409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles

1. 0:00 – 0:11

   Intro

   1. PAPeter Attia0:00

      [upbeat music] Hey everyone. Welcome to "The Drive" podcast. I'm your host, Peter Attia. [upbeat music]

2. 0:11 – 9:21

   Lloyd’s path from academic medicine to translational drug development

   1. PAPeter Attia0:11

      Lloyd, thanks so much for coming out to Austin. Great to see you again in person. It's been, uh, probably six, seven, maybe eight years since we were last in person.

   2. LKLloyd B. Klickstein0:19

      It might well be that long, yes.

   3. PAPeter Attia0:21

      Yeah. So, um, look, for, for folks who don't know you, um, as, as well as, as some of us do, um, tell us just a little bit about your background. Uh, you're a physician and a scientist, but talk a little bit about how those two paths came together.

   4. LKLloyd B. Klickstein0:38

      Right. Uh, so my original plan when I finished college was to go to medical school, following is basically the family business. And, um, but between college and medical school, I worked in a laboratory at Brigham and Women's Hospital in Boston and, uh, found two things: one, that I loved doing science, and two, that I was pretty good at it. And I ended up doing an MD-PhD degree, um, and that is the training, not required, but helpful for becoming a physician-scientist. And, uh, from there, I did medicine training. I was, uh, rheumatology training, and I practiced rheumatology for maybe 10 years and, uh, also had an NIH-funded research lab doing very basic science on, um, adhesion molecules in the immune system.

   5. PAPeter Attia1:34

      And that was also at the Brigham? Did you stay there after you finished your training?

   6. LKLloyd B. Klickstein1:37

      I pretty much-- I have a high activation energy for moving and doing other things.

   7. PAPeter Attia1:41

      Okay.

   8. LKLloyd B. Klickstein1:41

      And, uh, so I stayed there the, my whole academic career.

   9. PAPeter Attia1:45

      Yeah, that's right. Medical school, MD, PhD, the whole thing.

   10. LKLloyd B. Klickstein1:47

       It's the only job I ever had, uh, until I left and went to industry-

   11. PAPeter Attia1:52

       Yep

   12. LKLloyd B. Klickstein1:52

       ... which was a little over 20 years ago. And I went to Novartis Institutes, uh, which was founded by Mark Fishman when he was recruited by the then CEO of Novartis, Dan Vasella, to, uh, reimagine how research and early clinical development are done in industry. And they basically brought the whole concept of translational medicine to industry. Now, that term I think was coined at Oxford, somewhere in the UK-

   13. PAPeter Attia2:23

       Mm-hmm

   14. LKLloyd B. Klickstein2:23

       ... for sure. And, um, this was the first industry manifestation of it.

   15. PAPeter Attia2:30

       So Lloyd, there are a lot of specific drugs and indications, pathways, and targets that I want to talk about today. But I think before I go there, there is a, there's a black box that exists that is the world you occupy that I really think is, i-is just, it's unknown by the public, but I think it would be very, um, insightful if people understood it, and it is the process by which a drug is discovered. Um, the first person who I ever, uh, read articulating this was Steve Rosenberg-

   16. LKLloyd B. Klickstein3:03

       Mm-hmm

   17. PAPeter Attia3:03

       ... wrote one of my favorite books about science called "The Transformed Cell." This book is, uh, over 30 years old. I probably read it cover to cover, uh, 10 times during the course of my life. But he starts with a question, which was, hey, he's at a party one day and someone says, "Hey, how do you discover new drugs for cancer? Do you just go into the kitchen sink and kind of grab things and experiment?" So, so again, it's, it's a, a, a very intelligent person can still have an enormous blind spot to what it is people like you do.

   18. LKLloyd B. Klickstein3:32

       Mm-hmm.

   19. PAPeter Attia3:32

       So take that in any way you want, but I think it might be a great foundation.

   20. LKLloyd B. Klickstein3:36

       Let, let's start from a very broad area of medicine, not just focus on cancer, 'cause cancer is a special case of a more general, um, concept. Um, so I personally, and this may be different for different people, but I personally start with the patients and the clinical indications. And essentially you're looking for what's not there. So you're looking for, um, a drug that doesn't exist or a therapy that doesn't exist but is needed. Um, and my... And, and then there are two broad categories. There are incremental improvements, and then there are quantum steps in the concept of drug discovery. Incremental improvements are, are making a drug that you have to take less frequently, or as we've seen a lot in the press recently, an oral drug instead of an injectable drug, uh, or the same kind of drug but works better, and there have been great examples of that. Think atorvastatin and rosuvastatin in Amevacor's Zocor world. Um, s- and, and those have been enormous commercial successes, and there's a strong bias throughout the drug development infrastructure to, to do those kinds of things because they're relatively low risk, and there's not so much uncertainty. On the other hand, to see indications that may not even have been described yet and don't have ICD 10 or 11 codes and, um, have to deal with the whole complexity of create, of making physicians and patients and payers and everybody else aware of this and then creating a regulatory path for it, it's, it's a heavier lift. Uh, but I think that's where the biggest value comes to society and individuals and patients in, in creating new therapies, and that's, that's kind of what I do. And it, there's a lot of failure involved in there. And the things that we can talk about are, um, how do you get a new regulatory pathway established? Um, we've, uh, been part of that once, um, soup to nuts. And, um, and, and then how do you sort of create new indications? That's also a, a, a challenge. Maybe it would be informative to think about how, uh, uh, my team and I started something called the New Indication Discovery Unit at Novartis. So Mark Fishman, who was the president of Novartis Research at the time, um, had a few of us come into his office and said, "We need to make the most needed medicines and, um, find out what we're not doing that we should be doing and get it started." And, and we had a budget for that, so super. Um, a- as I mentioned, I start with patients and indications and medical need. So starting there, uh, we made a list of about 7,000 clinical indications that were unmet. All clinical indications. We just made a list of all the clinical indications.

   21. PAPeter Attia6:55

       Oh, I see. Okay.

   22. LKLloyd B. Klickstein6:56

       And, um, it didn't have everything there. It only had the ones that people had recognized at the time. But, um, it gave us a framework in which we could start thinking, and then, uh, it sounds like a lot, but surprisingly it isn't. It's maybe 10 or 20 pages of, of paper at the time [laughs] . And we, um, we, we grouped them into things that we were already working on, things that were rare genetic developmental things that would be difficult to, uh, approach, and, and the remainder fell into maybe seven or eight different buckets, and then we started working on those. One of them was healthy aging, and one of them was ENT, and one of them at the time was renal diseases, and we should talk about that some more because that's the regulatory endpoint. Um, Novartis wasn't at the time working on liver diseases. One of them was those, uh, sort of fibrotic diseases in general. Um, and, uh, and, and there were some others. But, and, and we started our program, and it eventually grew to have dozens of projects and, uh, became a bit of a monster, and then we had to sort of whittle it down a little. Um, but some really interesting studies came out of that. Um, one of them, which I know we're gonna get to later, is, uh, bimagrumab for muscle diseases, and, uh, we c- there's a long story there. But, but again, it came out of a medical need of frail elderly people, um, and, and I was very mindful. As a rheumatologist, I saw some of these people. Um, if you h- at the time, I'm not-- I haven't looked at the data recently, but at the time, if a patient had to go to a nursing home, not wanted to go or whatever, but had to go, uh, the three-year mortality rate approached 90%.

   23. PAPeter Attia8:57

       Mm.

   24. LKLloyd B. Klickstein8:57

       So being a frail elderly person who has to go to a nursing home was worse than most cancers.

   25. PAPeter Attia9:02

       Worse than cancer, yep.

   26. LKLloyd B. Klickstein9:04

       And there are a lot of serious diseases in medicine that are worse than cancer in terms of clinical outcomes, but we don't treat them the same way, and, and I think we should. But so we, we really embraced the concept of being a frail elderly person and what could we do to, number one, treat it, but then prevent it down the

3. 9:21 – 22:08

   Drug modalities, patents, and the economics of innovation

   1. LKLloyd B. Klickstein9:21

      road.

   2. PAPeter Attia9:22

      I, I didn't know it was that-- I didn't know the three-year mortality for frailty in that specific indication-

   3. LKLloyd B. Klickstein9:27

      Yeah

   4. PAPeter Attia9:27

      ... uh, was so high, but that's a staggering statistic.

   5. LKLloyd B. Klickstein9:29

      It was terrible. I, I, again, it might be a little better now, but it's not good.

   6. PAPeter Attia9:34

      Yeah. Um, okay, so let's now talk about that next leap. So let's assume you or the scientists and the team have decided we have an indication. We-- there's, there's a target we wanna go for, um, an unmet clinical need, and there's not an incremental opportunity, right? The example you gave is a great one.

   7. LKLloyd B. Klickstein9:53

      Mm.

   8. PAPeter Attia9:53

      I have six statins already. I'm gonna come up with the seventh.

   9. LKLloyd B. Klickstein9:57

      Mm-hmm.

   10. PAPeter Attia9:57

       That's-- let's put, take that one off the table. Um, how do you begin the thinking around what we're gonna do? And, and maybe, by the way, for the listener, can you explain some of the different classes of molecules? I also think we talk very quickly and casually about monoclonal antibodies, small molecules, biologics, but I, I think that that nomenclature might not be clear to everybody-

   11. LKLloyd B. Klickstein10:24

       Mm-hmm

   12. PAPeter Attia10:24

       ... and, and maybe provide a little bit of that as well.

   13. LKLloyd B. Klickstein10:26

       Sure. So, so let's start with what we call small molecules, which is industry jargon. It basically means a chemical. It, historically, uh, the companies that became our biggest drug companies started over 100 years ago as dye companies because the, the chemistry is very similar for making a dye as for making a drug. Um, so these are just chemicals. Um, the other class are biologicals, which is pretty much everything that's not a chemical. And within that broader group of biologicals, a- and actually there's a third group, w- let's say devices. Um, so for biologicals, that could be an antibody. It could be some other protein like a peptide or a soluble receptor. Um, and I, I think we're now creating a separate category of gene therapies, uh, which themselves can be complex based on how they're delivered or targeted. Um, and then let's talk about devices 'cause that's a completely different, uh, animal, and it's regulated by its own group called CDRH at, uh, in the FDA. And that could include things like, um, a gadget you make in a workshop. It could be an app It could be, uh, uh, something simple like a syringe that you use to inject a drug or an auto-injector, which are very common nowadays, um, or some combination of those things.

   14. PAPeter Attia12:18

       And include all the way up to implantable?

   15. LKLloyd B. Klickstein12:21

       Yes, absolutely.

   16. PAPeter Attia12:23

       We don't have to go into it, but are there differences in the IP treatment of small molecules and biologics? Are there longer patent lives or anything like that?

   17. LKLloyd B. Klickstein12:31

       Patent law, I think, is the same for anything, but there are other regulatory, uh, con- uh, conditions that apply to one kind of treatment or another. For example, there are different exclusivity periods for s- a small molecule versus a biologic. Um, a- and they change periodically. So, um, and, and all of this is something that's considered as you're working on how do you protect the drug you're making. This is a really important point, and it's very topical now with the concern about expensive new drugs and how do we make them available for people. And, uh, I, I don't think it's well understood or adequately understood, um, how patent law works about drugs. May- maybe we could take a few minutes and talk about that.

   18. PAPeter Attia13:27

       Sure.

   19. LKLloyd B. Klickstein13:28

       Um, I'm gonna preface my remarks by saying I'm not a lawyer, I don't play one on TV, and I wouldn't if I were asked to. But-

   20. PAPeter Attia13:38

       But you've been to the rodeo many-

   21. LKLloyd B. Klickstein13:39

       But [laughs]

   22. PAPeter Attia13:39

       ... many times.

   23. LKLloyd B. Klickstein13:40

       [laughs] Yes. Uh, I was the clown.

   24. PAPeter Attia13:43

       [laughs]

   25. LKLloyd B. Klickstein13:44

       Um, so the way this works is if you think about at a very high level, making a new, uh, drug that's used by many people takes longer, is more expensive, and takes as many people as building the biggest skyscraper in the world. Think, you know, that, the, the Burj Khalifa.

   26. PAPeter Attia14:12

       Yep.

   27. LKLloyd B. Klickstein14:14

       Um, just think about that for a minute. That's thousands of people, many years, more than a billion dollars. And unlike a building which can ultimately pay for itself and pay all the bond holders and provide a return to the investors over decades, patent law gives a very limited term in which all of the investment and potential profit can be recovered. And at the end of the drug's patent life, it is freely available for anybody to make for the rest of eternity. That's the deal you make with getting a patent. A patent is essentially a monopoly on being able to make, use, and sell the drug, uh, in exchange for telling everybody how to do it. That's, that's basically what a patent is. Now, the term of the patent from the time you file it is 20 years, and there are a few little things about extending it for a small further period based on how much time it took to work on it. Um, practically, you get 10 to 15 years of exclusivity from the time it can be launched.

   28. PAPeter Attia15:31

       So a couple points I'll add just for-

   29. LKLloyd B. Klickstein15:32

       Mm

   30. PAPeter Attia15:33

       ... you to expand on if you ch- if you like.
4. 22:08 – 36:54

   Choosing sarcopenia as a target for drug development, and confronting the problem of measuring falls

   1. PAPeter Attia22:08

      So then how do you begin the screening process? How do you begin to identify molecules? And, um, again, I think we should assume that our listeners, um, who are otherwise well-informed won't know the details of what an IND is.

   2. LKLloyd B. Klickstein22:22

      Mm-hmm.

   3. PAPeter Attia22:23

      What we use Phase I, II, III, IV, and what has to happen prior to the IND. Like, let's just start from the very beginning.

   4. LKLloyd B. Klickstein22:29

      Right. So, um, with the, with the preamble that this, this would be about a year-long course.

   5. PAPeter Attia22:37

      Yes, if we did this as a seminar at Harvard-

   6. LKLloyd B. Klickstein22:39

      Yes [laughs]

   7. PAPeter Attia22:39

      ... this would take you a year, yeah.

   8. LKLloyd B. Klickstein22:41

      Um, but, but to cover it at a high level, um, starting from the idea and the medical indication, and it might be useful to think about, um, one specific example, and we can... Let's, let's think about muscle weakness and which can be described as sarcopenia or, um, th- and the definition of that is still evolving, frankly. Um, I, I've gone to some of these s- uh, specialty meetings like the Cachexia Consensus Conference when it's a topic of discussion every year. Um, but I think one, w- we seem to be converging on the concept of, uh, decreased muscle mass with impaired muscle function as, as a good definition of sarcopenia, and, and whether the function is grip strength or gait speed or stair climb or, uh, people use different ones. Um, okay, so we'll, we'll talk about that as a specific indication. So, um, impaired muscle function with low muscle volume.

   9. PAPeter Attia23:47

      Which to your point, by the way, nobody listening to this doesn't care about this.

   10. LKLloyd B. Klickstein23:51

       [laughs]

   11. PAPeter Attia23:51

       So this is, this is a very topical consideration.

   12. LKLloyd B. Klickstein23:53

       Yeah. Yeah.

   13. PAPeter Attia23:53

       It's not esoteric.

   14. LKLloyd B. Klickstein23:54

       It's something I've, I've personally been working on for 20 years, as you know. Um, so what should be the drug format? Well, the patient population are likely to be older adults, so we need to be-- it needs to be a drug format that'll be suitable to them. And shouldn't underestimate the importance of this. It's what's most likely to work. 'Cause in a, in a drug development program, especially with a new target and a new indication, there are so many unknowns, and all of the risks multiply across a drug development program. So if you have, if you have, say, 20 risks you're taking in a drug development program, whether it's target and format and bioavailability, which-

   15. PAPeter Attia24:38

       Toxicity.

   16. LKLloyd B. Klickstein24:39

       Tox-

   17. PAPeter Attia24:39

       The whole thing

   18. LKLloyd B. Klickstein24:39

       ... everything, and you mu- and all of them have, have maybe a 90% chance of success, you multiply all that out 10 or 20 times, it's zero.

   19. PAPeter Attia24:47

       That's, it's a huge failure.

   20. LKLloyd B. Klickstein24:48

       Yes.

   21. PAPeter Attia24:49

       Yeah, yeah.

   22. LKLloyd B. Klickstein24:49

       So, so you have to minimize risks at every step other than the ones that you sort of identify and accept, and this is the big question that, that, that we don't know and we have to answer early. Um, so we want-

   23. PAPeter Attia25:05

       And you wanna fail fast.

   24. LKLloyd B. Klickstein25:07

       If you can.

   25. PAPeter Attia25:08

       Yes.

   26. LKLloyd B. Klickstein25:08

       Yeah, absolutely. The, the, the worst outcome in drug development is failing in phase three.

   27. PAPeter Attia25:14

       Ugh, yeah.

   28. LKLloyd B. Klickstein25:15

       Actually, that's probably not true. The worst outcome is succeeding in phase three and failing commercially. Failing early, super important.

   29. PAPeter Attia25:21

       Now let me just ask a question about this specific indication.

   30. LKLloyd B. Klickstein25:25

       Mm-hmm.
5. 36:54 – 44:47

   The rationale for bimagrumab: improving muscle mass and strength by targeting myostatin and activin signaling (and why follistatin failed)

   1. LKLloyd B. Klickstein36:55

      this, this kinda brings us to sarcopenia and muscle mass and strength, which was the, uh, genesis of bimagrumab, um, and, uh, activin receptor antagonists in general. Um, now we knew at the time about myostatin. So Se-Jin Lee is sort of the father of myostatin. He discovered the biology. Um, and in rodents, myostatin is, you know, kind of amazing. You can, you can turn a mouse into an Arnold Schwarzenegger mouse by, by blocking myostatin.

   2. PAPeter Attia37:34

      This was in the mid-'90s, right?

   3. LKLloyd B. Klickstein37:37

      Oh, I think so, yeah.

   4. PAPeter Attia37:39

      Yeah. I mean, I rem- this was-

   5. LKLloyd B. Klickstein37:40

      Yeah

   6. PAPeter Attia37:40

      ... when I was in medical school, I remember in-

   7. LKLloyd B. Klickstein37:43

      Hmm

   8. PAPeter Attia37:43

      ... '97 seeing the images of the mice, the chickens, the-

   9. LKLloyd B. Klickstein37:48

      Dogs, cattle

   10. PAPeter Attia37:49

       ... the cows.

   11. LKLloyd B. Klickstein37:49

       Yeah.

   12. PAPeter Attia37:49

       I mean, we, we couldn't get enough of these myostatin knockout animals. We thought it was the greatest thing we'd ever seen as students.

   13. LKLloyd B. Klickstein37:57

       There were no people who had that, though.

   14. PAPeter Attia37:58

       No.

   15. LKLloyd B. Klickstein38:00

       So, so at the time, um, the, the, the, the people who led the discovery project, so this is the laboratory research, were... So Chris Liu and his team and, uh, David Glass and his team. Um, and, and, and that's where the, the original code of bimagrumab was BYM three three eight, and that's where, that's where the VAT came from. Um, I was part of that team on the clinical side, um, and if they made the drug, how would we test it?

   16. PAPeter Attia38:38

       I sort of interrupted you, but do you wanna explain how myostatin inhibition would lead to enormous muscles?

   17. LKLloyd B. Klickstein38:47

       Yes. So the, the broader question is what governs the size of your muscles? Um, and we know it's nutrition, and we know it's, uh, use, and then there are biochemical things that regulate it. And, um, myostatin is an inhibitor of muscle growth. So if you blo- so if you inhibit the inhibitor or block myostatin, muscles get larger up to another point where there's something that regulates them, and we don't know what that is. Um, and that's ge- and that's most of the inhibitory effect biochemically in animal species. In humans, it turns out that it's more complex. It's myostatin plus activins, mostly activin A. Um, and this is the advantage of inhibiting myostatin and activin A together or blocking the receptor, which is what bimagrumab does. So w-

   18. PAPeter Attia39:55

       What was the evolutionary re- I mean, I'm asking you as though you were there during the design phase, but, uh [chuckles]

   19. LKLloyd B. Klickstein39:59

       [laughs]

   20. PAPeter Attia40:00

       What, what is your best guess for what the evolutionary reason was to limit muscle growth? Was it simply a nutrient management system, which was like, "Hey, we grew up in a nutrient, uh, s- sparse environment. We can't-"

   21. LKLloyd B. Klickstein40:12

       Yeah

   22. PAPeter Attia40:12

       ... "just have muscles demanding all of this protein"?

   23. LKLloyd B. Klickstein40:15

       I, I would, I would have to guess that based on everything else about people, there were times during our evolution when resources were very scarce, and we had to conserve.

   24. PAPeter Attia40:25

       Yeah.

   25. LKLloyd B. Klickstein40:26

       But, but I don't know. Your guess is as good as mine.

   26. PAPeter Attia40:28

       But it is interesting because-

   27. LKLloyd B. Klickstein40:29

       Hmm

   28. PAPeter Attia40:29

       ... uh, the other way that nature could have solved that problem was just to make it completely, uh, supply limited and just say-

   29. LKLloyd B. Klickstein40:38

       Could be.

   30. PAPeter Attia40:38

       Yeah. But anyway, okay. So we don't really have a great teleologic reason.
6. 44:47 – 56:07

   Engineering and screening the bimagrumab antibody, and the cost of developing a new drug

   1. PAPeter Attia44:47

      Can you tell people... I, I... That's a good point. Can you tell people why an Fc fusion pro... I mean, I think we have to talk about some of this technical stuff, unfortunately. I was-

   2. LKLloyd B. Klickstein44:53

      Okay.

   3. PAPeter Attia44:54

      I almost caught myself as I was asking the question, but, but e-explain what an Fc fusion protein is and why that might be able to, like, keep it in place longer.

   4. LKLloyd B. Klickstein45:01

      Sure. You can, you can edit this out later if it gets too technical. I'll try to make it, uh... I'll try to speak in s- in plain English.

   5. PAPeter Attia45:07

      Well, yeah. Just think about it-

   6. LKLloyd B. Klickstein45:08

      Yeah

   7. PAPeter Attia45:08

      ... through the lens of, like, how-

   8. LKLloyd B. Klickstein45:10

      Yeah

   9. PAPeter Attia45:10

      ... you manipulate drugs. Like I think of this-

   10. LKLloyd B. Klickstein45:12

       Yeah

   11. PAPeter Attia45:12

       ... as part of the story.

   12. LKLloyd B. Klickstein45:13

       If I remember correctly, the technology that we use now for Fc fusion proteins was originally developed by Brian Seed at the Mass General. And the very first drug that used it was Enbrel-

   13. PAPeter Attia45:27

       Hmm

   14. LKLloyd B. Klickstein45:27

       ... which is etanercept. It's, um... Which is itself a really interesting story because T... This is a TNF inhibitor that's now approved in rheumatoid arthritis and psoriasis and some other things, but it was first tested in sepsis.

   15. PAPeter Attia45:43

       Oh, I didn't know that.

   16. LKLloyd B. Klickstein45:44

       Um, and it made people worse.

   17. PAPeter Attia45:47

       Hmm.

   18. LKLloyd B. Klickstein45:47

       Well, because I think physicians and scientists at the time knew that sepsis was, um, w-was an exuberant inflammatory reaction to an infectious stimulus, and they thought by tamping down the inflammatory component, you might be able to have better outcomes, and it turned out it made people worse. But ultimately, it was then tested in rheumatoid arthritis, and it was amazing. And, and you know the story after that.

   19. PAPeter Attia46:14

       Yep.

   20. LKLloyd B. Klickstein46:14

       But a company called Immunex at the time licensed the technology from Mass General to make etanercept. And essentially what it does, it does two things. So the soluble receptor, which was the, which was the low affinity regulatory TNF receptor, I think at the time. Gotta double-check that. I haven't thought about etanercept in like 20 years. Um, had a relatively short half-life just as a, as a protein injected all by itself. And, um, doing the, uh, recombinant DNA technology to attach it to this part of an antibody called the Fc region did two things. One is it extended the half-life of the protein in the circulation by allowing it to recirculate the way some s- blood proteins are recirculated normally. So you're sort of hijacking an endogenous mechanism to preserve proteins in the bloodstream and doing it the same way. And the second thing it did is it put a hook on the protein to allow you to purify it easily, because the protein G and protein A columns were well established at the time and easy to use to purify proteins. So, so that's, that's what it did for the drug developers.

   21. PAPeter Attia47:34

       Yeah.

   22. LKLloyd B. Klickstein47:35

       And, and since then, people-- The technology-- This is a great example of going back to our patent discussion. Originally, that was patented technology, and only Immunex could use it or some other licensee-

   23. PAPeter Attia47:46

       Hmm

   24. LKLloyd B. Klickstein47:46

       ... of the Mass General. But the patents expired, and now it's, the technology's freely available to the rest of the world for the rest of eternity. And many, many, many companies use this technology to make drugs, and, and we're all better off for it.

   25. PAPeter Attia48:02

       So how did you guys discover Bema? How did you create it?

   26. LKLloyd B. Klickstein48:09

       Yep. So a-again, the original-- the, the earliest biology was done by Chris Liu's team in the Pathways group at Novartis Institutes. Jeff Porter was the leader of that group. Um, and the, the, the idea was we wanted to inhibit the receptors, not go after all the possible ligands, 'cause we knew that myostatin wasn't the whole story in humans. Um, we didn't know which actins, which activins it was. Um, thought it was probably activin A, but it could have been others too, and, and that story and that thinking has panned out subsequently, as we can get into later. Um, and At the time, therapeutic antibodies were the, were, were the best technology to do this. Um, remember the affinity of the ligands, myostatin and activins for the receptors, was, um, nanomolar, low nanomolar, maybe high picomolar. So we needed an inhibitor that could bind down in the low picomolar range in order to effectively prevent ligands from binding. Can't really do that easily with small molecules.

   27. PAPeter Attia49:26

       Okay, this is a great example of the importance of understanding that distinction.

   28. LKLloyd B. Klickstein49:30

       Yes. Um-

   29. PAPeter Attia49:32

       I'm gonna explain what you just said-

   30. LKLloyd B. Klickstein49:34

       Mm-hmm
7. 56:07 – 1:05:16

   From candidate antibodies to animal proof of concept (impressive muscle hypertrophy)

   1. PAPeter Attia56:08

      a candidate or several candidates that you now wanna take to the next step, which is, "Hey, in vivo, does this thing work?"

   2. LKLloyd B. Klickstein56:14

      Yeah. So we would typically have two to 10-

   3. PAPeter Attia56:19

      Okay

   4. LKLloyd B. Klickstein56:20

      ... at this stage. Um, and it, and it's taken years because we have to, we have to work through the biology and make sure that we understand what's going to happen, not because we wanna save the cells in the Petri dish, but because we don't wanna start something unless we have confidence it'll succeed if we pass each step. So, um, we have to work through the biology. We have to make all the tools we need, which are these glowing cells in response to myostatin, for example, and there's plenty of other tools that we need too. Um, we need to make the reagents. We need to make the myostatin and the activin A and, um, uh, all the tools we need to do these experiments. So... And then run the experiments, and, uh, then we have to make the antibodies, and that takes quite a bit of time, as well as, um, developability on the antibodies, which means we need to, at the very earliest stage, have high confidence that we're gonna make an antibody that we could give to people, and it'll be stable, and it'll have predictable physical func- physical properties, and it'll have a shelf life, and it'll... All of these things are what we build into the antibodies that is at this very early stage.

   5. PAPeter Attia57:35

      How confident are you at that stage, Lloyd, that the antibody won't elicit an immune response in a human?

   6. LKLloyd B. Klickstein57:41

      [chuckles] It's, it's still one of the biggest unknowns. Um, and, and the best way to do it is to use fully human-

   7. PAPeter Attia57:48

      Humanized

   8. LKLloyd B. Klickstein57:48

      ... antibody.

   9. PAPeter Attia57:49

      Yep.

   10. LKLloyd B. Klickstein57:49

       Not humanized.

   11. PAPeter Attia57:50

       Human.

   12. LKLloyd B. Klickstein57:50

       Fully human.

   13. PAPeter Attia57:51

       Full, straight-up human.

   14. LKLloyd B. Klickstein57:52

       Yeah. Hu-

   15. PAPeter Attia57:52

       Can you explain to folks the distinction there?

   16. LKLloyd B. Klickstein57:54

       Yeah. Well, there's... Um, humanized is used to describe taking a mouse or other species antibody and replacing as much of it as you can with human sequences based on what we know about human, human antibody codon usage and amino acid preference and so forth, whereas, um, fully human means you're starting with human genetic material antibodies.

   17. PAPeter Attia58:23

       But ultimately, it still has something in it that's foreign.

   18. LKLloyd B. Klickstein58:27

       Uh, as little as possible.

   19. PAPeter Attia58:28

       Part of the sequence. I mean-

   20. LKLloyd B. Klickstein58:29

       As little as... Well, there's, there's gonna be something new because antibodies-

   21. PAPeter Attia58:32

       By definition

   22. LKLloyd B. Klickstein58:32

       ... have this in, in, in, in intrinsic ability to recombine and create new sequences.

   23. PAPeter Attia58:37

       Yep.

   24. LKLloyd B. Klickstein58:38

       Now, in, in vivo, in people, so if you make some brand-new antibody and it's not suitable for some reason, it gets selected out.

   25. PAPeter Attia58:47

       Yeah.

   26. LKLloyd B. Klickstein58:47

       Whereas when we do this in vitro, in a test tube, that doesn't happen. We do the best we can and try to end up with sort of common codon usages, common antibody sequences, even pairwise and so forth. Um, but you don't really know until you, um, put it into people. There, there, there are some in, there are some in silico screens you can do by looking at what peptides are likely to be generated in a lysosome, and are they gonna have high affinity bou- binding to an MHC molecule and so forth, and we do all that stuff. But you still don't know until you do it.

   27. PAPeter Attia59:23

       Yeah.

   28. LKLloyd B. Klickstein59:25

       Um, now it's, it's an interesting historical perspective 'cause I'm getting old enough to be interested in history now. [chuckles] Um, the very first antibodies tested in humans were mouse antibodies, and there's still one that's used to this day as a therapeutic, so it's OKT3. So this is, this is an antibody used to prevent transplant rejection. Uh, it's an anti-T cell antibody, human T cell antibody, and we still use it to this day.

   29. PAPeter Attia59:55

       And what is it targeting? Is it literally targeting CD3?

   30. LKLloyd B. Klickstein59:58

       Yep.
8. 1:05:16 – 1:18:04

   Toxicology, capital allocation, and the path to an IND

   1. PAPeter Attia1:05:16

      Um, okay. So after the, you get the home run in mice, do you wanna go into a primate? Where do you typically go from mice?

   2. LKLloyd B. Klickstein1:05:26

      So for therapeutic antibodies, often it includes a primate simply because we, we, we wanna have one of the two toxicology species in whom the antibody has the expected pharmacology, so we can look at sort of on-pathway and off-pathway toxicity of the therapeutic. And since the, the... Anyway, so we, we, we, we typically use non-human primates for this.

   3. PAPeter Attia1:05:57

      When you're at the mouse stage, Lloyd, is-- how, how are you screening for tox besides the most obvious, right? Obviously, if mortality or something catastrophic is obvious. But, um, for non-apparent or non-mortality-based toxicity, what are you looking for? And is any toxicity at the mouse level disqualifying to go forward, or are you evaluating it case by case and saying, "Look. Okay, this ended up being pretty bad for the mice despite the efficacy. We don't think that's going to be an issue, or we think we got the dose wrong," or do you basically keep going back and perfecting it in the mice until you get the dose response right before you move up? Or do you just sometimes say, "No, we're gonna go to the primate or whatever other model we're gonna look at and as- reassess tox as we get closer to our species of interest"?

   4. LKLloyd B. Klickstein1:06:43

      Yeah. So with, with the, with the, uh, caveat that I'm not a toxicologist, um, the fundamental principles are you use a weight of evidence approach based on all the, all the data that accumulates. Um, from a clinical perspective, we try to balance risk and benefit with new medicines in general. So if, if it turned out that bimagrumab had some... And bimagrumab has some tox, but we'll c- we'll get into. Um, but if it were unsuitable for use in a big population that we then think about higher medical need patients

   5. PAPeter Attia1:07:20

      That's when you would go from maybe sarcopenia to Duchenne's muscular dystrophy-

   6. LKLloyd B. Klickstein1:07:24

      For example, yes

   7. PAPeter Attia1:07:24

      ... if we... Yep.

   8. LKLloyd B. Klickstein1:07:26

      Um, and where whatever the, the adverse effects are would be outmatched by the potential benefits.

   9. PAPeter Attia1:07:34

      Yep.

   10. LKLloyd B. Klickstein1:07:35

       Um, but secondly, we wanna know precisely what the toxicology is, and the two big things we look for are whether it's monitorable, whether it's reversible. So if we have irreversible cardiac toxicity with a therapeutic, that's-

   11. PAPeter Attia1:07:55

       Yeah

   12. LKLloyd B. Klickstein1:07:55

       ... that's usually the end, for example, or neurologic. Um, if it's, if it's serious organ toxicity-

   13. PAPeter Attia1:08:05

       But there's enough of a prodrome, so for example, if it's... Well, you lo-look at a drug like, um, Lamisil.

   14. LKLloyd B. Klickstein1:08:13

       Mm-hmm.

   15. PAPeter Attia1:08:13

       Right? Something as supposedly benign as Lamisil. I mean, that can destroy your liver.

   16. LKLloyd B. Klickstein1:08:19

       Yes.

   17. PAPeter Attia1:08:20

       But if you're checking liver function tests, transaminases, the war- the writing's on the wall long before you get there.

   18. LKLloyd B. Klickstein1:08:27

       Mm-hmm.

   19. PAPeter Attia1:08:27

       You can stop the drug. So that's your point. It's monitorable-

   20. LKLloyd B. Klickstein1:08:30

       Yes

   21. PAPeter Attia1:08:30

       ... monitorable and reversible-

   22. LKLloyd B. Klickstein1:08:32

       Yes

   23. PAPeter Attia1:08:32

       ... if you stop it and you get a long enough warning.

   24. LKLloyd B. Klickstein1:08:35

       Yeah.

   25. PAPeter Attia1:08:35

       'Cause otherwise, if it would just automatically destroy a person's liver at a frequency of one in 100 people using it, you could never justify it.

   26. LKLloyd B. Klickstein1:08:43

       So you're, you're describing, um, idiosyncratic liver toxicity, which is the most common reason drugs get pulled off the market still.

   27. PAPeter Attia1:08:52

       Yeah.

   28. LKLloyd B. Klickstein1:08:53

       Um, and I personally have killed drug programs for that. Um, and it's hard to... Can't predict it preclinically.

   29. PAPeter Attia1:09:03

       Yeah. So you get bima into the primates?

   30. LKLloyd B. Klickstein1:09:07

       Yes.
9. 1:18:04 – 1:24:54

   IND requirements, GMP manufacturing, and gray market peptides

   1. LKLloyd B. Klickstein1:18:04

      Um-

   2. PAPeter Attia1:18:04

      So now you're-- Let's skip, so you file the IND and you're now ready to start a Phase 1.

   3. LKLloyd B. Klickstein1:18:10

      So, so an, an IND is requesting-

   4. PAPeter Attia1:18:11

      Yeah, we should tell people what it is. Yeah

   5. LKLloyd B. Klickstein1:18:12

      ... regulatory permission to, uh, administer the drug to people. It's-

   6. PAPeter Attia1:18:17

      And you've already filed your patent at this point?

   7. LKLloyd B. Klickstein1:18:20

      Yes. Pat-

   8. PAPeter Attia1:18:21

      Yeah, where in that process did you file?

   9. LKLloyd B. Klickstein1:18:22

      Patents typically get filed... Again, there's a-

   10. PAPeter Attia1:18:27

       You wanna do it as late as possible, but while still protected.

   11. LKLloyd B. Klickstein1:18:30

       Exactly. So typically around the point where you have a group of, a group of candidates from which your final drug will be selected, that's typically when we would do it.

   12. PAPeter Attia1:18:42

       Okay. Wow.

   13. LKLloyd B. Klickstein1:18:42

       Because you want the patent to last as long as possible, but once, once information about what you're doing is getting out, you, you wanna have it protected.

   14. PAPeter Attia1:18:52

       So from the time you file the IND with the FDA until-- And you have to show them everything that you, we've talked about. Do you also have to, at the IND, show them that you can manufacture in GMP?

   15. LKLloyd B. Klickstein1:19:05

       Yes. So the manufacturing is a core element of the, of the, uh, common application that you do for an IND. And r- and this, this is US-specific nomenclature. IND stands for investigational new drug. In Europe, it's called a clinical trial application, um, CTA Um, there are other countries that have different nomenclature, and you-- companies can do the first in-human study, uh, anywhere in the world that's got a proper regulatory environment and suitable investigators and clinical sites and h- with, with adequate quality and so forth. Um, but maybe, maybe we'll be US-centric for this discussion.

   16. PAPeter Attia1:19:51

       Sure. Can you explain to folks what the hurdle is to, to GMP or good manufacturing processes and why it's so important? And again, I'll, I, I call this out to listeners because we live in an era now where these peptide therapeutics are very prevalent, these sort of gray market peptides, and there are people out there that think, "Hey, I'm buying retatrutide."

   17. LKLloyd B. Klickstein1:20:13

       Yeah, no they're not.

   18. PAPeter Attia1:20:14

       Yeah, exactly. Maybe, uh, uh, use the GMP-

   19. LKLloyd B. Klickstein1:20:18

       Yeah

   20. PAPeter Attia1:20:18

       ... uh, process as a way to explain why when you think you're buying retatrutide peptide for research purposes only, you are definitely not buying what Eli Lilly is going to eventually sell if they get FDA approval.

   21. LKLloyd B. Klickstein1:20:32

       Right. So GMP stands for good manufacturing process, and it's basically a commitment by the manufacturer to u- to use high-quality standards with extensive documentation to s- be able to prove what they've made, um, and so that everybody can have confidence that this is, this is a good quality material and they know that what's on the label is what's in the bottle, basically.

   22. PAPeter Attia1:21:06

       And that there's nothing in the bottle that's not on the label.

   23. LKLloyd B. Klickstein1:21:10

       E-exactly. It's, it's, it's purity, it's activity, it's contamination or lack thereof, it's, uh, s-sterility, if you will. Um, it's all of those things. It's that the material that's being purchased eventually commercially is the same material as what was tested clinically and, and, and we can have confidence in it. It me- basically, the factories are inspected, and the factories that make it have the-- and, and typically there are many manufacturers involved. When, when, when you buy a, um, you know, with the exception of saying buying a bottle of, um, tirzepatide from Eli Lilly, but it-- typically, when you buy a drug from somebody, the drug substance, the chemical is manufactured by one company, and then it is formulated or put into a, um, a mixture that makes it predictably absorbed or administered, is done by another company, and then it's put into a package by a third company, and then it's distributed by a fourth company. So there's a lot of people involved, and this, this whole manufacturing, uh, infrastructure and pipeline is, uh, the, is, is well controlled and well documented and, um, you can buy online peptides that may be the same as retatrutide. They might not. You have no way of knowing.

   24. PAPeter Attia1:22:42

       Yeah, and, and in many ways, that's the premium you're paying when you're buying the drug from Novo Nordisk or Eli Lilly or Novartis or whatever is the, the part of the premium is it's very expensive to manufacture under GMP conditions.

   25. LKLloyd B. Klickstein1:22:57

       Yes.

   26. PAPeter Attia1:22:57

       Um, so it's a, it's a bit of a buyer beware when you decide not to.

   27. LKLloyd B. Klickstein1:23:01

       I think it's a big mistake to buy these peptides from, from, you know, from fly-by-night manufacturers. Conceptually, it's no different than going and, and, than a drug user going and buying some opioid from a street corner drug dealer. You have no idea what's in that. Could it have fentanyl in it? Could it have carfentanil in it, which is even worse than fentanyl? Um, um, you know, baking soda. You have no idea what's in there. It's the same thing with these peptides. You have no idea.

   28. PAPeter Attia1:23:30

       Yeah.

   29. LKLloyd B. Klickstein1:23:31

       Uh, I think it's, I, I think it's a mistake. And, and plus, even if you were to have confidence that those peptides were what they're saying they were, the data to support what they do are almost nonexistent. Um, I, I've been reading in the popular literature about this one that's-- I think it's called BP-197. Is that right?

   30. PAPeter Attia1:23:51

       BPC-157.
10. 1:24:54 – 1:39:00

    First in-human study design, patient selection, and protection of healthy volunteers

    1. LKLloyd B. Klickstein1:24:54

       okay, so we, we've made bemagramab, and it's made it through all of the, um, IND-enabling study activities, and we're ready to give it to people. Who do we give it to? And this depends on what we need to measure and what the expected safety and tolerability issues are in people. Again, we talk about tox- toxicology in animal species. We talk about safety and tolerability in humans. And Again, most antibodies, including bimagrumab, won't have, um, safety and tolerability issues that are off the pathway that it's-

    2. PAPeter Attia1:25:37

       Yeah

    3. LKLloyd B. Klickstein1:25:37

       ... working on. Um, and didn't really see any safety and to- any toxicology to speak of in the animals. The only thing that I was a little worried about that we saw was in the rats, uh, they had, um, cardiac hypertrophy. However, the... remember, the animals had enormous change in their body size because of the muscle hypertrophy, and if you normalize the heart size to the body size, it was normal.

    4. PAPeter Attia1:26:08

       So does that mean that you didn't know if the cardiac hypertrophy was in response to more re- you know, SVRs, you know, uh, more resistance that the heart had to work against-

    5. LKLloyd B. Klickstein1:26:22

       Mm-hmm

    6. PAPeter Attia1:26:22

       ... or whether the antibody was working directly on the cardiac myocytes and increasing hypertrophy there as it was in the-

    7. LKLloyd B. Klickstein1:26:28

       Or both

    8. PAPeter Attia1:26:28

       ... skeletal muscle directly?

    9. LKLloyd B. Klickstein1:26:29

       Exactly.

    10. PAPeter Attia1:26:29

        Yeah.

    11. LKLloyd B. Klickstein1:26:30

        Exactly. We didn't know, but we could make an argument that rats of the size that they became-

    12. PAPeter Attia1:26:37

        Should have bigger hearts

    13. LKLloyd B. Klickstein1:26:38

        ... should have bigger hearts. And, and that was the argument we made to regulators, and so we didn't think there was any specific cardiac toxicity. And, and typically in toxicology studies, you have something we call a recovery period, where the, the drug is withdrawn and some of the animals are followed to look and see whether any toxic effects that did occur are reversible. And in fact, when you stop giving the animals bimagrumab, the muscles got smaller and the heart got a little smaller too.

    14. PAPeter Attia1:27:09

        How often was it dosed? Is it a-

    15. LKLloyd B. Klickstein1:27:13

        So the way you dose in the toxicology studies is you want the exposure, which means the amount of drug in the blood, to be ideally higher than what we ever expect to get in humans.

    16. PAPeter Attia1:27:29

        And then when you got to the humans-

    17. LKLloyd B. Klickstein1:27:30

        So, so we, we dosed... So the, so that was, that was the preamble to the answer to your question, which was weekly. So we gave the animals the drug weekly.

    18. PAPeter Attia1:27:38

        And the, um, the half-life of the drug presumably is short, but-

    19. LKLloyd B. Klickstein1:27:43

        It, it's shorter in animals, but again, you, you drive the dosing in the toxicology studies to make the amount of drug in their blood ideally higher-

    20. PAPeter Attia1:27:53

        Yep

    21. LKLloyd B. Klickstein1:27:54

        ... than we will get in people so that we have what we call a, a safety margin of exposure.

    22. PAPeter Attia1:27:58

        Now, how do you know at that point, Lloyd, Lloyd, if toxicology is driven by peak or trough? 'Cause some drugs are-

    23. LKLloyd B. Klickstein1:28:05

        You don't.

    24. PAPeter Attia1:28:05

        You don't.

    25. LKLloyd B. Klickstein1:28:06

        You don't. You c- you make a best judge- judgment, but-

    26. PAPeter Attia1:28:08

        Is there a general rule of thumb?

    27. LKLloyd B. Klickstein1:28:10

        You measure both, and you want both of them to be higher-

    28. PAPeter Attia1:28:13

        To be above what's predicted

    29. LKLloyd B. Klickstein1:28:13

        ... in the animals than what you get in your people.

    30. PAPeter Attia1:28:15

        Okay.
11. 1:39:00 – 1:50:05

    Phase 1 dosing, pharmacodynamics, and global trial strategy

    1. PAPeter Attia1:39:00

       Did you see any adverse effects in the Phase 1?

    2. LKLloyd B. Klickstein1:39:03

       So th- yes. So the, the, the three adverse effects that are evident with Bema that we think are on target, um, and that were assessed in that study were muscle spasms or cramps. Um, acne is rare in older adults, and it was rare in this study 'cause those were older adults. But when... Skipping ahead, when we've tested younger people, acne's more common. We don't understand why. And then there are GI symptoms of diarrhea that happen. Um, they tend to be first-dose related and less common subsequently, but they s- they're reproducible, and we think they're real. And we, and we saw that stuff.

    3. PAPeter Attia1:39:45

       And how many steps of dose escalation did you do in that study? Or, and by the way, if that's too much detail to remember, don't worry about it.

    4. LKLloyd B. Klickstein1:39:51

       Yeah.

    5. PAPeter Attia1:39:51

       But just I'm wondering if you remember how high you got relative to what was an efficacious dose.

    6. LKLloyd B. Klickstein1:39:56

       So there's some principles here. Um, I personally like to dose as high as we can in the first in-human study to understand if there is going to be any, uh, safety or tolerability issues in people, while at the same time never exceeding the exposures we've tested in animals. Um, s- so we would've... Uh, so the study designs include the opportunity to go as high as we can. Um, typically in antibodies, that ends up being as, as high as is feasible. Um, and there are a lot of technical details here we don't need to get into, but when your antibodies are made from cell culture and they're highly purified, but there's still some measurable contaminants in them, and the amount of contaminants... Or of course, they're also tested as part of the toxicology studies 'cause they're in the drug we give the animals. Um, but we can't exceed the exposure to the contaminants either in the clinical study. So sometimes that... Sometimes it's the volume we can administer, the mass we can administer, and so forth. So, um, so I think the highest dose that we ended up doing in bemagromab was something like 50 to 100 milligrams per kilogram. But I, you know, I don't remember.

    7. PAPeter Attia1:41:21

       And in that study in humans, you're administering once a month?

    8. LKLloyd B. Klickstein1:41:24

       Uh, initially you'd administer once, and then based on the emerging results for how long that lasts.

    9. PAPeter Attia1:41:32

       I see.

    10. LKLloyd B. Klickstein1:41:33

        Um, and, and we knew what exposures we needed to reach in order to get maximal efficacy based on the culture data. Um, there, there were a lot of, um, cell culture experiments we did that we haven't talked about. Like we... You can culture muscle cells in a dish, and we did that and looked at the ability of the drug to cause hypertrophy of those cells. So we, we, we knew what exposures we needed to get to and how long we, we wanted to do it. Um, but again, we don't exceed the exposures that we get in animals. So I think after the single-dose study, we probably did, um, three doses. Um, and, and that was it for the first in-human study.

    11. PAPeter Attia1:42:17

        Okay.

    12. LKLloyd B. Klickstein1:42:17

        And, and, and typically you need multiple doses in order to be able to see the, um, the technical term is pharmacodynamic effect, so the, the effects on the body that the drug causes.

    13. PAPeter Attia1:42:30

        So the endpoint for the Phase 1 before you move to Phase 2, where you're really going to actually look as your primary... And you're always looking obviously for safety, but now you're really pivoting to efficacy being the thing that you're, you're trying to chase.

    14. LKLloyd B. Klickstein1:42:44

        Yes.

    15. PAPeter Attia1:42:44

        Um, what, what did you need to submit to the FB- the FDA to say, "Okay, we have... We checked our Phase 1 box"?

    16. LKLloyd B. Klickstein1:42:54

        So typically you're in reasonable communication with regulators, whether it's the FDA or whether you're overseas elsewhere, and you, you provide them with a report.

    17. PAPeter Attia1:43:04

        And Novartis is a European company, right?

    18. LKLloyd B. Klickstein1:43:07

        Yes.

    19. PAPeter Attia1:43:07

        They're based in Switzerland. But this work was being done in the U.S.?

    20. LKLloyd B. Klickstein1:43:10

        I think we did do the first in-human study in the U.S., yeah.

    21. PAPeter Attia1:43:13

        Any reason for that? Is it, uh... Are Europe, uh, European and U.S. regulators so comparable on this point that it's really just a question of where your teams are or?

    22. LKLloyd B. Klickstein1:43:23

        So every country's a little different. Um, Europe is somewhat homogeneous, but not completely so. Every country's a little different. Um- A- and I think it's true both for large companies and small companies that you go wherever makes the most sense. It's where you can... Remember, the, the three biggest challenges of any clinical study are recruitment, recruitment, and recruitment. So you have to be able to get the subjects or the patients or the participants. You need qualified, experienced, reliable clinical investigators. You need a regulatory environment that's supportive for what you're trying to do. Um, and then you think about cost of the study. They're different in different countries. Um, and so you integrate all of that stuff, and that chooses where, at least personally, where I would go to do a first in-human study. Um, countries that are often used nowadays are Germany, uh, US-

    23. PAPeter Attia1:44:32

        Australia's pretty popular. New Zealand.

    24. LKLloyd B. Klickstein1:44:33

        Australia, New Zealand's very popular now. Um, things have really changed, I guess maybe in the past year or two, about China being really popular because China has, um, uh, uh, a regulatory environment that's become more favorable, and they can do investigator-initiated studies with, um, um, less supporting data than we require for a typical IND. So it can often be a faster way to test something. Um, and of course, China has a lot of patients, um, so that's something that's being done now too. Um, I personally love doing studies in the US and Taiwan. Um, Taiwan has, you know, they, they, they have wonderful investigators. They speak English better than we do. They have a very centralized clinical environment, so they have many patients at a limited number of, uh, clinical sites. The regulatory environment, uh, is very similar to the US. Um, Australia and New Zealand is, is favorable because they have a, especially this is Australia now, they have a different regulatory construct where safety is assessed by the ethics committee and, um, and CM's drug quality is assessed by the regulators, so they have a clinical trial notification process rather than a approval process. Um, and, and plus the, the exchange rate's favorable now so too. So if we get back to what is the trial gonna cost, that's useful.

    25. PAPeter Attia1:46:16

        And how much reciprocity is there between agencies? So if you, um... Well, I should clarify the question. You can conduct the trial in Australia, but under the auspices of the FDA where they're issuing, or does it have to be in the US if the FDA is overseeing?

    26. LKLloyd B. Klickstein1:46:33

        If the FDA is overseeing, the study's done in the US.

    27. PAPeter Attia1:46:36

        Okay. So if you do a study in Europe and get European approval, or you do a study in Australia and get Australian re- approval, how much of an additional hurdle is there for the FDA to typically approve a drug?

    28. LKLloyd B. Klickstein1:46:48

        L- let's talk about running a study versus marketing approval. Very different. So for running a study, if you're doing it in, say, Australia, you apply to the Australian regulat- regulatory authorities and the ethics committee for the study, and they do the review and, uh, request modifications and eventually approve, and then the study's run in Australia. Um, if you want to then do a study in the US, you have to apply for an IND, just as you would if you were doing it any other time, but you include all the data that you got in Australia as well. And if you were doing it the other way around, it would be the same thing, and it's true for any two countries.

    29. PAPeter Attia1:47:29

        Meaning if you had a drug that went all the way to the equivalent of a Phase 3 ready for approval in Australia, and you come back to the US from scratch and say, "We wanna do-- We wanna be able to sell this drug in the United States," they're gonna say, "Submit an IND." The FDA would-

    30. LKLloyd B. Klickstein1:47:44

        Yeah. I, I think so, yes.
12. 1:50:05 – 1:57:40

    Phase 2 lessons on muscle mass, function, and nutrition

    1. LKLloyd B. Klickstein1:50:05

       is in China.

    2. PAPeter Attia1:50:05

       All right. So let's go back to Bema.

    3. LKLloyd B. Klickstein1:50:07

       Bema.

    4. PAPeter Attia1:50:08

       We've, um... You go into phase two now. By the way, at some point, doesn't Novartis sell this asset?

    5. LKLloyd B. Klickstein1:50:15

       Yes. So No-Novartis had strong confidence in bimagrumab. It was first in class, had really obvious biology in humans, and basically, Novartis ran maybe, I think, 16 phase two studies of one sort or another.

    6. PAPeter Attia1:50:41

       Wow.

    7. LKLloyd B. Klickstein1:50:42

       Phase one, phase two study and different indications. Tried very hard. So the drug reliably and predictably increases muscle size, but not performance assessments in a, in a major way. And, and I think that's because, remember in the rodents in whom we saw both size increase and performance increase, the mass increase was large, 20% to 30% or more. In humans, it's 4% to 8%, and eight is the absolute max.

    8. PAPeter Attia1:51:15

       And were those differences based on dose or starting mass?

    9. LKLloyd B. Klickstein1:51:20

       Biology. People are just not mice.

    10. PAPeter Attia1:51:23

        Oh, sorry.

    11. LKLloyd B. Klickstein1:51:23

        Or rats. Yeah.

    12. PAPeter Attia1:51:24

        Um, I mean, the difference between the four and the eight.

    13. LKLloyd B. Klickstein1:51:26

        Yeah.

    14. PAPeter Attia1:51:26

        How much of that is dose dependent versus other demographic dependent on the pa- like, you know, do you get more muscle mass in younger people, more muscle mass in people starting with more muscle mass?

    15. LKLloyd B. Klickstein1:51:37

        Yeah. There's a, there's a trend to more in, in, in males versus females, a trend to more in, uh, younger versus older, but there's a lot of variability.

    16. PAPeter Attia1:51:47

        Do we know if other variables such as resistance training, nutrition, protein consumption would have augmented these findings? And how much were those variables controlled in these studies?

    17. LKLloyd B. Klickstein1:51:59

        So we know some of that. We try to control as much as we can. Um, there was one study that has not been published in peer-reviewed form yet, but there is an abstract for it. Uh, if people want to find it, they can look at... So the, the Be- the BELIEVE study of bimagrumab in, um, in obesity was just published a few months ago in Nature Medicine. If you look in there, this, this nutrition study is referenced. But there was this-

    18. PAPeter Attia1:52:26

        We'll link to it in the show notes.

    19. LKLloyd B. Klickstein1:52:27

        Yeah. There was a, there was a study of bimagrumab in patients who were dosed at three different levels of protein calorie nutrition.

    20. PAPeter Attia1:52:38

        Mm.

    21. LKLloyd B. Klickstein1:52:39

        And the bottom line is the more pro... And, and it was the recommended daily amount, half of that-

    22. PAPeter Attia1:52:47

        Twice that

    23. LKLloyd B. Klickstein1:52:47

        ... or, or one and a half times that, I think. Um, and basically within those boundaries, the more protein you ate, the more muscle you built, which probably shouldn't surprise anybody. The other really interesting finding-

    24. PAPeter Attia1:53:00

        And by the way, twice the RDA is only 1.2 grams per kilogram.

    25. LKLloyd B. Klickstein1:53:04

        Yeah, maybe that's what we used. It was 1.2.

    26. PAPeter Attia1:53:06

        Yeah. I, I would argue had you gone to 1.6 or two, you probably would've seen more hypertrophy.

    27. LKLloyd B. Klickstein1:53:12

        It's not been tested. I think you're probably right, but it hasn't been tested.

    28. PAPeter Attia1:53:15

        It's interesting. So it su- it suggests that in humans you might have been substrate limited.

    29. LKLloyd B. Klickstein1:53:21

        Could be.

    30. PAPeter Attia1:53:21

        Amino acid limited or protein synthesis limited.
13. 1:57:40 – 2:07:30

    Bimagrumab’s effects on fat mass and type 2 diabetes

    1. LKLloyd B. Klickstein1:57:40

       but Novart-- the very last study Novartis did was a study in type 2 diabetics. And 'cause w-we, we had h- we had had data that, um, hemoglobin A1Cs decreased in patients given bimagrumab. Um, and that study, which ran for 48 weeks, so it was, it was 10 mgs per kg monthly for 12 doses.

    2. PAPeter Attia1:58:10

       Okay. So a lower dose than you were giving for hypertrophy?

    3. LKLloyd B. Klickstein1:58:14

       No, this, this maximized the-

    4. PAPeter Attia1:58:16

       Oh, why did I think you said earlier 50 m-mgs per kg? Is that in the-

    5. LKLloyd B. Klickstein1:58:19

       In the phase one, we went up higher.

    6. PAPeter Attia1:58:20

       You went up that high. Got it. Got it.

    7. LKLloyd B. Klickstein1:58:21

       We went up as high as we could 'cause we wanted to know what would happen if people were overdosed later.

    8. PAPeter Attia1:58:26

       Got it. Okay.

    9. LKLloyd B. Klickstein1:58:26

       Um, and the answer was nothing.

    10. PAPeter Attia1:58:28

        So at 10 mgs per kg monthly over 48 weeks?

    11. LKLloyd B. Klickstein1:58:31

        Yeah. Was, was, was a, was a maximal dose in terms of effect size, and they saw the expected muscle mass increase. Interestingly, they saw a substantial fat mass decrease, and hemoglobin A1C in these type 2 diabetics decreased by about 0.7 or 0.8% absolute, which is a pretty good effect.

    12. PAPeter Attia1:58:55

        Yeah. And do you think that that was on account of just more insulin sensitivity, or was it a larger reservoir for glucose disposal?

    13. LKLloyd B. Klickstein1:59:03

        Both of those things, I think.

    14. PAPeter Attia1:59:07

        And these patients didn't have to do anything else. It wasn't-

    15. LKLloyd B. Klickstein1:59:10

        No

    16. PAPeter Attia1:59:10

        ... like in addition to that, they changed the way they ate or they exercised more. You gave them a drug that added muscle mass, took off fat mass, and lowered A1C by 0.7%.

    17. LKLloyd B. Klickstein1:59:20

        Yep, and, and they had standardized dietary advice to try-

    18. PAPeter Attia1:59:25

        Yeah, both group-

    19. LKLloyd B. Klickstein1:59:25

        You know, the 500kg

    20. PAPeter Attia1:59:26

        Okay. So who-- Did Novartis run that study?

    21. LKLloyd B. Klickstein1:59:28

        Novartis did the whole study, and then they made a strategic decision that the effect size wasn't big enough. I mean, actually, I don't know what their strategic decision was, but they decided-

    22. PAPeter Attia1:59:38

        The output was, "We're gonna spin it out."

    23. LKLloyd B. Klickstein1:59:39

        The out- the output was to spin it out, and at the time, I was working with, uh, Joe Jimenez and Mark Fishman and Pravina Kandula at Adietum Bio as, as an advisor, and w-we really wanted bimagrumab.

    24. PAPeter Attia1:59:56

        What year is this approximately?

    25. LKLloyd B. Klickstein1:59:57

        That it spun out was 2021.

    26. PAPeter Attia2:00:02

        Okay.

    27. LKLloyd B. Klickstein2:00:04

        I think it was 2021. '20... Yeah. Um, th-th-discussions had been ongoing in 2020, but I think it finally happened in 2021.

    28. PAPeter Attia2:00:14

        Okay. So you guys acquire the asset obviously for a lot less than you could have produced it.

    29. LKLloyd B. Klickstein2:00:19

        Yeah. Still wasn't cheap because it was a phase two r-ready program.

    30. PAPeter Attia2:00:23

        Yep.
14. 2:07:30 – 2:20:40

    The BELIEVE trial of bimagrumab plus semaglutide

    1. PAPeter Attia2:07:30

       ran BELIEVE.

    2. LKLloyd B. Klickstein2:07:31

       Yes. So, so BELIEVE w- it was originally planned to be a 24-week study in patients with sarcopenic obesity. That was what we were going to do. But then when Novo's data came out and we got super excited about obesity, we said, "Oh my God, we gotta do a bigger study. We're gonna do it in combination with semaglutide." And this was during the pandemic. So there was a lot of complexity and supply chain disruptions, but, um... And remember with semaglutide, it was a proprietary drug of Novo. We couldn't get the drug substance, and so we had to use the commercial presentation of semaglutide-

    3. PAPeter Attia2:08:15

       Which is super expensive

    4. LKLloyd B. Klickstein2:08:16

       ... which was expensive, and it's an auto-injector, and we couldn't make a placebo for that. So the study design included semaglutide as open label, but we did a, we, we did placebo-controlled bimagrumab 'cause we had control of that. Um, we used bimagrumab intravenously, uh, just because it was the fastest, most straightforward way to get into the clinic. Um, not public was that we were working hard on an auto-injector, and we would've been ready in the next study for an auto-injector, but, um, but it was, it was intravenous for bimagrumab. Um, and then what combination should we use? We ended up doing something called a full factorial design. So we did all possible combinations of low-dose semaglutide, high-dose semaglutide, low-dose bimagrumab, high-dose bimagrumab, and placebo. So it's a nine-arm study.

    5. PAPeter Attia2:09:18

       Why?

    6. LKLloyd B. Klickstein2:09:20

       Because we didn't know in humans what would happen with those different combinations. We didn't know if there would be adverse effects of the drug combinations or not. They did have a couple of adverse effects in common, diarrhea in, in, for example.

    7. PAPeter Attia2:09:35

       And-

    8. LKLloyd B. Klickstein2:09:35

       And this is in part why I did that pharmacology study in rodents, 'cause if there was anything unexpected that would happen with the drug combination, I wanted to know about it. Um, technically-- Actually, we... And we had to do this because we weren't using the semaglutide in its intended population. I think it, it wasn't registered yet, I guess was the issue. We had the data, but it wasn't registered, so it wasn't indicated in obesity. So if you're using an ex-

    9. PAPeter Attia2:10:04

       And so yeah, you were using Ozempic, not Wegovy. You were still using-

    10. LKLloyd B. Klickstein2:10:07

        We used them both, actually.

    11. PAPeter Attia2:10:08

        Oh, you did?

    12. LKLloyd B. Klickstein2:10:08

        Whatever we could get. Remember, they were in short supply.

    13. PAPeter Attia2:10:10

        Yeah.

    14. LKLloyd B. Klickstein2:10:13

        And, and to the regulators' credit, uh, they recognized all of this and were, um, willing to allow us to substitute interchangeably Ozempic and Wegovy.

    15. PAPeter Attia2:10:26

        The brands, yeah.

    16. LKLloyd B. Klickstein2:10:26

        Yeah.

    17. PAPeter Attia2:10:27

        So what were the findings of this six-month, nine-arm study?

    18. LKLloyd B. Klickstein2:10:32

        So it was originally gonna be six months, but we changed it from the original plan with bimagrumab alone to the combination, and it eventually became 72 weeks of treatment. 48 weeks was the primary endpoint, and then we had a six-month follow-up period, so 104 weeks total study. Two years.

    19. PAPeter Attia2:10:52

        Did you have to raise more money?

    20. LKLloyd B. Klickstein2:10:54

        We did.

    21. PAPeter Attia2:10:55

        I was gonna say, that's, that's a hard study to do for $70 million bucks.

    22. LKLloyd B. Klickstein2:10:58

        Yes. We, we, we did, and it was 500 people enr- enrolled, roughly.

    23. PAPeter Attia2:11:02

        Yeah.

    24. LKLloyd B. Klickstein2:11:03

        507 was the exact number. Um, so we found... So I guess number one, and one of the things I'm kind of proud of, is I got the doses right, because you wanted to see a partial response with the low dose, a full response with the high dose for both of the drugs, and see those kinds of dose responses in the combination arms. Remember, there's four combination arms.

    25. PAPeter Attia2:11:30

        Yep.

    26. LKLloyd B. Klickstein2:11:31

        Right? There's, there's low-dose bima, high-dose bima, low-dose sema, high-dose sema-

    27. PAPeter Attia2:11:35

        Yeah

    28. LKLloyd B. Klickstein2:11:35

        ... four combinations, and then placebo. Um, and we saw the dose effects in all the arms, so that was good, and the primary endpoint was body weight. Wasn't what I wanted for a primary endpoint. I wanted waist circumference.

    29. PAPeter Attia2:11:50

        Why couldn't you get DEXA? Too expensive?

    30. LKLloyd B. Klickstein2:11:53

        We thought that since the registration decision is made on the basis of body weight loss, we wanted that as the primary endpoint. We included DEXA in every single patient.
15. 2:20:40 – 2:25:13

    Selective mTORC1 inhibition and the challenge of testing geroprotection

    1. PAPeter Attia2:20:40

       Um, okay, I wanna pivot and talk about one other thing, um, which is also an area where you know a lot about it, which is selective mTOR inhibition.

    2. LKLloyd B. Klickstein2:20:51

       [laughs]

    3. PAPeter Attia2:20:51

       [laughs] Um, we're not gonna spend as much time on it, of course, but-

    4. LKLloyd B. Klickstein2:20:55

       Yeah

    5. PAPeter Attia2:20:55

       ... a-again, talk to me about where your head is at these days on that pathway in general. Um, do you believe that there are... That this is geroprotective in, in humans? I mean, it's, it's been well established how geroprotective this is in mice. Um, almost assuredly, I think it'll end up being geroprotective in dogs. Um, so it might be safe to say that inhibiting mTOR in everything from yeast to dogs and maybe even primates extends life. We don't have a clue if it's going to in humans.

    6. LKLloyd B. Klickstein2:21:32

       Yeah.

    7. PAPeter Attia2:21:32

       We'll never probably get to directly test it. Um, there are really good compelling arguments on both sides of why it may or may not be the case in humans-

    8. LKLloyd B. Klickstein2:21:42

       Mm-hmm

    9. PAPeter Attia2:21:42

       ... uh, including the, uh, longevity quotient argument and things like that. What are your thoughts?

    10. LKLloyd B. Klickstein2:21:48

        I th-think it probably will. It's highly conserved biology across evolution. Um, so I, I, I think so. If, if, if reductively if you envision mTORC1 as a master regulator of, um, sensing... Sort of s- integrating nutritional inputs and then deciding to grow or not grow, um, uh, or... And not grow means circling the wagon, upregulating autophagy and recycling pathways. Um, I, I think it probably would. I think the effect size is gonna be modest, as it-- just as it has been preclinically. Um, and I think it's TORC1.

    11. PAPeter Attia2:22:36

        Mm-hmm.

    12. LKLloyd B. Klickstein2:22:37

        Um, haven't seen a lot of new data on that.

    13. PAPeter Attia2:22:41

        Well, there was that study somewhat recently suggesting that rapamycin impaired... I don't know if it was impairing MPS or, um, some other metric of physical performance or something. Um, obviously, you're familiar with the agents you've tested. Um, you know, we're still at sort of the infancy of these drugs, right? What, what do you think is standing in the way of more drug development on more and more selective, potentially higher efficacy, but potentially lower side effect burden versions of drugs that can, um, inhibit mTOR complex 1?

    14. LKLloyd B. Klickstein2:23:21

        The, the, the selectivity is the, is the big challenge because with rapalogs, a-as you know, there's... They're, they're, they're TORC1 selective, but there's a down-regulation of TORC2 with sustained exposure, and I don't know that we... You know, so in, in, uh, Restore Bio, we tried to manage that by a combination of a catalytic and an allosteric inhibitor, um, [clears throat] which seemed to do it. Um, and, and I know there are other companies that are working on other ways to get TORC1 selective inhibition, and I think that's what we need, is a real TORC1 selective inhibitor, and then we can, we can test the biology.

    15. PAPeter Attia2:24:02

        And do you think that just intermittent dosing of everolimus or sirolimus gets that?

    16. LKLloyd B. Klickstein2:24:08

        Maybe. Again, it's hard to tell in healthy people because, you know, in, in cancer, when you study mTOR inhibitors, the, the cancers have a highly upregulated pathway, and it's easy to see the biology. You can't really see the active biology in humans measuring blood, and it's not necessarily the tissue you want anyway. When we do this in rodents, we measure their liver activity. Um, and I think we mentioned... You and I discussed this before, that in, in, um, in young rodents with fasting, they, um, they down-regulate mTOR, as you would expect.

    17. PAPeter Attia2:24:43

        Mm-hmm.

    18. LKLloyd B. Klickstein2:24:44

        In old rodents, they didn't. So it, it makes me call into question the whole concept of intermittent fasting in older people 'cause I don't know if it'll do the same thing.

    19. PAPeter Attia2:24:58

        Yeah. Again, imminently testable.

    20. LKLloyd B. Klickstein2:25:00

        Nobody's lining up for liver biopsies, though.

    21. PAPeter Attia2:25:03

        No.

    22. LKLloyd B. Klickstein2:25:03

        And, and, and there's-

    23. PAPeter Attia2:25:04

        And we can't get that with MRS or anything else.

    24. LKLloyd B. Klickstein2:25:07

        I don't think so. It's just-

    25. PAPeter Attia2:25:09

        Yeah. Again, the price of admission is so great on that.

16. 2:25:13 – 2:35:04

    A new pharmacologic approach to cancer prevention

    1. LKLloyd B. Klickstein2:25:13

       Yeah.

    2. PAPeter Attia2:25:13

       Okay, final question/topic.

    3. LKLloyd B. Klickstein2:25:15

       Hmm.

    4. PAPeter Attia2:25:16

       As you think about drug discovery over the next decade, I'm not gonna ask you the question everybody's thinking. That's, how is AI gonna help? We'll punt that for now.

    5. LKLloyd B. Klickstein2:25:24

       Thank you.

    6. PAPeter Attia2:25:25

       Yeah. What are you most optimistic about in terms of pathway, disease? Uh, wh-where are you most excited? Where do you think we're gonna be in 10 years where there's been a step function change?

    7. LKLloyd B. Klickstein2:25:42

       I think we're starting to wake up to the concept of real medicine prev- real medical prevention. I mean, th-this is something I've been saying for years, you've talked about it a lot, is that we need to get away from being a sick care system to a healthcare system, and the way you do that is with preventive medicine. Um, and the way to implement it is you need better primary care, and you need codes for preventive visits 'cause right now they're... If, if I wanted to see a patient for prevention of cancer, for example, so my new company is cancer prevention, there's not codes for that So he can't bill for it. So there's, there's a lot of institutional, uh, uh, hurdles that we need to get through. But I, I think people are waking up to the concept of, "I wanna stay healthy rather than get sick and get treated."

    8. PAPeter Attia2:26:36

       Say a bit more about your current company and how, how could one develop a drug for cancer prevention?

    9. LKLloyd B. Klickstein2:26:42

       Yeah, so this is, this is conceptually difficult to wrap your head around. Um, but again, where do new drugs come from? They come from reading the literature and thinking, which is sort of what I did after, um, after Versanis ended for me. Ver- s- it's still ongoing in Lilly. Um, and there's s- there's some papers published over the past five to 10 years about drugs that cause cancer. So if a drug causes cancer, it must be most likely inhibiting a cancer protective pathway. Most drugs are inhibitors of things. Um, the, the prototype for this is sorafenib, which is a multi-kinase inhibitor that's used to treat renal cell carcinoma and, and hepatocellular carcinoma primarily. Um, if you g- if you give that drug to people, about 10% of the patients, of the, of the older patients get skin cancers. Why is that?

    10. PAPeter Attia2:27:43

        And w- are these melanomas or are these squamous or basal cells?

    11. LKLloyd B. Klickstein2:27:47

        The, the cancers they get seem to be the prevalence that's reflected in the normal population. So almost everything that's ascertained-

    12. PAPeter Attia2:27:55

        Got it

    13. LKLloyd B. Klickstein2:27:55

        ... is basal cell and squamous cell. So... And, and, and more recently, we understand the pathway biology of that. These are-- Sorafenib is a, is a multi-kinase inhibitor. It hi- inhibits a lot of kinases, but one of the ones that it inhibits is the sensing kinase that triggers something called ribotoxic stress, and this is a pathway that causes cell death. Um, and that pathway, if you turn it on irreversibly and covalently, is the target of some of the nastiest toxins that you know about, like diptheria toxin, sarsin, ricin. It's a very, very potent pathway. My innovation is putting together different parts of the literature. I've-- I came up with a way to turn it on in a gentle and controlled fashion. Remember, it's on constitutively in people because if you turn it off with these multi-kinase inhibitors, you get cancer. So the hypothesis of the company is if we turn that pathway on a little more, we'll prevent cancers. Not all of them, but maybe 50% is what I'm hoping. And since skin cancer is almost as common as all other cancers put together, we gotta start there. But in a phase two study of older adults, and older adults in this context means 50 and up. Sorry, Peter.

    14. PAPeter Attia2:29:23

        I'm, uh, I'm in that category squarely. Don't worry.

    15. LKLloyd B. Klickstein2:29:26

        [laughs] I have been for a while. And, um, and who have had at least five skin cancers in the past, those people have a 50% chance of having another skin cancer within a year. So if we recruit a cohort of 100 or 120 of those, we would be able to test the low dose, high dose placebo and actually measure cancer prevention in a phase two study.

    16. PAPeter Attia2:29:48

        Now, is there a risk that it will only work in preventing squamous cell and basal cell carcinoma, but will not progress an epithelial tumor? Or prevent, I'm sorry.

    17. LKLloyd B. Klickstein2:29:58

        That's, that's possible because the only data we have are for skin cancer. But even if it only prevented skin cancer, that's a really big medical need. But I think it will work on multiple cancers. But it's gonna be almost impossible to test that before approval, just because cancer incidence is a really rare event.

    18. PAPeter Attia2:30:20

        I guess the next thing that would be an interesting question, Lloyd, would be you take a bunch of patients who have successfully undergone adjuvant therapy for a stage three epithelial cancer. So I would think colon cancer or breast cancer. Um, they're NED, uh, no evidence of disease-

    19. LKLloyd B. Klickstein2:30:43

        Mm-hmm

    20. PAPeter Attia2:30:43

        ... for the listener, but there's a 50% chance they're gonna have a recurrence. Uh, y- you know, you stratify it in a way that you, you basically find people who have a very high risk of a cancer recurrence, and then you, you treat them.

    21. LKLloyd B. Klickstein2:30:56

        I, I think that's one way to do the other study. What, what I've done in Coslape Therapeutics is, um, a collaboration with the Broad Institute where we took our tool compound. Now, we don't quite have a development candidate yet, but the-- we took the tool compound, which is good enough, and run it through their panel of 1,000 cancer cell lines to see what tumors are sensitive to it. So this would be a treatment mode-

    22. PAPeter Attia2:31:24

        Yeah, yeah, yeah

    23. LKLloyd B. Klickstein2:31:24

        ... rather than a prevention mode. And, um, well-

    24. PAPeter Attia2:31:27

        And do you think it could have efficacy in treatment as well?

    25. LKLloyd B. Klickstein2:31:31

        That's the question we were asking.

    26. PAPeter Attia2:31:32

        Okay.

    27. LKLloyd B. Klickstein2:31:33

        Um, and, uh, melanomas emerged as by far the most sensitive tumor. Now, I'm not sure why, because my, my hypothesis-- The thing about skin cancer is it's got a heavy mutational burden because-

    28. PAPeter Attia2:31:47

        The heaviest

    29. LKLloyd B. Klickstein2:31:47

        ... of all the UV exposure.

    30. PAPeter Attia2:31:48

        Yep.

Episode duration: 2:35:04