Invest Like the Best with Patrick O'Shaughnessy
· 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…
· Patrick O'Shaughnessy, Alex Karnal
[00:00:00] S0: Replicate this. [00:00:00] S1: Exactly. How do we get that advantage into the hands of people? And so they came up with injectable biologic medicines at first, that you can inject and would go and find their way in your body to that PCSK9 protein and bind to it, and make it so that protein couldn't bind to your LDL receptor. And that was the beginnings of those medicines. But what innovators then sought to do next was, how do we make it easier for people to take those medicines and get the benefit? And so the next big innovation in that space was moving from injectable biologics or monoclonal antibodies to what's a new modality called RNA interference. And what these are is another form of subcutaneously injected medicine that makes its way down into your liver. And it had the attributes of these being very long duration molecules and made it so that we didn't have to inject ourselves 26 times a year, but maybe only twice.
· Patrick O'Shaughnessy
[00:00:00] S0: It's incredible when you think about seeking out a population that has a natural advantage, figuring out what it is, and then conferring it to others through a drug like this. The dramatic reduction in cardiovascular incidents of people – of course, the genetic group, 88% – but also the people that take this drug is so interesting. I always wonder, the body is such a complex system. There seems to be very few things in biology that just are one use or one explanation. There's all sorts of stuff going on. What are the trade-offs? I'm interested in both PCSK9 and GLP-1 since we've talked about both. It just seems like there's always a trade-off. There really aren't usually free lunches in markets, in nature, and in biology. What's the skeptic's point of view? If I could somehow fly in the smartest, data-driven, scientific skeptic of the use of these drugs, what would that person say?
· Alex Karnal
[00:00:00] S1: I think PCSK9s are very much more that free lunch than GLP-1s. GLP-1s have real toxicity associated with them. We see in the clinical studies, significant rates of nausea, vomiting, and diarrhea are the first symptoms that emerge that cause a lot of people to quit these medicines early. If you look past that and you look to people that have been on these medicines for longer and longer periods of time, you look at the labels of these medicines in the clinical studies, there's risk of the development of gallstones and pancreatitis. Of course, these are issues that would emerge just from having weight loss in general, which you can add to that list muscle decline as well. These are all consequences of losing weight and losing weight quickly over a period of time. But when you look at the other side of the equation, the benefit that you get, the fact that these are so protective across so many different axes and the data is pretty clear. Not only will they protect us from developing diabetes, obesity, and cardiovascular disease. When you look at the implication of those diseases on expected human lifespan – we're talking about the aggregate of those diseases costing us 5 to 10 years. It's very much well worth it for people to take the risk of developing these other sub-liabilities that you can do something about by just stopping the medicine, for the benefit. There is a real trade-off. Without a doubt, it is not a free lunch for GLP-1s, but for PCSK9, it's pretty much a free lunch. There was a ton of concern in the early days – what happens if your LDL goes down to zero?