Invest Like the Best with Patrick O'Shaughnessy
· Alex Karnal
[00:00:00] S1: It's been a wasteland for decades. I think we've finally cracked the beginning of the code, but not the full answer. What we've found today is in patients that have confirmed levels of plaques that have developed over decades in their brains, we now have medicines that people can take that will start to break up those plaques and remove them. Unfortunately, and this will be intuitive – if you get to the patient that late in the disease, a lot of damage to the brain has already happened. Because you can imagine these plaques are building, they have to go somewhere, they're causing death and destruction of the tissue around them. Today, we've got some amazing medicines that are both Biogen and Eli Lilly that if you are late in the disease progression of Alzheimer's, you can start to slow the decline. And we can slow that decline by about 30%. And so intuitively, that just gives us a lot more years at the baseline level of cognition that we have, versus declining much more rapidly. It turns out that if we can identify a patient that's at risk for Alzheimer's disease earlier and earlier and earlier. If there's a test available to do that, well then it makes perfect sense that if we can start giving people these medicines as early as possible, not only will you be there in the early stages before a lot of damage is done, but you can think about it as turning off the faucet. So as these new amyloid plaques are produced, you can be attacking them with a medicine that helps to accelerate their clearance. And oh my goodness, maybe that has a dramatic effect on long-term decline. Maybe it reduces those rates by 40, 50, or more percent over a longer period of time. Which means the earlier we can get them and the better those medicines are at interacting with those plaques, and the easier it is for the people to stay on those medicines – we might be able to wake up in a world where we live without this disease. We know that that's possible with GLP-1s for diabetes and obesity. If you take them early enough, you will not become diabetic, you will not become obese. We know that's possible for cardiovascular disease. If you start taking a PCSK9 inhibitor earlier in your life – which by the way, I think the risk-reward is actually even more favorable than statins in terms of human health – but we know that you won't progress to cardiovascular disease.
· Alex Karnal, Patrick O'Shaughnessy
The same is true for Alzheimer's. [00:00:00] S0: So up to this point, we can imagine a future world, as I know you do, where everyone can enjoy the benefits of protective, defensive measures in our health stack for these three specific killers. What about cancer? Cancer is the last one that in some ways feels the most visceral and the scariest. You hear you have cancer or someone has cancer, it feels like this death knell or just terrifying piece of news. I think we've made huge strides in treating cancer, but I'm curious how you would frame up the problem that is dealing with, preventing, treating all different kinds of cancer.
· Alex Karnal
[00:00:00] S1: If we are successful in mobilizing people around a health stack and we can move from reactively treating disease to helping people be as proactive about their health as possible. I think the unintended consequence of that is people live longer. Eventually, something's going to get us. The incidence of cancer being the issue that brings us down, the disease that brings us down, could rise. I think the unfortunate reality is that cancer is hard, both because we often identify it too late, and then when we do – cancer is like a sneaky devil. You might have an angle of attack to go and beat that cancer that presents itself early, and as soon as you're making progress with a medicine against that angle of attack, all of a sudden the cancer has a survival instinct and it redirects. Now, a medicine that was working incredibly well, that had shrunk a tumor completely to zero, is having no effect because while that medicine eliminated the cells that were most vulnerable to the medicine, guess what? The cells that were left behind – even if it's just a few – now had the advantage in growing rapidly and causing a new set of harm and setting a patient on a horrific direction. It's hard because we tend to identify cancer too late, and then when we do, it's shifty. Now, there's also the opportunity for optimism around it. I think it gets to the topic you and I have spent some time talking about, which is testing. The areas of testing today that I find most exciting are across being proactive, and early identification of the risk. And then once a cancer emerges, what do we do about it? And so, talking maybe across both of those modalities, and then come back to the medicines that are associated with that. In terms of identifying cancer early, there are companies like Exact Sciences and Guardant Health that have gone really hard at breakthrough innovations to help us screen for colorectal cancer. Now, of course, we have the gold standard that's available, which is a colonoscopy, and I have to go get one next year. But none of us are ever looking forward to that. Because it's something people don't look forward to, even though everybody should be getting them, and with regular periodicity, most people don't, and I think that's really tragic.
· Alex Karnal, Patrick O'Shaughnessy
Because by not getting your colonoscopy, you're putting yourself at risk for colon cancer, which is an incredibly slow-growing cancer, and if you just got the colonoscopy, I think we could very much live in a world today with very low incidence of colorectal cancer. Guardant Health and Exact Sciences went directly at this problem. Exact Sciences has a stool-based test that has incredible ability to predict people being at risk of cancer. Same thing for Guardant Health. Guardant Health took it to the next step in terms of knowing that you can go after markers that would predict colorectal cancer, but recognizing that the commercial model around being able to get people to not just receive the prescription for a stool-based test, but the complexity of people being able to complete the test and get that sample back, was one that just could never have the scale as a simple blood test. And so Guardant learned from Exact Sciences' advancement and then came up with a next-gen version that's a simple blood test that you can get done just about anywhere. And it's been amazing to see that not only are both of those markets continuing to grow, but the blood test is inflecting. That, to me, is exciting because it means that, again... [00:00:00] S0: People care.
· Alex Karnal
[00:00:00] S1: Doctors care. People care. They're getting it done, and that means we're going to be safer and safer from these. But I think it's important for people to realize that not all tests are created equally. When I look at a new diagnostic in this space, I care deeply about two metrics. One is the sensitivity, and the other is specificity. One of them tells us, of all the people that could have cancer, what percentage of those samples are we actually getting back that is an accurate diagnosis of cancer? So if there are a hundred cancers in a sample, what percentage of them actually get picked up as cancer? That's the sensitivity. And then the specificity is, if there's a hundred samples that don't have cancer, what percentage of those give us a false positive saying that you have cancer when you don't? I think both of those are really important metrics. And at the same time, I think that there's a whole other industry around multi-cancer early detection that's evolving right now and unfolding right before our eyes. These are companies moving from not just having single cancer tests, but having multi-cancer tests across large numbers of tumor types that can be really dangerous. When you think about how I describe the offensive and defensive side of the health stack, the defensive medicines that we can take to keep us maximally protected – what's not in there is anything to protect us directly from cancer. But that's because I tried to attack cancer from the screening perspective and made that part of offense. Over time, I think at a minimum, people should be doing a colonoscopy. I think that the next best-in-class version of that is colonoscopy married with either a blood test or a stool-based test with some regular periodicity to it. And I think over the next three to five years, particularly with how AI and the evolution of these tests are really converging to help them to move faster and faster and to be better and better, I think we're going to wake up within the next five years with really awesome multi-cancer early detection tests. And when we have them, then shame on us if we're not getting them and shame on us if we're not acting on the learnings that come from them. This will be obvious, but the earlier we know that we have a cancer, the greater the range of options are for us to go do something about it.
· Alex Karnal
And I think we're finding that across lots of different cancers, there's opportunities to have amazing results. Sadly, my brother-in-law's father passed from multiple myeloma, maybe almost a decade ago. If he had been diagnosed today with multiple myeloma, his outcome, his prognosis is dramatically different. Because not only is our ability to test and identify that people are developing cancers getting better, not only do we have other types of tests that we can look at what are the mutational drivers of that cancer, that help to connect not just cancer, but the type of cancer to the best medicine that we have today to go treat it. But the medicines are getting better and better. While cancer medicines began, as many medicines do, with just pills and injectable biologics, today we have an entirely new class of medicines that are these CAR T-cells, that are either cells that we take out of a patient's body and arm them with the ability to go attack the cancer directly. Or, companies like Capstan just came up with the next-gen version of that where they can inject, on an IV basis, that can attack the cancer cells directly without having to even take cells out of a patient's body and have that happen within the patient's own body. And what we're seeing from these medicines is dramatic efficacy. So we're seeing that they have the potential to reduce tumors by 100 percent and to do that in 70 percent plus of patients, and to keep them at bay for really long periods of time. While we haven't yet cured cancer, to me I think the slope of the line is really exciting, both from the testing angle and the earlier we can identify these cancers. And from the increasing range of modalities and options that we have to go after and destroy them.