Invest Like the Best with Patrick O'Shaughnessy
· 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?
· Patrick O'Shaughnessy, Alex Karnal
[00:00:00] S0: Yeah, doesn't LDL do good things? [00:00:00] S1: Exactly. [00:00:00] S0: It's there for some reason. [00:00:00] S1: It turns out that LDL is produced in lots of different places in our bodies. It turns out that you can basically pin that PCSK9 bad protein down to zero. The best we can do in terms of reduction of our LDL from – really not even in humans, but in animal models – is something in the 80 to 90% zone. Because we have people that are walking around with mutations where they don't produce any PCSK9, and they live incredibly long, healthy lives, and don't have the vicious fate of having a heart attack or stroke. I think we've got the combination of animal model evidence that suggests we really can't get LDL to zero, combined with the fact that we've got genetically advantaged people walking around that aren't even producing the protein to the same degree as others, that this one is very much a free lunch. [00:00:00] S0: Do you think everyone in the world will be on this particular drug at some point?
· Alex Karnal
[00:00:00] S1: That would be a dream for me. A big dream for me is that everybody, anywhere, who wants to have the maximum level of cardio protection could get access to this medicine and could stay on it. Because it is more asymmetric, it is more in the degree of that free lunch, I would argue that if you just project down the road longer term, this medicine should be far bigger in terms of the number of people that are on it and the revenues that are associated with it than GLP-1s. That's not what's playing out right now. And it's not playing out right now really for two reasons. One, GLP-1s have this amazing attribute to them that you take them and very quickly you start to have some side effects so you know you're on them, and you start to see the benefits. When you compare the two, it's easier for medicines where there's an acute, clear, easily measurable benefit, for people to stay on them. Unfortunately, in the setting of cardiovascular disease and particularly thinking about bad cholesterol, this is to me the most dangerous setup because you don't feel anything if you have a high level of bad cholesterol. You could think of it as a silent killer that's just working in the background, slowly accumulating in our bodies. You can be doing everything right and being at your peak physical shape and then all of a sudden out of nowhere, you can have a heart attack or a stroke, because if we don't pay attention to the levels of this bad cholesterol in our body, they can sneak up on us and claim our lives. So to me, because the reward is so asymmetrically favorable versus the risk, because the earlier we can intervene with the accumulation of cholesterol in our body and keep that at bay, the greater the likelihood is that we're going to get through the rest of our lives. Even if other things manifest like diabetes or high inflammation or our blood pressure goes up, we're going to be able to be right at the core of the problem and keep that as low as possible – meaning that we've got the lowest level of accumulation across our vasculature.
· Patrick O'Shaughnessy
[00:00:00] S0: I think the number three and four killers – we've talked about, metabolic disorders and cardiovascular – are neurodegenerative and cancers. So I'd love to spend a couple minutes on each of those. Neurodegenerative, in particular Alzheimer's drugs, seems to have been kind of this wasteland. We really don't understand what's going on. As a result, we haven't made a lot of progress at either protecting against or treating something like dementia or Alzheimer's. What is going on in the world of science and in the business of pharmaceuticals to address this specific problem?