a little bit and tell me about alpha emitters, beta emitters, and here how MacroPa fits in.
• 21:28
  David: Yeah, sure.
• 21:28
  David: I, I hesi- I hesitate to ask, but, uh, I think that's the other key platform, uh, or technology that you use.
• 21:35
  John: Yeah.
• 21:35
  John: So, you know, again, the molecular basket's important, right?
• 21:38
  John: So since most of the metals are, most of the isotopes are metals.
• 21:42
  John: And some of the, uh… So, so y- y- think about this, the, the molecule has to carry some cargo to the tumor.
• 21:49
  John: That cargo is a radioisotope If you pick the wrong chelator, that metal can come out, and so basically you're losing, you know, y- as I mentioned earlier, the c- the molecule could get excreted.
• 22:01
  John: That's one way to lose it.
• 22:02
  John: But if your mole- if your molecule is losing the isotope, then you're, you really don't have a good molecule at all because during that process, you're not gonna direct that, that radiation to the tumor.
• 22:11
  John: It's gonna go elsewhere and could be deleterious.
• 22:14
  John: So you want to make sure that you pick a chelator that's good for the metal that you pick.
• 22:18
  John: Now, actinium, uh, is a very large metal, and it is an alpha emitter, so two things that are, uh, quite unique about it.
• 22:26
  John: Um, it has a 10-day half-life, and you know, alphas l- it just gives off many alpha particles.
• 22:33
  John: And so you have, you have this problem of I want to make sure that I can do a labeling of a molecule, uh, efficiently, quickly, efficiently, because I, I want to make sure that I don't have to… First of all, if I have to heat the molecule in the presence of radioactive material, uh, for, for ex- extended period of time, the radiation and the heat are going to do things to the molecule I don't want to happen, right?
• 22:57
  John: They will, they will start to decompose the molecule.
• 23:00
  John: And so ac- actinium being a very, I'd say a very attractive therapeutic, right?
• 23:05
  John: So alpha particles are basically helium nuclei.
• 23:08
  John: They're, they're two, two neutrons, two protons.
• 23:11
  John: They carry a tremendous amount of energy.
• 23:13
  John: They're so big they don't go very far, so they're very short, what's known as a path length, and very high LET, which is linear energy transfer.
• 23:21
  John: So they drop a lot of energy in a very short period of time, which makes them very lethal to cells.
• 23:27
  John: Beta particles, on the other hand, are electrons, and so while they can still i- ionize bonds and break bonds as they traverse, they, they, they're a lot weaker, and they go a lot farther away.
• 23:37
  John: So they have a lower LET So let's go back to the chelate.
• 23:42
  John: So if you have the ability to label a molecule with actinium very quickly and under neutral conditions, like very favorable biological conditions, you can label a lot of different molecules without it-- with taking, at least taking away the need to heat it and the need to, uh, leave it for, you know, half hour in a reaction.
• 24:03
  John: So if you can do this in five minutes or 10 minutes at neutral pH at room temperature, that takes away some of the potential of the damage that you may cause while you're doing the actual reaction to make the drug.
• 24:15
  John: And so actinium becomes, you know, very attractive, but with the right setup, and the right setup being the right chelator.
• 24:21
  John: Turns out that me- macroppa is a extraordinarily specific chelator for actinium.
• 24:28
  John: It will bind actinium almost you r-really can't get it out of the chelator unless you've used super harsh conditions.
• 24:35
  John: It will get in there within five minutes quantitatively at room temperature, neutral pH, and that will stay on the molecule for, you know… If you put it on the shelf in a, in a, in a solution and just tested it, it will stay on that molecule for a very long, longer than you'll want to assay it.
• 24:52
  John: So, you know, we're talking about days if we're not weeks.
• 24:55
  John: And then in vivo, it's not gonna come out of the chelator either, so you don't, you don't lose it to, you know, you know, sort of things falling out of the back of a dump truck on a way down the highway.
• 25:06
  John: You know, it, it's not gonna go elsewhere.
• 25:08
  John: It's gonna go where the molecule takes it.
• 25:10
  John: So it's, it's a very useful isotope-- uh, chelator for that specific isotope actinium, and that we like it a lot.
• 25:18
  David: So there's a lot of scientific complexity to this field, but there's also a lot in terms of just the overall, uh, logistics and manufacturing and pulling everything together.
• 25:28
  David: I mean, starting with actinium, my understanding is that supply constraint of actinium is a big deal in the industry.
• 25:34
  David: Is that right?
• 25:35
  David: I mean, you described how great it is, but can you get it?
• 25:38
  John: So we can get it, and I think, you know, this is a, a problem that's being solved in real time by some big players.
• 25:45
  John: Um, there are… You know, if we went back five years ago, I would say the, the issue is in process to be… You know, there's a lot of people talking about solving the problem.
• 25:55
  John: I think right now we're very, we're very bullish on the groups that have entered the field to actually solve the problem of actinium availability.
• 26:06
  John: You know, the-- Ten years ago, it was lutetium availability, and now that's been solved, and people have walked into the, into that marketplace and with significant in-advancements technologically and, and, and even on scale, right?
• 26:21
  John: So it's, it's one thing to have technology, another thing to scale it properly.
• 26:25
  John: And so we have several, I would say several, uh, groups, uh, that have- Basically, it, um, I guess mitigated the need for the Department of Energy in the United States to be the supplier.
• 26:38
  John: They used to be the sole supplier.
• 26:40
  John: And now we have TerraPower, which is-- TerraPower Isotopes, which is a division of TerraPower, uh, out in, uh, the Northwest.
• 26:47
  John: Uh, they have huge resources, uh, to, to bear on this and are expanding.
• 26:53
  John: There's a company called Panterra in, in Europe that's also has-- heavily involved.
• 26:59
  John: Uh, Niawave, uh, which is again in, in, in the United States.
• 27:04
  John: People have different ways of making the isotope, but they have basically scaled it now.
• 27:09
  John: And I think when, you know, five years ago everyone's scratching their head how we're gonna get enough actinium.
• 27:13
  John: I think right now we, we see the, we see the path to that.
• 27:16
  John: NuSano is another company which is adjacent to our facility at, in Salt Lake City.
• 27:22
  John: They're gonna be coming online fairly s-shortly with a linear accelerator approach, and I think they're gonna have another way of, uh, making, uh, high, high amounts of actinium.
• 27:33
  John: So I think, I think that solution is in process, and I think the actinium availability won't be an issue to be talked about at any, at any length, you know, three, four, five years from now.
• 27:45
  John: Right now I think there's enough to run all our clinical trials that people have, have lined up.
• 27:50
  John: I think that's where we're at in this, in this regard.
• 27:53
  John: I think people are making big bets and big pharmas, you know, putting down money to have access.
• 27:59
  John: And then when they-- and they want-- when they put money down to have access, they want access for their approval, not just for their trials.
• 28:05
  John: And so people are shooting way ahead of the duck, I think, when it comes to getting the infrastructure together.
• 28:10
  John: So I'm very bullish that we're gonna have more than enough actinium supply in this space
• 28:15
  David: Great.
• 28:16
  David: So you mentioned big pharma, and you also mentioned how, uh, you know, Pluvicto anyway is coming to, uh, you know, any given Sunday.
• 28:22
  David: You can see it on the screen in the NFL.
• 28:24
  David: So how do-- I mean, I've heard about, you know, Novartis, BMS, Lilly, maybe others who are, who are getting into this space.
• 28:30
  David: What, um, what does that mean for the industry, and what does it mean for, for you?
• 28:34
  David: Is it a positive or is it a, or is it a negative, or it doesn't matter?
• 28:37
  David: I
• 28:37
  John: think it's a huge positive.
• 28:38
  John: Uh, you know, to go back to our earlier conversations about the, um, let's say the ma-maturation of the field, right?
• 28:47
  John: Coming out of that endocrine sort of niche orphan market to s- large market opportunities where you have very good comparisons in, a-against, say, the chemotherapy standard of care.
• 29:01
  John: Um, you then have the opportunity to think about radiotherapeutics for other diseases beyond prostate cancer.
• 29:07
  John: Now we need, we need to go back to the targets then, right?
• 29:10
  John: We say, "Okay, what's a good target? What, what's the, what's the clinical need right now?" Right?
• 29:14
  John: Where, where, where could we benefit by having a radioligand therapy?
• 29:18
  John: Um, you know, is it pancreatic cancer?
• 29:20
  John: Is it head and neck cancer?
• 29:22
  John: Is it colorectal cancer?
• 29:24
  John: You know, you, you can go down a list of, of, of, of needs.
• 29:27
  John: Uh, breast cancer.
• 29:30
  John: You really have to now find where the clinical need is, and then you have to find what are the targets that you would pursue for radioligand therapy.
• 29:40
  John: And you could take a page out of the ADC book, right?
• 29:42
  John: The antibody drug conjugate book.
• 29:44
  John: What are they going after?
• 29:45
  John: You know, you, you saw the Enhertu, the success of Enhertu, which a Hertu drug antibody drug conjugate.
• 29:51
  John: Uh, there's lots of other work going on in the space with ADCs.
• 29:55
  John: Those targets are, I would say, available to the RLT world, right?
• 30:01
  John: You just have to figure out how do you make an, you know… We, we don't like antibodies for RLT for solid tumors because of the, the, the time it takes for them to penetrate and circulate, so on and so forth.
• 30:13
  John: You, you, you're running against the clock while you're irradiating the blood and doing other things.
• 30:18
  John: So we-- Another reason we like Trillium is that we can manipulate the PK.
• 30:22
  John: We're not making it into a protein, but we can get it beyond, you know, minutes in, in s- in circulation to hours, but not days, right?
• 30:31
  John: We don't wanna, you know… If you have too much albumin binding, you basically have an albumin construct.
• 30:36
  John: We don't want that.
• 30:36
  John: We want something in the middle.
• 30:38
  John: We want this sort of Goldilocks PK that we can get maximal uptake in the tumor without irradiating, say, the bone marrow, which is a typical, um, fallout from, from, you know, persistence in the blood for too long
• 30:53
  David: So as we wrap things up, I, I wanna ask you to look ahead.
• 30:56
  David: You, you could pick your timeframe, maybe 10 years or, or something like that.
• 30:59
  David: You started off talking about, you know, the three main things people do are s- you know, surgery, chemo, external beam radiation.
• 31:06
  David: Now, depending on who I'm talking to, sometimes people say, well, the fourth one is immunotherapy, you kind of put that in with chemotherapy.
• 31:12
  David: Now we're talking about, uh, radiopharmaceuticals.
• 31:15
  David: What do things look like in a decade?
• 31:17
  David: What's the relative role of these different pieces?
• 31:20
  David: How does radiopharmaceuticals in particular change, uh, the overall equation?
• 31:24
  John: Yeah, so I-- So that's a great question, right?
• 31:26
  John: And so I'll, I'll, I'll take, uh, let's say, artistic license here.
• 31:30
  John: Um, I, I see the field… First of all, I think everything I've mentioned about the therapeutic index, you know, we're just starting to understand the limitations and what we need to do to make these drugs safer and more effective, right?
• 31:43
  John: We, we, we see benefits, but we'd love to improve upon those benefits, right?
• 31:47
  John: You like to drive towards a cure, and right now there are very few cures in the world for, you know, um, cancers that have spread.
• 31:56
  John: And so if, if you think about it that way, I think we can have the ability to have a improve the therapeutic index, and that, that allows you to do a couple of things, right?
• 32:04
  John: You can use the drug more frequently.
• 32:06
  John: We, we talked about the lack of side effects, so you have a better quality of life while you're extending life, and that's a big, that's a big, you know, philosophy of ours.
• 32:14
  John: We want to extend life with quality.
• 32:17
  John: So, you know, if I can give you eight more months, I'd like to give you eight more months where you can go out and run around with your kids or, you know, take a trip you wanted to go on or at least be functional and not be, you know, housebound and, or bedbound.
• 32:28
  John: I think the other thing is you're gonna see the combination of radioligand therapies with other therapies.
• 32:34
  John: And I think when we s- we think about… You know, there's one thing that we're very excited about.
• 32:39
  John: Our FAP therapeutic, while we're in sarcoma now, where FAP is on the sarcoma cancer cells as well as the stromal piece FAP is also on, in the stroma of many other cancers, such as breast cancer, such as non-small cell lung cancer, pancreatic cancer.
• 32:55
  John: And the stroma is a bad actor.
• 32:56
  John: It basically clogs up the system for drugs to get access to it, and it also gives off biochemical messaging that basically stops the immune system from recognizing what's going on in this gemish.
• 33:09
  John: And so we believe that the opportunity, the one big opportunity here is modulate the stroma while you bring in orthogonal therapies, whether that's immune checkpoint, whether that's chemotherapy.
• 33:21
  John: There's some nice data, you know, that's being generated now in preclinical models and clinical, uh, ex- trials where priming the ther- you know, priming with a radioligand therapy might be very beneficial to other therapies coming in, whether they're immune checkpoint or chemotherapy.
• 33:36
  John: So I think we're gonna see combinations, and I think we're gonna see, you know, the other point about what does it look like, I think to be, they will, there will be private therapeutic clinics, uh, in the community, which, you know, it started off as hospital-based therapies.
• 33:50
  John: I think it's gonna wind up in, you know, there'll be community theranostics or nuclear medicine specialties that'll, you know, this will not be, um, you know, only the big medical centers have it.
• 34:02
  John: This will be in the community, and it'll be, uh, something that people will seek out because of the, the, the lack of side effects and the extension of life.
• 34:11
  John: So I think this is where we're heading.
• 34:13
  David: Well, by that time, maybe you'll be, uh, I don't wanna comment on your career plans, but maybe you go back to community pharmacy and offer a radioligand, uh, right there.
• 34:22
  David: In any case, that's it for another episode of the Health Biz Podcast.
• 34:25
  David: I'm David Williams, president of Health Business Group.
• 34:27
  David: My guest today has been John Babich.
• 34:29
  David: He's president and chief scientific officer of Ratio Therapeutics.
• 34:33
  David: If you like what you heard, please subscribe on your favorite podcast platform.
• 34:37
  David: And thank you, John.
• 34:39
  John: Thank you, David.
• 34:39
  John: It's a pleasure.
• 34:40
  John: Have a good day