Emerging Options for Elevated LDL Cholesterol: Focus on PCSK9 Inhibitors

Transcription

1 Emerging Options for Elevated LDL Cholesterol: Focus on PCSK9 Inhibitors Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC Executive Director of Interventional Cardiovascular Programs Brigham and Women s Hospital Heart & Vascular Center Professor of Medicine Harvard Medical School Boston, Massachusetts Deepak L. Bhatt, MD: Hello and welcome to Emerging Options for Elevated LDL Cholesterol: Focus on PCSK9 Inhibitors. I'm Dr. Deepak Bhatt from Brigham and Women's Hospital and Harvard Medical School. Before getting started, just a couple of housekeeping issues. First, a disclaimer and a disclosure of unlabeled use. Here are the learning objectives for this activity. So, now let's get started. As you probably know, there is a very high prevalence of elevated LDL [low-density lipoprotein] cholesterol. This slide shows some data from 2011 to 2012 for US adults over 20 years of age, and one can see that the mean LDL cholesterol was approximately 115 mg/dl. The mean LDL cholesterol levels were about 10 or so mg/dl higher approximately a decade previously. The age-adjusted prevalence of high LDL cholesterol is 32.2% in 2011 to 2012, and that compares with 42.9%, again, from a decade prior. So

2 the prevalence is declining in some respects, most likely due to increased use of cholesterol-lowering medications. This slide shows some trends in high LDL cholesterol management in terms of percentages of patients treated and the percentages of patients whose LDL cholesterol is controlled. However, despite some advances in the management of high LDL cholesterol, this remains a problem because the majority of patients in the US are still uncontrolled. In fact, I would say even of those who are controlled, that a proportion are suboptimally controlled, since the targets for optimal therapy keep shifting and keep dropping. What exactly are the consequences of an elevated LDL cholesterol? This slide nicely summarizes the relationships between the number of risk factors, baseline cholesterol, and subsequent cardiovascular event rates. And here the cardiovascular events we're talking about are nonfatal myocardial infarction and stroke, and coronary heart disease death. As you can see, there is a relationship between various degrees of cholesterol elevation and risk, even in patients without cardiovascular disease and without diabetes. As the LDL cholesterol levels increase from 70 to 130 to 190 mg/dl, there is an increase in risk of cardiovascular events over the next 5 years. When diabetes is added to the mix, that risk is further increased, and when coronary heart disease is added to the mix, again, the risk is increased. When both are present, seen in the last row of the table, the risk gets really quite high. So with the combination of elevated LDL-cholesterol, say 190 mg/dl, coronary heart disease, and diabetes, there is a 62% rate of a cardiovascular event over the next 5 years. So this really allows us to see the important relationship between cholesterol and other risk factors in cardiovascular risk. Elevated cholesterol certainly is a risk factor for

3 cardiovascular disease, but it further amplifies other risk factors and is amplified by other risk factors with respect to subsequent cardiovascular risk. Fortunately, reducing LDL cholesterol improves cardiovascular outcomes. With respect to stroke, for example, there is a 4.5% decrease in the adjusted relative risk for stroke per 10 mg/dl reduction in LDL cholesterol. Paralleling that, carotid atherosclerosis and its progression is also reduced with lowering of cholesterol, and nonfatal myocardial infarction is also lower when LDL cholesterol is lower. Let's move on now to a little bit of a discussion of the cholesterol guidelines and goals for therapy. Let's go back in time a little bit to the ATP III guidelines and the 2004 update, which, of course, now is more than a decade old, but still interesting and informative to see what these guidelines had said. In patients at various levels of risk, different LDL cholesterol goals were set. And depending on what these goals were, consideration for drug therapy was also recommended. And you can see the relationships, with the added proviso that in patients who were very high risk, there was an optional goal of less than 70 mg/dl. So these guidelines were released in 2004, but we've gotten a lot of data since then. In fact, these guidelines, especially with respect to that goal of less than 70 mg/dl in very high-risk patients were a bit ahead of their time and really quite right. And the goal in these guidelines was essentially to achieve a 30% to 40% reduction in LDL cholesterol levels in high-risk and moderately high-risk patients. Let's jump forward in time to the 2013 ACC/AHA guidelines. These guidelines identify 4 groups of individuals who are most likely to benefit from statin therapy: those with clinical atherosclerotic cardiovascular disease, which includes acute coronary syndromes,

4 history of MI [myocardial infarction], stable or unstable angina coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin so basically evidence of plaque in the coronary, cerebrovascular, or peripheral circulations. For patients who don't have clinical atherosclerotic cardiovascular disease and who have an LDL cholesterol greater than or equal to 190 mg/dl, there, again, statin therapy would be of benefit. Those are folks that likely have some form of familial hypercholesterolemia (FH), typically, if we're talking about our adult population's heterozygous familial hypercholesterolemia, and that should be treated. The next category of patients without clinical atherosclerotic cardiovascular disease, but who would benefit from being on statins and the guidelines say to do it, are those aged 40 to 75 with diabetes whose LDL is between 70 and 189 mg/dl. And then the final category of those without actual atherosclerosis but who may benefit from statins are those aged 40 to 75 without diabetes, with LDLs in the range of 70 to 189 mg/dl, but who have an estimated 10-year risk for clinical disease of 7.5%. The guidelines also say to consider treatment for a 5% to <7.5% risk, but there's a need for more detailed patient-physician discussion. Other considerations that the guidelines mention are that a healthy lifestyle should, of course, be encouraged in all individuals; that age, diabetes; and 10-year risk for clinical atherosclerotic cardiovascular disease influence the intensity of statin therapy (and in the case of intolerance to recommended intensity of statin, to use whatever the maximally tolerated intensity might be, as good common clinical sense would suggest); and that adherence to healthy lifestyle and statin therapy should be monitored. This slide provides a summary of the guidelines and the algorithm. Green means treatment should be administered, yellow means it's reasonable to administer treatment. And basically this is what I just said, if the patient has evident atherosclerotic cardiovascular disease, I think they should be treated.

5 Now, this flow chart says exactly how; if their age is 75, it should be a high-intensity statin (low or moderate intensity if for whatever reason they can't take or tolerate high intensity), but for those >75, the guidelines say that they should get a moderateintensity statin. That is a controversial recommendation; I am not sure the data really support that, but at least that is what this version of the guidelines currently are saying. For patients whose LDL is greater than or equal to 190 mg/dl, they should be treated with a high-intensity statin, assuming it can be tolerated; if not, use a moderateintensity statin. For patients with diabetes, one can prescribe a moderate-intensity statin, though if their atherosclerotic risk is high, a high-intensity statin might be considered. Again, a lot of this is rather controversial and debatable, given the newest data, but this is just what this version of the guidelines say. And then for that last cohort of timely prevention where they haven't had any sort of evident atherosclerosis, don't have diabetes, LDL is not above that threshold of 190 mg/dl, there it comes back to what their atherosclerotic cardiovascular risk is and assessing it, and based on that a decision to go ahead and use either moderate- or highintensity statin if their risk is 7.5%, and moderate intensity if it's between 5% and 7.5%. So good general guidance of probably what the minimum levels of therapy should be. The 2014 National Lipid Association [NLA] guidelines are actually very clear and easy to use, and I'm going to just say a couple of things about them. There are 2 parts: Part 1 covers the core principles of management where there's high-quality evidence, but part 2 covers areas where there may not be as much robust evidence, but where still you've got to do what you've got to do for the patient in front of you. Part 1 is summarized on this slide. If the patient's very high risk, the LDL goal is less than 70 mg/dl, and drug therapy should be considered if they're above that. So that very high-risk group includes patients with atherosclerotic cardiovascular disease, and also patients with diabetes with 2 or more risk factors, or patients with evidence of endorgan damage. So I would agree that's a very good set of guidance for 2014 in particular.

6 High risk includes 3 or more major atherosclerotic cardiovascular disease risk factors, or diabetes and less than or equal to 1 risk factor, or advanced chronic kidney disease, or an LDL cholesterol greater than or equal to 190 mg/dl, or just risk scoring that takes a patient to high risk. And there, the goal is less than 100 mg/dl, and again therapy gets started if above 100 mg/dl. For moderate-risk patients, you see the goals there. As well as low risk or less than 100 mg/dl. But the threshold to initiate drug therapy is a little bit different, 130 mg/dl and 160 mg/dl, respectively, for moderate and low risk; so a very rational set of guidelines. There are other guidelines out there as well; the European guidelines and Canadian guidelines that more or less are pretty similar to the 2014 NLA guidelines. So let's move now to discussion about LDL-cholesterol lowering and why to do it. Well, the reason to do it is because lower does seem to be better with respect to the risk of cardiovascular disease. And it is the absolute level, not the percent of LDL cholesterol reduction, that defines the risk for cardiovascular disease in the minds at least of some experts; and I'm really talking now about what defines the level of actual risk, not so much what to do with therapy. And the risk of cardiovascular events is clearly lower at very low levels of LDL cholesterol than at moderately low levels. So, for example, 75 to 100 mg/dl is better than over 100 mg/dl, and less than 50 mg/dl seems to be better than just 75 to 100 mg/dl. But it's important to realize that these data when we're talking about pharmacological lowering have to do with achieved LDL cholesterol levels, which is a combination of lifestyle, drug, and, importantly, adherence to drug or drugs. So it's a bit of a confounded relationship. Part of it is almost certainly causal, that is, drugs that lower the cholesterol to lower levels are associated in general with cardiovascular benefit, but part of it might also be that on a given regimen, a patient that achieves a lower LDL cholesterol is more adherent to that medicine, and it's actually that adherence and the other things, the other good things that go with adherence that also, in part, accounts

7 for their better cardiovascular outcome. So it is a bit hard just to tease out whether the achieved LDL per se should be a target LDL, but in general the epidemiology data, the pharmacotherapy trial data all are reasonably consistent, showing that lower is better. This slide summarizes that concept with the randomized clinical trials, showing that reductions in LDL cholesterol are associated with reductions in cardiovascular events in a way that's almost linear, at least within the range of cholesterols that's been well studied. So, indeed, so far it does appear that lower is better. And a greater reduction in LDL cholesterol levels seems to be associated with a greater reduction in major cardiovascular disease event rates. Now, there have been a lot of trials in terms of statins at this point in time both for primary and secondary prevention, and there certainly appears to be a lower cardiovascular disease risk and event rate at lower levels of LDL cholesterol. The cardiovascular disease [CVD] risk reduction depends not only on the amount of LDL reduction, but also on duration of therapy; in some of the trials, in particular low-risk patients, there's a bit of a lag effect before the curves start to diverge and treatment benefit is evident. In some of the higher-risk trials, for example, evaluating patients with ACS [acute coronary syndrome], there the benefits seem to occur even sooner. Most experts would probably say that the evidence is insufficient to set specific LDL cholesterol treatment goals for both primary and secondary prevention. Similar statins and their doses were used in primary and secondary prevention trials, and statin intensity was directly associated with greater benefit, in particular in secondary prevention. So we have a general sense that lower is better, but exactly what the targets should be, is a matter of great ongoing debate. So let's review some of the key trials. The PROVE-IT-TIMI 22 study was a trial that evaluated patients with recent acute coronary syndromes randomized to a moderate statin approach (pravastatin 40 mg daily) or to an intensive statin approach (atorvastatin

8 80 mg daily). The mean follow up was 24 months, so a reasonable study duration, and a well-designed trial. Regarding LDL cholesterol in the pravastatin arm, the medians dropped from 106 mg/dl at baseline to 95 mg/dl. In the atorvastatin arm, it dropped from 106 to 62 mg/dl. So basically this is a comparison of different doses of different drugs, atorvastatin versus pravastatin, and there are different achieved LDL levels 95 mg/dl versus 62 mg/dl. Just to keep it all straight in my head, I like to think of it as 90 versus 60 mg/dl. So going to that level of LDL cholesterol reduction for those on atorvastain, one was hoping, would have greater benefit. And, indeed, that was the case. The primary endpoint of this trial death from any cause, MI, documented unstable angina requiring hospitalization, revascularization performed at least 30 days after randomization, and stroke was lower in the atorvastatin group, at 2 years. The event rates for pravastatin and atorvastatin were 26.3% versus 22.4%, respectively. And that 16% reduction in the hazard ratio favored atorvastatin, a statistically significant finding. The discontinuation rates for pravastatin and atorvastatin were 33% versus 30.4% at 2 years, so really no significant difference, and certainly wasn't worse for atorvastatin. Overall these were really powerful data supporting the benefit of a more intense regimen in ACS patients. Now what actually happened to patients in that atorvastatin arm? I just showed you the mean levels of LDL cholesterol achieved was 62 mg/dl, but a proportion of patients didn't have such a great reduction, and some had a really whopping reduction; 11% of patients achieved an LDL cholesterol of <40 mg/dl.

9 As it turned out, those patients who achieved a lower LDL cholesterol level had lower rates of cardiovascular events, which strongly suggests that lower is better. Now this is still different than doing a randomized clinical trial and saying I'm going to target you to 80 to 100 mg/dl versus less than or equal to 40 mg/dl; patients weren't randomized to strategies of LDL targets, but rather to 2 different doses of 2 different drugs, an intense versus a moderate strategy. So we can't say that the observations on this slide necessarily should point to what the target LDL should be. But it is strongly suggestive. Let me move on now to a primary prevention-type trial, the JUPITER trial. JUPITER was designed to see if statins would be useful in patients who had an elevated highsensitivity C-reactive protein but not out of control cholesterol; patients had to have an LDL cholesterol <130 mg/dl, a high-sensitivity C-reactive protein 2 mg/l. Patients were randomized to rosuvastatin 20 mg once daily or placebo. The trial was a large study with about 8,900 patients in each arm with a median follow-up of a little under 2 years. With respect to cholesterol achieved, those in both treatment arms started off with a median LDL cholesterol level of 108 mg/dl. After 48 months, the levels in the placebo arm was basically unchanged, at 109 mg/dl. In the rosuvastatin arm, however, median levels dropped from 108 to 55 mg/dl, so about a 50% reduction in LDL cholesterol levels, on average, in the population with rosuvastatin at 12 months, which was sustained out to 48 monhts. So that shows the degree of LDL reduction that can be achieved with this dose of rosuvastatin. And this LDL reduction translated into a reduction in the rate of the primary endpoint of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or confirmed death from cardiovascular causes. The hazard ratio was 0.56, so about a 50% reduction, which was statistically significant, and included in this was a reduction in all-cause mortality that was significant.

10 The rate of overall adverse events was quite comparable. One notable difference was physician-reported new-onset diabetes, which was more common with rosuvastatin, 3% versus 2.4% with placebo, with P value of.01. So small but statistically significant differences between the groups. This has been reproduced in other analyses of highintensity statin regimens. So the price to pay for a high-intensity statin is a slight, but what appears to be real, increase in the diagnosis of diabetes. However, I think it's important to put this in perspective. The increase is small, and in the context of drugs that are reducing important ischemic events, and in some populations in some trials even all-cause mortality, I think this small risk is acceptable, though something that we need to keep an eye on in future trials, and even in ongoing trials. and We also need to keep this in mind for the patients we see in practice; that is, be vigilant for the development of metabolic syndrome and diabetes. Of course, in this hyperlipidemic population or primary prevention population, in general primary care physicians would be screening for diabetes, but it is important just to be vigilant for that potential side effect. Let's move on now to a relatively recent trial, the IMPROVE-IT trial. Data from this trial were published in 2015 and the goal of the trial was to evaluate patients with a recent acute coronary syndrome with an LDL cholesterol of between 50 and 100 mg/dl if on lipid-lowering therapy, or between 50 and 125 mg/dl if not on lipid-lowering therapy. Patients were randomized to simvastatin plus ezetimibe or simvastatin plus placebo; and the simvastatin dose was 40 mg, the ezetimibe dose was 10 mg. So, basically the study is evaluating ezetimibe versus placebo with a background treatment of a good statin. The median follow-up was 6 years in each arm. Data on the LDL cholesterol levels are shown on this slide. The simvastatin-only arm went from 93.8 at baseline to 69.9 mg/dl at 1 year, or I like to think just from 90 to 70 mg/dl. The simvastatin plus ezetimibe arm went from a baseline value of 93.8 to 53.2 mg/dl at 1 year. The way I like to think of it is just to round things off and keep the numbers easy to keep track of; so a difference of approximately 70 and 50 mg/dl in terms of the achieved LDL cholesterol in these 2 treatment arms.

11 The next question is did this matter? Did this modest difference in cholesterol translate into improved outcomes? Yes, indeed it did. The primary endpoint a composite of death from cardiovascular disease, nonfatal MI, documented unstable angina requiring hospital admission, coronary revascularization 30 days after randomization, or nonfatal stroke was lowered with the combination therapy at 7 years, with rates of 32.7% versus 34.7%, respectively, in favor of the ezetimibe arm. So that worked out to a hazard ratio of 0.936, and that was a significant finding. There was similar safety in the 2 groups, so no real difference with safety concerns. There had previously been some issues raised about ezetimibe causing cancer, but in this longterm study there was no hint of that. So data from this trial provide further evidence that lower is better, but now using a non-statin compound with ezetimibe. So despite all the good data for statins, the reality is that patients remain undertreated with statins. These are some data from the International REACH registry of patients with atherosclerosis or multiple risk factors for atherosclerosis, showing a fair amount of undertreatment with respect to statin therapy, or lipid-lowering therapy in general. This is true in coronary artery disease, it's true in peripheral artery disease, and it was true in cerebrovascular disease. It was true in all the geographic regions we examined North America as well as other parts of the world. And it was also true across different physician specialties. Of course there was some variation, but overall even the best rates by region or physician specialty were lower than optimal. This slide shows additional data from the REACH registry regarding the percentage of statin use. Shown are the rates for all patients, for patients with prior ischemic events,

12 with stable atherosclerosis without a prior ischemic event at baseline, and with risk factors only. Across the board, there's just a less than optimal rate of statin use. Even though these data could be looked at in cup is half full sort of way; that is, the majority of patients were being treated, clearly these rates are not ideal and they didn't improve over the time of the study, at least not to the degree that we would have liked, given all the emerging data. Shown here are data from a meta-analysis of statin trials. This study showed that 40.4% of patients on high-dose statins failed to reach an LDL cholesterol <70 mg/dl, despite the fact that lower LDL cholesterol levels are associated with a lower risk of cardiovascular events. This analysis showed, interestingly, that the risk of major cardiovascular events was lower even at very low levels of LDL cholesterol, more so than moderately low levels; say less than 50 mg/dl versus in the 70 to 100 mg/dl range. So why is it that patients might not use, or use but not benefit from statins? Well, here are some potential reasons for lack of statin benefit. FH with high LDL cholesterol, intolerance to high statin doses, or high cardiovascular risk and failure to achieve target LDL cholesterol levels in patients who are already on high-intensity statin, and now I'd say even including ezetimibe. But patients who are still at high cardiovascular risk and still have LDL cholesterol levels that are suboptimal are ones who aren't really deriving a full cardiovascular protection and might need more. So let me first talk about FH. This is, as I'm sure you know, a genetic disorder. It's characterized by very high levels of LDL cholesterol due to decreased LDL cholesterol clearance from the plasma. It leads to premature coronary heart disease. The severity of symptoms varies; it depends on the extent and the exact type of genetic mutations. The diagnosis of FH can be made on the basis of clinical, biochemical, and if one chooses, genetic criteria.

13 Traditional management for FH has been statin and lifestyle measures; I'm really talking about familial heterozygous hypercholesterolemia here. Most cases of FH are undetected or it is treated but sort-of accidentally treated; that is, a patient s cholesterol is noted to be high, the patient is treated, but it's not really appreciated that she/he has FH and so they end up being treated inadequately. FH is the most common monogenetic disorder of lipid metabolism. It's estimated to be at least about 1 in 500 individuals or so in the general population; of course, it depends on the exact population, and some can be as high as about 1 in 250. It's an autosomal codominant mode of inheritance: heterozygous parents have a 50% chance of passing it on to their offspring. In heterozygous FH, the LDL cholesterol can increase to the 200 mg/dl range. In homozygous FH, the LDL cholesterol increases even beyond that range. With homozygous FH, the cholesterol levels actually can be really extraordinarily high. The mutations that can cause FH include mutations in the LDL receptor gene, the APOB gene, and a gene for PCSK9 [proprotein convertase subtilisin kexin type 9]. This slide shows the mechanism of action of PCSK9, and then ultimately the basis of PCSK9 inhibitors. The biology is really pretty elegant. The LDL receptors on a cell membrane bind to LDL cholesterol, but PCSK9 can also bind to LDL receptors, ultimately leading to their degradation. Blocking PCSK9 with a PCSK9 inhibitor allows LDL receptor recycling, hence more clearance of LDL particles from the bloodstream. That is a sort-of PCSK9 101 version of something that is actually pretty sophisticated and pretty complex. And it turns out the concentrations of PCSK9 and LDL cholesterol correlate rather positively. Regarding different types of PCSK9 mutations, there are gain-of-function mutations that result in high LDL cholesterol levels. One example is a single nucleotide polymorphism listed on this slide, which is linked to increased LDL cholesterol levels. And if a patient has the minor allele and is a homozygote, the LDL cholesterol levels can be

14 approximately 89 mg/dl. If they are heterozygotes, then they can be approximately 146 mg/dl. For major allele homozygotes, they could have LDL cholesterol levels of about 161 mg/dl. So you can how gain-of-function mutations can increase cholesterol by pretty sizeable amounts, especially if you think about this is a lifetime increase and a lifetime exposure. There can also be loss-of-function by any variety of mechanisms, including nonsense mutations in the PCSK9 gene. And the loss-of-function results in low LDL cholesterol levels. In the relatively small number of people who have been seen with these, they appear to have a markedly reduced risk of developing atherosclerosis and its complications. It is important to keep in mind, of course, that there aren't very many patients who have been studied that fall into those extremes. So let me talk now about PCSK9 inhibitors. There are a number of different agents new and emerging agents. The 2 listed at the top of this slide are human monoclonal antibodies, alirocumab and evolocumab, and have been approved by the US Food and Drug Administration [FDA]. There are other monoclonal antibodies, as you can see, in phase 2 and phase 3 trials. Then there are other types of compounds as well, for example, sirna oligonucleotides and antisense oligonucleotides that are in very early stages of testing. So there will be a lot of data on these agents coming out in the future. Let me review now the alirocumab studies. As you can see on this slide, there have been a lot of studies, and for the sake of time I'm not going to go through every single detail about each one, because there are certain themes that emerge that I think are more important to know and understand than necessarily knowing every detail of each trial. But as part of the ODYSSEY program, alirocumab was extensively studied with respect to its effect on lipid parameters. And these studies, as you can see on the right-hand

15 column, for the most part had intensive statin therapy as a background therapy; in one case, ODYSSEY ALTERNATIVE, that wasn't so. The control arms were, in many cases, placebo, and in some cases ezetimibe 10 mg. The populations studied are listed in that third column from the left. Some studies evaluated patients with FH and other studies evaluated patients with hypercholesterolemia. Here are additional studies; again, you can see the control arms were either placebo or ezetimibe, and there were various degrees here of background statin therapy: intensive in some cases, and none in some cases, and not so intensive statin therapy. And, again, a variety of different patient populations being studied, largely FH or hypercholesterolemia. The evolocumab studies are pretty similar in terms of the characteristics I just described. Their acronyms are listed on this slide and there is a theme here of different names that you can probably see DESCARTES, GAUSS, LAPLACE, MENDEL. These different trials had either intensive statin therapy as a background, nonintensive statin therapy, or no statin therapy, and the control arms again were either placebo or ezetimibe 10 mg daily. The populations studied included those with hypercholesterolemia, those patients who were statin intolerant, and patients who had various degrees of FH. This slide shows additional evolocumab studies, the RUTHERFORD, TESLA, and YUKAWA and MENDEL-2 studies; they show similar sorts of populations covered, whether there's intensive background statin therapy in both arms, or no therapy, and controls of placebo and ezetimibe. And, again, heterozygous or homozygous FH in TESLA, and hypercholesterolemia studied in these various trials. I don't know that I would spend a lot of your energy trying to figure out which trial was which specific population; it's hard to keep track of and there are lots of nice review articles some of which are referenced in this transcript if you really wanted to go back for that level of detail.

16 But from a clinician's perspective, here's the bottom line. For alirocumab, as you can see in these various studies, significant reductions in LDL cholesterol. There also are reductions in other important parameters, like ApoB, non- HDL [high-density lipoprotein] cholesterol, triglycerides, and some improvements in HDL cholesterol. And perhaps importantly, some significant reductions in Lp(a), which at least according to some experts and in some studies, seems to be a bad player and a marker of cardiovascular risk. But at any rate, primarily significant reductions in LDL cholesterol in all these different populations that were studied. I should point out when I'm talking about these LDL reductions in this and subsequent slides, that the effect of treatment shown here is a change from baseline and adjusted for the specific comparator arm. Now, let me just show you the evolocumab summary, and it's really very consistent with alirocumab where those same parameters I just mentioned are influenced in the same way. Particularly notable again are reductions in LDL cholesterol that's the main goal of these studies but also nice to see reductions in ApoB and Lp(a), and perhaps that latter mechanism of action will translate into some meaningful clinical benefit, but we'll have to see with different ongoing trials. This slide shows additional results from the evolocumab trials; significant reductions in LDL cholesterol, in most cases exceeding a 50% reduction. So that's what happens to LDL with these 2 PCSK9 inhibitors, alirocumab and evolocumab, large, impressive reductions in LDL across wide ranges of populations. Does any of this translate into reductions in clinical events? That's the question everyone, of course, asks. And the answer is, outcome trials are ongoing; there aren't any completed outcome trials to date.

17 However, of the trials that have been designed to look at LDL cholesterol and other biochemical parameters, of course adverse events were recorded and mortality was recorded. If you pool data from all these trials again, these are trials designed to look for cholesterol reduction but if you do just pool the all-cause mortality data, it's a small number of events, as you can see overall. But pooling the data interestingly, provocatively, reassuringly one sees a reduction in all-cause mortality, with an odds ratio of 0.45; so more than a 50% reduction in LDL cholesterol and about a 50% lower mortality. But, again, while this is very scientifically exciting, it's important to be extremely cautious about these data. The number of events is extremely low and these trials weren't designed to look at cardiovascular outcomes. But at any rate, this is what mortality shows in the meta-analysis. Similarly, cardiovascular mortality is directionally reduced not quite statistically significantly, but directionally reduced by 50%. The rate of MI decreased by approximately 50%, which was statistically significant. This slide shows the rates of unstable angina. Here the P value wasn't significant, but there were a really a low number of events, and the odds ratio is going in the right direction, but clearly not statistically significant. Well, what about CK [creatine kinase] levels; do PCSK9 inhibitors increase CK levels? Well to date, as one can see from this meta-analysis, most of the studies have not found that, and in pooling the data together there does not appear to be an increase in CK levels with PCSK9 inhibition.

18 What about the effect of this new class of injectable drugs on serious adverse events (SAEs)? Of course, SAEs were captured in all clinical trials, and the odds ratio seen in this metaanalysis is 1. So at least in the context of carefully selected, relatively healthy patients entering lipid-lowering trials, there was no significant difference in the rate of SAEs. That is very reassuring realizing that the duration of follow-up here in these studies for the most part is relatively short, so we do need larger numbers of patients longer-term studies to make sure these drugs are as safe as they appear to be based on the limited number of patients to date. Let me now discuss a couple of the studies in detail. Again, the aim of these studies was to look at the safety of these drugs and their efficacy on LDL reduction. The ODYSSEY long-term trial was a trial of high-risk cardiovascular event patients, who had LDL cholesterol levels of 70 mg/dl and who were on a statin at a maximally tolerated dose, with or without other lipid-lowering therapy. Patients were randomized to alirocumab 150 mg subcutaneously every 2 weeks or to placebo. The treatment duration was 78 weeks in each arm, and outcomes were assessed at week 24 in each arm. The LDL cholesterol at 24 weeks was lower in the alirocumab trial. The mean percentage change from baseline was 61%. The actual numbers are a reduction in the alirocumab arm from 122 mg/dl to 48 mg/dl, hence the 61% percent reduction; so very large reduction in LDL cholesterol, and of course in the placebo arm there was not much change over that period of time. The LDL cholesterol remained low in the alirocumab arm over that full 78-week period that I mentioned. Now the interesting part of this study; here the rate of major adverse cardiovascular events was also lower with the PCSK9 inhibitor, alirocumab, versus placebo: 1.7% versus 3.3%. That is a hazard ratio of 0.52, so again about an approximately 50% lower rate of cardiovascular events. And this was in the context of "any adverse event" being similar between the 2 groups. So a very interesting signal of potential cardiovascular benefit. Event rates were low, the number of events were low. The follow-up duration is not

19 particularly long in the context of cardiovascular outcome trials, so one needs to be really cautious about embracing these outcome data prematurely. But this early signal of cardiovascular efficacy does look good. Let me move on now to the OSLER study, one of the trials I mentioned of evolocumab. This study randomized patients to evolocumab plus standard therapy versus standard therapy alone. The sample size overall was a bit over 4,000 patients, and the median follow-up was 11.1 months in each arm. The LDL cholesterol was lowered by 61% at 12 weeks with evolocumab, remarkably similar to what was seen with alirocumab. But now it's important to realize beyond just the LDL reductions at 12 weeks that sustained reduction were seen over 48 weeks. CV events at 1 year was lower in the evolocumab group versus the standard group 0.95% versus 2.18%, for a hazard ratio of 0.47; so again about a 50% reduction in this separate trial program, looking at a different PCSK9 injectable compound, in the same class as alirocumab. And, again, the rate of adverse events was similar between the 2 arms, so very reassuring early data with both these PCSK9 inhibitors. But I'll state again that the major caveat: that these trials were not designed, not powered to look at cardiovascular outcomes. So we really do need to see what the dedicated cardiovascular outcome trials show before assuming that LDL reduction from these potent compounds is translating into cardiovascular benefit. But it sure is exciting and I think a promising early signal to see these lower event rates. There are a number of ongoing trials for both of these approved PCSK9 inhibitors. Let me start with a review of alirocumab studies. ODYSSEY OUTCOMES is a study of alirocumab versus placebo in patients with recent acute coronary syndromes. The target completion date is listed on this slide. It is hard to know with these trials exactly when data will be available and reported, in many cases

20 the trials are event-driven, so it depends how quickly the trials enroll when the events accrue. So the target completion dates really are estimates from ClinicalTrials.gov that are listed here. This slide shows a table of ongoing evolocumab studies. The GLAGOV study is examining patients with coronary heart disease and an indication for coronary catheterization to see what the effect is on progression of atherosclerosis. The large outcome trial is FOURIER, examining evolocumab versus placebo on a background of statins, in patients with clinical cardiovascular disease who are at high risk for recurrence. And then TAUSSIG is also ongoing. This study is specifically evaluating patients with homozygous FH or PCSK9 mutations with elevated LDL cholesterol levels or receiving apheresis. So there is a nice development program between these 2 different compounds, and we'll have data from many patients who have been in these outcomes studies. Bococizumab is another compound that I mentioned earlier that is a bit earlier in its development and is not currently FDA approved or available outside of clinical trials. It is also a PCSK9 inhibitor that is given by subcutaneous injection, and it is being studied in the SPIRE program. A number of SPIRE trials are looking at patients at various degrees of risk and with various degrees of LDL elevation. It will be nice to see if this program finds concordant reductions in not only lipid parameters I'm sure that will be the case but also if there is some reduction in cardiovascular events. Here are the outcome trials for bococizumab, the SPIRE-1 and SPIRE-2. These trials are ongoing and data from these will help show what the definitive effect is on cardiovascular outcomes with this compound.

21 Now let me just mention some of the completed phase 3 trials. ODYSSEY ALTERNATIVE had patients randomized to alirocumab versus ezetimibe and alirocumab versus atorvastatin. Patients had statin intolerance and primary hypercholesterolemia and moderate, high, or very high cardiovascular disease risk. I think a fascinating trial beyond just the aspect of its studying a novel drug. Just studying the statin-intolerant population is very interesting. It is interesting because there definitely are patients who are statin intolerant, but other studies have shown us that there are patients who also are statin intolerant, and even if you put them on placebo they have "statin intolerance"; so it is a very challenging population because some of the intolerance is not related to the drug, and some of it actually is related to the specific drug and sometimes to the class of drug. So a lot of work going on out there on statin intolerance, and we need to learn a lot more about it. ODYSSEY FH I, also looking at alirocumab, examined heterozygous FH. ODYSSEY FH II also examined heterozygous FH, but with a little bit of a different comparator with respect to statin. And these trials, at least at the time of this presentation, have not been published, but the preliminary results have been presented. So we will see what the exact findings are, but in terms of LDL reduction, there were significant reductions in LDL. A couple of other completed trials to mention with alirocumab. There's ODYSSEY OPTIONS I, ODYSSEY OPTIONS II. These are all really variations on the theme different background and comparator lipid cocktails in patients with hypercholesterolemia and high cardiovascular risk, but in whom their hypercholesterolemia is not well controlled. And, again, these aren't published, but the preliminary results have been presented and have shown consistent findings of LDL reduction across the board. So what is the actual prescribing information in the US per the FDA labeling? That's shown here, with the links to the full prescribing information on the slide (and below, in the reference list) as well, for anyone who wants to go into greater detail.

22 Alirocumab is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous FH or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. It is recommended at a starting dose of 75 mg subcutaneously every 2 weeks. If the LDL cholesterol response is inadequate, then the dosage can be increased to 150 mg every 2 weeks. Evolocumab also is indicated as an adjunct to diet and maximally tolerated statin therapy for adults with heterozygous FH or with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. It is also indicated for patients with homozygous FH who require additional lowering of LDL cholesterol. So that is 1 slight difference between indications for the 2 agents, the inclusion specifically of homozygous FH in the evolocumab label. And the dosing administration for evolocumab is as follows: For primary hyperlipidemia with established clinical atherosclerotic cardiovascular disease or heterozygous FH, the dose is 140 mg every 2 weeks, or 420 mg once a month. For homozygous FH, it's 420 mg once a month. Just a practical point regarding administration: to administer 420 mg of evolocumab, give 3 injections of 140 mg consecutively within 30 minutes; and to emphasize, these are subcutaneous routes of administration. To date, patients have at least from what I've seen tolerated these subcutaneous injections pretty well. There is a slight increase in cutaneous site injection reactions versus obviously not getting the injections, but still overall appear to be very well tolerated. As far as how these are supplied, with alirocumab, it's supplied as either a 75 mg/ml or 150 mg/ml solution in a single-dose prefilled pen or single-dose prefilled syringe. The evolocumab is suppled as a 140 mg/ml solution in a single-use prefilled syringe or a single-use proprietary auto-injector. So, again, if you want to get to the 420 mg dose, that would be 3 injections of the 140 mg/dl. As far as the storage and handling, the details are listed on this slide; you can review that at your leisure. There are some things to be aware of in terms of how to store them,

23 and refrigeration, and issues like that. So if you're involved with that aspect of the drugs, make sure you're familiar with this information. Most commonly occurring adverse reactions defined as 5% in treated patients and occurring more frequently than placebo although not necessarily statistically significantly more frequently but what's listed in the label is nasopharyngitis, injection site reactions, and influenza with alirocumab. And with evolocumab, nasopharyngitis, upper respiratory tract infections, influenza, back pain, and injection site reactions. And of all of these, the one that most commonly occurs and is causally related to the drug would be the injection site reactions. Potential, theoretical safety concerns that had been raised with the possibility of patients achieving very low LDL cholesterol levels with these drugs were that they might interfere with vitamin E synthesis, they might interfere with steroid hormones, gonadal hormone oogenesis. Well as it turns out, there's no evidence supporting these concerns. Recent 1-year data from the DESCARTES study suggest no adverse effect on vitamin E or steroid hormone formation. So at least with a reasonably large number of patients seen in DESCARTES we don't see this problem, with the caveat that these were 1-year data. But for these particular parameters, we would likely have seen something even by a year. What about issues of cost? That's a real issue. The annual wholesale prices are listed here for the US, slightly more than $14,000. Regarding whether this is cost-effective or not, there have been a couple of different analyses. Information from one is listed on this slide, from the Institute for Clinical and Economic Review. This report suggested that to achieve cost effectiveness, the price of these agents would need to be reduced substantially. The same report suggests that to avoid cost burden to the US healthcare system, the price needs to be reduced. Now, obviously, the cost of these agents is probably out of the control of learners of this activity, who are actually taking care of patients, so we have to figure out how to bring

24 these therapies to the patients that are most likely to benefit, but at the same time try to be careful stewards of the collective healthcare dollars. So how then might PCSK9 inhibitors be integrated into clinical practice? Well, potential populations in which to consider these agents include patients with FH and high LDL cholesterol, patients who are intolerant to maximal statin doses, and patients with high cardiovascular risk who fail to achieve target LDL cholesterol levels on high-intensity statins or high-intensity statin plus ezetimibe. These are patients for whom to consider the use of PCSK9 inhibition, especially if they are at high cardiovascular risk. So to conclude then: LDL cholesterol is a potent risk factor for cardiovascular disease, although it remains suboptimally treated especially as we start recommending LDL cholesterol goals that are lower and lower based on randomized clinical trial data. This undertreatment is particularly true in FH, which is pretty under-recognized, especially about heterozygous FH. Also undertreatment is an issue in statin-intolerant patients, because other than ezetimibe there have been limited evidence-based options other than going back a bit in time. And in patients who are at very high cardiovascular risk, those are patients where LDL also is undertreated, and that is corroborated by some of the registry data I've showed you and other registry data that I didn't show you, including very contemporary data. Statins clearly reduce cardiovascular risk across a broad range of baseline cardiovascular risk, so that s an important point. They reduce risk in patients with ACS and in lower-risk secondary prevention, and even lower-risk primary prevention patients, such as those in JUPITER with an elevated C-reactive protein. So this reduction in clinical events with statins seems to be true across a variety of levels of baseline risk strata, and also across a variety of baseline LDL cholesterol levels. And the latest cardiovascular outcome data, as I mentioned with IMPROVE-IT, also support the role of ezetimibe when added to statins.

25 Finally, the PCSK9 inhibitors are potent LDL-cholesterol lowering drugs, but ongoing clinical trials will be very important to determine their effects on cardiovascular outcomes. There's no question that the PCSK9 inhibitors lower LDL cholesterol and also seem to lower some other biochemical parameters that might be useful, such as Lp(a), but we really need to see what the ongoing cardiovascular outcome trials show before deciding that this LDL reduction is definitely reducing cardiovascular risk. The early signals certainly suggest that it does, but we do need larger numbers of patients from longer-term trials to make sure that the LDL reduction mediated by PCSK9 inhibition indeed does translate into cardiovascular risk reduction. We also need these longerterm data to make sure that there aren't some unexpected safety signals that emerge. I talked about the steroidogenesis that doesn't seem to be affected, but some have raised concerns about issues like diabetes. And to date, that doesn't seem to be a concern with new-onset diabetes being an issue with the PCSK9 inhibitors. Other issues that have been raised have to do with subtle effects on neurocognitive function, and part of the ongoing evaluations of these agents includes long-term studies looking for subtle changes in neurocognitive function. But to date, the safety data look very reassuring, and how to integrate these agents into clinical practice, I think, will really depend on the specific risk profile of your patients as well as what the evolving data show. Thank you very much for your attention. I hope this review of what has been going on in the lipid-lowering field lately and what had preceded it was useful and educational.

26 REFERENCES Anderson TJ, Grégoire J, Hegele RA, et al update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2012;29(2): Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010;304(12): Bhatt DL, Steg PG, Ohman EM, et al; for the REACH Registry Investigators. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295(2): Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and risk of cardiovascular events; a meta-analysis of statin trials. J Am Coll Cardiol. 2014;64(5): Cannon CP, Blazing MA, Giugliano RP, et al; for the IMPROVE-IT investigators. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25): Cannon CP, Braunwald E, McCabe CH, et al; for the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350: Cholesterol Treatment Trialists (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380(9841): Grundy SM, Cleeman JI, Merz CN, et al; Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Arterioscler Thromb Vasc Biol. 2004;24(8):e149-e161.