Invest Like the Best with Patrick O'Shaughnessy
· Alex Karnal
[00:00:00] S1: Eating is definitely a part of it, and it's a major part of it. So, look, if we could all be disciplined and we could all get on a proper diet where we're selecting the right foods, eating the right amounts of them, and staying disciplined, you wouldn't really need these medicines for the purposes of managing our weight. But I think that's only going to cut at the weight part of it. I think, unfortunately, if your biology is wired such that you have a family history of diabetes and you are pre-diabetic and on the precipice of turning diabetic, we're starting to be in a place where we're just not producing the insulin that's required to be able to take up that glucose that's coming from the food that we're eating. So yes, by consuming fewer calories and less food, we can hit part of that. I think it's unknown as to whether that'll be enough to be able to undo your progression to diabetes, and so I might say you probably still need those medicines for that. I think the other side of the equation, connected to that, has to do with addiction. In some sense, you could say that food is a form of addiction. While consuming fewer calories will help protect us from the vicious cycle of over-consuming food, in terms of the addiction data that'll start coming out over the next year or so, you would lose that benefit. You would lose the free gift of protecting yourself from being addicted to drugs, alcohol, or gambling. There's an open question on what just consuming food would do for cardiovascular outcomes. We've got compelling data right now at Novo Nordisk over the last year that basically shows that by taking GLP-1 medicines, there is a north of 20% reduction in our risk of having a heart attack or a stroke. And what I thought was pretty profound about the full data that they put out is that that was independent of weight loss. That speaks to me that there's just another axis and another biological driver that's driving this cardioprotective result. We might forfeit that. But without a doubt, if we could actually get access to great food and we can eat the right amount of it and stay disciplined, that would take us a little while.
· Patrick O'Shaughnessy
[00:00:00] S0: But it seems like, summarized, there is more going on than just that. The data seems to suggest that even if I could perfectly eat, I might still reap benefits in other ways from these drugs. To really drive home the point of existing drugs – before we get to all the exciting new stuff, which we'll talk about as well – that there are existing drugs which could have radical impact if everyone was on them. Anything else on GLP-1 that you feel like is especially notable that we haven't talked about?
· Alex Karnal
[00:00:00] S1: The other aspect to it is, we want to start chipping away at what are the layers that exist in between that could prevent people from actually getting the benefit of GLP-1s. When I think about that continuum and I think about that gap, there are basically three different dimensions that are preventing people from getting maximal benefit of a breakthrough medicine that exists and is right here for all of us. Those break up into, in my mind – complexity, cost, and convenience. I started on my journey two years ago, and to practically have to deal with our health system – all of the different branches that it took from recognizing that I had a cholesterol problem, to two years later finally getting access to the medicine that could help protect me from that problem. It's everything from you want to go see a doctor because you get a blood test that says, hey, I got a problem. To learning that, well, the next appointment's only six weeks out. And then I go, and of course, they want to redo the blood test. The friction in our system mounts and mounts and mounts. And eventually, I think a lot of people just give up. It is really hard to navigate that system. Given what we're seeing with GLP-1 medicines, and how we're seeing that the direct-to-consumer side of that is driving most of the adoption today, I think we have to start asking ourselves – why is it that I can go on my iPhone, I can go to Amazon, I click a button, and the next day I can have toothpaste? But it takes me an incredible journey, hundreds of phone calls, multiple doctor visits, being pricked and prodded multiple times, just to protect myself from having a heart attack. That doesn't make sense. I think we have to balance the opportunity for health impact of this amazing medicine that we have, with the reality of how darn complicated it is to navigate through our system. Next is cost. Most medicines that we need to be on for the rest of our lives that are going to be providing the chronic care – the different layers of that defensive health stack that will protect us from these diseases. Those medicines today are priced as similarly to acute treatments, yet they need to be taken over decades. So we have a timeline problem, we have a horizon problem.
· Alex Karnal
And I think that there's a lot of innovation that can occur around pricing models, if the world is moved from where we are today, which is waiting until there's a problem, waiting until it's almost too late and reactively treating it, to proactively getting out ahead of disease. The final part of that is compliance, and we alluded to that a little bit. But the reality of it is we all know that medicine only works if we take it. And it turns out that because of the complexity of the system and getting it, because of how expensive these things are, and at the end of the day, because we're all human. The more frequently we have to take a medicine, the harder it is to go get it, the more times we have to go to the pharmacy, the more times we have to make that decision. Over the course of the year, the higher the probability we're just going to quit. And that's just human nature, myself included. Your compliance is this invisible barrier to all of us realizing our best health outcome. On one hand – wow, I mean, GLP-1 medicines is an example. It's miraculous, we went from twice a day to once a week, and now we've got versions that are once a month, maybe once a quarter. That's a huge unlock, in my opinion.
· Patrick O'Shaughnessy
[00:00:00] S0: Maybe now's the time to tell a second drug story, a far less well-known one than GLP-1, which is PCSK9. I find this story to be so interesting for so many different reasons, but maybe most of all, because it seems closest to a free lunch drug that exists, and because it helps deal with cardiovascular disease, which is something that everyone has, in their family or themselves, probably dealt with at some point. It seems incredibly important, close to as important as the first one we talked about. Can you tell the story of this specific drug? What it does, how it works, the impact it might have?
· Alex Karnal
[00:00:00] S1: The headline here is PCSK9 medicines are amazing, because what they do is they today can lower our bad cholesterol, that LDL cholesterol, by 50%. And we now have outcome studies in patients at different degrees of having high cholesterol, having significant protection from ever developing and having a heart attack or a stroke. And so in patients that have previously had a heart attack or stroke, we can reduce that risk by over 20% in the future. And for people that are at high risk of having a heart attack or a stroke, the medicines that are approved and on the market today can lower that risk by about 25%. And so these are incredible medicines, particularly because heart disease is still the number one killer in the U.S. today. These medicines are profound because they hit right at the heart of the biological driver of high cholesterol. The way these medicines were discovered is from human genetics. What we can do from a human genetic perspective is go around the world and look at different populations of people, and study what are some of the attributes and some of the advantages of different populations. It turns out that there's a population of people in the world that have a genetic mutation that conveys a massive advantage. They have a mutation in their PCSK9 gene, which means they don't produce the PCSK9 protein. Now, what we've learned from both observing that village and understanding the cardioprotective nature of that genetic defect, what we learned is that the production of this PCSK9 protein interferes with our body's own ability to clear LDL cholesterol. And so what happens is the more PCSK9 we're producing, the fewer particles of LDL that we can clear. The higher our cholesterol grows over time, the more those little particles are invading our vasculature and starting to mount up until we get to a point where there's a blockage. Recognizing the import of that PCSK9 protein, driven from the observation of human genetics, and from data that showed in these populations of people with longitudinal studies over 15 years. The fact that they were genetically deficient in the production of the PCSK9 protein led to them having an 88% reduction in the risk of ever developing cardiovascular disease. That was miraculous. And so what the pharmaceutical industry sought to do was, how can we…