Hi. I'm Anne Marie Navar. I'm an associate professor of cardiology at UT Southwestern Medical Center in Dallas. Today, I'm going to talk about targeting the PCSK9 pathway and give an overview of therapies and talk a little bit about where they might fit in, in our lipid management paradigm. These are my relevant disclosures.

I want to start off by talking about the most important foundation of lipid management, which is to not forget that while we talk about all of the exciting new therapies around lipids, we always have to remember we have to start with statins. Statins remain the foundation of lipid lowering for cardiovascular disease prevention and prevention of events in patients with stable CVD. All of the studies that I'll be talking about today are testing PCSK9 inhibitor therapy on top of a base of statins.

Excited about new therapies, but let's not forget about starting with the old.

There's a lot of other therapies that we have in addition to statins to help lower LDL cholesterol in people who are either intolerant to statins or who have continued elevations and LDL cholesterol levels in spite of statin therapy. This is a great illustration made by a fellow in a recent review article in JACC in 2021, showing all of the different ways that we can target either LDL, HDL, or triglyceride pathways to help lower triglycerides or lower LDL cholesterol.

Let's zoom in a little bit on the PCSK9 pathway because that's where we've seen some of the most innovations. Here's a little bit of a more detailed schematic on how the PCSK9 pathway impacts LDL cholesterol. On the left, we have basically what happens in a cell when PCSK9 is present. PCSK9 protein which is represented in this figure as this little purple dot, binds the LDL receptor, targets it for endocytosis into the hepatocyte, and then that LDL receptor undergoes degradation and can't go back up to the cell membrane to help pull more LDL cholesterol out of the plasma. When we have the presence of a monoclonal antibody, that mops up the PCSK9 protein in the plasma, and that protein can't get on the hepatocyte or can't get on the LDL receptor that's sitting on the hepatocyte wall. What happens then is the LDL receptor when it binds LDL cholesterol is pulled into the hepatocyte via endocytosis, but rather than undergoing degradation, that LDL receptor is recycled back up to the hepatocyte wall, where it can continue to bind LDL cholesterol and pull it out of our bloodstream. The monoclonal PCSK9 antibodies prevent the PCSK9 protein from degrading the LDL receptor by mopping it up.

We have two different PCSK9 inhibitor monoclonal antibodies, evolocumab and alirocumab. The FOURIER study first showed us that evolocumab can lower cardiovascular disease events. This was the study design, randomized patients with stable ASCVD, who were on a background of statin therapy to every two-week 140 milligram dose of evolocumab or placebo, and followed them over time for a composite MACE endpoint, which included hospitalization for unstable angina.

These data show the LDL reduction for evolocumab over time. We see a 59% average reduction in LDL cholesterol, which corresponded to a 56 milligram per deciliter reduction in LDL cholesterol over time.

We saw a corresponding 15% reduction in the composite MACE endpoint, which was a 2% absolute risk reduction over a 36 month follow-up. Now, importantly what I want to show you is that those curves actually separate over time. We see this getting wider and wider, and this is consistent with what has been shown with other lipid-lowering therapies, including statins, which is that the longer someone's on therapy, the more benefit that we start to see over time.

Some additional subgroup data from the FOURIER trial help us refine how we think about the monoclonal antibodies and our overall pathway around lipid lowering. This is the subgroup of the forest plot showing that relative risk reduction in people treated with evolocumab compared with placebo by baseline LDL cholesterol stratified by quartile. What we see is no interaction on the relative scale between people with lower versus higher starting LDL cholesterol and the benefit of evolocumab on cardiovascular events. In fact, we actually see numerically the lowest hazard ratio in those with the lowest starting LDL cholesterol. However, a reminder that at least in the group studied with an LDL of 70 or above, there is no additional minimum requirement in LDL cholesterol that leads to benefit from alirocumab.

Here's another graph that helps remind us that there's really no floor to the benefit of LDL reduction. This graph shows cardiovascular event rates in the FOURIER treatment arm versus LDL cholesterol on treatment. We see a relatively linear relationship between lower on-treatment LDL cholesterol values and lower cardiovascular event rates. Again, a reminder that our paradigm really should be lower is better.

Now, ODYSSEY studied alirocumab and this, unlike FOURIER, actually required people to have an acute coronary syndrome event within the past 12 months. It also had a slightly different study design. While FOURIER studied a fixed dose of evolocumab, ODYSSEY had two different doses and allowed dose titration if people's LDL cholesterol in the study fell below a target range of less than 15 milligrams per deciliter.

In spite of these slight differences, we still saw a 15% relative risk reduction in the overall MACE event rate in people treated with alirocumab compared with placebo on a background of maximally tolerated statin therapy. This corresponded to an absolute risk reduction of 1.6% Note, we see a similar separation of curves over time, where it looks like you need to continue to treatment, and with continued treatment over time, we see accumulating benefit similar to what we've seen for statins and similar for what we saw for evolocumab.

Now will there be a number of additional subgroup analyses on ODYSSEY and FOURIER. I want to highlight this one because I think it helps to remind us that the people that we need to be thinking about the most for these additional treatments are the people who have the highest cardiovascular risk to begin with. This graph shows cardiovascular event rates in both the treatment and the placebo arm, and the dotted lines and the solid lines respectively, stratified by how many vascular beds are affected. In blue we have event rates for people with one vascular bed. In red are curves for people with two vascular beds affected, and then in green, we have people who had three vascular beds affected. These are people with PAD, coronary disease and cerebrovascular disease. What we see is that although there was no interaction on the relative scale, meaning that evolocumab reduced cardiovascular event rates by the same relative amount in each of these groups. Because the absolute risk of cardiovascular events was so high in those who had three vascular beds affected, the absolute risk reduction was greatest in that group, such that we had a 13% absolute risk reduction in the overall MACE event rate in the group with three vascular beds affected. This is a reminder to us that although in both ODYSSEY and FOURIER, neither study found a subgroup that had any interaction on the relative scale, because the event rates are so much higher in those with higher number of risk factors or more vascular beds affected, those people tended to benefit the most on the absolute scale.

US guidelines take this and stratify people with clinical ASCVD into one of two groups. People with ASCVD who are not at very high-risk and people with ASCVD who are considered at very high-risk. Now, that group includes people with multiple vascular beds affected, people with multiple prior cardiovascular events, or people with ASCVD and multiple risk factors. In that highest risk group, the recommendations are to start with ezetimibe if LDL cholesterol is still over 70. Then if it remains over 70, to add on a PCSK9 monoclonal antibody such as evolocumab or alirocumab to continue to drive LDLs even lower, consistent with what we've seen in the trials, again, that lower is better.

Now, the European guidelines are a little bit more simple. Rather than try to stratify people with ASCVD into buckets ,they recognize that everybody with ASCVD is at high risk of ASCVD events and recommend that a target LDL cholesterol of 55 milligrams per deciliter or 1.4 millimoles per liter be achieved in all patients with established ASCVD. Recognizing that people with multiple events are at the highest recurrent event rate, there's an additional group, those who are very high-risk, which are people with ASCVD and who've had a second event within two years. In that group, the ESC/EAS recommend that we try to get LDL cholesterol into the 40 milligram per deciliter range or less than 1 millimole per liter.

Now, that's data for alirocumab and evolocumab, the monoclonal antibodies. Here on the left is just a reminder of how those work, mopping up the PCSK9 protein, preventing it from interacting with the LDL receptor. Inclisiran also works on the PCSK9 pathway, but it works a little bit differently. Rather than mopping up the protein after it's made, inclisiran actually shuts off the protein synthesis to begin with. We don't even make the PCSK9 protein, so there's nothing for us to mop up.

Let's zoom in a little bit and look a little bit more closely at how inclisiran works. Inclisiran includes a sense and antisense strand, and it gets into the hepatocyte via this GaINAc-tail. Once in the hepatocyte, those two uncouple, and it binds to the PCSK9 mRNA in the hepatocyte. That then targets that PCSK9 mRNA for degradation via our hepatocyte's native RNA induced silencing complexes. What essentially happens is inclisiran gets into our hepatocyte, binds the PCSK9 RNA, and degrades it before that RNA can be translated into the PCSK9 protein. That leads to a dramatic reduction in the level of PCSK9 protein, and that allows our LDL receptors to live longer on our cell membranes and then to be recycled, rather than degraded when endocytosed into the hepatocyte.

Inclisiran has been studied in almost 4000 patients in the ORION Phase III program. This includes people with heterozygous familial hypercholesterolemia, ASCVD, and a subgroup of patients who don't have ASCVD, but who are at very high risk. These people all had LDL cholesterol over 70 and over 90% were on a statin and about 14% are on ezetimibe.

Although we're still waiting for outcomes trial data, we have a lot of data around efficacy and safety of inclisiran so far. Here's what's really exciting about inclisiran is that unlike evolocumab or alirocumab, which require every two or four-week injections, we actually can dose inclisiran at 0, 3 and then Q6 months after that. Once somebody gets their first two doses, it's an every six months subcutaneous injection. Here are the efficacy data on LDL lowering for this dosing regimen of inclisiran. We see a time average LDL reduction of 50% with only two doses per year, or a delta of about 50 milligrams per deciliter if LDL cholesterol over time, in the ORION Phase III program.

We also see that inclisiran is incredibly safe. This is a really busy table showing the risk ratio in placebo versus inclisiran, for a number of treatment-emergent adverse events that have been studied in the ORION program. The only adverse effect that is dramatically increased is injection site reactions, which isn't a surprise, and these are mostly mild. Otherwise, we see mostly statistical noise around the majority of treatment adverse events studied. I do want to point out, unlike statins, there's actually no difference in the rate of diabetes in those treated with inclisiran and placebo. Some reassuring data that the PCSK9 pathway does not lead to changes in the risk of diabetes.

Based on the data from the ORION Phase III program, inclisiran has been approved in both the US and in the European Union in 2020 and 2021 respectively. Now it's available for our patients, as an additional LDL-lowering therapy in addition to the PCSK9 monoclonals, ezetimibe, and bempedoic acid, which is also approved as a non-statin.

This is a field that is right within innovation. This is a great graphic from Lale Tokgözoğlu and Peter Libby recently in the European Heart Journal, showing where we've evolved for lipid lowering starting with daily pills, moving to every two-week monoclonal antibody injections. Now we're studying antisense oligonucleotides, siRNAs that can be dosed weekly, monthly, twice a year in the case of inclisiran. There's even companies that are studying vaccination to develop antibodies against PCSK9 inhibitor and perhaps the most exciting innovation that we may see, the possibility of gene editing, leading to essentially LDL lowering for life.

This is being head by Verve Therapeutics. Here's a quote from their CEO, "That some genes truly are spare parts." Thinking about the PCSK9 protein as the appendix or the left atrial appendage of our genetic code, can we turn it off and essentially recapitulate a phenotype of lifetime LDL lowering by shutting off synthesis of the PCSK9 protein at the DNA level?

This is one of many different technologies being studied in the PCSK9 world. For people who are interested in drug development, there's probably no field more exciting than PCSK9, showing all of the different potentials that we have for new molecule synthesis. Beyond things like antisense oligonucleotides and small peptides, we have people setting gene therapy, vaccines, and all sorts of other innovative small molecules to try to make not only long-acting PCSK9s, but even oral PCSK9s that maybe nice alternatives for people who don't like injections.

Why is this important? Well, we have to have more competition because the biggest barrier for our patients to get on these novel therapies right now is the price. We studied this early on in the United States looking at the impact of medication copay on whether or not somebody filled the medication at the pharmacy. We studied the variability in copay that people faced when they went to the pharmacy and looked at what proportion actually picked it up. What we see is that when the copay was $20 or less, almost 100% of patients filled the prescription at the pharmacy. Once the copay exceeded $20 a month, the likelihood that somebody actually filled the medication started to drop dramatically. Right now, all of the PCSK9 inhibiting therapies that we have are fairly expensive from a sticker price standpoint. The patients in the United States that are forced to pay a percentage of that as their copay are really going to have limited options as it comes to therapy. I sincerely hope that with additional competition those price goes down and we can continue to extend access to this therapy to more and more patients.

In the meantime, we should be thinking about PCSK9 inhibition in patients who don't achieve target LDL lowering really 55 or less in people with ASCVD, or 40 or less in people at the highest risk according to the European guidelines. Once we have them on maximally tolerated statin and ezetimibe, thinking about monoclonal antibody PCSK9 inhibitors to continue to lower LDL cholesterol. Then as we evolve and develop outcomes trial data for things like inclisiran, bempedoic acid, I think we'll see guidelines also evolve to incorporate those therapies as options for patients who either can't tolerate the monoclonals, can't afford the monoclonals, or who seek to have other options that may be more convenient to them to achieve LDL lowering sustained over time. Thanks for joining.

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