#409 ‒ Inside modern drug development: the science, economics, and regulatory hurdles behind bringing new medicines to patients | Lloyd Klickstein, M.D., Ph.D.

View the Show Notes Page for This Episode https://peterattiamd.com/lloydklickstein2/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260928-pod-lloydklickstein2&utm_content=260928-pod-lloydklickstein2-podfeed Become a Member to Receive Exclusive Content https://peterattiamd.com/subscribe/?utm_source=podcast-feed&lloydklickstein2%20=referral&utm_campaign=260928-pod-lloydklickstein2&utm_content=260928-pod-lloydklickstein2-podfeed Sign Up to Receive Peter's Weekly Newsletter https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=260928-pod-lloydklickstein2&utm_content=260928-pod-lloydklickstein2-podfeed Lloyd B. Klickstein is a physician-scientist who has spent more than 20 years at the intersection of drug discovery, healthy aging, and preventive medicine. Drawing on his experience in academic medicine, translational research, and biotechnology, Lloyd walks through the full arc of modern drug development. He explains how scientists identify an unmet medical need and decide which diseases and therapeutic targets are worth pursuing. From there, he takes us through the process of engineering a drug, testing it in animals, and navigating clinical trials and regulatory approval. Using bimagrumab as a case study, Lloyd explains the rationale for targeting myostatin and activin signaling to increase muscle mass and strength and describes how the antibody was engineered and screened. He then walks through what was learned from early clinical trials. Unexpected effects on fat mass and type 2 diabetes helped reshape bimagrumab's development as a potential treatment for obesity, including its use in combination with semaglutide. Along the way, Peter and Lloyd explore the differences among drug modalities, including biologics and small-molecule therapeutics. They discuss the roles of patents and capital allocation in drug development, along with the requirements for IND submission and GMP manufacturing. They also examine why developing a new drug takes so long and costs so much, and why identifying failures early is critical. At the end of the episode, the conversation turns to mTOR inhibition and geroprotection, as well as Lloyd's current work on a novel pharmacologic approach to cancer prevention. This episode provides a rare behind-the-scenes look at how new medicines are actually created and the scientific, regulatory, and economic decisions that determine which ideas ultimately make it to patients. We discuss: Lloyd's path from academic medicine to translational drug development [3:15]; Drug modalities, patents, and the economics of innovation [11:30]; Choosing sarcopenia as a target for drug development, and confronting the problem of measuring falls [23:00]; The rationale for bimagrumab: improving muscle mass and strength by targeting myostatin and activin signaling (and why follistatin failed) [36:45]; Engineering and screening the bimagrumab antibody, and the cost of developing a new drug [43:45]; From candidate antibodies to animal proof of concept (impressive muscle hypertrophy) [54:15]; Toxicology, capital allocation, and the path to an IND [1:02:45]; IND requirements, GMP manufacturing, and gray market peptides [1:14:45]; First in-human study design, patient selection, and protection of healthy volunteers [1:22:00]; Phase 1 dosing, pharmacodynamics, and global trial strategy [1:33:45]; Phase 2 lessons on muscle mass, function, and nutrition [1:43:30]; Bimagrumab's effects on fat mass and type 2 diabetes [1:50:45]; The BELIEVE trial of bimagrumab plus semaglutide [1:59:30]; Selective mTORC1 inhibition and the challenge of testing geroprotection [2:11:45]; A new pharmacologic approach to cancer prevention [2:15:45]; and More. Connect With Peter on Twitter https://twitter.com/PeterAttiaMD, Instagram https://www.instagram.com/peterattiamd/, Facebook https://www.facebook.com/peterattiamd/ and YouTube https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:11Dr. Peter Attia?

  Hey, everyone. Welcome to the Drive Podcast. I'm your host, Peter Attia. This podcast, my website, and my weekly newsletter all focus on the goal of translating the science of longevity into something accessible for everyone. Our goal is to provide the best content in health and wellness, and we've established a great team of analysts to make this happen. It is extremely important to me to provide all of this content without relying on paid ads. To do this, our work is made entirely possible by our members, and in return, we offer exclusive, member-only content and benefits above and beyond what is available for free. If you want to take your knowledge of this space to the next level, it's our goal to ensure members get back much more than the price of the subscription.

• 0:54Dr. Peter Attia?

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• 1:04Dr. Peter Attia?

  My guest this week is Dr. Lloyd Clickstein, a physician, scientist, rheumatologist, and drug developer who has spent more than two decades helping discover and develop new medicines. After beginning his career as a physician scientist at Harvard Medical School and the Brigham and Women's Hospital, Lloyd joined Novartis, where he helped pioneer translational medicine and led the company's new indication discovery unit, identifying entirely new disease and therapeutic opportunities. He later held leadership roles at several biotechnology companies, including Versantis Bio, where he led the development of BIMA before the company was acquired by Eli Lilly. Today, he serves as the CEO of Coslap Therapeutics.

• 1:45Dr. Peter Attia?

  I wanted to have Lloyd on because very few people have had a front-row seat to every stage of modern drug development, from identifying the unmet medical need, to the discovery of new therapeutic targets, to navigating clinical trials, regulatory approval, and even commercialization. While we use BIMA as a case study throughout this conversation, the real goal is to pull back the curtain on how new medicines are actually created, why the process takes so long and costs so much, and how scientists decide which areas are worth pursuing in the first place. In the episode, we talk about how new drugs are discovered, developed, and ultimately brought to patients, the science and economics behind choosing which diseases and therapeutic targets to pursue, the differences between

• 2:30Dr. Peter Attia?

  small molecules, biologics, gene therapy, and other drug platforms, why drug development takes so long, costs billions of dollars, and so often fails, the story behind this one particular drug from its discovery at Novartis to its development as a therapy for muscle loss and obesity, what clinical trials, FDA approval, and patent protection actually involve, and how the next generation of obesity and muscle-preserving therapies may reshape the treatment of metabolic disease. So, without further delay, please enjoy my conversation with Dr. Lloyd Klickstein.

• 3:12Dr. Peter Attia?

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

• 3:20Speaker 01

  It might well be that long, yes.

• 3:22Dr. Peter Attia?

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

• 3:36Speaker 01

  Right. So, my original plan, when I finished college, was to go to medical school, following is basically the family business. But between college and medical school, I worked in a laboratory at Brigham and Women's Hospital in Boston, and 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, and that is the training, not required, but helpful, for becoming a physician scientist. And from there, I did medicine training, I was rheumatology

• 4:15Speaker 01

  training, and I practiced rheumatology for maybe 10 years, and also had an NIH-funded research lab doing very basic science on adhesion molecules in the immune system.

• 4:27Dr. Peter Attia?

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

• 4:31Speaker 01

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

• 4:35Dr. Peter Attia?

  Okay.

• 4:35Speaker 01

  So, I stayed there my whole academic career.

• 4:38Dr. Peter Attia?

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

• 4:40Speaker 01

  Only job I ever had until I left and went to industry--

• 4:45Dr. Peter Attia?

  Yeah.

• 4:45Speaker 01

  --which was a little over 20 years ago. And I went to Novartis Institutes, which was founded by Mark Fishman when he was recruited by the then-CEO of Novartis, Dan DeSella, to 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, for sure, and this was the first industry manifestation of it.

• 5:21Dr. Peter Attia?

  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's a black box that exists that is the world you occupy, that I really think--it's unknown by the public, but I think it would be very insightful if people understood it. And it is the process by which a drug is discovered. The first person who I ever read articulating this was Steve Rosenberg, wrote one of my favorite books about science called The Transformed Cell. This book is over 30 years old. I probably read it cover to cover 10 times during the course of my life. But he starts with a question, which was, hey, he's at a party one day,

• 6:06Dr. Peter Attia?

  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, again, it's a very intelligent person can still have an enormous blind spot to what it is people like you do. So, take that any way you want, but I think it might be a great foundation.

• 6:23Speaker 01

  Let's start from a very broad area of medicine, not just focus on cancer, because cancer is a special case of a more general concept. 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 a drug that doesn't exist, or a therapy that doesn't exist but is needed. 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 making a drug that you have to take less frequently, or, as we've seen a lot in the press recently,

• 7:06Speaker 01

  an oral drug instead of an injectable drug, or the same kind of drug, but works better. And there have been great examples of that. Think atorvastatin and risuvastatin in a mevacorzocor world. And those have been enormous commercial successes, and there's a strong bias throughout the drug development infrastructure 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 have to deal with the whole complexity of making physicians and patients and payers and everybody

• 7:51Speaker 01

  else aware of this, and then creating a regulatory path for it, it's a heavier lift. But I think that's where the biggest value comes to society and individuals and patients in creating new therapies. And that's kind of what I do. And there's a lot of failure involved in there. And the things that we can talk about are, how do you get a new regulatory pathway established? Been part of that once, soup to nuts. And then, how do you sort of create new indications? That's also a challenge. Maybe it would be informative to think about

• 8:34Speaker 01

  how 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, had a few of us come into his office and said, we need to make the most needed medicines, and find out what we're not doing that we should be doing, and get it started. And we had a budget for that, so, super. As I mentioned, I start with patients and indications and medical need. So, starting there, 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.

• 9:17Speaker 01

  It didn't have everything there. It only had the ones that people had recognized at the time. But it gave us a framework in which we could start thinking. And then it sounds like a lot, but surprisingly, it isn't. It's maybe 10 or 20 pages of of paper at the time.

• 9:35Speaker 01

  And we grouped them into things that we were already working on. Things that were rare genetic developmental things that would be difficult to approach. 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. Novartis wasn't at the time working on liver diseases. One of them was those sort of fibrotic diseases in general. And there were some others. And we started our program and it eventually grew to have dozens of projects.

• 10:18Speaker 01

  And became a bit of a monster and then we had to sort of whittle it down a little. But some really interesting studies came out of that. One of them, which I know we're going to get to later, is the magramab for muscle diseases. There's a long story there, but but again, it came out of a medical need of frail elderly people. And I was very mindful as a rheumatologist, I saw some of these people. If you, at the time, 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. The three-year mortality rate approached 90%.

• 10:59Speaker 01

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

• 11:23Dr. Peter Attia?

  Yeah. I didn't know that was that. I didn't know the three-year mortality for frailty in that specific indication was so high, but that's a staggering statistic.

• 11:32Speaker 01

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

• 11:36Dr. Peter Attia?

  Yeah. 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, there's a target we want to go for, an unmet clinical need. And there's not an incremental opportunity, right? The example you gave is a great one. I have six statins already. I'm going to come up with the seventh. That's let's take that one off the table. How do you begin the thinking around what we're going to do? 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.

• 12:20Dr. Peter Attia?

  But I think that that nomenclature might not be clear to everybody and maybe provide a little bit of that as well.

• 12:26Speaker 01

  Sure. So so let's start with what we call small molecules, which is industry jargon. It basically means a chemical.

• 12:36Speaker 01

  Historically, 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 is for making a drug. So these are just chemicals. The other class are biologicals, which is pretty much everything that's not a chemical. Within that broader group of biologicals, and actually, there's a third group, let's say, devices. So for biologicals, that could be an antibody. It could be some other protein like a peptide or a soluble receptor. And

• 13:22Speaker 01

  I think we're now creating a separate category of gene therapies, which themselves can be complex based on how they're delivered or targeted. And then let's talk about devices because that's a completely different animal. And it's regulated by its own group called CDRH in the FDA. And that could include things like a gadget you make in a workshop. It could be an app. It could be something simple like a syringe that you use to inject a drug or an auto-injector, which are very common nowadays. Or some combination of those things.

• 14:06Dr. Peter Attia?

  And include all the way up to implantable?

• 14:09Speaker 01

  Yes, absolutely.

• 14:11Dr. Peter Attia?

  And 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?

• 14:21Speaker 01

  So patent law, I think, is the same for anything. But there are other regulatory conditions that apply to one kind of treatment or another. For example, there are different exclusivity periods for a small molecule versus a biologic. And they change periodically. 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 I don't think it's well understood or adequately understood

• 15:06Speaker 01

  how patent law works about drugs. Maybe we could take a few minutes and talk about that. I'm going to 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

• 15:19Dr. Peter Attia?

  But you've been to the rodeo many, many times.

• 15:22Speaker 01

  Yes, I was the clown.

• 15:26Speaker 01

  So the way this works is if you think about at a very high level, making a new a 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 Burj Khalifa. 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

• 16:06Speaker 01

  ultimately pay for itself and pay all the bondholders 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. Patent is essentially a monopoly on being able to make, use, and sell the drug in exchange for telling everybody how to do it. That's basically what a patent is.

• 16:49Speaker 01

  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. Practically, you get 10 to 15 years of exclusivity from the time it can be launched.

• 17:07Dr. Peter Attia?

  So a couple of points I'll add just for you to expand on if you if you like. Some people might also be aware of the idea that not everything has to be patented. So for example, the classic example is Coca-Cola. Had they patented the formula for Coca-Cola hundreds of years, or I guess, I don't remember when Coke started, but call it 150 years ago or something like that, we wouldn't be drinking the same thing today. So they chose a different route, which is we are never going to make this secret public. And in exchange for that, we will have no protection.

• 17:36Speaker 01

  That's correct. So you're describing a trade secret.

• 17:39Dr. Peter Attia?

  Correct.

• 17:39Speaker 01

  That's that's another form of intellectual property.

• 17:42Dr. Peter Attia?

  Now, I assume that is not an option in pharma.

• 17:46Speaker 01

  Well, surprisingly, it is.

• 17:47Dr. Peter Attia?

  Interesting.

• 17:48Speaker 01

  There are some specific drugs where they were protected by trade secrets. So a couple of my favorite examples are Armour Thyroid, which was thyroid

• 17:59Dr. Peter Attia?

  Desiccated thyroid hormone, yeah.

• 18:01Speaker 01

  Yep. It was the thyroid hormone for people who needed replacement therapy. And it was before we could make it synthetically. And the process by which that was made was kept secret. Now, it didn't stop other people from trying, but they had to copy exactly the composition of all the peptides, as well as the impurities in the final preparation in order to be able to use the clinical and filing package that Armour used at the FDA to get FDA approval.

• 18:33Speaker 01

  Turned out that was technically really hard. Another one I really like is Acthar Gel. So this was purified from pig pituitaries. And it was ACTH, basically. That's the Acth, A C T H A R Gel. I used to love it. I used it in the emergency room a lot because it was a rheumatology smart missile. Patients could come in with acute gout and be miserable. You give them one shot of that and it gives them endogenous steroid taper over a period of several days. It was great.

• 19:06Dr. Peter Attia?

  Totally unaware of that myself.

• 19:07Speaker 01

  Yeah, it was a funny story behind that one, too. It was, it was cheap and widely available. Until the BSE scare, the bovine spongiform encephalopathy scare happened. And then because it was purified from pig pituitaries, the company was worried that it was going to be, there's going to be something similar in pigs and we know pigs have endogenous viruses. So it was pulled off the market. And then it was bought by a very small company. Who eventually recommersalized it for infantile seizures. And they jacked the price up a hundred or a thousand fold. And so it hasn't been available for rheumatologists to use since then.

• 19:47Dr. Peter Attia?

  Yeah.

• 19:48Speaker 01

  Um, it's stupid, bad pharma trick.

• 19:51Dr. Peter Attia?

  Yeah, well, I'd like to actually talk about a few more examples of that because there are several.

• 19:55Speaker 01

  Hmm.

• 19:56Dr. Peter Attia?

  Going back to the patent. In classic pharma, are patents primarily issued only for decomposition of matter? Or are companies trying to get patents for process manufacturing and other things? Or is the playbook that, hey, if there's a really complicated process required to make this drug? I'm going to file my patent on composition of matter. I'm going to keep the process as trade secret. So even when this thing runs off patent, you might know what the finished product looks like. You'll never figure out how to make it.

• 20:30Speaker 01

  So both of those things happen depending on the drug, exactly. So one good example would be, let's say, Abvi and Humira. They patented every single little thing around that drug that they could. It was a huge winner for them and they wanted to keep it protected as long as they possibly could.

• 20:47Dr. Peter Attia?

  And they would stagger it. So they would first patent composition of matter, wait 10 years, patent this step in process, wait five years, and you just keep doing it, doing it. And you sort of effectively extend the patent life of the molecule and process.

• 21:01Speaker 01

  Exactly, and that, that can be abused, I, I think personally.

• 21:07Dr. Peter Attia?

  Okay.

• 21:08Speaker 01

  But exactly, they'll, they'll patent the, the drug, they'll patent the formulation, they'll patent the salts, they'll patent the auto injector, they'll patent the, of course, the indication right at the beginning to the extent that they can, which is sort of method of use. And they'll patent the dose, they'll patent the route of administration, everything.

• 21:28Dr. Peter Attia?

  Yeah, combining it with some else, okay.

• 21:29Speaker 01

  Going back. And the method of manufacturing.

• 21:32Dr. Peter Attia?

  Yes. Uh, going back to the, the clinical team, the scientific team that is beginning the exploration of what to do. Are you at the outset completely agnostic to whether you're looking for or entertaining small molecules or biologics as targets? Do certain disease states lend themselves for you to go looking in one path versus the other?

• 21:56Speaker 01

  I think there's two considerations. One, one is that there are some conditions that might suggest one, one route or the other. But there are also sometimes companies or, or infrastructure that would make it better to use one format or the other. I think big companies are format agnostic because the, all the big drug companies are now doing small molecules and biologics and some, and many gene therapies and, and even some now cell therapies, which are sort of the, the frontier of complex medical therapeutics.

• 22:33Speaker 01

  For example, if, if you're treating a childhood disease, then you need to make something that is oral and tastes good. All the parents out there are going to remember, um, you know, the, the grape and the cherry flavored.

• 22:47Dr. Peter Attia?

  Tylenol or Advil or something.

• 22:49Speaker 01

  Grape Scepter was, was a particular favorite of mine when I was giving my kids drugs. Yeah, so that's one example. Uh, others are, there are inhaled drugs for specific lung conditions. And so some formats will, will make sense. And, and there's a medical rationale for that.

• 23:06Dr. Peter Attia?

  So then how do you begin the screening process? How do you begin to identify molecules? And again, I think we should assume that our listeners, who are otherwise well informed, won't know the details of what an IND is, what we use phase one, two, three, four, and what has to happen prior to the IND. Like, let's just start from the very beginning.

• 23:25Speaker 01

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

• 23:32Dr. Peter Attia?

  Yeah, if we did this as a seminar at Harvard, this would take you a year, yeah.

• 23:35Speaker 01

  But to cover it at a high level, starting from the idea and the medical indication, and it might be useful to think about one specific example. And we can, let's, let's think about muscle weakness and, which can be described as sarcopenia or, and the definition of that is still evolving, frankly. I've gone to some of these specialty meetings, like the Gekexia consensus conference. And it's a topic of discussion every year. But I think one, we seem to be converging on the concept of decreased muscle mass with impaired muscle function as, as a good definition of sarcopenia.

• 24:15Speaker 01

  And whether the function is grip strength or gait speed or stair climb, or people use different ones. Okay, so we'll, we'll talk about that as a specific indication. So impaired muscle function with low muscle volume.

• 24:29Dr. Peter Attia?

  Which to your point, by the way, nobody listening to this doesn't care about this. So this is, this is a very topical consideration. It's not esoteric.

• 24:36Speaker 01

  It's something I, I've personally been working on for 20 years, as you know.

• 24:40Dr. Peter Attia?

  Yeah.

• 24:40Speaker 01

  So what should be the drug format? Well, the patient population are likely to be older adults. So we need to, 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. Because 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.

• 25:19Dr. Peter Attia?

  Toxicity, the whole thing.

• 25:20Speaker 01

  Everything. And all of them have, have maybe a 90% chance of success. You multiply all that out 10 or 20 times, it's zero.

• 25:27Dr. Peter Attia?

  It's a huge failure, yes, yeah.

• 25:29Speaker 01

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

• 25:43Dr. Peter Attia?

  You want to fail fast.

• 25:45Speaker 01

  If you can, yeah, absolutely. The, the, the worst outcome in drug development is failing in phase three.

• 25:52Dr. Peter Attia?

  Oh, yeah.

• 25:53Speaker 01

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

• 26:00Dr. Peter Attia?

  Now, let me just ask a question about this specific indication. So you've already made a decision, which is we're going after sarcopenia. And you've decided to do that as opposed to say, we're going to go after muscular dystrophy. So are you doing that because sarcopenia is a much, much, much bigger market? Which is the obvious choice? Or are you saying it's easier to get approval there? And then ultimately we can also demonstrate that this will work in Duchenne's muscular dystrophy? How would you think about those two ways to proceed?

• 26:33Speaker 01

  So my personal bias is I have a limited amount of time on this earth to develop medicines and help people. I want to help as many people as I can. So I mostly do large indications and, and that's, that's my personal choice.

• 26:50Dr. Peter Attia?

  Now, in that situation, regulatory pathway might be harder for sarcopenia if it is not yet identified clearly as a disease.

• 26:58Speaker 01

  No question, no question.

• 26:58Dr. Peter Attia?

  Whereas Duchenne's muscular dystrophy, that's an orphan disease. You would probably get a quicker regulatory pathway to approval.

• 27:05Speaker 01

  Yes, yes.

• 27:07Dr. Peter Attia?

  And so a different strategy might be, we go after Duchenne's because we can get there faster. And then once we have demonstrated a drug that works in that category, we then chase the approval pathway to help as many people as possible. Would those just be two different strategies?

• 27:22Speaker 01

  Yes, and frankly, I've done both.

• 27:25Dr. Peter Attia?

  Okay.

• 27:25Speaker 01

  Depending on the, on the circumstance and the mechanism of the drug and so forth. And frankly, I'm doing that right now with one of the two companies that I work with.

• 27:34Dr. Peter Attia?

  Okay, so let's go back to your example though.

• 27:36Speaker 01

  Let's get back to sarcopenia. The very first thing that I tried to do in sarcopenia was prevent falls. Now.

• 27:48Speaker 01

  How do you measure a fall, Peter?

• 27:50Dr. Peter Attia?

  Well, I was gonna ask a harder question, which is, which are the muscles that are most responsible for a fall? And maybe that's part of what you could test. It turns out, I think it's very complicated, right? I've had a guest on this podcast who presented data that suggested something that's seemingly as innocuous as great toe strength is an enormous predictor of falls. Now, there's a very objective way to measure the force that a person can generate with their great toe. And as that force gets below certain thresholds relative to their body weight, the probability of falls just starts to go straight up. Balance, obviously.

• 28:24Speaker 01

  I would argue that they don't really know that.

• 28:28Dr. Peter Attia?

  Okay.

• 28:28Speaker 01

  Because I asked the question, you know, what first, what causes falls? There's about 11 different things that cause falls. And people can think, think through themselves. There are the obvious ones like weakness and dizziness, which dizziness itself is very complicated, but also vision, also attention. Lots of things can cause falls.

• 28:50Dr. Peter Attia?

  Yeah, I mean, I think another big one that we see clinically, Lloyd, is loss of reactivity. So foot speed and reactivity. So you and I, if we went for a walk today around Lake Austin, so there's a 10-mile beautiful loop around Lake Austin, the probability that on that 10-mile loop, you and I wouldn't stumble once, at least once, and miss our footing is zero. But I would venture that neither of us would fall. And so the question is why? Why wouldn't we fall despite being challenged at a great level? You know, stepping on a twig, missing a branch or a root or something like that. And the reason is, we have the reactive speed of our feet to catch ourselves. And that, to me, is one of the

• 29:33Dr. Peter Attia?

  things that's missing. And that tends to come down to the type 2A muscle fiber, right? Like, that's a very explosive.

• 29:40Speaker 01

  But also proprioception?

• 29:41Dr. Peter Attia?

  Yes, absolutely. Vision, all the things that we're talking about. But maybe, maybe the broader point is, this is multifaceted. There is an atrophy that is beginning of various systems in the body, and it's creating this perfect storm where, when you watch an elderly person fall, you realize that that's a situation where they would have saved that fall. It's not the insult that's the problem, whatever caused the perturbation in the step. It's the inability to catch it.

• 30:09Speaker 01

  I think that's exactly right. So let's get back to the issue of.

• 30:13Dr. Peter Attia?

  But that's hard.

• 30:14Speaker 01

  Measuring falls.

• 30:15Dr. Peter Attia?

  Yeah, but that this is becomes a very hard problem.

• 30:17Speaker 01

  So I tried to do that. Because in a, in a clinical environment, the only falls that are ascertained are those that cause injury. Right? From, from our perspective as physicians, those are the patients we see. And patients are reticent about reporting falls because they know they could potentially be taken out of their home environment if they were felt to be unsafe. And frankly, I would do exactly the same thing if I were in that circumstance. I want to stay home.

• 30:49Dr. Peter Attia?

  Yeah.

• 30:49Speaker 01

  So we developed a study to try to measure falls. And so we worked with a, with a large company that manufactures triaxial accelerometers. And we made a, we made a research device for this, for this effort. And, and I designed a wonderful study. So the study was, we were first going to put the device on bad ice skaters in Boston in the winter, and videotape the rink. And so the videotape results are the positive controls for actual falls. And then we would look at the device telemetry and look at the sensitivity and specificity of the device.

• 31:31Dr. Peter Attia?

  It's worn on the ankle, the wrist, where?

• 31:33Speaker 01

  This was going to be a pendant.

• 31:35Dr. Peter Attia?

  Okay.

• 31:36Speaker 01

  And then the second part of the study is, if the first part worked, and the device worked on falls that were real, we were going to put it on elderly nursing home residents. And there, and there, the positive control was little old lady found on the floor because the people were old and frail and unable to get up themselves. So when the nurses or the staff found them on the floor, that was, that was a fall, however they got there. And then we look at the device telemetry and see.

• 32:03Dr. Peter Attia?

  And sorry, was the purpose of that exercise, Lloyd, to see if the ice skating telemetry could predict a fall on ice? And was it offering the same insight that you were seeing in the actual field with the elderly people?

• 32:15Speaker 01

  Well, it's a little bit that falls are like the Supreme Court in pornography. You know, you say you know it when you see it. And so we wanted to see it on the ice skating rink, and then look at the device telemetry and see, was it reporting falls when they actually happened? Was it reporting falls when they didn't? You know, was it missing things? Basically, to see if the device worked. So I put that through the, the institutional processes for funding, and I was told, cut the first part out. And so just put it on the older adults. So I worked with a really good geriatrician named Lou Lipsitz. And we did that study. Kiran Dole was the operation, clinical operations person. And it, it was

• 32:58Speaker 01

  really a good study execution, because working with patients and research subjects, participants in their 80s, up to a little over 100, is challenging.

• 33:10Dr. Peter Attia?

  And these were all individuals in one living environment or across?

• 33:13Speaker 01

  Yes, they were in one living environment. We wanted to make it as, we wanted to minimize the variables.

• 33:19Dr. Peter Attia?

  How many subjects were?

• 33:20Speaker 01

  We had 60 subjects.

• 33:21Dr. Peter Attia?

  And you followed them for how many months?

• 33:23Speaker 01

  We followed them for six months. And these, these were people who had fallen at least once in the prior six months. So we, we knew they're at a high risk for more falls. And remember, this institution has a lot of protocols and procedures in place to try to prevent falls, and they're still falling now and then.

• 33:41Dr. Peter Attia?

  So Lloyd, 60 subjects followed by six months, how many falls did you capture?

• 33:46Speaker 01

  Well, we ended up 117, I think, was the number of events that actually happened based on someone found on the floor. However, the device was awful. In that, I think it had about, it detected 17% of the real falls, and only 17% of the device actuations where it said somebody fell were false. So it was just not useful. And it was the best we could come up with.

• 34:16Dr. Peter Attia?

  And just to be clear, you weren't asking it to predict antecedent movement pattern of fall?

• 34:23Speaker 01

  No, no.

• 34:23Dr. Peter Attia?

  You were just asking, once a person has fallen, do you know?

• 34:27Speaker 01

  Yes. Very simple.

• 34:29Dr. Peter Attia?

  I would have guessed that you would have been higher.

• 34:31Speaker 01

  So did I. But we were wrong. This study is actually published now. But then we couldn't use it for measuring falls.

• 34:38Dr. Peter Attia?

  Yeah.

• 34:39Speaker 01

  We tried one more thing. There is a Massachusetts Institute of Technology professor named Dina Katabi, who was using Wi-Fi type devices to measure people's movements in their homes. And it is a little scary. It could, it could measure wherever you were and whatever you were doing. And so we thought that would be a great way to assess falls. But ultimately, there, I don't remember the issue, but we could, ended up not being able to use it. So we had to stop our whole program for making drugs to prevent falls because we couldn't measure them.

• 35:15Dr. Peter Attia?

  Now, let me play devil's advocate for a moment. Couldn't you have just said, we want everyone involved in a study to report if they fell because it's going to help us get better data for the study? And, I mean, given that you're, you're going to capture all the reported falls, and really, all you're trying to do is capture the signal of unreported falls. But if you ask the people, say, look, we're not taking away your driver's light, you know, whatever it is that you're afraid of losing, that's, we are just trying to report this as an AE or as an outcome. I mean, it seems to me you'd have a much higher chance of capturing it than any sort of device at this point.

• 35:56Speaker 01

  That would be true. We were just worried about the data quality. Because people, you know, the, remember, these are older adults who were frail. And we were worried about the, you know, recall bias. And we were worried about whether they would have something to write it down with. And people generally weren't device savvy at the time. I think that might be better now. Anyway, we didn't.

• 36:20Dr. Peter Attia?

  I have to think there's some AI way to do, like, there must be. I mean, were these accelerometers using any AI?

• 36:27Speaker 01

  This was a long time ago. This was 10 years ago.

• 36:29Dr. Peter Attia?

  Got it. Okay.

• 36:29Speaker 01

  Or more. So there was no AI in those days. Well, some people would take issue with that.

• 36:34Dr. Peter Attia?

  Yeah, yeah.

• 36:35Speaker 01

  Not the way, not the way we see it today.

• 36:36Dr. Peter Attia?

  Yeah.

• 36:37Speaker 01

  Anyway, it was a interesting example of a lot of ideas are conceptualized, and we have to be able to objectively measure things ideally in drug development. And we tried, and we couldn't, and we moved on. So this kind of brings us to sarcopenia and muscle mass and strength, which was the genesis of bemagromab, and active and receptor antagonists in general. Now, we knew at the time about myostatin. So Sejin Lee is sort of the father of myostatin. He discovered the biology. And in rodents, myostatin is, you know, kind

• 37:18Speaker 01

  of amazing. You can, you can turn a mouse into an Arnold Schwarzenegger mouse by, by blocking myostatin.

• 37:25Dr. Peter Attia?

  This was in the mid 90s, right?

• 37:28Speaker 01

  I think so, yeah.

• 37:28Dr. Peter Attia?

  Yeah. I mean, I remember, this was, when I was in medical school, I remember in 97, seeing the images of the mice, the chickens, the.

• 37:38Speaker 01

  Dogs, cattle.

• 37:39Dr. Peter Attia?

  Cows. 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.

• 37:47Speaker 01

  There were no people who had that, though.

• 37:49Dr. Peter Attia?

  No.

• 37:51Speaker 01

  So.

• 37:53Speaker 01

  So at the time, the people who led the discovery project, so this is the laboratory research, where so Chris Liu and his team and David Glass and his team. And that's where the, the original code of bemagromab was BYM338. And that's where, that's where the VAT came from. I was part of that team on the clinical side. And if they made the drug, how would we test it?

• 38:20Dr. Peter Attia?

  Do you want to explain how myostatin inhibition would lead to enormous muscles?

• 38:27Speaker 01

  Yes. So the broader question is what governs the size of your muscles? And we know it's nutrition and we know it's use. And then there are biochemical things that regulate it. And myostatin is an inhibitor of muscle growth. 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. 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 activans, mostly activin A.

• 39:10Speaker 01

  And this is the advantage of inhibiting myostatin and activin A together or blocking the receptor, which is what bemagromab does.

• 39:22Dr. Peter Attia?

  What was the evolutionary, I mean, I'm asking you as though you were there during the design phase, but 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 sparse environment? We can't just have muscles demanding all of this protein?

• 39:41Speaker 01

  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.

• 39:50Dr. Peter Attia?

  Yeah.

• 39:51Speaker 01

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

• 39:54Dr. Peter Attia?

  But it is interesting because the other way that nature could have solved that problem was just to make it completely supply limited and just say, yeah. But anyway, okay. So we don't really have a great teleologic reason.

• 40:06Speaker 01

  That's kind of the way it works with adipose tissue.

• 40:08Dr. Peter Attia?

  Yeah. Yeah, exactly. That's right. So we don't have a great explanation for why, but regardless, in humans, myostatin plays a smaller role than it does in these less, presumably slightly less complex mammals. And what is the actual mechanism by which myostatin is inhibiting? Is it, is it doing something in actin myosin filaments? What is, what is it doing to prevent hypertrophy?

• 40:34Speaker 01

  Complicated. But to summarize it briefly, the receptors are part of this larger TGF beta superfamily of receptors, and there's dozens of them. There's type one, type two, type threes, and they all signal via mostly a common pathway of called SMADS, which was named by those whimsical Drosophila geneticists. It stands for similar to mothers against decapentaplegic, which people don't need to know. But, um, and, and those are transcription factors and they govern a whole lot of gene programs.

• 41:11Speaker 01

  Some of the more important ones are muscle, so muscle size is regulated by nutritional availability and then muscle protein synthesis versus muscle protein turnover. And the proteins that turnover muscle are MRF1 and MTHbox are atrogen. And David Glass was one of the discoverers of, of this pathway, uh, who I mentioned earlier. And myostatin signaling via the activin receptors suppresses the proteins that are involved in targeting muscle proteins for degradation.

• 41:54Dr. Peter Attia?

  So before we leave myostatin to talk about BMA, do you want to say anything about folistatin? And I don't even know if you're aware, but folistatin became a very popular recreational sort of gray market agent that was sold for research purposes only in quotes. And the marketing material suggested, look, if you take folistatin, folistatin inhibits myostatin, you're going to get really big muscles. And so people were pumping themselves full of folistatin. Actually, that's not really true. I think the folistatin was so expensive, they weren't doing that. They were doing some attempt at folistatin gene therapy.

• 42:32Speaker 01

  Oh.

• 42:33Dr. Peter Attia?

  So do you want to just explain what folistatin is or, or why it may not be as, uh, as, as holy grail as it was made out to be?

• 42:41Speaker 01

  So folistatin, and then there's folistatin like proteins are endogenous inhibitors of this pathway we've been talking about. And it does, if you do a gene therapy in rodents, result in larger muscles. But it's a small protein with a relatively short half-life, and I don't think dosing it systemically now and then would be successful.

• 43:03Dr. Peter Attia?

  We did the math on this and you would need to give it several times a day. And given the price of folistatin, you'd be spending above, I don't know, you'd be spending a million dollars a month on folistatin. But also it wasn't clear that it would do anything in an adult. In other words, it seemed that there might've been a critical window during which administration of folistatin or folistatin gene therapy would have an impact, but it had to be pretty young, it had to be during the development of the muscle more so than a mature phase of the muscle.

• 43:37Speaker 01

  I, I think it would work in adults if you could solve the half-life. And I know there are companies working on this with FC fusion proteins and other half-life extended versions.

• 43:47Dr. Peter Attia?

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

• 44:00Speaker 01

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

• 44:06Dr. Peter Attia?

  Well, yeah, just think about it through the lens of like how you manipulate drugs. Like I think of this as part of the story.

• 44:11Speaker 01

  Right. So 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 ENBROL, which is etanrecept. It's, 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.

• 44:41Dr. Peter Attia?

  I didn't know that.

• 44:42Speaker 01

  And it made people worse. Well, because I think physicians and scientists at the time knew that sepsis was an exuberant inflammatory reaction to an infectious stimulus. And but felt 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 you know the story after that. But a company called Immunex at the time licensed the technology from Mass General to make etanrecept. And essentially what it does, it does two things. So the soluble receptor, which was the, which was the low affinity regulatory TNF receptor,

• 45:26Speaker 01

  I think at the time, had to double check that. I haven't thought about etanrecept in like 20 years. Had a relatively short half-life, just as a, as a protein injected all by itself. And doing the 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 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.

• 46:06Speaker 01

  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. And, and since then, 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 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 the eternity. And many, many, many companies use this technology to make drugs and, and we're all better off for it.

• 46:52Dr. Peter Attia?

  Okay. So, how did you guys discover Bima? How did you create it?

• 47:00Speaker 01

  So, again, the earliest biology was done by Chris Liu's team in the pathways group at Navarre's institutes. Jeff Porter was the leader of that group. And the idea was, we wanted to inhibit the receptors, not go after all the possible ligands, because we knew that myostatin wasn't the whole story in humans. We didn't know which activins it was, thought it was probably activin A, but it could have been others too. And that story and that thinking has panned out subsequently, as we can get into later. And at the time, therapeutic antibodies were the best technology to do this.

• 47:41Speaker 01

  Remember, the affinity of the ligands, myostatin and activins for the receptors was 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.

• 48:05Dr. Peter Attia?

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

• 48:10Speaker 01

  Yes.

• 48:10Dr. Peter Attia?

  I'm going to explain what you just said, and then I want to have you state that last point again. So, people, when they're talking about pharmacokinetics, and they're talking about affinity. You'd have to talk about a concentration. So, what concentration of this hormone or this ligand is necessary to get into this? And when you start talking about, you know, we could talk about millimoles, micromoles, nanomoles, as we get smaller and smaller and smaller, as those numbers get smaller and smaller and smaller, it means you don't need very much of the thing to get in the receptor. And therefore, if you're trying to develop something to block that, it becomes a harder problem. Because you better figure out a way to usurp this guy getting in, and this guy gets in

• 48:55Dr. Peter Attia?

  very easily.

• 48:56Speaker 01

  Yes, exactly.

• 48:57Dr. Peter Attia?

  Okay.

• 48:58Speaker 01

  Exactly.

• 48:58Dr. Peter Attia?

  So, and you're saying, to get a small molecule, to have that degree of sensitivity, is very challenging?

• 49:05Speaker 01

  Yes.

• 49:05Dr. Peter Attia?

  And therefore, something that's biologic makes more sense?

• 49:08Speaker 01

  Yes.

• 49:08Dr. Peter Attia?

  And is that due to just the physics of the conformational fit?

• 49:14Speaker 01

  Yeah, I think you could describe it that way. It's essentially this, it's more complicated than this, but think about it as the surface of interaction of the, of the two molecules binding together. Essentially, we need, if the ligand, myostatin and activin for the receptor, is sticky, you need an inhibitor that's even stickier.

• 49:34Dr. Peter Attia?

  Stickier, yeah.

• 49:35Speaker 01

  And that would be very challenging to do with a small molecule. So, in this case, we went with the biologic route. Sort of ran a therapeutic antibody project, in collaboration with Morphosis, with whom we had a collaboration at the time. And had a bunch of candidate antibodies, and then ran through the usual developability, maturation, improvement of what we get in the screen, until we have what we think could be a therapeutic drug.

• 50:04Dr. Peter Attia?

  How many molecules enter the top of that funnel?

• 50:07Speaker 01

  Oh, there might be thousands of antibodies that get tested initially. This is done with something called phage display technology. So, I would say for the past 15 to 20 years, we don't make antibodies in mice anymore. It's all done in, by recombinant DNA.

• 50:25Dr. Peter Attia?

  Recombinant DNA, using these viruses. Okay.

• 50:27Speaker 01

  And I think back, I've been in the business long enough, you know, I've made antibodies by immunizing mice, and fusing cells, and growing them up, and putting them back into mice as a site's tumors, to get enough antibody to do experiments with. I mean, it was terrible. It's much better now.

• 50:46Dr. Peter Attia?

  So, you're literally running a screen with all of these antibodies, and you're screening for two things, but, well, basically, one thing. What is going to give me the lowest concentration that binds to this ligand? That binds, sorry, to this receptor?

• 51:01Speaker 01

  Yes, so...

• 51:02Dr. Peter Attia?

  Knowing that you have to be below a certain concentration?

• 51:05Speaker 01

  We knew we needed really high affinity antibodies. There were some things we didn't know. So, in the laboratory, most of the time, you can measure a cell's surface receptor on the surface of the cell, pretty easily, using things like flow cytometry. The activin type 2 receptors are actually expressed at such low levels, you can't see them by flow cytometry, unless you somehow very artificially manipulate the cell. So, we had to create a screening assay, that was essentially a reporter assay. So, we couldn't measure the receptor on the surface of the cell. We could have developed an assay to do that, but it would have been very laborious, radioactivity, not necessary.

• 51:47Speaker 01

  So, we put in a reporter gene, which is, and basically made the cells glow with firefly luciferase, if the ligand bound, myostatin or activin. And then we were looking for decrease in the glowing.

• 52:02Dr. Peter Attia?

  Yep.

• 52:03Speaker 01

  With therapeutic intervention. And we also didn't know whether we needed to inhibit activin receptor type 2A, or B, or both. Most of the work in vitro suggested, for muscle hypertrophy, most of it was driven by 2B, but we weren't sure. And we ended up getting a 2B preferential drug, but it also hits 2A.

• 52:31Dr. Peter Attia?

  And this has nothing to do with muscle fiber type?

• 52:34Speaker 01

  No, this works on all fiber types.

• 52:36Dr. Peter Attia?

  Oh, okay.

• 52:38Speaker 01

  And then we looked for antibodies that worked in that cellular assay, where we wanted to prevent cells from glowing, when we added myostatin and activin. It had to work on both of them. So, it was, it shouldn't matter which ligand you put in, the antibodies should block their activity. And the affinity of the antibodies had to be really good. So, it had to be much stickier than the ligands for the receptor. And so, we had that. And then, the real important experiment is, could we block the activity in an animal?

• 53:11Dr. Peter Attia?

  But just that first step, Lloyd, until you could identify candidates, how many months was that?

• 53:17Speaker 01

  Years.

• 53:17Dr. Peter Attia?

  That was years. So, again, just going back to the analogy of building a skyscraper, that's the planning phase of the skyscraper, that's the excavation of the hole, that's probably the laying the foundation. You haven't actually put any of the big pillars up yet.

• 53:33Speaker 01

  Right. It's the permitting, it's securing the funding.

• 53:36Dr. Peter Attia?

  Yeah.

• 53:36Speaker 01

  It's the, it's sort of the site planning, it's all of that, from your building perspective.

• 53:42Dr. Peter Attia?

  And, by the way, I assume that the standard estimate 20 years ago was, every approved drug is approximately 10 years and a billion dollars. That's got to be pretty low today. What's the, do you have a sense of what the more accurate dollar figure is? It's got to be more than a billion today, per approved drug.

• 54:01Speaker 01

  Oh, yeah. There's a Tufts organization for the study of drug development, and they think it's, I don't know, 2, 3, 4 billion, something like that.

• 54:10Dr. Peter Attia?

  Yeah. The part you're doing now is time consuming? Luckily, it's not that expensive, correct?

• 54:14Speaker 01

  Right.

• 54:14Dr. Peter Attia?

  You're spending millions of dollars, but not necessarily, you know, tens of millions at this point.

• 54:20Speaker 01

  Yes, yes.

• 54:21Dr. Peter Attia?

  So, you finally identify a candidate, or several candidates that you now want to take to the next step, which is, hey, in vivo, does this thing work?

• 54:30Speaker 01

  Yeah, so, we would typically have 2 to 10 at this stage. And it's taken years, because we have to work through the biology, and make sure that we understand what's going to happen. Not because we want to save the cells in the Petri dish, but because we don't want to start something unless we have confidence it'll succeed if we pass each step. So, 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. We need to make the reagents, we need to make the myostatin and the activin A, and all the tools we need to do these experiments.

• 55:14Speaker 01

  So, and then run the experiments. And we have to make the antibodies, and that takes quite a bit of time, as well as developability on the antibodies, which means, we need to, at the very earliest stage, have high confidence that we're going to make an antibody that we could give to people, and it'll be stable. And it'll have predictable physical properties, and it'll have a shelf life. And all of these things are what we build into the antibodies at this very early stage.

• 55:43Dr. Peter Attia?

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

• 55:50Speaker 01

  It's still one of the biggest unknowns. And the best way to do it is to use fully human antibody.

• 55:57Dr. Peter Attia?

  Humanized, yeah.

• 55:57Speaker 01

  Not humanized, fully human.

• 55:59Dr. Peter Attia?

  Full, straight up human.

• 56:00Speaker 01

  Yeah.

• 56:00Dr. Peter Attia?

  Can you explain to folks the distinction there?

• 56:02Speaker 01

  Yeah, well, there's, 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 antibody codon usage, and amino acid preference, and so forth. Whereas, fully human means you're starting with human genetic material antibodies.

• 56:29Dr. Peter Attia?

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

• 56:35Speaker 01

  As little as possible.

• 56:35Dr. Peter Attia?

  Part of the sequence.

• 56:36Speaker 01

  As little as possible. There's going to be something new because antibodies have this

• 56:40Dr. Peter Attia?

  By definition, yeah.

• 56:41Speaker 01

  intrinsic ability to recombine and create new sequences.

• 56:44Dr. Peter Attia?

  Yep.

• 56:44Speaker 01

  Now, in vivo, in people, so if you make some brand-new antibody and it's not suitable for some reason, it gets selected out. 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 pair-wise and so forth. But you don't really know until you put it into people. 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 going to have high-affinity binding to an MHC molecule and so forth? And we do all that stuff. But you still don't

• 57:27Speaker 01

  know until you do it. Now, it's an interesting historical perspective because I'm getting old enough to be interested in history now. 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. It's an anti-T cell antibody, human T cell antibody, and we still use it to this day.

• 57:55Dr. Peter Attia?

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

• 57:58Speaker 01

  Yep.

• 57:59Dr. Peter Attia?

  Wow. So it's, it's broad.

• 58:01Speaker 01

  Yes.

• 58:02Dr. Peter Attia?

  It's going after every T cell.

• 58:03Speaker 01

  Yes. Right. And there's, there's, there's, there's rabbit anti-thymocyte globulin, too, that's still used clinically.

• 58:09Dr. Peter Attia?

  That's a blast from the past.

• 58:11Speaker 01

  It's still used, yeah. And these were the first antibodies used in people. And of course, the other antibody, the other foreign antibodies that are still used are antivenoms. Most of them are horse serum. As you can imagine, you only want to get bitten by a snake once and need that. Because when you need it the second time, you have kind of a ferocious serum sickness response.

• 58:34Dr. Peter Attia?

  Great point. So you identify BEMA plus a few others, and you start now running these into the mice?

• 58:43Speaker 01

  Yes.

• 58:44Dr. Peter Attia?

  Is there another chance that because you've gone to all the trouble to make sure you have a human antibody, it won't work in the mice when it otherwise would have worked in humans?

• 58:55Speaker 01

  We test that beforehand.

• 58:57Dr. Peter Attia?

  Okay, got it.

• 58:58Speaker 01

  So this is, this is again, part, there's an enormous amount of detail in drug development. And one of the things is that your drug has to cross-react, I mean, work also in at least one of the two species we're going to use later for toxicology. And it has to work in a species we're going to use for pharmacology. If it doesn't, then you need to make surrogate drugs to do that. But in our case, we made one that worked in rodents. Now, it turns out that bemagromab is, is pretty immunogenic in mice, but not in rats. Although...

• 59:41Dr. Peter Attia?

  How common is that?

• 59:42Speaker 01

  It's kind of idiosyncratic. So the construct we ended up using in mouse experiments was something called CDD866, which was, you talked about humanizing antibodies. We murinized bemagromab so that we could use it in mice.

• 1:00:00Dr. Peter Attia?

  So you could go back and use it?

• 1:00:01Speaker 01

  Yeah.

• 1:00:01Dr. Peter Attia?

  That makes sense.

• 1:00:02Speaker 01

  And, and to make a long story short, we were able to give these antibodies to mice and see if it caused muscle hypertrophy or not.

• 1:00:10Dr. Peter Attia?

  And how much did it do so relative to the pure myostatin knockouts that were enormous?

• 1:00:16Speaker 01

  Probably more so than the myostatin knockouts.

• 1:00:19Dr. Peter Attia?

  Wow.

• 1:00:19Speaker 01

  It was really impressive.

• 1:00:22Dr. Peter Attia?

  Again, we're, we're going to link in the show notes to what these images look like. But it is, it is truly a caricature.

• 1:00:30Speaker 01

  It's impressive in the mice. Look at also the whipet dogs, the Belgian blue cattle that are double muscled. It's, it's impressive.

• 1:00:39Dr. Peter Attia?

  Did you do anything else, Lloyd, at that time? So when you demonstrate that BEMA is making bodybuilding mice, was there any assessment of muscle function?

• 1:00:51Speaker 01

  Yes.

• 1:00:52Dr. Peter Attia?

  Okay. And what did you find?

• 1:00:54Speaker 01

  The mice were stronger and could run faster.

• 1:00:57Dr. Peter Attia?

  Okay.

• 1:00:57Speaker 01

  But remember, they had perhaps a 30% increase in their muscle mass. I mean, which is, which is huge. And people can look at the pictures online and see, it's, it's quite obvious. So it, it doesn't work this well in humans. Because just, just skipping all the way ahead, and we'll come back, humans get about 4% to 8% increase in muscle mass. Most of the people we've tested have been older people, which is one caveat, whereas...

• 1:01:27Dr. Peter Attia?

  Did you do it in old mice?

• 1:01:30Speaker 01

  Not in old mice. I think David Glass did some experiments in older rats. And it still worked, but not quite, not as well as in younger ones. And remember, when people do these muscle experiments in rodents, they almost always do males because it works better in males than females.

• 1:01:47Dr. Peter Attia?

  Cool thyself. It would be interesting to know, as you ran it across a continuum of escalating age, what the, what, what accounts for the reduction in efficacy, right? Is it, is it substrate limited? Is it a muscle protein synthesis problem? I mean, what, what is, you know?

• 1:02:06Speaker 01

  I don't think, I don't, I don't think that's been studied formally by scientists. It might be known in the, in the bodybuilding community. And just, just a heads up to the, to the listeners who might be bodybuilders, the first thing that any company does when they're working on a drug that has the potential for abuse is we work with WADA, the World Anti-Doping Agency, to make sure that they can screen for these things.

• 1:02:32Dr. Peter Attia?

  So where in the pathway of BEMA did you begin notifying WADA that we're working on this thing?

• 1:02:39Speaker 01

  Soon as we had a ther, soon as we had a therapeutic antibody.

• 1:02:42Dr. Peter Attia?

  Soon as it worked in the mice.

• 1:02:42Speaker 01

  We started that process. And, and basically, they've, they've had an assay for more than 10 years.

• 1:02:53Dr. Peter Attia?

  Have they ever caught it? Have they ever screened?

• 1:02:54Speaker 01

  I have no idea.

• 1:02:56Dr. Peter Attia?

  That's funny. Okay. So after the, you get the home run in mice, do you want to go into a primate? Where do you typically go for mice?

• 1:03:06Speaker 01

  So for therapeutic antibodies, often it includes a primate, simply because we want to 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. So we, we typically use non-human primates for this.

• 1:03:32Dr. Peter Attia?

  When you're at the mouse stage, Lloyd, how, how are you screening for tox besides the most obvious, right? Obviously, mortality or something catastrophic is obvious. But 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 going to go to the primate or whatever other model we're going to look at and reassess tox as we get closer to our species of interest?

• 1:04:16Speaker 01

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

• 1:04:49Dr. Peter Attia?

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

• 1:04:53Speaker 01

  For example, yes.

• 1:04:53Dr. Peter Attia?

  If we, yeah.

• 1:04:54Speaker 01

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

• 1:05:01Dr. Peter Attia?

  Yep.

• 1:05:02Speaker 01

  But secondly, we want to 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 usually the end, for example, or neurologic. If it's serious organ toxicity...

• 1:05:27Dr. Peter Attia?

  But there's enough of a prodrom. So for example, if it's...

• 1:05:32Dr. Peter Attia?

  Well, you look at a drug like Lamisil, right? Something as supposedly benign as Lamisil. I mean, that can destroy your liver.

• 1:05:41Speaker 01

  Yes.

• 1:05:42Dr. Peter Attia?

  There you can stop the drug. So that's your point. It's monitorable and reversible.

• 1:05:46Speaker 01

  Yes.

• 1:05:47Dr. Peter Attia?

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

• 1:05:49Speaker 01

  Yeah.

• 1:05:50Dr. Peter Attia?

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

• 1:05:58Speaker 01

  So you're describing idiosyncratic liver toxicity, which is the most common reason drugs get pulled off the market still. And I personally have killed drug programs for that. And it's hard to, can't predict it pre-clinically.

• 1:06:14Dr. Peter Attia?

  Yeah.

• 1:06:15Speaker 01

  Yeah, so, so let's get back.

• 1:06:16Dr. Peter Attia?

  You get Bima into the primates?

• 1:06:19Speaker 01

  Yes.

• 1:06:19Dr. Peter Attia?

  And how does it, how does it perform?

• 1:06:22Speaker 01

  Well, in order to do toxicology studies, you have to know how much to give them and how long it's going to last and what it's doing. So there are, there are preliminary studies in a small number of animals. And so we did those, but we did them long enough so that we could see the muscle hypertrophy of what were going to happen. And it did work, not as well as in the rodents, but it did work. So it gave us confidence that we could move ahead with the rest of the activities. Now, manufacturing enough antibodies for use in larger animals is, you know, is, is time and expense. And so all of that was going on in parallel.

• 1:07:01Dr. Peter Attia?

  And each of these decisions, so you're doing this all inside of Novartis. Is there an IC, is there an investment committee that basically revisits every time there is a new, you know, allocation of capital to move from one thing to the other where everybody presents? And how, how does that typically work in a large company?

• 1:07:19Speaker 01

  All big drug companies work kind of the same way in that there are, there are typically two or three or four, depending on the company, major checkpoints where all the data are assembled and, and made into a slide decks and presented and feedbacks obtained and programs, courses adjusted. And, and so that happens. And I, and I think it's, it's more frequent, but faster at small companies. But things are constantly being reevaluated and reassessed.

• 1:07:49Dr. Peter Attia?

  Yeah, and what's interesting for, for folks listening to us is we're talking about this in the context of a large company that doesn't have to go out and raise capital every time it does this. But the exact same idea that you just described, everything you've just said, could have been done by a startup. But now it would have a totally different look and feel in that, hey, we're going to go raise some seed funding to go test this idea. Okay, guess what? We were able to find the antibody. We're going to have to go raise another, you know, $20 million and boom, boom. And now they'd be at the stage where they'd be probably raising a Series B? Or no, probably this would be, still be an A, I think, as they go into the primate.

• 1:08:26Speaker 01

  Whatever you call it, you.

• 1:08:29Dr. Peter Attia?

  But give folks a sense of how much you'd have to raise for this next stage, which is basically your pre IND.

• 1:08:36Speaker 01

  So if it includes many, so you have to manufacture.

• 1:08:40Dr. Peter Attia?

  It's going to include the primate.

• 1:08:41Speaker 01

  Toxicology and clinical material. You have to run the IND enabling studies, which is toxicology and, and some other things. And frankly, investors want value creation for their money and reasonably so. So I would think for bemagromab, if this were in a small company, the value creation step would be showing muscle hypertrophy in the very first clinical study. So I, so the funding that I would raise would be IND enabling.

• 1:09:14Dr. Peter Attia?

  Plus phase one.

• 1:09:15Speaker 01

  Plus phase one, plus a runway to raise the next round.

• 1:09:19Dr. Peter Attia?

  Yep. And you would structure your phase one to demonstrate efficacy, even though technically you only need to do tox.

• 1:09:26Speaker 01

  Yes.

• 1:09:26Dr. Peter Attia?

  You would have it long enough, big enough.

• 1:09:29Speaker 01

  Not, not tox, but safety.

• 1:09:30Dr. Peter Attia?

  That's right.

• 1:09:30Speaker 01

  And tolerability.

• 1:09:31Dr. Peter Attia?

  Yeah, yeah. So, okay, and then just for using Bima as an example, how many dollars would that be from where we are now to give you that runway into two A?

• 1:09:40Speaker 01

  In today's dollars, probably $20 million.

• 1:09:43Dr. Peter Attia?

  Okay, yeah. So Series A.

• 1:09:45Speaker 01

  Thereabout, yeah.

• 1:09:46Dr. Peter Attia?

  Okay.

• 1:09:47Speaker 01

  Maybe.

• 1:09:48Dr. Peter Attia?

  That's lower than I would have guessed, by the way.

• 1:09:50Speaker 01

  Maybe a little more.

• 1:09:51Dr. Peter Attia?

  Okay.

• 1:09:51Speaker 01

  It depends on where you do the manufacturing and.

• 1:09:54Dr. Peter Attia?

  So for, for Novartis, this is nothing. For a startup, this is everything. You're betting the farm.

• 1:10:00Speaker 01

  Well.

• 1:10:01Dr. Peter Attia?

  I don't want to make light of it inside of Novartis, but the point is, Novartis doesn't have to go back to the public market to say, I need to raise another $25 million to fund this. They're doing a lot of these in parallel.

• 1:10:09Speaker 01

  Big companies, though, have, their, their resources are stretched too. It's kind of funny thinking about it, looking from the outside, but having been inside a big company,

• 1:10:21Speaker 01

  people are competing for a fixed amount of research dollars, the, the people within the company. And resources are allocated based on company strategy. And ironically, sometimes there's more project capital available in a small company than in a big company. Because the, the small company's got one or two or three.

• 1:10:40Dr. Peter Attia?

  Right, they're taking fewer shots on goal.

• 1:10:42Speaker 01

  All the money's going there.

• 1:10:43Dr. Peter Attia?

  Yeah.

• 1:10:43Speaker 01

  Whereas there are hundreds in the big companies. So, and I've seen it both ways. I've seen some big company projects get high profile, high importance, well-funded. So, yeah, so we'll say 20 to 30 million dollars maybe at, at this stage. And bemagromab at that point made it through rodent and non-rodent toxicology studies and what we call DMPK, which is distribution metabolism pharmacokinetics. It's knowing that when you give a participant or a patient, a subject, a medicine, does it get into their body?

• 1:11:27Speaker 01

  Does it go to where you want it to be? Does it do what you expect it to do? You have to know all that stuff before you go into patients for the first time. And we assess that in animals. You asked earlier, what do you actually do to measure the toxic effects of a medicine? And animals receive courses of therapy and we do blood tests, just like we do in people. Sometimes we would do X-rays if it was warranted. And then they get autopsied to look at all the organs and look for microscopic changes that you might not perceive clinically. And we know, we have to know all of that before we give people an experimental medicine for the first time.

• 1:12:09Dr. Peter Attia?

  So any red flags whatsoever as you, or anything that is of concern, not necessarily a red flag, but anything that's, that's still an unknown as you're going into the phase one?

• 1:12:22Speaker 01

  Lots, lots of unknowns going in. And there are always things of concern. I've never seen a drug development program that couldn't be stopped for some reason. And you, you have to balance the unknowns and the uncertainties and the risks with the potential benefits and make it, and make a decision about whether you move forward or not. It, it's kind of a joke in the industry that every really successful program has been almost killed or killed several times before it eventually makes it out into, into humans and then eventually commercialization.

• 1:13:01Dr. Peter Attia?

  What's the approximate attrition from that first candidate drug discovery to the IND filing? That's a winnowing down of what to, what to one?

• 1:13:15Speaker 01

  It's hard to put it in aggregate because it depends based on the format of the drug. And then there's other factors like strategy and funding and everything else. But for, for biologics like bemagromab and a therapeutic antibody, it's, it's pretty low, actually.

• 1:13:34Dr. Peter Attia?

  Five to one, six to one?

• 1:13:36Speaker 01

  I, I would say maybe 30% of them actually could get into humans.

• 1:13:41Dr. Peter Attia?

  Okay. Yeah, more than I would have thought.

• 1:13:43Speaker 01

  Yeah. It, it's simply because there are no off-target adverse effects with antibodies in general. There are some specific counterexamples to that, but in general, an antibody is not like a small molecule that could have liver tox or some other tox that you can't predict for reasons that you don't understand.

• 1:14:03Dr. Peter Attia?

  That's a great point. Yeah. So maybe I'll restate that so folks get it because, because the antibody is so specific, by definition, it can't bind to many other things.

• 1:14:14Speaker 01

  And in fact, we screen to make sure it doesn't.

• 1:14:16Dr. Peter Attia?

  Yeah, yeah. Whereas the chemical can do lots of things off target. You know, I had on, recently, we had a podcast talking about CTEP inhibition. And, you know, the very first version of that drug lowered LDL cholesterol.

• 1:14:32Speaker 01

  But raised blood pressure.

• 1:14:33Dr. Peter Attia?

  Blood pressure. And that was a completely off-target complication of the drug.

• 1:14:36Speaker 01

  Yep, exactly. So that doesn't generally happen with biologists.

• 1:14:41Dr. Peter Attia?

  Got it. So that's why you have the higher throughput.

• 1:14:42Speaker 01

  Yeah.

• 1:14:43Dr. Peter Attia?

  Okay. Let's skip, so you filed the IND and you're now ready to start a phase one.

• 1:14:48Speaker 01

  So an IND is requesting.

• 1:14:50Dr. Peter Attia?

  We should tell people what it is.

• 1:14:51Speaker 01

  Regulatory permission to administer the drug to people.

• 1:14:56Dr. Peter Attia?

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

• 1:14:58Speaker 01

  Yes.

• 1:14:59Dr. Peter Attia?

  Yeah, where in that process did you file?

• 1:15:01Speaker 01

  Patents typically get filed.

• 1:15:04Speaker 01

  Again, there's a.

• 1:15:06Dr. Peter Attia?

  You want to do it as late as possible, but while still protecting.

• 1:15:09Speaker 01

  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.

• 1:15:21Dr. Peter Attia?

  Okay, wow.

• 1:15:22Speaker 01

  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 want to have it protected.

• 1:15:31Dr. Peter Attia?

  Okay. 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?

• 1:15:46Speaker 01

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

• 1:16:26Dr. Peter Attia?

  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 retitrutide.

• 1:16:48Speaker 01

  Yeah, no, they're not.

• 1:16:49Dr. Peter Attia?

  Yeah, exactly. Maybe, eh, eh, use the GMP

• 1:16:52Speaker 01

  Yeah.

• 1:16:53Dr. Peter Attia?

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

• 1:17:07Speaker 01

  Right. So GMP stands for good manufacturing process. And it's basically a commitment by the manufacturer to use high quality standards with extensive documentation to be able to prove what they've made 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.

• 1:17:38Dr. Peter Attia?

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

• 1:17:41Speaker 01

  Exactly. It's purity, it's activity, it's contamination or lack thereof, it's sterility, if you will. 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 we can have confidence in it. Basically, the factories are inspected and the factories that make it have. And typically there are many manufacturers involved. When, when you buy a, with the exception of saying, buying a bottle of tirzepatide from Eli Lilly. But typically when you buy a drug from somebody,

• 1:18:23Speaker 01

  the drug's substance, the chemical is manufactured by one company. And then it is formulated or put into a, 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 in this, this whole manufacturing, uh, infrastructure and pipeline is, is well controlled and well documented and you can buy online peptides that may be the same as retitrutide, they might not, you have no way of knowing.

• 1:19:03Dr. Peter Attia?

  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.

• 1:19:18Speaker 01

  Yes.

• 1:19:19Dr. Peter Attia?

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

• 1:19:22Speaker 01

  I, I think it's a big mistake to buy these peptides from, from fly by night manufacturers. Conceptually, it's no different than going in, in 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? Baking soda, you have no idea what's in there. It's the same thing with these peptides. You have no idea. 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 non-existent. I, I've been reading in the popular literature about this one that's, I think it's called BP197.

• 1:20:03Dr. Peter Attia?

  BPC157.

• 1:20:05Speaker 01

  157, yeah. All of the data for that peptide come from one investigator who's the only person published on it. And remember, the fundamental tenet of science is if it's real, it's reproducible. This has not been reproduced.

• 1:20:21Speaker 01

  What the hell is it? It's not encoded in the human genome, so it's not a human peptide.

• 1:20:27Dr. Peter Attia?

  And it, it has no known receptor.

• 1:20:30Speaker 01

  Yeah. So we don't even know how it works. There's so many red flags for this.

• 1:20:35Dr. Peter Attia?

  No, it's the, it's the poster child for what I would argue is the absolute greatest grift of the entire health and wellness industry.

• 1:20:44Speaker 01

  There's a lot of, I'm sorry if I'm insulting you, Peter. There's a lot of grift in the health and wellness industry.

• 1:20:49Dr. Peter Attia?

  Ah, you're not insulting me.

• 1:20:50Speaker 01

  Um.

• 1:20:51Dr. Peter Attia?

  But that, but that's my point. Despite how much grift there is in the health and wellness industry, I'm, I'm putting BPC157 on the podium at least.

• 1:20:59Speaker 01

  I would too. Yeah. I would too. Okay. So we, we've made bemagromab and it's made it through all of the 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 toxicology in animal species. We talk about safety and tolerability in humans. And again, most antibodies, including bemagromab, won't have safety and tolerability issues that are off the pathway that it's working on.

• 1:21:42Speaker 01

  And didn't really see any safety and top, 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, they had cardiac hypertrophy. However, 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.

• 1:22:10Dr. Peter Attia?

  So does that mean that you didn't know if the cardiac hypertrophy was in response to more, more resistance that the heart had to work against? Or whether the antibody was working directly on the cardiac myocytes and increasing hypertrophy there as it was in skeletal muscle or both?

• 1:22:28Speaker 01

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

• 1:22:37Dr. Peter Attia?

  Should have bigger hearts.

• 1:22:38Speaker 01

  Should have bigger hearts. And that was the argument we made to regulators. And so we didn't think there was any specific cardiac toxicity. And typically in toxicology studies, you have something we call a recovery period where 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 bemagromab, the muscles got smaller and the heart got a little smaller.

• 1:23:06Dr. Peter Attia?

  How often was it dosed?

• 1:23:07Speaker 01

  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.

• 1:23:22Dr. Peter Attia?

  And then when you got to the humans?

• 1:23:24Speaker 01

  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.

• 1:23:32Dr. Peter Attia?

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

• 1:23:35Speaker 01

  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

• 1:23:45Speaker 01

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

• 1:23:50Dr. Peter Attia?

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

• 1:23:57Speaker 01

  You don't.

• 1:23:58Dr. Peter Attia?

  You don't.

• 1:23:58Speaker 01

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

• 1:24:01Dr. Peter Attia?

  Is there a general rule of thumb?

• 1:24:03Speaker 01

  You measure both and you want both of them to be higher in the animals than what you get in people.

• 1:24:07Dr. Peter Attia?

  Okay.

• 1:24:08Speaker 01

  Now, this is in general medicine therapeutic indications. In some nasty oncology drugs, toxic effects and therapeutic effects are at the same exposure or even lower sometimes.

• 1:24:20Dr. Peter Attia?

  Yeah.

• 1:24:21Speaker 01

  But the medical need is so great that you accept the toxicity.

• 1:24:24Dr. Peter Attia?

  Well, I was going to actually use that as an example. We, we sort of skipped ahead a little bit on the phase one patient selection. We, we rushed through that, but, or actually we, we didn't answer it. We got, we, we, we went off topic. We're going to come back to which patients do you select for the phase one? And that really depends on the drug. Cause in an oncology drug, you're going to test it on the most recalcitrant cancer patient, right? You're going to test it on a patient who's progressed through every therapeutic. They have stage four version of whatever cancer you're testing. And this is the hail Mary. And you're not just testing for tolerance and side effects, you're hoping to get a sliver of efficacy.

• 1:25:02Speaker 01

  Yeah, that's the most common.

• 1:25:03Dr. Peter Attia?

  Escalation.

• 1:25:03Speaker 01

  That's the most common scenario in cancer.

• 1:25:06Dr. Peter Attia?

  But here, what are you doing? Are you going out to the most frail sarcopenic elderly person? Or are you going to test it in?

• 1:25:12Speaker 01

  So, so what I do personally and, uh, and a very experienced drug developer named Bob Schmouter taught me this, and I, I think he's right. Is.

• 1:25:24Speaker 01

  Ideally, you'd like to test this, a new medicine, in the cleanest population you possibly can, where anything you measure is related to the drug and not some underlying disease or other thing. However, we do not want to expose healthy volunteers to risks if we possibly can.

• 1:25:46Dr. Peter Attia?

  Right.

• 1:25:47Speaker 01

  So we use our best clinical judgment to say that I don't want to expose people to a risk greater than that of a lightning strike in a year.

• 1:25:58Dr. Peter Attia?

  Is that literally a probabilistic formula you use?

• 1:26:01Speaker 01

  Yep, that's what I use.

• 1:26:02Dr. Peter Attia?

  Interesting.

• 1:26:02Speaker 01

  So the risk of being struck by lightning in the US in a year is about 1 in 100,000.

• 1:26:09Dr. Peter Attia?

  It's actually, that's actually higher than I would have thought.

• 1:26:11Speaker 01

  Me too.

• 1:26:12Dr. Peter Attia?

  That's a little scary.

• 1:26:13Speaker 01

  But that's what it is.

• 1:26:14Dr. Peter Attia?

  Okay.

• 1:26:15Speaker 01

  And so I don't want the risk of something bad happening to one of my volunteers to be greater than that. And that's frankly, how I explain it to them. So if I can have some confidence that that's true, we will test drugs in healthy volunteers. If we're worried about a toxicity or a risk, then we will go into people who have a potential benefit from the therapy. So you can make a risk benefit argument. And this is all laid out in plain English in the consent forms.

• 1:26:48Dr. Peter Attia?

  But I mean, so first of all, that's a great framework, Lloyd, which is if the, if the risk of adverse event is greater than 1 in 100,000, we must move to a population that is going to potentially get benefit to justify it.

• 1:26:59Speaker 01

  Serious adverse.

• 1:27:00Dr. Peter Attia?

  Yeah. Is that a Lloydism? Or is that a truism across the entire industry? Is that something the FDA would ask of every company?

• 1:27:07Speaker 01

  It's a schmouterism. But Bob, if you're listening, thank you. But.

• 1:27:12Dr. Peter Attia?

  But the FDA doesn't force that?

• 1:27:14Speaker 01

  The FDA doesn't force that, but the, the principle is still there.

• 1:27:19Dr. Peter Attia?

  Okay, but it's a great standard.

• 1:27:20Speaker 01

  Yeah, I, again, and if you think about the industry as a whole, how do we do in bringing new medicines into healthy volunteer populations? I've been in this business, partially in academia, wholly in industry, for maybe 30 years total where I've been watching this. And about once every 10 years, we see something serious happen to healthy volunteers. Once every 10 years in a study. So that's pretty good. And we learn something when those happen. So we're talking about therapeutic antibodies. The one that comes to my mind and maybe to others is the T genero incident.

• 1:28:02Dr. Peter Attia?

  Say more about that. I don't remember that.

• 1:28:03Speaker 01

  This was a therapeutic antibody that was directed against CD28. It was an agonist antibody.

• 1:28:09Dr. Peter Attia?

  Okay.

• 1:28:09Speaker 01

  Now, CD28 is an inhibitory receptor on T cells. And the idea was, I'm sorry, is it, is it activating receptor on T cells? And I forget the actual therapeutic indication they were going for. But they tested the antibody pre-clinically. Everything was fine. And then they started at a very low dose in humans. And what we think happened is they cross-linked the CD28 receptor. And they had extremely strong T cell activation and an acute cytokine release syndrome in healthy volunteers. Some of them died. I mean, it was terrible.

• 1:28:45Dr. Peter Attia?

  I mean, why did more than one of them die? In other words, why didn't they figure this out the very first time they administered this?

• 1:28:50Speaker 01

  That's super important. So that study, which that happened, boy, more than 20 years ago. That experience is why ever since, we typically have sentinel patients in dosing cohorts when we're bringing something brand new into people. So they dosed, I think, six people at once with the active drug.

• 1:29:12Dr. Peter Attia?

  Oh, my God.

• 1:29:13Speaker 01

  We don't do that anymore.

• 1:29:14Dr. Peter Attia?

  Yeah, wow.

• 1:29:16Speaker 01

  The other one, there was a example with a small molecule, Bi-A-L, I think was the, was the example. B I A L, people can look it up. But it's, it's extremely uncommon to have healthy volunteers have anything bad happen to them in a, in a drug study. Extremely uncommon. If you think of the.

• 1:29:36Dr. Peter Attia?

  I remember there was one at Hopkins when I was there. It was, it was an, oh, no, no. You know what it was? I'm sorry, that was not a, it was a woman that, a healthy volunteer that underwent a bronchoscopy and I think had a horrible bronchospasm.

• 1:29:51Speaker 01

  That.

• 1:29:52Dr. Peter Attia?

  So it was, if I'm remembering correctly, it wasn't a drug that caused the issue, but it was a horrible adverse event to.

• 1:29:59Speaker 01

  Procedures can have.

• 1:29:59Dr. Peter Attia?

  But anyways, but she, she died.

• 1:30:01Speaker 01

  Ooh, procedures can have.

• 1:30:02Dr. Peter Attia?

  Yeah.

• 1:30:03Speaker 01

  Adverse consequences, which, which are known and disclosed in the, in the consent forms.

• 1:30:07Dr. Peter Attia?

  This gave me a lot of, when I was in medical school, I was, I mean, I was so broke and doing anything I could to generate a buck. I vol, I was probably one of the most volunteered people for studies at Stanford. And like, if, if there was a study that paid $1,000, it didn't matter what it asked of me, I would do it. And I, I remember coming away from that. I mean, I had radial lines in my, I had, you know, as you know what a radial line is, but arterial lines into my radial arteries that to this day, I still have scars over my wrists. Can you, can you imagine that I subjected myself to that?

• 1:30:45Speaker 01

  That, that seems a little much. My, I think many of us as medical students volunteered for this stuff. My personal favorite was, there was, there was a study called brain electrical activity mapping that Children's Hospital was running when I was a medical student. And essentially, they, they attach electrodes to your head. And then you go sleep in the lab and they monitor that and video, video you while, while you're sleeping. They loved me as a subject because I was bald as a medical student. It was really easy to put electrodes on and off. I loved it because all I had to do is go in and go to sleep. But there were, there were some others, like inhaling radioactive microspheres.

• 1:31:25Dr. Peter Attia?

  I used to donate plasma via plasma foresis as often as I could when I was at the NIH. And on one occasion, I was in there, and this was like a lymphocyte plasma foresis. It's a four hour procedure. And again, it probably paid 200 bucks, which seemed like.

• 1:31:41Speaker 01

  It was a lot of money in those days.

• 1:31:42Dr. Peter Attia?

  When you're a medical student, that is, that's infinite money. And then at one point, somehow the nurse stepped out and the lab locked. And I was stuck in their lock and they could not find a key. So they couldn't get back in. They were losing their minds, but I didn't know it. I was just in there watching whatever movie was on the thing. It turned out to be like one of the most stressful moments in the, in the NCI history, you know, trying to figure out a way to get a spare key to get into the lab and, and take, and I was completely oblivious to it.

• 1:32:14Speaker 01

  Oh, yeah.

• 1:32:15Dr. Peter Attia?

  Okay, so back to patient selection.

• 1:32:17Speaker 01

  Yes.

• 1:32:18Dr. Peter Attia?

  So ultimately for BIMA.

• 1:32:19Speaker 01

  Ultimately for BIMA, a healthy volunteer study.

• 1:32:22Dr. Peter Attia?

  You did go with healthy volunteers?

• 1:32:24Speaker 01

  Older volunteers.

• 1:32:26Dr. Peter Attia?

  Okay.

• 1:32:26Speaker 01

  So people.

• 1:32:27Dr. Peter Attia?

  What was your criteria specifically in terms of muscle mass?

• 1:32:31Speaker 01

  So I actually didn't run these studies. The clinicians involved were Dan Rux and Ronan Rubenoff at the time. But the, the principle here is healthy volunteers doesn't necessarily mean you're 20 something year old with no problems. It means people without typically diagnosable disease or concomitant medications that could confuse.

• 1:32:54Dr. Peter Attia?

  Yeah.

• 1:32:54Speaker 01

  Any, any assessments. In the case of BIMA, because we were thinking older adults, these were older healthy volunteers and people in whom we would be able to measure some of the effects of BIMA, we hope. And again, what you measure in a healthy volunteer study depends on what the drug is expected to do and what, and what adverse effects you might expect. So there's some things you always do, like a set of standard blood tests. But in, in the case of BIMA, we were assessing people's muscle mass.

• 1:33:26Dr. Peter Attia?

  Via DEXA?

• 1:33:27Speaker 01

  And strength. This, this is almost archaeology at this point, thinking of what, you know, what's, what we measured. But we would have measured muscle mass. And at different times, we used MRI and we used DEXA.

• 1:33:38Dr. Peter Attia?

  Okay.

• 1:33:38Speaker 01

  I don't remember what that study had.

• 1:33:40Dr. Peter Attia?

  Got it.

• 1:33:41Speaker 01

  But we, we would have measured muscle mass. We measure soluble muscle proteins in the blood like CK and aldolase and LDH and so forth.

• 1:33:51Dr. Peter Attia?

  Did you see any adverse effects in the phase one?

• 1:33:53Speaker 01

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

• 1:34:32Dr. Peter Attia?

  And how many steps of dose escalation did you do in that study? Or by the way, if that's too much detail to remember, don't worry about it. But just, I'm wondering if you remember how high you got relative to what was an efficacious dose?

• 1:34:44Speaker 01

  So there's some principles here. 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 safety and tolerability issues in people, while at the same time, never exceeding the exposures we've tested in animals. So the study designs include the opportunity to go as high as we can. Typically in antibodies, that ends up being as, as high as is feasible.

• 1:35:13Speaker 01

  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, of course, they're also tested as part of the toxicology studies because they're in the drug we give the animals. But we can't exceed the exposure to the contaminants either in the clinical studies. So sometimes that, sometimes it's the volume we can administer, the mass we can administer and so forth. So, so I think the highest dose that we ended up doing in bemagromab was something like 50 to 100 milligrams per kilogram, but you know, I don't remember.

• 1:35:55Dr. Peter Attia?

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

• 1:35:59Speaker 01

  Initially you'd administer once, then based on the emerging results for how long that lasts. And we knew what exposures we needed to reach in order to get maximal efficacy based on the culture data. There were a lot of 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. But again, we don't exceed the exposures that we get in animals. So I think after the single dose study, we probably did three doses. And, and that was it for the first in human study.

• 1:36:42Speaker 01

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

• 1:36:54Dr. Peter Attia?

  So the end point for the phase one, before you move to phase two, 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?

• 1:37:08Speaker 01

  Yes.

• 1:37:08Dr. Peter Attia?

  What did you need to submit to the FDA to say, okay, we, have we checked our phase one box?

• 1:37:15Speaker 01

  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.

• 1:37:24Dr. Peter Attia?

  And Novartis is a European company, right?

• 1:37:27Speaker 01

  Yes.

• 1:37:27Dr. Peter Attia?

  Based in Switzerland, but this work was being done in the US?

• 1:37:31Speaker 01

  I think we did do the first in human study in the US, yeah.

• 1:37:34Dr. Peter Attia?

  Any reason for that? Are European and US regulators so comparable on this point that it's really just a question of where your teams are or?

• 1:37:42Speaker 01

  So every country's a little different. Europe is somewhat homogeneous, but not completely so. Every country's a little different. 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. And then you think about cost of the study, they're different in different countries. And so you integrate all of that stuff.

• 1:38:27Speaker 01

  And that chooses where, at least personally, where I would go to do a first in human study. Countries that are often used nowadays are Germany, uh,

• 1:38:39Dr. Peter Attia?

  Australia is pretty popular, New Zealand.

• 1:38:41Speaker 01

  Australia, New Zealand's very popular now. Things have really changed, I guess, maybe in the past year or two about China being really popular because China has a regulatory environment that's become more favorable. And they can do investigator initiated studies with less supporting data than we require for a typical IND. So it can often be a faster way to test something. And of course China has a lot of patients. So that's something that's being done now too. I personally love doing studies in the US and Taiwan. Taiwan has, they, they have wonderful investigators. They speak English better than we do.

• 1:39:25Speaker 01

  They have a very centralized clinical environment, so they have many patients at a limited number of clinical sites. The regulatory environment is very similar to the US. Australia, 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 CM's drug quality is assessed by the regulators. So they have a clinical trial notification process rather than a approval process. And plus the exchange rate's favorable now so too. So if we get back to what is the trial going to cost, that's useful.

• 1:40:06Dr. Peter Attia?

  And how much reciprocity is there between agencies? So if you, 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?

• 1:40:22Speaker 01

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

• 1:40:24Dr. Peter Attia?

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

• 1:40:37Speaker 01

  So it's, it's, 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 regulator, regulatory authorities and the ethics committee for the study. And they do the review and request modifications and eventually approve. And then the study's run in Australia. 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.

• 1:41:19Dr. Peter Attia?

  Meaning if you had a drug that went all the way to the equivalent of a phase three ready for approval in Australia, and you come back to the US from scratch and say, we want to do, we want to be able to sell this drug in the United States, they're going to say, submit an IND.

• 1:41:33Speaker 01

  Yeah, I, I think so, yes.

• 1:41:34Dr. Peter Attia?

  Yeah, wow. And, but how much do you get the shortcut? Would they still make you do a phase one and a phase two?

• 1:41:40Speaker 01

  No.

• 1:41:40Dr. Peter Attia?

  Or would they let you go straight to phase three?

• 1:41:42Speaker 01

  I would think you could go right to a regulatory study, I mean, to a registration study.

• 1:41:47Dr. Peter Attia?

  Okay.

• 1:41:47Speaker 01

  And, and in fact, this kind of thing is often done if, because typically you do the phase one study somewhere, but rarely in more than one, two or three countries. And then you can use that data to go to many countries for a phase two and then use that data to go globally. There are a few specific examples where you do have to run a phase one study before you go into that country. Best examples, the best defined examples are Japan. So to run a, to run a large study in Japan, you need to have run a phase one study in Japanese people. And there is a formal regulatory definition of who is Japanese from the Japanese regulators.

• 1:42:30Speaker 01

  And you have to provide that data before you can do a larger study in Japan. They're called ethnic sensitivity studies. And scientific rationale for this is that the genetic background of Japanese people can be a little different. Average body size is often different from people in the West. And you want to make sure that the dosing and exposure will be safe and tolerable. But because the Japanese are so well organized and specific about what a Japanese person is, you can do these ethnic sensitivity studies in, in Hawaii, for example, or, or even California, or you can do them in Japan. And I like to do them in, in Hawaii.

• 1:43:13Speaker 01

  China generally requires an ethnic sensitivity study also for the same reasons. And, and there are some specific examples of where there's toxicity of drugs in people of un-Chinese ethnicity, but they have a less specific definition of who's Chinese. Easiest way to do it is in, is in China.

• 1:43:35Dr. Peter Attia?

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

• 1:43:37Speaker 01

  BIMA.

• 1:43:38Dr. Peter Attia?

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

• 1:43:44Speaker 01

  Yes. So Novartis had strong confidence in bemagromab. 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, or a phase one, phase two study in different indications. Tried very hard. So the drug reliably and predictably increases muscle size, but not performance assessments in a major way. And, and I think that's because, remember in the rodents in whom we saw both, size

• 1:44:28Speaker 01

  increase and performance increase, the mass increase was large, 20 to 30% or more. In humans, it's four to eight percent. And eight is the absolute max.

• 1:44:40Dr. Peter Attia?

  Were those differences based on dose or starting mass?

• 1:44:45Speaker 01

  Biology. People are just not mice.

• 1:44:48Dr. Peter Attia?

  Oh, sorry.

• 1:44:48Speaker 01

  Yeah.

• 1:44:49Dr. Peter Attia?

  I mean, the difference between the four and the eight, how much of that is dose dependent versus other demographic dependent on the pay, like, you know, do you get more muscle mass in younger people, more muscle mass in people starting with more muscle mass?

• 1:45:02Speaker 01

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

• 1:45:12Dr. Peter Attia?

  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?

• 1:45:24Speaker 01

  So we know some of that. We try to control as much as we can. There was one study that has not been published in peer reviewed form yet, but there is an abstract for it. If people want to find it, they can look at, so the believe study of bemagromab in, 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 a

• 1:45:48Dr. Peter Attia?

  We'll link to it in the show notes.

• 1:45:49Speaker 01

  Yeah. There was a, there was a study of bemagromab in patients who were dosed at three different levels of protein calorie nutrition. And the bottom line is the more protein, and it was the recommended daily amount, half of that.

• 1:46:09Dr. Peter Attia?

  Twice that?

• 1:46:09Speaker 01

  Or one and a half times that, I think. And basically within those boundaries, the more protein you ate, the more muscle you built. Probably shouldn't surprise anybody. The other really interesting finding

• 1:46:21Dr. Peter Attia?

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

• 1:46:25Speaker 01

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

• 1:46:27Dr. Peter Attia?

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

• 1:46:32Speaker 01

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

• 1:46:36Dr. Peter Attia?

  It's interesting. So it's, it suggests that in humans, you might've been substrate limited.

• 1:46:42Dr. Peter Attia?

  Amino acid limited or protein synthesis limited?

• 1:46:44Speaker 01

  It's a possibility.

• 1:46:46Dr. Peter Attia?

  And not drug limited?

• 1:46:47Speaker 01

  I'll tell you a funny story about that in just a minute, but just to finish that study. The other very cool thing we found is that as you would expect, if you have half the recommended daily amount of protein, calorie, nutrients, you lost muscle mass, but bemagromab prevented that.

• 1:47:04Dr. Peter Attia?

  So there was, there was some, some biology working there for sure.

• 1:47:07Speaker 01

  No question, no question. So the really interesting story is that when the bemagromab project, when it was still in the research stage, moved from Chris Liu's lab to David Glass's department, which I was part of is the clinical side of that. One of the things we really wanted to do was co-develop a nutritional component to this therapy for the exact reasons that you brought up.

• 1:47:30Dr. Peter Attia?

  Yep.

• 1:47:31Speaker 01

  And at the time Novartis had a nutrition arm.

• 1:47:36Speaker 01

  And so we were working with them to develop a specific nutritional supplement for what became bemagromab. At the time, it didn't even have a code yet. But then Novartis sold their nutrition unit, I think to Nestle. And so got the rug pulled out from under us on that side and we were never able to fully pursue that, but in retrospect, I really wish we had.

• 1:47:58Dr. Peter Attia?

  Do you think this is a blind spot for Big Pharma? Just the, the role of nutrition and other behaviors that can potentiate drugs?

• 1:48:09Speaker 01

  Big Pharma tries to control it, but they don't see that as their core mission.

• 1:48:13Dr. Peter Attia?

  Yeah, but I'm, I'm saying a blind spot. I appreciate that they want to control it and that makes sense. But I'm saying like, it's an opportunity lost, right?

• 1:48:22Speaker 01

  Probably.

• 1:48:22Dr. Peter Attia?

  Like, here's a great example, right?

• 1:48:24Speaker 01

  Yeah.

• 1:48:24Dr. Peter Attia?

  Like

• 1:48:26Dr. Peter Attia?

  Bema could have been more of a hit if maybe, and maybe not, but, but a drug like that could have been a hit had it been appreciated that, oh, by the way, like you actually have to kind of do something to reap the benefits of this.

• 1:48:39Speaker 01

  We would have figured this out many years sooner if we had kept that nutrition element. But again, one of the challenges of big companies is there's so many people involved. They don't all know what the others are doing.

• 1:48:50Dr. Peter Attia?

  Yeah.

• 1:48:50Speaker 01

  Despite everyone's best efforts.

• 1:48:52Dr. Peter Attia?

  So basically.

• 1:48:54Speaker 01

  It was a missed opportunity.

• 1:48:55Dr. Peter Attia?

  And, and so did Novartis then spin it out after the less than expected findings in humans?

• 1:49:03Speaker 01

  So, so what happened was we saw muscle mass get larger, but not stronger. And parenthetically, that's the same as was seen with IGF-1 agonists and with androgen agonists. Remember the SARMs were extensively studied. Is that you can make muscles larger, they don't get stronger in the absence of resistance training. So it's not unique to the activin receptor antagonist pathway. And

• 1:49:28Speaker 01

  in a meta-analysis of the Novartis studies, where they looked at muscle hypertrophy and sarcopenia, the meta-analysis showed an increased six-minute walk distance.

• 1:49:42Speaker 01

  Six meters, uh, nine meters, so a small effect.

• 1:49:47Dr. Peter Attia?

  That's my least favorite test in the world.

• 1:49:49Speaker 01

  It's surprisingly hard to standardize.

• 1:49:52Dr. Peter Attia?

  Why wouldn't they just do something like, uh, you know, a wall sit? Or, you know, something that really tests strength?

• 1:50:00Speaker 01

  Many other things were done, the, the timed up and go test, the short physical performance batteries. But six-minute walk was included in multiple studies, so you were able to do a meta-analysis of that.

• 1:50:13Dr. Peter Attia?

  Got it.

• 1:50:13Speaker 01

  So the, an academic group did this and they published it and so the, the four to, I don't know, eight percent increase in muscle mass that these older adults got yielded a nine-minute in nine meter increased in six-minute walk distance.

• 1:50:30Dr. Peter Attia?

  Yeah, I'm not convinced that's going to help anybody not fall.

• 1:50:34Speaker 01

  No, I don't think it will either. And, and, and Novartis didn't think so either. I guess, I don't, I wasn't an insider at the time. I don't know why they out-licensed it. I was the recipient of that.

• 1:50:43Dr. Peter Attia?

  Yep.

• 1:50:43Speaker 01

  We were on the outside pulling. But the very last study Novartis did was a study in type 2 diabetics. Cause we had had data that hemoglobin A1Cs decreased in patients given bemagromab. And that study, which ran for 48 weeks, so it was, it was 10 migs per kg monthly for 12 doses.

• 1:51:10Dr. Peter Attia?

  Okay, so a lower dose than you were giving for hypertrophy?

• 1:51:14Speaker 01

  No, this, this maximized the.

• 1:51:16Dr. Peter Attia?

  Oh, why did I think you said earlier 50 migs per kg?

• 1:51:19Speaker 01

  In the phase one, we went up higher.

• 1:51:21Dr. Peter Attia?

  You went up that high, got it.

• 1:51:22Speaker 01

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

• 1:51:26Dr. Peter Attia?

  Okay.

• 1:51:27Speaker 01

  And the answer was nothing.

• 1:51:28Dr. Peter Attia?

  Okay. So at 10 migs per kg monthly over 48 weeks?

• 1:51:32Speaker 01

  Yeah, was, was, 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.

• 1:51:55Dr. Peter Attia?

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

• 1:52:04Speaker 01

  Both of those things. I think.

• 1:52:07Dr. Peter Attia?

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

• 1:52:20Speaker 01

  Yep, and, and they had standardized dietary advice to

• 1:52:26Speaker 01

  the 500.

• 1:52:27Dr. Peter Attia?

  So who, did Novartis run that study?

• 1:52:28Speaker 01

  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.

• 1:52:38Dr. Peter Attia?

  The output was we're going to spin it out.

• 1:52:40Speaker 01

  Yep, the output was to spin it out. And at the time I was working with Joe Jimenez and Mark Fishman and Pravina Kandula at Adidas Bio as, as an advisor. And we really wanted bemagromab.

• 1:52:56Dr. Peter Attia?

  What year is this approximately?

• 1:52:58Speaker 01

  That it spun out was 2021.

• 1:53:05Speaker 01

  I think it was 2021. Yeah, discussions had been ongoing in 2020, but I think it finally happened in 2021.

• 1:53:11Dr. Peter Attia?

  Okay, so you guys acquired the asset obviously for a lot less than you could have produced it?

• 1:53:16Speaker 01

  Yeah, still wasn't cheap because it was a phase two ready program.

• 1:53:21Dr. Peter Attia?

  Yep.

• 1:53:22Speaker 01

  But we, we acquired.

• 1:53:24Dr. Peter Attia?

  Did you guys raise money for that acquisition?

• 1:53:27Speaker 01

  Adidas did it all themselves.

• 1:53:28Dr. Peter Attia?

  Okay.

• 1:53:30Speaker 01

  To their credit. And the plan was we were going to develop it in older adults with low muscle mass and impaired muscle function. Because we thought, who were also obese, because we thought this was the patient population most likely to benefit. Losing fat and building muscle and maintaining muscle in the, in the context of, of weight loss. We thought would be super important for those people. And remember, all of this happened in the context of nobody being interested in obesity. Everybody thought it was a wasteland for drug development. Every drug that had been developed in obesity had failed. Commercially, I mean, people, there are some that had been registered, right?

• 1:54:14Dr. Peter Attia?

  But by 21, you're saying pre-21?

• 1:54:17Speaker 01

  This was before Novo's semaglutide data.

• 1:54:20Dr. Peter Attia?

  Yeah, okay, that's right, yep.

• 1:54:22Speaker 01

  And, and I'll tell you, I.

• 1:54:23Dr. Peter Attia?

  Cause that was 21, wasn't it?

• 1:54:26Speaker 01

  Later in 21.

• 1:54:28Dr. Peter Attia?

  Okay, so it's November of 21.

• 1:54:29Speaker 01

  Yeah, I think February 21, we started Versanis Bio, which is the company that licensed bemagromab from Novartis. So at, at that point, so I was the founding CEO. I was working with Elon Zipkin and we went out to raise money from investors. Cause now, all right, great, we had this asset. We needed to run a big phase two study and we went out to raise money. I think we talked to 53 investors. Almost none were interested.

• 1:54:58Dr. Peter Attia?

  Because you told them indication sarcopenia still.

• 1:55:02Speaker 01

  Well, it was, it was sarcopenic obesity.

• 1:55:04Dr. Peter Attia?

  Yep.

• 1:55:05Speaker 01

  And obesity was just not a successful area for drug development. So people weren't interested.

• 1:55:12Dr. Peter Attia?

  How much did you need to raise?

• 1:55:14Speaker 01

  We ended up, how much did we need versus how much we got or different issues?

• 1:55:18Dr. Peter Attia?

  Yeah, I know, that's why I asked.

• 1:55:20Speaker 01

  But we ended up raising 70 million.

• 1:55:22Dr. Peter Attia?

  And what was your, if you could have had your wish list, what would you have raised?

• 1:55:26Speaker 01

  About 100.

• 1:55:26Dr. Peter Attia?

  Okay.

• 1:55:28Speaker 01

  However, Atlas Venture and Medici liked the story. And I had worked with Atlas before. And Michael Gladstone was the partner. And it was Vani Marigi and Nick at Medici, Nick Williams. And we then built an investment syndicate and they funded the company. And then everything, everything changed when Novo's data came out with semaglutide, which was amazing. It was the first really effective obesity medical therapeutic. But then, when you're doing drug development, you skate where the puck is going to be. It's Jay Bradner's favorite saying.

• 1:56:12Speaker 01

  But the puck was going someplace else now. Right? Semaglutide was going to become the standard of Claire or some incretin agonist. We knew it. So, so what we did is we quickly repositioned the company to think about, what is bimagromab going to do on top of that? Because that's going to be the standard of care. So I quickly ran a bunch of mouse studies. And the efficacy was additive. When you, when you took bimagromab with semaglutide or terzepatide or liraglutide, you did them all. And, and the efficacy was sort of unprecedented, never seen.

• 1:56:53Dr. Peter Attia?

  For both fat loss and obviously for preservation of lean mass.

• 1:56:56Speaker 01

  Exactly. For, for weight loss, especially fat loss and preservation of lean mass. It was, it was amazing. So, the opportunity became much larger. And the board then, and I was part of the board, the board then brought in a super experienced CEO, this was Mark Krasinski, to lead the company then because we had a really big opportunity and we knew it. And we brought in a CMO, Ken Addy, because I had been serving as the CMO also. And, and then I stepped into president and CSO role, just in terms of company organization. But we all kept working on the program. We ultimately ran what became the BELIEF study.

• 1:57:39Speaker 01

  And the, the story, we spent a lot of time thinking about what we would name our studies. The plan was BELIEF was going to be phase two, BECOME was going to be phase three, and BEHOLD was going to be post-registration studies.

• 1:57:53Dr. Peter Attia?

  And then you actually have to come up with what those things stand for, knowing only what the B stands for when you start. I mean, this is so funny how drug name studies work.

• 1:58:00Speaker 01

  Yeah, you know how it goes.

• 1:58:01Dr. Peter Attia?

  I know the drill.

• 1:58:02Speaker 01

  But it was, they all became with B for bimagromab.

• 1:58:05Dr. Peter Attia?

  Yeah.

• 1:58:06Speaker 01

  Now, you haven't asked me where bimagromab came from. So this is, this is another interesting, wonky drug development thing. So the generic name is called the INN name for, I think, international nomenclature. I'm not sure what it's an acronym for.

• 1:58:22Dr. Peter Attia?

  Which is why it ends in MAB, obviously.

• 1:58:24Speaker 01

  So the suffix of a drug generic name is pre-specified based on the class. If you're the first in class, you'll pick a new one. But the company gets to recommend the prefix and sometimes the suffix. So, Bima is the Indian god who's as strong as 10,000 elephants.

• 1:58:48Dr. Peter Attia?

  Hmm.

• 1:58:49Speaker 01

  And that's why bimagromab is bimagromab.

• 1:58:52Dr. Peter Attia?

  And then ends in MAB monoclonal antibody.

• 1:58:55Speaker 01

  The Groomab is a monoclonal antibody suffix.

• 1:58:58Dr. Peter Attia?

  So any other drug that comes along in that class, what would be the nomenclature naming options?

• 1:59:04Speaker 01

  Antibodies are just complicated. There's a lot of different criteria for naming antibodies and you have options for infixes and suffixes.

• 1:59:12Dr. Peter Attia?

  And what was the, what was the GLP-1 before liraglutide?

• 1:59:16Speaker 01

  There's, there's exenatide.

• 1:59:18Dr. Peter Attia?

  Exenatide, right? So the tide became the thing that everybody had to link to going forward?

• 1:59:24Speaker 01

  Tide is peptide. There's a.

• 1:59:26Dr. Peter Attia?

  So any, but they, they, were they forced into semaglutide, liraglutide, semaglutide, terzepatide?

• 1:59:33Speaker 01

  The tide is the, is used for that class, but there are other peptides that end in tide.

• 1:59:38Dr. Peter Attia?

  Yeah. Okay, so you guys ran BELIEF.

• 1:59:41Speaker 01

  Yes. So, so BELIEF, 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 got to do a bigger study. We're going to do it in combination with semaglutide. And this was during the pandemic. So there was a lot of complexity and supply chain disruptions, but, and remember with semaglutide, it was a proprietary drug of Novo. We couldn't get the drug substance. So we had to use the commercial presentation of semaglutide.

• 2:00:22Dr. Peter Attia?

  Super expensive.

• 2:00:23Speaker 01

  Which was expensive and it's an auto-injector. We couldn't make a placebo for that. So the study design included semaglutide as open label, but we did a, we did placebo-controlled bimagromab, because we had control of that. We used bimagromab intravenously, just because it was the fastest, most straightforward way to get into the clinic. Not public was that we were working hard on an auto-injector and we would have been ready in the next study for an auto-injector, but, but it was, it was intravenous for bimagromab. And then, what combination should we use? We ended up doing something called a full factorial design.

• 2:01:05Speaker 01

  So we did all possible combinations of low dose semaglutide, high dose semaglutide, low dose bimagromab, high dose bimagromab in placebo. So it's a nine-arm study.

• 2:01:17Dr. Peter Attia?

  Why?

• 2:01:18Speaker 01

  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, for example.

• 2:01:33Dr. Peter Attia?

  And?

• 2:01:34Speaker 01

  And this is in part why I did that pharmacology study in rodents, because if there was anything unexpected that would happen with the drug combination, I wanted to know about it. 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.

• 2:02:01Dr. Peter Attia?

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

• 2:02:05Speaker 01

  We used them both.

• 2:02:06Dr. Peter Attia?

  Oh, you did.

• 2:02:07Speaker 01

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

• 2:02:09Dr. Peter Attia?

  Yeah.

• 2:02:10Speaker 01

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

• 2:02:22Dr. Peter Attia?

  The brands, yeah. So what were the findings of this six-month, nine-arm study?

• 2:02:27Speaker 01

  So it was originally going to be six months, but we changed it from the original plan with bimagromab 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.

• 2:02:47Dr. Peter Attia?

  Did you have to raise more money?

• 2:02:49Speaker 01

  We did.

• 2:02:50Dr. Peter Attia?

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

• 2:02:54Speaker 01

  Yes. We, we did, and it was 500 people enrolled, roughly. 507 was the exact number. 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.

• 2:03:25Dr. Peter Attia?

  Yep.

• 2:03:26Speaker 01

  Right? There's, there's low dose Bima, high dose Bima, low dose SEMA, high dose SEMA, four combinations, and then placebo. 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.

• 2:03:44Dr. Peter Attia?

  Why couldn't you get DEXA? Too expensive?

• 2:03:47Speaker 01

  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.

• 2:04:00Dr. Peter Attia?

  Yeah, it's crazy to me that, that you would be held to the standard of weight loss when in reality, a better outcome might be less weight loss.

• 2:04:09Speaker 01

  That is true.

• 2:04:11Dr. Peter Attia?

  If you're preserving muscle.

• 2:04:13Speaker 01

  We were acutely aware of that.

• 2:04:14Dr. Peter Attia?

  Yeah, that's awful.

• 2:04:15Speaker 01

  But it is not what, it's not what the field was, was thinking at the time.

• 2:04:19Dr. Peter Attia?

  No, I know, but it's just, I mean, it's, it's, good biology abuts regulatory simplicity for a lot of.

• 2:04:27Speaker 01

  Yeah, yeah, yeah.

• 2:04:28Dr. Peter Attia?

  That would be charitable.

• 2:04:29Speaker 01

  I personally wanted waist circumference. And I wrote a long white paper about this. Because waist circumference is more closely linked to important clinical outcomes than is BMI or body.

• 2:04:41Dr. Peter Attia?

  Yep, for sure. Yeah.

• 2:04:43Speaker 01

  So body mass index is, if you're following longitudinally, is essentially the same as body weight.

• 2:04:50Dr. Peter Attia?

  Same as weight.

• 2:04:51Speaker 01

  Because height doesn't change.

• 2:04:52Dr. Peter Attia?

  Exactly.

• 2:04:53Speaker 01

  Over a short term. Just for listeners. So, we ended up using body weight as the primary endpoint. And it wasn't just regulatory and transigence, it was also what do investors and potential acquirers think? Everybody cares about what the approval endpoint's going to be. We wanted that to be the primary endpoint. But we measured all these other things. And to sort of zip ahead to the end, in the high-dose combination group, the body weight lost at 72 weeks was 22%, 23% of starting body weight.

• 2:05:24Dr. Peter Attia?

  High, high.

• 2:05:25Speaker 01

  Yeah.

• 2:05:26Dr. Peter Attia?

  Double positive.

• 2:05:27Speaker 01

  The high, high combination.

• 2:05:28Dr. Peter Attia?

  And what was the high?

• 2:05:29Speaker 01

  But the fat loss was 45.7% of starting body fat. Now that's what you get with bariatric surgery. So this, to me, this is the first medical therapy that gives fat loss equivalent to or superior than bariatric surgery. That's amazing.

• 2:05:51Dr. Peter Attia?

  Did you do any functional testing in that study?

• 2:05:54Speaker 01

  We did. We did. And we even did a preliminary observational study in overweight adults at different age cohorts. And we tested a few different things. We tested essentially timed up and go, for short physical performance battery. We tested the 30-second chair-stand test, which is my personal favorite, and we tested grip strength. But ultimately, we went with grip strength in the BELIEF study because it was the one most closely linked to clinical outcomes.

• 2:06:26Dr. Peter Attia?

  And did you see an improvement in strength?

• 2:06:28Speaker 01

  Small. But also it was a variable assessment.

• 2:06:31Dr. Peter Attia?

  Okay.

• 2:06:32Speaker 01

  It's, and it's in the published study that came out a few months ago.

• 2:06:37Dr. Peter Attia?

  Now, Novo bought this asset from you guys, right?

• 2:06:41Speaker 01

  No, Lilly did.

• 2:06:42Dr. Peter Attia?

  Oh, Lilly did?

• 2:06:43Speaker 01

  Yeah. So, we were super excited about the study. It was ongoing. We were enthusiastic.

• 2:06:52Speaker 01

  We closed a series B in two tranches and we'd called the first tranche. And then the company got bought by Eli Lilly. And so they have bimagromab now.

• 2:07:04Dr. Peter Attia?

  What are they doing with it?

• 2:07:06Speaker 01

  You have to ask Lilly.

• 2:07:07Dr. Peter Attia?

  But they made some noise last fall that they were pausing the program or?

• 2:07:12Speaker 01

  No, they just, they, they paused one study, but they still have other studies in clinicaltrials.gov.

• 2:07:18Dr. Peter Attia?

  Okay.

• 2:07:19Speaker 01

  But you gotta ask them.

• 2:07:20Dr. Peter Attia?

  I see. So publicly, the only thing we know is they're still doing something with it, presumably testing it with tirzepatide, I'm guessing, or retitrutide?

• 2:07:30Speaker 01

  Yeah, the, the, the study that's in clinicaltrials.gov is a complex combination study with tirzepatide. I, I do think it's fair to mention the one adverse, adverse outcome that happened in the believe study that we weren't really expecting, which is an increase in LDL.

• 2:07:46Dr. Peter Attia?

  Yeah, how much I remember that now, I thought, I'd already thought that was actually something that Lilly saw, but that was in your study.

• 2:07:53Speaker 01

  Yeah.

• 2:07:54Dr. Peter Attia?

  And how, how much of an increase was it?

• 2:07:55Speaker 01

  It's about 20%.

• 2:07:57Dr. Peter Attia?

  Why do you think that was biologically?

• 2:08:00Speaker 01

  It's a direct effect of the drug in the liver.

• 2:08:03Dr. Peter Attia?

  So interesting, again, you wouldn't expect this off target, would you?

• 2:08:07Speaker 01

  This is on target. But, because remember there's active in receptors everywhere.

• 2:08:12Dr. Peter Attia?

  Oh, I didn't realize that.

• 2:08:13Speaker 01

  Yeah.

• 2:08:14Dr. Peter Attia?

  Ah, so it's doing something to interfere with LDL clearance presumably.

• 2:08:21Speaker 01

  I guess, but I don't, I don't know what the biology is, it's, it hasn't been studied tonight.

• 2:08:25Dr. Peter Attia?

  Or, or no, maybe, I mean, what would be a more plot, I mean, that would be studyable, right? Is, is it, is it impeding LDL clearance or is it increasing LDL synthesis?

• 2:08:33Speaker 01

  I know who knows the answer to this, so, so Chris Liu, when he left Novartis, eventually founded a biotech called Lake Na in, in China. And he's made therapeutic antibodies to active and receptor type 2A, type 2B, and the combination, and he's studied them. So he knows the answer to this and I assume he'll publish it at some point.

• 2:08:53Dr. Peter Attia?

  And Lloyd, were there any adverse effects on glucose in the other direction? Did glucose ever go up?

• 2:08:58Speaker 01

  No.

• 2:08:59Dr. Peter Attia?

  Okay, so, and did you continue in the believe to see glucose go down the way you did in the diabetic studies?

• 2:09:04Speaker 01

  Yes.

• 2:09:05Dr. Peter Attia?

  Independent of what you would have seen from SEMA, I mean?

• 2:09:08Speaker 01

  Yes, so, so we have all of that data and it's published in the Nature Medicine paper. At EASD in September, which is a European meeting, we're going to publish the results of the six month off drug results. So that's.

• 2:09:24Dr. Peter Attia?

  That's off all, both drugs?

• 2:09:26Speaker 01

  Yes. And, and so the, the real issue is what's going to happen when you withdraw the drugs? And we know what happens when you withdraw semaglutide, right? Everything goes back towards where it was, doesn't quite get there. And we're going to find out with bimagromab. I, I expect some things are going to reverse, like we, we know that muscle mass with every muscle anabolic agent reverts towards baseline when you withdraw the therapy. I expect that's going to happen in the humans, it happens in the rodents. In believe, we deliberately included patients with metabolic syndrome. So these are people who are pre-diabetic. So we can measure diabetic endpoints in these people and it's going to be super interesting to see what happens there.

• 2:10:11Speaker 01

  Personally, if we had kept bimagromab in personas and have been a standalone entity, we would be, we would be well advanced into phase three by now. And the reason is because I believe even with those LDL effects, which, which, which are not favorable, LDL predicts cardio, adverse cardiovascular endpoints. But I believe that.

• 2:10:32Dr. Peter Attia?

  You can monitor it, you can treat it.

• 2:10:33Speaker 01

  Yes. Which, as an aside, since my, my personal interest is making drugs to prevent the most common causes of morbidity and mortality in older adults. Side effect of that is healthy longevity. That's what I do. I am not making cardiovascular drugs, even though it is the most, it is the number one cause of morbidity and mortality in, in adults in the US and in many developed countries around the world. The reason is we've already got a lot of good drugs, we're just not using them for primary prevention, which we need to be doing more of. So with that aside, I would be well advanced in developing bimagromab in phase three, but I would,

• 2:11:15Speaker 01

  I think the paradigm for managing obesity is going to be induction and maintenance of remission. Probably combination and injectable therapies to get people to their, you know, to move them categorically from obese to non-obese. And then they need something for maintenance, which might be something like orfoglipron or some oral GLP-1 agonist to maintain appetite and satiety.

• 2:11:43Dr. Peter Attia?

  And you don't think just a lower dose of the injectable could do?

• 2:11:46Speaker 01

  Absolutely it could.

• 2:11:47Dr. Peter Attia?

  You're just saying economically, it might be easier to make it orally.

• 2:11:50Speaker 01

  Exactly, exactly.

• 2:11:52Dr. Peter Attia?

  Okay, I want to pivot and talk about one other thing, which is also an area where you know a lot about it, which is selective mTOR inhibition. We're not going to spend as much time on it, of course, but again, talk to me about where your head is at these days on that pathway in general. Do you believe that there are, that this is giroprotective in, in humans? I mean, it's, it's been well established how giroprotective this is in mice, almost assuredly. I think it'll end up being giroprotective in dogs. So it might be safe to say that inhibiting mTOR in everything from yeast to dogs and maybe even primates extends life.

• 2:12:35Dr. Peter Attia?

  We don't have a clue if it's going to in humans. We'll never probably get to directly test it. There are really good compelling arguments on both sides of why it may or may not be the case in humans, including the longevity quotient argument and things like that. What are your thoughts?

• 2:12:52Speaker 01

  I think it probably will, it's highly conserved biology across evolution. So I, I, I think so. Reductively, if you envision mTOR1 as a master regulator of sensing, sort of integrating nutritional inputs and then deciding to grow or not grow. And not grow means circling the wagon up regulating autophagy and recycling pathways. I, I think it probably would. I think the effect size is going to be modest, is it just as it has been pre-clinically? And I think it's Torq1. Haven't seen a lot of new data on that.

• 2:13:32Dr. Peter Attia?

  Well, there was that study somewhat recently suggesting that rapamycin impaired, I don't know if it was impairing MPS or some other metric of physical performance or something. Obviously you're familiar with the agents you've tested. 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 inhibit mTOR complex one?

• 2:14:08Speaker 01

  The, the selectivity is the, is the big challenge because with rapalogs, as you know, there's, their Torq1 selective, but there's a down regulation of Torq2 with sustained exposure. And I don't know that we, you know, so in, in Restore Bio, we tried to manage that by a combination of a catalytic and an allosteric inhibitor, which seemed to do it. And, and I know there are other companies that are working on other ways to get Torq1 selective inhibition. And I think that's what we need is a real Torq1 selective inhibitor. And then we can, we can test the biology.

• 2:14:45Dr. Peter Attia?

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

• 2:14:51Speaker 01

  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. It is not necessarily the tissue you want anyway. When we do this in rodents, we measure their liver activity. And I think we mentioned, you and I discussed this before, that in, in young rodents with fasting, they down regulate mTOR as you would expect. In old rodents, they didn't. So 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.

• 2:15:36Dr. Peter Attia?

  Yeah. Again, imminently testable.

• 2:15:40Speaker 01

  Nobody's lining up for liver biopsies though.

• 2:15:42Dr. Peter Attia?

  No.

• 2:15:43Speaker 01

  And, and, and there's.

• 2:15:44Dr. Peter Attia?

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

• 2:15:47Speaker 01

  I don't think so, it's just.

• 2:15:48Dr. Peter Attia?

  Yeah. Again, the price of admission is so great on that. Okay, final question slash topic. As you think about drug discovery over the next decade, I'm not going to ask you the question everybody's thinking as, how is AI going to help? We'll punt that for now.

• 2:16:04Speaker 01

  Thank you.

• 2:16:05Dr. Peter Attia?

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

• 2:16:20Speaker 01

  I think we're starting to wake up to the concept of real medicine, real medical prevention. I mean, 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. 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.

• 2:16:59Speaker 01

  So you can't bill for it. So there's, there's a lot of institutional hurdles that we need to get through. But I, I think people are waking up to the concept of, I want to stay healthy rather than get sick and get treated.

• 2:17:14Dr. Peter Attia?

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

• 2:17:20Speaker 01

  Yeah. So this is, this is conceptually difficult to wrap your head around.

• 2:17:24Dr. Peter Attia?

  Uh huh.

• 2:17:25Speaker 01

  But again, where do new drugs come from? They come from reading the literature and thinking, which is sort of what I did after Versanis ended for me, it's still ongoing in Lilly. And there are 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. The, the prototype for this is serafinib, which is a multi kinase inhibitor that's used to treat renal cell carcinoma and hepatocellular carcinoma primarily. If you give that drug to people, about 10% of

• 2:18:08Speaker 01

  the patients, of the, of the older patients get skin cancers. Why is that?

• 2:18:13Dr. Peter Attia?

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

• 2:18:17Speaker 01

  The, the cancers they get seem to be the prevalence that's reflected in the normal population. So almost everything that's ascertained is basal cell and squamous cell. And more recently, we understand the pathway biology of that. These are, serafinib is a multi kinase inhibitor. It 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. That pathway, if you turn it on irreversibly and covalently, is the target of some of the nastiest toxins that you know about, like diphtheria toxin,

• 2:18:58Speaker 01

  sarcin, ricin. It's a very, very potent pathway. My innovation is putting together different parts of the literature. I, 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

• 2:19:37Speaker 01

  put together, we got to start there. But in a phase two study of older adults, and older adults in this context means 50 and up. Sorry, Peter.

• 2:19:47Dr. Peter Attia?

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

• 2:19:50Speaker 01

  I have been for a while 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.

• 2:20:11Dr. Peter Attia?

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

• 2:20:21Speaker 01

  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 going to be almost impossible to test that before approval, just because cancer incidence is a really rare event.

• 2:20:42Dr. Peter Attia?

  Yeah. Yeah. 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, breast cancer, they're NED, no evidence of disease for the listener, but there's a 50% chance they're going to have a recurrence. 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.

• 2:21:19Speaker 01

  I, I think that's one way to do the other study. What, what I've done in co-slap therapeutics is 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 a thousand cancer cell lines to see what tumors are sensitive to it. So this would be a treatment mode rather than prevention mode. And.

• 2:21:49Dr. Peter Attia?

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

• 2:21:52Speaker 01

  That's the question we were asking.

• 2:21:54Dr. Peter Attia?

  Okay.

• 2:21:54Speaker 01

  And 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 of all the UV exposure.

• 2:22:08Dr. Peter Attia?

  Yep.

• 2:22:09Speaker 01

  It's the highest mutational burden organ we have in normal people. And I thought that was going to be it. And there, and there was a correlation between mutational burden of the cell lines and susceptibility to this mechanism. But it wasn't great enough to explain the tumor susceptibility. So it's something else.

• 2:22:27Dr. Peter Attia?

  That would be good news.

• 2:22:29Speaker 01

  Yeah. It's, it's there, but it's not good enough. So I don't know why melanomas are so sensitive, but they're enormously sensitive. So I'm very confident this will be a therapeutic for melanoma as well. And it augurs well to the idea of preventing melanoma, which is also testable and has been proven with a therapeutic intervention in a wonderful study conducted in Australia. The intervention was intensive sunscreen use compared to usual practice. So it's going to be testable in a, in a large phase three study, but not, not before that. So, yeah. So that's what I'm doing. And I think preventing cancers.

• 2:23:09Dr. Peter Attia?

  That's a, that's a very interesting idea. I mean, that talk about a new, a whole new playing field, right? Pharmacologically.

• 2:23:16Speaker 01

  Yep. Nobody's, nobody's made a drug for this mechanism.

• 2:23:19Dr. Peter Attia?

  Because we usually think avoiding cancer or preventing cancer comes down to avoiding carcinogens.

• 2:23:26Speaker 01

  Which is, which we should definitely do.

• 2:23:28Dr. Peter Attia?

  Yes, yes, absolutely.

• 2:23:28Speaker 01

  So don't drink alcohol.

• 2:23:30Dr. Peter Attia?

  Yeah. Or, you know, don't smoke, be, be as insulin sensitive as possible.

• 2:23:35Speaker 01

  Yes.

• 2:23:35Dr. Peter Attia?

  Yeah. All, all of these things.

• 2:23:36Speaker 01

  All of those things. Lose weight if you're overweight. We, we know that successfully treating obesity prevents a bunch of cancers.

• 2:23:44Dr. Peter Attia?

  Yep.

• 2:23:44Speaker 01

  And we know that from the Swedish obesity study, which is an observational cohort of Swedish patients who've undergone bariatric surgery. And these, these people are being followed for decades. It's doing all the good things you'd expect of successfully managing obesity.

• 2:24:05Dr. Peter Attia?

  Well, Lloyd, this has been great. This has been kind of a, a wonderful education on drug discovery using, I think, a very interesting drug in BIMA as a, as a case study for the complexity and the nuance of the process. And by the way, I don't think I realized that the BIMA story is still ongoing. So that's great. So we're going to continue to follow this biology and it'll be interesting to see where Eli Lilly goes with this drug. But it sounds like based on what's showing up on clinicaltrials.gov, they're following in your footsteps in that they're probably testing this in parallel with the newer generation GLP-1 agonists and the.

• 2:24:41Speaker 01

  As best I can tell, that's what they're doing. And it's not now just Eli Lilly because many other companies, you know, who have seen the believe data, because we've been presenting it at national meetings, are, and international meetings for that matter. There's a lot of other pathway inhibitors that are, that are under development.

• 2:25:01Dr. Peter Attia?

  Yeah. Well, really appreciate your time, Lloyd, and obviously.

• 2:25:04Speaker 01

  It's been a pleasure to chat again.

• 2:25:05Dr. Peter Attia?

  Your great efforts. Yeah. Thank you.

• 2:25:07Speaker 01

  Thank you.

• 2:25:08Dr. Peter Attia?

  Thank you for listening to this week's episode of The Drive. Head over to peteratia MD dot com forward slash show notes if you want to dig deeper into this episode. You can also find me on YouTube, Instagram and Twitter, all with the handle peteratia MD. You can also leave us a review on Apple Podcasts or whatever podcast player you use. This podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. No doctor-patient relationship is formed. The use of this information and the materials linked to this podcast is at the user's own risk. The content on this

• 2:25:50Dr. Peter Attia?

  podcast is not intended to be a substitute for professional medical advice, diagnosis or treatment. Users should not disregard or delay in obtaining medical advice from any medical condition they have, and they should seek the assistance of their healthcare professionals for any such conditions. Finally, I take all conflicts of interest very seriously. For all of my disclosures and the companies I invest in or advise, please visit peteratia MD dot com forward slash about where I keep an up to date and active list of all disclosures.