Celine Halioua- "Save The Dogs, Save The World"

Our next speaker is Celine Halioua, and she's the founder and CEO of Loyal, which is developing drugs to extend lifespan in dogs. And she used to be a PhD student at Oxford and a chief of staff with Laura Deming at Longevity Fund. Today, I guess she's going to talk to us about her company.

So round of applause.

Hello. I'm happy that I'm following two of my favorite people in the aging field. This is awesome. So I was trying to decide what to talk about today. And I'm going to talk a little bit about the thesis, but I mean, the TL;DR, it's the same thesis that a dog aging project has. So I thought instead what would be more interesting would be to talk about how we are thinking about our regulatory strategy to what I think is the most important thing that Loyal is doing, which is trying to prove that you can get a drug approved for lifespan extension, for aging, and that aging itself can be an indication and can be an area of interest just as boring as oncology and other areas today. So really the thesis of the company is giving our best friends more time. And you'll notice it in the theme of these slides is they're very consumer marketed, and that's very intentional. We want to build a brand that people love around something that— I love you guys, but the aging field's been a bit sketchy for decades, right? It's been really this idea of contrarian and weird and we're going to make billionaires live forever. And really actually what we're trying to do as a group is very objectively good. It's helping people live longer, healthier lives, helping people have more autonomy in what they want to do, letting people have second careers. And really, one of the secondary goals of the company has been how can we take this idea, this idea that we've all dedicated our lives to, and help the average American, the average individual who doesn't have a scientific background, who's just going to read fluff pieces, and really emotionally attach to this? Because I think that's In addition to some of the specific regulatory work we're doing that I'll go into, I think that's one of the most important things is building that societal support of this idea to grease the wheels as we're going through regulatory change. It does also help that dogs are incredibly cute, as Yali the pug is here, in all of our marketing. And so really the thesis of Loyal is dogs first to unlock human aging. We are building a consumer-focused dog aging company, hopefully a dog aging pharma company. We have a robust dog aging pipeline. But the broader goal and the broader thesis and why I started Loyal was that the conclusion I came to when I was working for Laura at the Longevity Fund is that you can't get a drug approved today for aging. Um, you can't— almost every company we funded, uh, while at Longevity Fund was not straight working on aging. They were working on aging via indications. And this is valuable work. We need to do this. This is how we push forward novel drugs, novel mechanisms of action. But I think the key part that's been missing is that regulatory path for a drug for lifespan extension for aging. The key thesis of Loyal and the key reason I decided to leave Laura, leave Longevity Fund and start this company is that the master plan really is to get the first ever drug approved for lifespan extension in dogs. I'll talk a bit about some of the reasons why this is, we believe, uniquely possible in dogs while it's not obviously possible in people today. And then while we're doing this, build these aging biology models, this regulatory strategy, and also revenue, which is actually very, very important to everything we're doing, to then facilitate dogs as a wedge into human lifespan extension. We haven't been talking publicly yet about the regulatory progress we've made. We're also running a longevity pivotal study, which we'll be able to talk publicly about if and when we get FDA concurrence on it. But really our philosophy at a high level is build the path and then facilitate the field doing it. So I'm really excited to, if and when we get there with the FDA, to be able to talk about all of this publicly so we can all share in these learnings and all push forward novel drugs through the paths that we're forging. So again, Matt went through the high-level thesis, so I won't go too much on this, but why does this make sense? Why would going dogs first potentially help human aging? The first and most important point is that dogs age like us. They are well considered one of the best models of human aging. Again, this is a high-level slide, but at the high level, we have this unique dog-human co-evolutionary relationship. We've shared an environment for tens of thousands of years, and we have some preliminary data that I don't have here today, but I'm happy to talk about verbally, which is we've actually been able to show a correlation between the pollution levels that a dog lives in, and their epigenetic age, or specifically, actually, the dogs that we mispredicted the age of, in that they were older, or we predicted them older than they actually were from validated age records, were dogs that were living within a radius of formaldehyde-releasing plant in the East Bay. Again, super high level, you know, this is not some, like, rigorous scientific discovery yet. It's really more of a directional discovery, But it's interesting because who lives with those dogs? The human does, the pet parent does. You can learn a lot about dogs and pets and humans from them. They also develop the same age-related diseases we do at approximately the same time in their lifespan. The big exception being cardiac disease, potentially because there isn't a doggie McDonald's yet, although that might be a billion-dollar business too. They develop them at the same time in their lifespan, which is really interesting. Then finally, most importantly, is that our largest medical market behind humans. This is important for twofold. One, the revenue aspect, which I'll talk about. It's allowed us to raise money from venture capital. It's allowed me to tell a genuine story of, if we're successful, Loyal being a billion-dollar company, which I guess is great for me, but more importantly allowed us to raise venture capital to fund all of this work that we're doing. But it's also important because it means we've been able to layer the biological data we're getting with the EMR data, with the clinical data, with the qualitative data of how is a pet doing over the time of their lifespan. It also has meant that pet parents have been very excited to work with us in our studies. Again, the Dog Aging Project really forged this idea. I'm sure you talked about the exact numbers, but tens of thousands of dogs in their study. We haven't done studies that large yet, but we've been able to recruit— we recruited a 2,000-dog study in less than 24 hours from pet parents, and then we're able to pull in their medical data, able to pull in their data that we collected, and this is uniquely possible in dogs because it's such a large medical market, and then there's also not, you know, doggie HIPAA. And there's also structural regulatory advantages, and I think this is actually the most interesting aspect of what Loyal is doing. So again, you guys all know this, but at a super high level, you know, there's a number of challenges for going straight for human aging. There's an extremely long feedback loop to see any aging benefit. There's no regulatory path as far as I know. There's incentive challenges too, which is one of the other interesting things, especially in the US where preventative care is not as insurance incentivized as it might be in another single-payer healthcare system, and of course all the standard stats about it's extremely expensive, low probability of success, long time to build a drug. We all know these stats, right? The more interesting thing is that how are dogs different? So we've been able to show biological aging, quantitative biological aging in a dog in about 6 months. So that means that you can run a 6-month study, see that dog naturally age over time, and by the way, laboratory dogs are not, um, They're not Great Danes. These are actually medium-sized dogs that we're able to see this aging in. Then you're able to see lifespan extension in 3-5 years. A 6-month study is a completely reasonable study to run. We've run multiple 6-month studies in dogs. We also do induced accelerated aging studies in dogs. But then even seeing lifespan extension is something that you can do suddenly in a company that's biologically reasonable. There's also an accelerated regulatory path uniquely through the veterinary FDA. This was really the catalyst and the activator of Loyal. So in September 2019, FDA CVM opened something called a conditional approval pathway, which means you have to show full safety, full manufacturing, but only reasonable expectation of efficacy. And so what Loyal has been building is a connection between healthspan extension, which we believe we have shown for both of our lead drug programs, and we submitted that package actually a couple weeks ago, and a link between that healthspan extension, which is relatively able to be quantified with the tools we have today, and lifespan extension. Again, we don't know if the FDA is going to go for it. We just submitted it. We'll know in about 6 months. We'll talk about it publicly regardless of what happens. But it suddenly has made possible, again, having a drug approved in a reasonable amount of time for something that's a long-term endpoint like lifespan. Three, there's aligned market incentives. It's cash pay market. And it's actually super important because a lot of what we've been trying to do in building this consumer brand around a pharma company that we hope people love around this idea of having more healthy years with your pet is building this consumer demand for what we're doing. And that's been a big aspect of how can we align incentives between us, between the veterinarian who wants a dog to be along longer because then it reduces that CAC to get that dog into the door of that veterinarian can pay out over a longer period of time. It aligns with the pet food companies who want the dog to live longer. It aligns with the drug companies because they want their dog to be on that anti-itch drug or whatever for much longer. You have all of these incentive aligned. Of course, a pet parent is the most aligned incentive because as somebody who spent probably $20K on vet bills in the last 2 months, I can tell you that I care about my dog's health today and I care about my dog's health in 2 years from now. The biggest challenge with this cash pay market is that our COGS are really important, and that's really one of the biggest challenges, vet med in general, is that at a high level, you really can't go for any complex modalities because you need to have COGS that are cash pay accessible. And then finally, and most excitingly, it's only about 3 to 4 years to get a dog drug approved. We're really close to hopefully, if everything continues to work out, getting our first drug approved. About $10 to $15 million worth of work, not including people costs. Historically in pet med, there's a 90% approval rate. This isn't because FDA CVM has a lower bar, anything like that. They have an incredibly high scientific bar. But fundamentally, you don't have this translational risk. You test a drug for whether it improves aging in dogs, and then you do a pivotal study to show that it improves aging in dogs. Of course, there's some risks there. Of course, a laboratory beagle or mongrel dogs, which is the other big laboratory population, is not the exact same genetically as a Labradoodle in San Francisco. But it's a much, much closer leap than mice to people. That's something that's been really exciting that you can tell this deeply technical biotech story that obviously, again, we— Loyal might not work, our drugs might not work, I'm not guaranteeing any of that. But there's a higher reason to believe that if we see early data of healthspan improvement, which we have, that that's going to translate into the companion dog. That's a really exciting story for multiple reasons. Then finally, one of the other reasons I decided that building Loyal was important is because it uniquely gives us an opportunity for revenue-generating biotech. Revenue is great. Biotechs almost never make revenue by the time they exit, But I think this is actually extremely important in an industry as moonshotty as longevity and aging, because it gives us freedom. If we're able to make money, if our drugs do make the amount of revenue we think they can— and happy to talk about that if it's interesting at all to this group— that'll fund all the ambitious, crazy shit we want to do on human longevity, right? Suddenly you don't have to go and convince some stodgy biopharma investor that longevity is where the world is going. We can just prove it. This is really, really important to everything we're doing. It's allowed us to take a— I'll talk a little bit in a minute about some of our philosophies towards a regulatory structure, but it's also been a structure in how we do our biology is how do we get to that point where we have independence, where we aren't beholden to needing to talk a certain line or needing to tell a certain story or certain ROI path so then we can do the research that needs to be done. That can facilitate this translational dog-to-human work. So again, really the most important goal of what we're doing at Loyal is getting the first ever drug approved for lifespan extension and healthspan extension. Again, I can't talk too much today about the explicit aspects of what we've done on the regulatory side so far and the pivotal study side so far, but I can talk a little bit about the fact that it's going well so far. And a little bit about our thesis on how we've been thinking about catalyzing the aging industry and specifically catalyzing a hopeful regulatory path for healthspan and lifespan extension. And these are ideas that we built through lots and lots and lots of time with regulators, with regulatory consultants, with people who've gotten drugs approved, people who have spent, you know, dozens and hundreds of hours with the FDA to try to understand not only the letter of the law of what can or cannot they approve, which is super important, but even more importantly is understanding the people side of it, understanding the cultural side of it, understanding the things that— the variables that matter to them when they're debating about whether to approve something or not beyond the data. I think we've all seen the role this plays with COVID and the COVID vaccines. And this is something that we think is really relevant to getting aging drugs through too. So kind of first and foremost, really LOYAL, and you'll hopefully notice this when I talk about LOYAL publicly no matter on what venue, and I'll be a little bit more, I don't know, contrarian or whatever when I'm talking with a group like this, but when I'm talking more publicly about LOYAL, we really are contrarian on one very specific idea and then radically boring about everything else. Loyal dies on this idea that a drug can be approved for lifespan and healthspan extension. That is the only thing we care about. We are working on doing that. That is the goal of the company. But everything else, completely boring. Standard science, we reference as much as possible. We use established measures of healthspan, for example. We pull from data that's existed for decades and we stitch a story, what we believe is a truthful story and a rigorous story, that supports our one contrarian idea. And this is really important because one thing we've learned with talking to regulatory agencies and talking to scientific fields is you can't ask them to make 5 jumps, and all the things that we think are really obvious are actually really non-obvious to somebody who hasn't been activated by the aging field or hasn't been exposed to the aging field before. And again, you have to remember the average person who encounters the aging field who doesn't have that much context for it often has a pretty negative impression of this field. Just because of the easy negative stories that are able to be told about longevity. So it's really about getting the buy-in to one contrarian idea, and then they don't have to take a leap on anything else. And the cool thing about this is if you get them to buy into this one idea, that lifespan can be an indication, then you can start pushing it forward, pushing it forward, pushing it forward from there. We've also had a lot of success of framing our thesis in already well-accepted frameworks. We started our first drug, LOY-1, is for the short lifespan of big dogs. We picked this very intentionally because even though it was actually a pretty pain in the ass mechanism to drug, because it allowed us to tell a story that again is true around a genetically associated disease. FDA knows that almost every dog breed has some genetically associated disease, hip dysplasia in German Shepherds. Breathing issues in brachycephalic dogs. Golden Retrievers get certain forms of cancer at a very high rate. And so we were able to link something that was already known, which is a genetically associated disease with a dog breed due to dog inbreeding, with something that they maybe haven't thought about before, which is like, hey, maybe the abnormally short lifespan, the 6 to 9 year average lifespan of a Great Dane versus, you know, 16 plus of Chihuahuas, isn't normal, isn't inherent. Maybe that's a disease too. But that's a much, much, much smaller leap because we're associating something which is what we want, which is again, hey, we're looking at aging in these dogs to something that they already know, which is genetically associated diseases. We also use the statins metaphor a lot. And this is around this basic idea of, you know, at a very high level, a statin is a drug that you take to reduce the probability of a future age-related disease incident, right? What will happen if you had statins? For multiple diseases at once? Wouldn't that objectively be better? And so we anchor on this idea of something that's very obvious, probably they take it, or their grandpa takes it, or their parent takes it, right? But then we expand out the possibility to almost tell a story. It's like, nobody's going to say, oh yeah, it'd be terrible to have a drug that reduced your risk of cancer and cardiac diseases, right? Like, that's a very obvious thing to say yes to, but it's starting with something that they're anchored on, that they already have a predisposed positive opinion of. And then finally, of course, is this idea of preventative medicine. I'm sure we all get the really common question of, are we not just furthering social inequality by making billionaires live forever, da, da, da, da, da. And really where I always circle it back to, and again, has been very successful, is this idea of, A, late-stage age-related disease treatment is incredibly inequitable, as we all know. But preventative medicine is always better for the patient, right? It's much, much better to reduce the risk of a future disease to not develop develop a cardiac disease, to not develop a neurodegenerative disorder, than develop it and have to treat it, and invariably it's a much harder problem. And again, these are all ideas that we know, these are all ideas that are core to the aging field, but the really— the important thing that we've found that's been very helpful is linking the two. So it's like they start to reassociate aging with these ideas instead of whatever ideas they had previously. Another thing that we've had a lot of success with is collaborating with non-aging scientists. And non-aging experts. We have a lot of aging scientists we work with. I mean, Matt is one, of course. But we also work with people who are completely unassociated with the field. We work with a lot of metabolic scientists, a lot of neurodegenerative scientists. And this has been important, again, because when you— they end up being a node to this whole field that might have never been exposed. And then you end up being that first person to introduce them to this idea. Safety first is super critical. The— we are able to say truthfully that our drugs might not work, but they're almost certainly safe. And we've been able to show safety margins for all of our drug programs to date that are way above anything the FDA requires. And again, this is super critical. This is critical both for adoption— nobody wants to give their dog an aging drug and the dog die tomorrow— but it's also been important with helping convince the FDA to work with us, right? Because if you think about One of these variables that you're not going to find written in any regulatory document, but is very relevant to anything when you're working with humans, is the embarrassment factor, right? Like imagine how embarrassed they would be if they go and they approve this first ever drug for lifespan and healthspan extension led by this like crazy late 20s female CEO who maybe is Holmes 2.0, like who knows, right? And then they have like all this like crazy adverse events and it's like super cute dog dies. Not obviously a variable that they should theoretically be making a decision on, but it does play into effect when these regulatory bodies, who again in the end are just people, are thinking about whether to bang their fist on the table about working with you or not working with you, whether it be collaborative or not be collaborative with you. And most importantly here is we've been able to cite data that isn't even created by Loyal, it's been created by others, which allows a degree of objectivity to it to say, look, you don't have to worry that we did something weird. This drug and this mechanism is objectively as safe as we can reasonably expect any pharmaceutical product to be, and here is all of the data that's way above anything you would ever need. And that's really taken us— that's really helped us in a lot of these conversations in a way that I think if we'd come with a drug that had any question marks, about safety, we would have had a lot harder problem. And of course, you guys all notice, but at a high level, the safety things that are really important here are mechanism of action. So what, you know, where are you targeting? But modality is also super important too. So we, again, we're going for pretty boring drugs. And to be clear, they're not, you know, rapamycin or metformin or any drug you would have thought of as an aging drug today. But they are drugs where we know the modality isn't going to introduce extra variability and safety. And then of course, API is super important too. Another thing we've done that's really helped is, and this is really hard for any new biotech company or any new group that's never done this before, but it's figuring out what does the bar look like and how can you exceed it. So we spent a lot of time working with animal health regulatory experts to understand what does a 99th percentile regulatory filing look like? And do it. And we trade off time. So we, like, for example, we have an important package that we could submit to the FDA today. We're probably going to take an extra quarter to do it because we want that package to be perfect. And again, there is no reason that it doesn't have to be perfect. You don't have to have it. In the end, it's about the data. But it's been helpful because it's like, how can you build trust in these filings? How can you build trust in the company and the ability to execute? On what you're saying to again not bring that embarrassment factor in. And that's been really hard to do this well, but if you can do this, if you can figure out what that calibration point is, it's extremely important for building trust. I'm over? Okay, sorry. I'll end with some cute dog photos. This is again, it's, I think what I'll end with on saying here is, We're super excited about building Dog Eating Drugs. We're excited about helping pet parents and helping companion dogs. And equally, we're excited about this idea of if we do succeed in doing this, and I really hope we do, we might not, how can we help the broader aging field by kind of bringing some of these regulatory challenges and question marks and pathways in a way that makes it incrementally easier to begin having that conversation. Thank you. [FOREIGN LANGUAGE] A couple of questions.

Hey, great talk, Celine Halioua. So you mentioned being kind of consumer, a consumer-focused company. Can you talk a little about how you decide how much you are, you know, pet owner focused versus vet focused? Who's going to lead adoption both in the scientific recruiting for the studies phase of the company and in the future successful— okay, you get something approved, you know, who's driving adoption? Is it the pet owners wanting, you know, requesting it, um, or even buying it directly? Or is it the vets driving, saying, you know, I want— you, you telling the pet owners you need this for care for your dog to make your dog healthier?

So it's both. So we kind of have two facets of the company. One is this consumer pet parent driven, and I lead a lot of that. And then we have the scientific veterinary side of the company, which is led by the veterinary team at Loyal. And that's really important because the vets don't want to hear from me, right? Like they want to hear from somebody who's actually a practicing veterinarian who understands the things they care about. And we've also brought them in-house because for the exact same reason that it kind of builds in that empathy. It's also important because there's incentives in terms of how is the drug priced and what type of delivery mechanism you give that will make a vet more or less likely to like a drug. And you really, again, you want to stack the stuff in your favor. So we've tried to make our drug programs and the way in which they're delivered something that a vet would objectively love, and then we just have to convince them that the aging thing makes sense. But yeah, we really, like really what we're trying to do is like not create We're trying to get everybody for us. And then also nobody's ever marketed a drug for lifespan extension, so we don't actually know what it's going to work. And so we want to see what works first and then kind of optimize from there.

This is a— the reason I asked the question is because this is a thing that happens in, you know, that's a problem in humans, right? You know, people don't— there aren't enough human physicians who are educated on this stuff. And, you know, I think that just like And, you know, the pets is a spearhead for that as well, for the veterinarians demonstrating how we can expand to the human physicians. So yeah, you're on the forefront there too.

I mean, we've started, um, so our first drug is projected to be approved if everything goes well end of 2024. We've been doing vet outreach for at least a year, and we'll be doing it in much more for the next 2 years. And that's been— honestly, I think if we fuck up something besides the science, it's going to be exactly what you're talking about. It's like not getting that right, because once you introduce that idea, you can't reintroduce it. First impressions really matter in this field.

So in terms of the transition from an approval in dogs to approval in humans, have you, you know, thought about doing dog clocks just to have a partner between what happens in the dog and what happens in the human? And it would kind of push the concept of the clock for earlier approval in aging studies in humans?

Yeah. We recruited it. That study I mentioned earlier was a 2,000-dog saliva-based epigenetic study, and it was exactly that idea. Could we build a surrogate biomarker that then we showed the causative link between a movement in a surrogate biomarker and an actual lifespan extension, and then use that to argue that just like how the primates, the canonical model organism for safety, is the dog canonical model organism for healthspan or lifespan. Efficacy in people. We decided to move away from that for a couple of reasons. One, we just didn't think the data was strong enough. Like, we were able to pretty well, like, predict age, for example, but it was just too variable, and it just kind of wasn't where we wanted to go as a company. Equally, we think that in the end, what we've seen when talking with veterinary FDA, and we think this will only be a higher bar in the human FDA, is they really want that functional link. They really want to reference things they already understand around, for example, we look a lot at metabolic fitness, which is something that's very well understood in human aging and actually was less well understood in dog aging. A lot of our work's been in understanding metabolic aging in dogs. We found that actually, or our current thesis which is changing a lot, and we're planning to start human FDA conversations next year, so I might change every opinion I have right now. But currently we think that linking the functional measures that they already understand, that they already believe are relevant, and then linking that to a drug around aging will be a more fruitful path, at least for the mechanisms we're looking at.

Hey, Celine, great talk. So thinking about the link, the smaller bridge between a dog and a human, have you looked at SNPs in dogs that have predisposition for certain diseases, and do they match human SNPs for the same diseases?

We haven't looked at that, but that's actually one of the— so this idea of dogs first to understand complex human diseases is not novel to anybody, right? They've been doing that in cancer for a long time. There are dogs that get certain retinal dystrophies, which is where some of the ocular gene therapy companies started. So absolutely, that's something to do. And one thing we want to do when we have a larger dataset is actually look at intra-breed variability. Is a Great Dane that lives to 12, what's going on in that Dane versus the 5-year-old Great Dane? We haven't done it yet, candidly, just for bandwidth concerns, but when we get more into the discovery side, absolutely, that is a low-hanging fruit. I think that's all the time I have. Thank you. Thank you.