Plain English with Derek Thompson - Would You Buy a Drug to Extend Your Dog’s Life?

Episode Date: February 16, 2024

Today’s episode is about the science of slowing down the aging process … and why one biotech company has found some success with dogs. Last November, the New York Times reported that a company called Loyal had reached a milestone in the development of safe life extension drugs for our pets. This drug, which is called LOY-1, works to slow the aging process in large breeds. But Loyal's work holds major promise for helping all dogs live longer. It could even crack open some of the mysteries of mammalian aging, which could lead to discoveries that extend the lives of humans. Today's guest is the CEO and founder of Loyal, Celine Halioua. We talk about her experience as a female biotech founder, the weird economics of pharma, the ethics of life extension, the science of why big dogs die young, her theories for how to slow down the aging process in dogs big and small, and the possibility spillover benefits for humans who would like a few more years with their family and friends. If you have questions, observations, or ideas for future episodes, email us at [e-mail]. Host: Derek Thompson Guest: Celine Halioua Producer: Devon Baroldi Learn more about your ad choices. Visit podcastchoices.com/adchoices

Did Don Draper really buy the world of Coke? Did Tony Soprano really die? Or just order more onion rings? The finalees of our favorite shows can make us argue, make us cry, and make us crazy. From Spotify and the Ringer, I'm Andy Greenwald, and this is Stick the Landing, a new podcast where we'll be telling the story of modern TV backwards, one fade out at a time. Find Stick the Landing on Wednesdays on the prestige TV feed, on Spotify or wherever you get your podcasts. Today's episode is about the science of slowing down the aging process and why one biotech company has found some success doing this with dogs.

Last November, the New York Times reported that a company called Loyal had reached a milestone in the development of safe life extension drugs for our pets. In a letter sent by the U.S. Food and Drug Administration to Loyal, the FDA said, quote, the data you have provided are sufficient to show that there is a reasonable expectation of effectiveness. End quote. That meant they believe Loyal has met a requirement for fast-tracked authorization for animal drugs. The drug they've developed, which is called Loy 1 or L-O-I-1, works to slow the aging process

in large breeds like mastiffs and Great Danes. The drug is not available yet, and the FDA has not approved it for use, but it's gotten just about as far as anyone has in getting the FDA to approve a life extension drug for any animal. The Times announcement made quite a stir. At the Emmys this year, the showrunner of the award-winning beef on Netflix said this. Everything I do is for my three dogs, so, um, the federal drug administration, if you could please fast track that a canine anti-aging pill. That would be so lovely. Thank you so much. Now, life extension science is as exciting to me as it is broadly controversial. If you're an advocate of this kind of work, you'll say,

who could possibly be against extending their dog's life from nine to ten years? Who could possibly be against extending their parents' lives by five or ten years? Especially if what you're extending are good years. Health span, not just lifespan. Indeed, the podcast and YouTube sphere is dense with people testing, promoting, and often dramatically over-promising the benefits of everything from bullshit it supplements to non-bullshit but still somewhat unknown drugs like rapamycin. But in my experience, there is something about the subject of longevity and life extension.

And maybe it's just those terms, longevity, life extension, that gets under some people's skin. Their mind goes to cultural representations of the search for eternal life, which, if we're honest, is almost always associated with evil. Voldemort is obsessed with his immortality. So is Emperor Palpatine from Star Wars. the picture of Dorian Gray. It does not turn out well for Mr. Gray. In one of my favorite movies as a kid, Indiana Jones in the Last Crusade,

the Nazi who first drinks from what he considers to be the cup of Christ, toasts to eternal life. He literally says, eternal life. Then he drinks from the cup and succumbs to what can only be described as rapid onset flesh-eating disease. So there is something in the storytelling spirit of humanity that seems to be telling us to fear those who search for extra years. Now, my response to these fears is always the same. No one's going to live forever.

Eternal life, no matter what some of these people are promoting, is not in the cards for any of us. What we're actually talking about here in the science of longevity is the study of age-related disease and the effort to discover causal mechanisms that can allow us to slow down the aging process, to spend more of our scarce years feeling healthy and young. In this respect, I consider myself an enormous fan of life extension research writ large, even though I am very critical of many of its drug promotions writ small. Both my childhood dogs died before the age of 10. Both of my parents died before the age of 70.

The concept of a scientific field devoted to identifying and solving the problems of age-related disease is absolutely thrilling to me. And that's why I'm very thrilled to have today's guest, the CEO and founder of Loyal, Celine Halewa. We talk about her experience as a female biotech founder, the weird economics of pharma, the science of why big dogs die young, her theories for how to slow down the aging process in dogs both big and small, and the possibility of spillover benefits for humans from her research, humans who would like to live a few more good years

with their family and friends. I'm Derek Thompson. This is Plain English. Celine Hollywa, welcome with the show. Thank you. It's great to be here. So I want to talk to you about dogs. I want to talk to you about life extension. And first, I want to talk to you about being a female founder right now.

Let's do a little personal history. Tell me what you were doing before you founded Loyal. Yeah. So I never thought I would start a company. There was no lemonade stand. I wasn't having a secret master plan of getting an idea or an insight so I could build a company and raise hundreds of millions of venture dollars or whatever it is. I actually got interested in the space because really kind of my North Star from day one is how can we increase the free will of humanity? And one of the things that I think takes away free will

the most is disease, specifically age-related diseases. And it was kind of this realization that there's many age-related diseases that you could get, you know, diagnosed with today when it's not really anything anybody could do with you, do for you, no matter how much effort, much time, much money, no matter much care, just because there's such currently untractable diseases. So I was in bio. I was doing it. I was working in a lab for four years, five years, six years straight.

There's pipetting, working with mice, the whole thing. I then went to Oxford. then we pretty quickly dropped out, join Laura Nemean the longevity fund, and I'm sure we'll talk more about it, but got the idea for loyal, and the conviction that I could do it while as that longevity fund. There is an impression, possibly unfair,

but definitely relatively well subscribed to, that life extension is kind of bullshit, that there's a lot of people that have talked about life extension for many, many years, and there's lots of gurus in California and maybe around the world that have promised some version of life extension that hasn't exactly panned out for people

because there is no one really living to 130, like barely anyone has ever lived to 120. So obviously the promises haven't exactly been realized. How hard is it to get people, maybe venture capitalists are the first line of credibility, but maybe there's other lines of credibility to talk about. How hard has it been to get people to take a project like this seriously?

Well, so it's interesting because there's been a lot of investment and interest in lifespan extension, but I would argue in a lot of categories like what you're describing, where there's lots of bold promises and reality is going to hit at some point if it's not going to give the end point that is being desired. And that net hurts the field. And that's what I'm actually I'm quite passionate about is this idea that if you're going to go and kind of try to take the reins in this field,

but you need to be, you know, having a higher degree of responsibility. You know, if you're working on a breast cancer drug and you fail, you know, nobody rethinks the legitimacy of targeting breast cancer. But if you're developing a longevity drug and it fails, people absolutely rethink the legitimacy of working on lifespan extension pharmaceuticals. And so this was something that I, I mean, honestly, has been a fear of mine from day one because, you know, we have done a lot of things right.

And I think we are kind of hitting that stage of the roller coaster where it's more downhill and uphill. But for a long time, I was very cognizant that, you know, if something went wrong, it would reflect, you know, badly on the field, even though there's many valid reasons to fail that have nothing to do as a legitimate idea. Unfortunately, I think a lot of the field doesn't think in that way. And it is quite easy to raise money if you're just saying like, oh, life span extension, it will happen in a year. And so it's something I'm always combating in terms of how can we demonstrate our legitimacy.

So like going for FDA approval, we could have developed a supplement in the middle markets in four years by now, right? But we from day one we're saying we want FDA approved longevity drug, we're doing all our studies in the United States. We are self-subjecting to the highest and most rigorous and most objective quality bar in the world, the one that many other regulatory jurisdictions follow. And that was just one part of many of how we kind of tried to. build an activity in the field right and showing that longevity is just as boring as you know cholesterol lowering drugs and why dogs because you can do well there's a couple of reasons that we said to go dogs first um one is i am a huge dog person i'm actually in um wohaka right now and there are senior street dogs everywhere and it's going to take all my willpower

not to take one home um so it came with the dog style right? But then also there's a logistics challenge in lifespan extension which is to begin and market and sell a drug for something. You have to show in a placebo-controlled, phase three, FDA sanction, double-blinded, local study that your drug does what you say it does. So you have to show it it extends

lifespan. And in a human, even the oldest humans, it could take a decade or more to actually show that reduction in early mortality relative to those treated. And so in a dog, you can see biological aging, a kind of, there's no like decently objective, aging parameters, but let's say like as objective as they come, aging biomarker, quote unquote, parameters in about six months. And then you can see lifespan extension and, you know,

depending who you ask, three to five years. And so it was a way to show definitive ethics, see quicker. And it's also a really important problem and a really important market to work on, which is kind of this Trojan horse, so to speak, too. No, if we only, the Trojan horse doesn't really work here anymore. I was going to say, if we only build the Trojan horse, even if it doesn't enter the case, that doesn't make sense. But basically, if we only do this, it's extremely valuable and extremely important to society, but also it doesn't up well to do human aging eventually too. Right. This is a beneficial Trojan horse in which the horse itself is

dog life extension and then the Greeks that come out of the horse is human life extension that might follow. I more or less pick up the metaphor. And then without the raising of the city. Yeah. Right. Exactly. Hopefully we don't have to metaphorically destroy Troy in order to make this happen. One of the papers that I find most persuasive in biology is a paper that Heidi Williams is a co-writer on on the mystery of why don't we have more cancer prevention drugs. almost all of the cancer drugs that we have are for late-stage cancer, where are the cancer prevention drugs? And she makes a version of exactly the point

that you just made. If you are trying to develop a drug that, you know, I'm 37 years old, if you're trying to develop a drug that stops a 37-year-old from getting, let's say, stomach cancer or pancreatic cancer in one 70s or 80s, well, you have to wait 40 years to get the relevant endpoint,

which is I am still alive without that cancer in 40 years. that's incredibly expensive to do a clinical trial that takes 40 years, unbelievably expensive. Whereas a clinical trial on late stage cancer, if you're only trying to extend a sick person's life by six months one year, well, you only have to wait six months or one year. So to your point, to take that metaphor and make it about, you know, dogs and people, you know, dogs, I guess the cliche is, and I'm interested in whether this cliche is wrong, you know, that dog's lives move seven times faster than a human life. so you need to wait seven times less to see if the life extension drug is having an effect.

It becomes really, really important from just a time and cost perspective if you're doing the kind of clinical trials that are necessary to get FDA approval which you're going for. Is that the same idea? Exactly. It's exactly the same idea. And I'd say another part

that's especially relevant in the U.S. is there's economic alignment with preventative medicine and dogs versus, you know, in humans is a bit of a bigger topic. There could be many podcasts just on this. But in general, reimbursement, economic incentives for preventative care,

especially expensive preventative care, is just not, it's much more challenging in the U.S.'s healthcare system. And in the UK, it's a little bit different on the other single-payer healthcare systems. The way I kind of think about the dog-owner relationship and each is a micro-single-payer health care system, right? I own Della today and I will own her for the rest of her life.

And I care about her health today and I care about her health in many years from now. And so I am economically incentivized to do whatever it takes to keep Della healthy today, but also to invest in preventative care so she stays healthy in the future. That combined is the fact that it's a cash pay market. So there is like some insurance mechanisms, but in the U.S., it's almost entirely cash pay. that was almost like romantic to me coming in because it was kind of like nobody was to tell you but the cogs of drugs super cheap.

So cheap. Very low. Very, very, very low. The actual material costs, not expensive. Now, everything else, you know, all the other failed drugs and the, you know, half a billion dollar clinical trials, like that gets like swatted into a too for a human.

But I really love the idea of romantically of developing a first in class drug. That is something that people have never, you know, thought was even possible for. sounds like magical, that's also inexpensive. That's also, you know, financially accessible to the majority of Americans. And that's something that's just like in humans, like, good luck.

We're going to talk about the medicine that you're developing in just a second. I do want to establish first some sort of ground basics about the science of dog longevity. I think most people understand that there is a relationship between a dog's size and its expected lifespan, that small dogs live longer than big dogs. I think the average lifespan, there was a Times article that sort of listed like dozens and dozens of dog breeds, and the average lifespan of a havenese, which weighs less than 15 pounds, is 15 years, the average life of a mastiff is nine years or less. Do we have a basic understanding of why this is the case, why small dogs live longer than big dogs? We have a very strong hypothesis, which is the baseline of Loewan,

the first drug. It actually was the baseline of what I started loyal around. So you're exactly right. The bigger dog is where their lifespan is and at the extremes without a 2x differential. So a Chihuah might live, you know, 15, 16, 17 years, while a great day might live, you know, seven or eight years. And it's not just that they're, you know, living their normal life and then dropping dead at age seven or eight. They're actually aging. A great day and will start going gray at age, you know, three, four, or five will start slowing down. It just literally is living what seems to be an accelerated aging trajectory within that duration that they are allotted, so to speak. And this is extremely abnormal.

There is, as far as I'm aware, no other species where you see a 2x differential and expected lifespan within the species. Short humans don't live twice as long as large humans. And in fact, there isn't really even a size gene for humans. I couldn't sequence you and be like, oh, you're like, you know, six foot five and three quarters or whatever. I'm definitely not six foot five. I was like, I was going to say five, six and I was like, wait, don't install. I'm also not five, six. I am five, eight and three quarters, ma'am.

Beautiful. You're taller than me. I am a little one, but I won't be living that much longer than the average, you know, six foot five person or. or a six-foot person or five-foot-eight-person because you're just in that relationship in humans. And so when you look at the genetics of dogs, you can actually see what's a dog and tell them about 10 pounds, basically like, you know, confidence interval being like how much they overfeed their dog, how big that dog is going to be.

And the reason is, is it only about six genes that control dog size versus, you know, the many, many that control human size. And the aha moment for me in starting loyal is if you look at those six genes, four of them are in this growth hormone IGF1 pathway. So they basically regulate the levels and the signaling of these little proteins called growth hormones that circulate the blood and basically bind the cells and tell the cells grow divide, grow divide, grow divide. And this was so interesting to me because this mechanism specifically growth hormone

IGF1, which was really, really high and big dogs and really, really low and small dogs, is actually the OG longevity mechanism. So it was actually the first genetic pathway that was shown back in the late 1980s, that if you made a worm, a C-Elegance, was low growth hormone IGF-1, that it would live almost 2x longer. And conversely, if you make an organism with really high-levels of the growth-HRef 1, you get a big organism that lives a very short lifespan. And this has been replicated over and over and over again across species,

and there's even correlation data in humans, including Ashtonazi Jews and Tenarians, have a genetic mutation, that means they have much lower IGF1 signaling stemically. Now, of course, nobody does what's causative, but the fact that you have strong positive data in lower organisms and model organisms and in correlation data in humans, like just might just be a foundational aspect of biology. So to find that in the dog, I was like, oh, my God, this is like the perfect place to start. The short-life genetic dogs isn't inherent. It's a disease due to historical and breeding for size.

Right. So essentially it's like over the last few hundred years, we have, through breeding dogs, created problems, like haphazardly or even accidentally selected for at the molecular level, IGF1 to produce mastiffs and other big dogs. We weren't trying to do anything with IGF1. We didn't know it existed. But we were in the process of breeding bigger dogs, creating dogs that had more of this growth hormone that has a negative association with long lives. And now you're essentially trying to, undo the breeding effects with your drug, right? It's like there's human action to create the dog breeds and now a new human technology to sort of unwind the problems created by the breeding. Is that essentially it? Yeah, that's exactly how to think about it. Basically, you know, dog breeds are artificial.

They're human creations, and it's kind of the way to think about it, it's artificial evolution. And the hand of evolution only lasts from the birth of the animal to its replication. I mean, the asterix, right? But in general, it's about that animal that you've selected for

breeding and passing on their genes. And so people back then didn't understand, you know, human genetics. They were in breeding themselves. And they were also breeding their dogs. And it was super effective at creating big dogs or dogs that were protective or dogs that were super cute or whatever they were looking for. But this also selected for genetic mistakes because it was only to, oh, dog grew really big, we breed it with the other dog that grew big.

So I get a puppy dog that grows. even bigger, they weren't following and being like, oh, did I also select for something that in the late stage of life causes something negative, aka shorter lifespan. And so that's what we're trying to fix it maybe too strong of a word, but compensate for in these big dogs to give them a longer, healthier life. Let's talk about the medicine itself. Your first drug, Loy 1, before we get into exactly how far down the FDA obstacle course you've made it, give me a clearer sense of what exactly this drug does? What does Loy 1 actually do? Yeah, so we have two drugs actually for big dog short lifespan. Lawy 1 is the first drug. It's an injectable. It'll be, there will be a

three months and a six-month version that basically go to a vet. The vet kind of pops it in similar to getting a microchip or my dog gets an osteoarthritis injection every month, similar process. It releases a drug consistently over time. And basically what it does is it will dampens it. down the growth hormone IGF1 singling in your dog, you know, somewhere between 30 to 50%, which we've shown in other studies to be sufficient to have benefit on, you know, age-related changes in dogs. We also, about a year ago, in licensed a pill version of this drug, it's a different active ingredient, but the same mechanism of action, same idea of reducing growth hormone IDF1, but able to be formulated really conveniently into a small cure to a pill,

So if somebody doesn't want to give an injectable or a dog's bouncy or they don't live near a veterinarian and can't go access it every time, they can have a daily pill that they can give their dog that will flavoring TBD, but, you know, our other one is beef, so maybe beef. Beef pill, that's kind of similar to a treat that they can give every day to hopefully extend their dog's lifespan. If you're inhibiting a growth hormone, then if someone gives, say, their puppy, Mastiff or their puppy Great Dane, this drug, are they inhibiting its growth as well? Yes, they should not do that. So basically, the way to think about it is growth hormone is completely natural, quote-unquote, and good. It's good in any cases, right?

You don't want to have too little, having too little also positive bad things because of the therapeutic window, right? But the idea is that, you know, relative to the size of the animal, so controlled for dog's size, big dogs have a much higher concentration, that's really helpful for getting them to grow big. We want them to grow big. I personally am a big, big dog person. So let's love the dogs grow large.

But then afterwards, we take it down to a concentration that's seen maybe in a, like an Aussie Shepherd, right? A dog that exists currently, that's healthy currently, that has a longer lifespan. But it's still within the range to the scene and an animal, seen in dogs. But yes, you don't want to go to a puppy. You would have a medium dane, microdain. which makes it sound better. It actually will be bad for the dogs to do that.

So the U.S. Food and Drug Administration has not approved Loy 1, but they have determined that it has a, quote, reasonable expectation of effectiveness. Help me understand what that means. Does that mean they approve of your trial methods, or is it an indication, furthermore, that they believe the drug might actually extend the lifespan of large breeds, but they're not yet ready to approve it? So it's, so the way to describe it is the FDA believes a drug has a reasonable expansion of effectiveness for extending the lifespan of large jobs. And that data is so reasonable, let's say, that once we finish the safety and manufacturing aspects of the kind of submission to market and sell this drug, that data is sufficient to begin selling this drug for life. extension. So in other words, we have finished the effectiveness portion that is necessary to

begin selling this drug for lifespan extension. Now that's for conditional approval. So one of the other kind of why now is of Loyal was the opening of this new regulatory pathway called expanded conditional approval where you have the exact same safety regulations, exact same manufacturing standards, but only reasonable expectation of efficacy. And that was really important because even in dog showing definitive lifespan extension would take about five years. And so what this pathway allows us to do is, you know, the drug has to be saying to drug has to be manufacturing the standards. We have to have really strong data to suggest it's going to do what we think it's going to do. And then we can conditionally market it, making it very clear that's

conditional approval while we're running that pivotal lifespan extension study. And so that actually only became available in 2019. And that was one of the big things that kind of made, oh, shit, like this company is now possible, not only scientifically, but also candidly, like from a, well, I'm sure we'll talk more about it, but from a funding perspective, which I'm not independently wealthy. I've raised investment for this company. It is very expensive to build a drug, even dog drugs. So it was very important to a path to market that is reasonable and fifth-as-in-a-venture kind of fund economics. Before we get to the economics, just two more questions about Loy 1. First, I have to imagine that anybody, especially those with a large breed,

are going to think, timeline, timeline, timeline. What is a reasonable expectation for when, if things continue at the rate that you hope they continue, when is this drug going to be available? So this drug is on market, or it's on track for 2026 approval. We have another drug that's for senior dog lifespan extension, so dogs of most sizes, most breeds, who are already showing signs of aging.

And that drug is actually on track for beginning of 2025 approval. We don't have the reasonable intention of activity, disapproval yet, but basically the thing that actually determines the drugs go to market timeline with manufacturing. And I actually have it. No, I guess people aren't going to be able to see it because there's no video. But I carried a drug with me all the time. You could say I have a drug dealer. Just kidding. I don't give the drugs to anybody FDA. It's all the placinos. But I do carrying them around. We have the commercial manufacturing done on this one. We believe it's done. Of course, it has been submitted. And so that drug will be on the market closer to 2025.

And side effects? From what we've seen, the drug's extremely safe. You mean, with any dog drug, you gastrointestinal distress, sometimes when you start something new. But we've had dogs eat many, many multiples of what they were supposed to at levels that, you know, if it was spinal, a paracetamol or something, would kill you or kill the dog, and they would completely fine. Do you have a specific goal in terms of how long you're hoping to increase lifespan?

Like, is there an interval of life expansion that you're, aiming for, say one year, or would even a small interval of life expansion discovered in the phase three clinical trial count as a victory for you? So the victory, quote unquote, will be statistically significant extension. And so that's all at the bar is. And the asterisk here is that it's not just lifespan. It's lifespan and quality of life. Right. So this is not what our approval is going for, but I think theoretically, if we only improve the quality of the life of the animal and maybe it's only a quantitative lifespan extension of one month, but that, you know, normal lifespan plus one month is 20% healthier than it would have otherwise been. I think that is

both a scientific success and a market success. Again, our label isn't designed to not show some degree of lifespan extension. You have to kind of pre-define what you're looking for to the FTAG from like a scientific integrity perspective, but I do think that would be acceptable. That's set scientifically. That said, we kind of base all of our statistical modeling around one year of healthier lifespan extension. We could detect shorter. We could obviously do it longer. But you kind of put your like stick in the sand, so to speak,

from a statistical perspective. Although this is the drug if you want to see it. I can see it. And indeed says Loi. And I think it says, well, I don't know how much of it. It looks like a- It says 81. Oh, it says L'I-A-1.

Yeah, it's the biggest dose we have. Several times what we've been talking, you've referred to the wacky economics of pharma. And while a lot of people working in tech are working on, you know, what I would call kind of commercialized innovation, the basics of their company already exists and they're trying to build an audience for it. You're inventing something. There is, there's no category here. The FDA has never approved anything for dog life extension and you're trying to build it. That means you have to raise a ton of money to funnel these clinical trials. It means there's a ton of expense before you even get a dollar back from consumers. I'm curious, you know, I've never talked to someone, I guess, from big pharma and you're kind of small pharma, or you're kind of small pharma, or or like maybe medium-sized pharma, scaling pharma. What has surprised you about this space? What has surprised me in terms of fundraising for it? Or what do you mean?

I mean, like about the economics of it. Like as someone who came into this, being interested in the science and being interested in the end point of extending, you know, dogs' lives, but not having come up in like the pharmaceutical industry and sort of, you know, learning the ropes as you're going through it,

you said something a couple of minutes ago that I don't know if it entirely surprised me, but I think it's an important point, which is that the cost structure in pharma isn't about the manufacturing of the pills themselves. Like the drugs are cheap. It's getting to the point when you've established you have a saleable and effective and safe drug that's really expensive. So I'm wondering if there's something about the economics of or mechanics of this sort of novel pharmaceutical innovation industry that you find is either has surprised you or you find to be

counterintuitive for people that you talk to. They don't get this big thing about what it is that you do, but it's like old hat to you. Oh my God. Well, how much time do you have? Let's do five minutes. No, this is something I think about a lot because a lot of the investors that we work with are often either deep tech or kind of consumer tech.

Investors, and often don't invest traditionally in pharma, in part because the market is very different, right? We're going for dogs, biotech investors only invest in human, But also, as we've learned, that was non-intuitive starting, is that Loyal doesn't fit the economic model of the traditional biotech fund. And the reason being is that the traditional biotech fund is built off of a very different type of company than me or you might be used to, kind of being in the valley and seeing tech companies growing up. And so one thing to think about is, so to take a human drug to market on average is about a billion dollars, right? but it's actually very rare for a company to go from zero to spending a billion dollars and getting a drummer market.

The way to think about kind of early-stage biotech is it's externalized R&D for big pharma. And so it's all about cash to milestone, cash-de-risking point. That's why you'll see these companies that are in, you know, early-stage clinical trials that are years away from making money actually being on the public markets because they're not betting, quote-to-quote on revenue growth or whatever, they're betting on, oh, this phase two study is going to read out positively. And then Pfizer has a gap in their portfolio, and they need a drug that's doing this, or it's a next gen of that.

So they're going to buy it, and they're going to buy it for half a billion, a billion, five billion, whatever it is, right? And so it's much higher risk in certain ways because, and one of the things is different about biotech VC versus a tech VC, is their ownership requirements are way higher. You often have free monies that are lower than the amount raised. One, because it takes so much damn money to develop a human drug. A dog drug is much cheaper, but the tenth of the cost,

which is one of the other reasons. It's kind of fun to build it in the space. But also because they are funding, you can't will a drug to work. If somebody has a hypothesis that there's a new way to do gene therapy, and they're wrong. That doesn't, it's done, right? And so you have to build that into your economic funding model. And so you can't be, you know,

you need to basically make so much money from the episodic winner that you get to offset all of the losers that you have. And so a company like Loyal, like loyal is not a single bad company. And we're just a thesis-based company that there should be a drug that extends lifespan and health span in dogs.

And if people will want this and you can build a farmer brand that people love and that is a multi-billion-dollar. market that's currently on tap. That's our thesis. And then we have, you know, that is almost certainly correct. It is almost certainly correct. You could extend a dog's lifespan with the pharmaceutical and it's almost certainly correct that people won't want it. Right. So then the question is, how do you do it? And so we have three drugs. We're going to, you know, expand that more. We've been very fortunate. Our three drugs that's, you know, so far worked very well. But any one of them could have failed and it wouldn't have been validated the thesis that is

loyal, right? And so that kind of model of it's more on traction to getting to revenue to launch us. The other thing we're doing different things, we're going to launch these drugs ourselves. We're going to, you know, I don't know

there are not that many good examples in at least the pharma side, the biocide, and definitely the animal health side of launching a drug and it being successful yourself. Traditionally, you would just go and like co-license it with some big pharma. but that's one of the other reasons we were able to raise

from this kind of tech bundle because in the economics of the product, not only a milestone unlocking of the product becomes relevant to the kind of economic argument I'm making to an investor of why it makes sense I invest in loyal now and why they can underwrite that we're going to be worth 10 to 100 X in the future. So it's kind of all over the place, but basically I think a big thing is just really understanding the differences of what games,

you're playing, what game the investors are playing. And it can be somewhat, for me, like, I didn't come, like, I worked in venture a bit, right? But honestly, I've learned all of this from building loyal, as I'm talking to hundreds of investors and failing on hundreds of pitches. Because that's how I kind of, like, coalesce. Like, oh, this is how I need to help people underwrite this company. We talked a bit about large breeds. Obviously, there's lots of people who have medium and small breeds that are

in their dogs living a little bit longer. If IGF1 is the predominant growth hormone in big dogs that you're targeting with Loy 1, it seems like you need a totally different mechanism to extend lifespans in medium and small dogs. So maybe talk to me a little bit about the, like just from a sort of conceptual level, like what kind of drugs you're trying to develop for medium and small dogs and how you're trying to extend their lives. The better here pulling back a little bit is we really tried to pick drugs. That's one of the interesting aspects of the longevity field. This has been a lot of work.

You know, some of it questionable, as you talked about at the top of this. But a lot of it not, because I think, academic sectors, where it has been a lot of mechanistic validation. There's been a lot of, you know, lifespan extension studies run in mice, lots of different, like, you intervene at this portion of the pathway in that portion and that portion and that portion and that portion, like quantifying what happens. And that's all been done. And usually when you have proof of concept or something,

some pharma company comes in or some VC comes in, they scoop it up and they create a company and they go down this whole path I just walk through. In longevity, it doesn't happen because there's no way to get a drug FDA approved currently, or maybe you could say there wasn't until Loyal came along, at least for dogs. We haven't done anything in human yet. There's no, like, market for that, right?

So you have all this, like, really interesting proof of concept data that's actually much more well validated than it would ever be for basically any other disease area because people are just cycling on it and there's nobody picking it up and continuing the development in a privatized company. And so going in, my thesis was, we're not going to be spicy. I'm not interested in like super fancy schmancy, like aging reversal, da da da da da da. No, like the baseline was a drug that's extremely safe as we've talked about. Like you need to be basically as safe as water. We can't do harm, right?

It might not work, but we can't do harm. That was first. And then second was we need to have the highest probability of success. And we're not going from maximized successfully, and we're going to have different generations of drugs that I'm sure we'll work on that. Right now it wasn't maximizing, you know, the radical lifespan extension of dogs

is just like definitive lifespan attention. And so we started with big dogs short lifespan because of that genetic link. Genetic links and genetic diseases are really interesting places. to do innovative medicine because you have kind of a toe hold on very, very complex biology. So, like, the first gene therapies were all in these genetic diseases, right? Like, what I worked on Oxford was a gene therapy, or worked in a lab that was developing a gene therapy for choryeremia,

which is a monogenic blindness disorder that people are obviously born with and become blind over 40. You said, kind of the CRISPR work is being done. It's all in these, like, simple diseases, even with, like, Brockettum mutation, the breast cancer and genetic drivers of Alzheimer's. People start there because you can understand a disease a little bit better. Then you can expand out and implicate that understanding to more wider costs. So Big Dog Short Lifesand was like the lowest, lowest risk way to go. The next then, it's like, okay, well, what is the next most well-validated longevity mechanism

that we think would be broadly applicable because you're totally right, even though I am not a small dog person, we want to help all the small dog people. And maybe I will become a small dog first. My EA is a really cute small dog. So I'm slowly getting there, slowly. But what's the next most well validated that we think would work in dogs of most sizes? And that was looking at the biology of floor restriction.

So chlor restriction is actually the first intervention that was ever shown to extend lifespan back in the 1930s. It's been replicated many, many, many times. From, you know, yeast, worms all the way up into primates. I'm sure we have mutual VC friends or whatever if it meant fast or floor restrict. It's all for this idea of exciting

lifespan. And at a high level, there's a lot of these theories out there, but at a high level, the most well-valided way floor restriction works is by improving metabolic fitness. So any aging drug that you've heard of, which I want to set the record straight, we're not developing these drugs, but drugs like reprimicin, like metformin, these classical drugs that are developed for longevity or proposed we develop for longevity, these all work by improving the

metabolic fitness of the organism. So our drug that will be for senior dog lifespan extension is targeting just kind of holistic metabolic fitness improvement. It's, and so far, like in dogs, we have seen very compelling evidence that it

does just that. Obviously, we haven't run the Lechman Extension Study yet, but we did start it in December with boo the whippitch. So that will hopefully establish a positive blink there. So that was kind of how we thought about creating this portfolio and we'll continue expanding that out. My last questions are about the proverbial Greeks

inside of the Trojan horse, the degree to which your research is going to have spillover effects on human longevity. I guess there's a really fundamental question here that I do not know the answer to at all. Do dogs and humans die in similar ways? Like is the portfolio of like death causes for dogs similar to that for modern humans, which, by the way, is very different from humans like 100 years ago. I was doing some research for the book that I'm writing right now. A hundred years ago, the most common ways that people died were all bacterial diseases. Like, even when people got the Spanish flu, most people who got viruses died from bacterial infection from the virus. And so we invented antimicrobials, penicillin, et cetera, and now bacterial diseases are not

even close to the number one cause of death in the modern or developed world, it's overwhelmingly things like cancer and cardiovascular disease. So I guess it's even hard to compare. It's like when I say compared to humans, it's like compared to its century of humans. But maybe you can take this question at like an abstract level. Do you have reason to believe that the mechanics of dog's senescence are similar or different to the mechanics of human senescence? Yes. Yes, yes, yes. And that was really kind of the other, one of my core thesis is that the fastest way to develop human lifespan extension drugs is developed

dog lifespan extension drugs first. And the fundamental reason is, there's actually a number of fundamental reasons, both biologically and logistically capital, etc. But on the biological side is dogs die of the same ageally diseases that humans do at a

possibly the same stage of their at the same rate as we see. The only big exemption is, cardiovascular disease because, you know, certain forms of cardiovascular disease, especially what humans get tends to be environmental or diet or activity-based and dogs generally, you know, don't have McDonald's. Don't sue me McDonald's. But they do get cancer at similar rates and diet at similar rates. They get discharity. They get dissonative disorders. They get dementia. It's not that they might get Alzheimer's. They get osteoarthritis. And the most important thing is that they

develop these diseases over time, right? you know, I do not have an acute age-related disease today. I am undoubtedly developing the foundations of the age-related disease that I will be diagnosed with in hopefully many decades from now. And that's because fundamentally these cases are age-related because you're degenerative and they occur over these decades. And so when you try to emulate that in a mouse, it's often acute, right? You'll, like day zero, mouse is healthy, day one, you give, you know,

whatever drug to kill certain subtype of neurons, day two, mouse has Parkinson's, right? Versus in a dog, a dog develops it naturally. A dog develops it in part due to environmental factors. A dog develops it because of behavioral patterns. And to be clear, with dog breeds,

you also have increased, you kind of have these like founder populations of increased incidence of, you know, certain cancers. For example, in Goldens, which to my previous point is a great way to better understand those cancers, it's kind of a nub in again. but at a high level, if something is working for doggy dementia,

you know, it's not one-to-one to work for a human, but it is way more compelling evidence that it might be biologically relevant to how humans get dementia, then it might be if you cured mousy dementia, which we've done many, many times. So that's why I think it's so important, and it's also because then you can capture the variability, right? Like, aging is variable, fundamentally variable.

And, you know, we can talk about personalized medicine, but at a high level preventative, that's going to be very, very difficult. Just from an economic perspective and everything you talk about, so really what we find that are generalized mechanisms by which we and our dogs

pathologically have time that on average will extend the healthy lifespan. Like, what is the statin for aging, right? The drug that the majority of older Americans take. I'm sorry, I probably took that away from you.

No, that's exactly where my next question was going to be. I was going to frame it a bit differently, which is that, I mean, you got to exactly where I was going, but the way I was going to frame it was it was, it seems like dog science, can spill over to inform human science,

and human science can spill over to inform dog science. And one conclusion you can draw from that is, well, what is the category of life extension that we've had the most success with humans that we could apply to dogs? And to my mind, heart disease and cardiovascular disease is probably right up there with the disease that we have had

the most breakthrough medicines in the last 50 years. Statins, PCSK9 inhibitors, I don't know if I got the consonants there correctly, but certain kind of hormone inhibitors that can also affect cardiovascular health, why aren't we just giving our dog statins? I mean, is the reason that the cardiovascular diseases that they have just are not anything like the cardiovascular diseases that humans have because they don't smoke, they don't eat our food, it's just an entirely different diet and lifestyle even though we share a house? Yeah, basically. Yeah, dogs do get certain forms of cardiovascular

disease, but it's not, it generally is not, like, arterial clogging that leads in, you know, cholesterol depositions and things like that. It generally is more like, you know, disorders with, like murmurs, right, and disorders with how the heart, like, pumps blood. That's mechanistically, it's aging related, but it's mechanistically very different. Last questions are about sort of the culture of life extension and some of the reactions to, I mean, the huge news that came out. You guys were the cover of, you know, Wired, huge story in the New York Times about the FDAs. I want to make sure I get the announcement exactly right. The FDA's announcement of reasonable expectation of effectiveness.

What's been the reaction like in your space? Have the reaction from dog owners been mostly just unbridled excitement? Like, give me these pills immediately? There we go. Well done. Or has there been also like sort of this undercurrent of, you know, We're playing God with our dog. And there seems like I feel from a naturalistic standpoint

that there's something not right about that. Because I, you know, you look at cultural representations of life extension. And in almost every single movie, I think you and I have talked about this before, but in almost every single movie, the character seeking to like seeking eternal life, which is not what you're seeking, but seeking something like a longer life tends to be evil, right?

It's either like an experiment gone bad like Frankenstein or it's like a Thanos situation where it's like, you know, I want to live forever. You know, good people in a lot of like culture representations of life and disease are supposed to, you know, live with this sort of symbiotic and Zen relationship with the inevitability of death. So I wonder what the portfolio of unbridled, unleashed, ha ha, excitement has been versus how much sort of uncomfortable skepticism has there been about this kind of project? I would say, so far, I would say it's almost, it's like 90 to 95% excitement, especially when it comes from dog owners, especially when it comes from people who have lost the dog, veterinarians.

I mean, we were at a veterinary conference a week after we announced it and literally got swarmed. Like, we had one of the smallest booths. And it was just, like, absolutely, like, overflowed as veterinarians the entire time. So I think there was a lot of excitement there. I think the broader communities, someone of the tenors of the things we've heard, like, oh, is it ethical, can the dog consent?

And I think the way I tend to think about this stuff is just sub-out lifespan extension and put in cancer, right? Like, oh, can the dog consent to cancer treatment? Can the dog, you know, is it messing with nature if we treat our dog's cancer? Right? Like, in all these things, they'd be like, of course, no.

Right? Like, of course you should, you know, if you have the financial means, treat your dog. In fact, I'll even say, like, in some ways, like, my previous dog won't be positive of cancer. And her, I was, like, freaking out, right? So she got, she had breast cancer. I got her mastectomy and all these things. And honestly, it was so bad for her. Like, she was in so much pain that with my, my current dog, Della, who, unfortunately, also has cancer, I decided, like, I'm just not going to intervene this time because I just, like, couldn't, like, do that. And I was just, like, a personal decision I had in this stage, you know, I got

these dogs when they were very old. So they had the disease for a while. So there wasn't like a lot to do. But I would say that is much more like, you know, we don't societally question that. So we should not also question an idea of a much safer drug that doesn't do really anything but taste good to the dog. There's no like negative impact the dog has to keep them healthy or longer. But I think it's inherent that people question it because of course we do. I think in some ways culturally, we have pretty negative feelings about medicine. I think the whole COVID fiasco really brought this out. And that's one of the things I'm really excited about is, you know, can we actually make people's

relationship with medicine and with new drugs more positive, right? Where the drug is accessible. It's, you know, as safe as, you know, we reasonably can hope for it to be. It's for something positive. it's keep your healthy dog healthy longer. And it's something where, you know, I don't want to at all use the word. Like,

magical is the wrong word, but like how can we bring this, like, you know, I try to learn a lot and borrow a lot from like, the right aspects of tech and consumer and this idea of like, how do you make this experience positive?

And I encourage people to learn more about science and get excited about medicine development and get excited about health care in a way that I think we're really lacking here. So long story short, I'm expecting more like more, controversy, so to speak, but I think I feel very confident that we're on the right side of what we're trying to do if we continue in the tenants that we've held today.

And I'm excited to kind of hopefully, like, responsibly help bring a better framework to how we think about medicine. Selina Halewa, thank you very much. Thank you. Thank you for listening. Plain English is produced by Devin Baroldi. We've got new episodes every Tuesday and Friday. If you like what you're hearing, give us five stars and a nice review on Apple Podcasts or Spotify or wherever you get your podcast.

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