[Ed note: Here is our latest piece from “Doc Gumshoe”, who is a medical writer (not a doctor) who shares his wisdom with us at Stock Gumshoe a couple times a month. As always, Michael’s words and opinions are his own.]

Lots of analysts and prognosticators give these cholesterol-lowering agents a big thumbs up. The dollar figures they throw around are in the $10 billion per year range in the aggregate, or upwards of $3 billion for any one of these drugs, which are:

• From Amgen (AMGN), evolocumab …
• From Pfizer (PFE), bococizumab …
• And from Regeneron (REGN) (with Sanofi [SNY]), alirocumab.

Before I go much farther with this, I need to reveal an underlying uneasiness whenever the term “blockbuster” turns up in connection with the prospects for a new drug, or, indeed, a new anything else. My initial association with that all-too-trendy word is that it might just as easily refer to a really big bomb – big enough to reduce to rubble an entire city block.

Eyes wide open, I do not think that potential potholes in the development path of any of these are deep enough to cause significant damage to any of those pharmas, nor do I think that their potential is large enough to be genuinely transformative to the developers, except Regeneron; another $3 billion or so would be nice for Amgen and Pfizer, but it wouldn’t rocket them to the moon.

But I do think that the path to becoming blockbusters, in that pleasing figurative sense, is complicated by more than the usual number of factors – which I will try to look at with a critical and skeptical eye and lay before you.

So, what are PCSK9 inhibitors & how do they work?

The full name of PCSK9 is proprotein convertase subtilisin/kexin type 9 (we won’t say that again). It plays a role in regulating cholesterol levels in the blood by affecting the number of receptors for low-density-lipoprotein cholesterol (LDL-C) receptors on cell surfaces. When this protein is overactive, it breaks down LDL-C receptors. These LDL-C receptors in the liver absorb LDL-C particles from the bloodstream for eventual excretion. As a result, overactive PCSK9 blocks one of the pathways through which our bodies get rid of excess cholesterol.

The discovery of PCSK9 came about accidentally, as do many discoveries in science. It started with the finding that some individuals have what might be considered freakishly low levels of LDL-cholesterol – somewhere in the range of a quarter or a fifth of the LDL-C levels in healthy individuals in the general population. In other words, if a normal healthy person has an LDL-C level around 100 milligrams per deciliter, there are a few – very, very few – persons whose LDL-C levels are down around 25 or 20 mg/dL.

After testing and analyzing every conceivable factor in these individuals, it was found that some had inherited genetic mutations in the production of PCSK9 from both parents, so that the protein that diminished the activity of the LDL-C receptors that took that form of cholesterol out of the circulation was not present in those persons. In short, no PCSK9 → undiminished LDL-C receptor activity → highly effective clearing of LDL-C from the circulation → extremely low LDL-C levels.

The number of people with inherited genetic mutations from both parents must be miniscule. However, there is a small but significant percentage – 2% to 3% – of persons with a single genetic mutation affecting the expression of PCSK9, and these persons also have quite low levels of LDL-C, although not as low as the “double-knock-out” individuals.

These findings were catnip to some pharma companies, which immediately launched programs to find drugs that would affect the cholesterol-raising activity of PCSK9. Initial findings from several drug companies were highly encouraging, and at least those three outfits mentioned above – Amgen, Regeneron/Sanofi, and Pfizer – have put the pedal to the metal with good results.

• Amgen’s evolocumab is, at the moment, in the lead. Amgen has completed six Phase 3 clinical trials with that agent, which lowered LDL-C by 53% to 75% compared with placebo (the 75% decrease was seen in combination with atorvastatin). As many as 8 more Phase 3 trials are recruiting or in progress. Amgen plans to file for FDA approval for evolocumab late this year.
• Regeneron/Sanofi’s alirocumab has completed one Phase 3 clinical trial, in which LDL-C levels were lowered by 48% compared with placebo. They expect to file for FDA approval for alirocumab early in 2015, as more trial results become known. Regeneron/Sanofi has 14 more clinical trials under way.
• Pfizer’s bococizumab, in contrast, has completed one Phase 2b trial, in which their drug lowered LDL-C by 52% in patients taking statins. Six more trials are recruiting or in progress. The plans for filing for FDA approval are at this time uncertain.

All three of these agents are injectable rather than oral, and it’s expected that they will be quite expensive, in the range of a thousand dollars a month or more. Both of these features are likely to be obstacles to the kind of widespread adoption that would lead to blockbuster status.

What kinds of patients would likely benefit from these drugs?

The obvious patients for PCSK9s are those who are at very high risk for cardiovascular events who have not been able to lower their LDL-C levels to the 70 mg/dL target using conventional drugs – i.e., statins – or who are intolerant to statins. Another group would be individuals with very high cholesterol levels related to genetic anomalies – a disorder called heterozygous familial hypercholesterolemia, which manifests in high levels of LDL-C unrelated to lifestyle.

Persons with this genetic disorder are prone to develop heart disease at an earlier age than the general population, i.e., in their 40s or even in their 30s. This defect is relatively uncommon, occurring in about 1 in 500 persons. Most people with this form of elevated LDL-C respond well to treatment with statins, so it’s by no means obvious that the entire global population of people with abnormally high LDL-C levels due to familial hypercholesterolemia would need treatment with PCSK9s.

(Note: the heterozygous familial hypercholesterolemia population inherited the culprit gene from one parent only. Unfortunate individuals who got the bad gene – i.e., homozygous – from both parents are at even higher risk for cardiovascular disease (CVD), and may have serious CV events much earlier in life, even in childhood. I hesitate to use the word “fortunately,” but it is a fortunate fact that homozygous familial hypercholesterolemia is extremely rare, affecting a tiny fraction of the total population, perhaps 1 in 25,000. It is doubtful whether clinical trials will be mounted in these patients, although they would surely be eligible for treatment with PCSK9 agents in an effort to do whatever possible to lower their LDL-cholesterol.)

What will it take to demonstrate efficacy?

Most efficacy trials to date have focused entirely on bringing down LDL-C levels, working on the premise that doing so will lessen CV risk and reduce the number of acute CV events such as heart attacks, strokes, and episodes of severe heart pain (angina) at rest. In fact, there is plenty of evidence that lowering LDL-C results in very clear benefits for patients with established heart disease or at high risk for heart disease. For example, the famous 4S trial (Scandinavian Simvastatin Survival Study, which enrolled patients with existing coronary heart disease and baseline mean total cholesterol of 261 mg/dL, reduced coronary death by 55% at 5.4 years.

Subsequent studies, in patients who were at somewhat lower risk reported somewhat less dramatic results. An example was the Heart Protection Study Collaborative Group trial in the UK, which enrolled patients with lower baseline lipid levels. In this case, mean LDL-C levels were 131 mg/dL, which, at the time of the trial, was below the recommended cut point for initiating drug treatment except in patients at very high risk. Treatment with simvastatin lowered all-cause mortality in these patients by 13%, and lowered the risk for any major coronary event by 27%.

So, those studies would certainly seem to support the use of statins in patients at significant risk for cardiovascular events.

The question remains, do PCSK9s need to do more than demonstrate that they can lower LDL-C by margins equal to or greater than what the statins can achieve? And do they need to demonstrate that lowering LDL-C in patients at low risk for cardiovascular events results in significant clinical benefit? In other words, in order to achieve blockbuster status and justify their high price, do PCSK9s need to demonstrate a benefit in primary (as distinct from secondary) prevention.

The distinction between primary and secondary prevention is more pragmatic than absolute. Primary prevention mostly means taking fairly routine precautions against medical threats that might affect anybody; e.g., we should all get our flu shots, because the flu is out there, and, believe me, you don’t want to catch it. Secondary prevention means addressing specific factors that put an individual at elevated risk for some bad medical outcome. The evidence supporting the benefits of cholesterol-lowering treatment in persons with acute coronary syndromes such as history of stroke or heart attack or unstable angina is extremely strong. But in the larger population, with less severe risk factors, the evidence is less robust.

Some of the evidence for cholesterol-lowering as primary prevention might be called circumstantial. It is a fact that heart disease rates in the U. S. have declined quite substantially in the past 50 years. For example, the American Heart Association calculates that if the CVD mortality rate had remained at its 1963 peak, 621,000 additional CVD deaths would have taken place annually just from about 1996 onward – that’s almost 10 million people.

What could account for that huge decrease? In part, it might be because lots of people quit smoking. And many more people were controlling their blood pressure. But it’s also a fact that it was in the mid-1990s that lots of Americans began to take statins. So, based on that association, an argument can be made that cholesterol-lowering treatment constitutes a form of primary prevention for cardiovascular disease. And the new statin guidelines, promulgated in November 2013, are clearly an effort to increase primary prevention of heart disease.

But how will the PCSK9 agents fit in with the new statin guidelines?

When these guidelines were handed down from on high (i.e., the American College of Cardiology and the American Heart Association – ACC/AHA), the controversy erupted immediately. Doc Gumshoe had his say about them in a piece in December, and at the risk of repeating myself, here are the essentials of what these guidelines state:

• They attempt to quantify total cardiovascular risk by arriving at a percentage figure for a ten-year risk of cardiovascular events (heart attack or stroke), based on an algorithm. Individuals aged 40 – 75 whose ten-year risk is 7.5% or higher are recommended to take statins.
• They recommend that persons whose LDL-cholesterol levels are 190 mg/dL or higher should take statins.
• They also recommend that all persons with existing heart disease or Type 2 diabetes should take statins.
• However, specific LDL-cholesterol goals are not part of the new guidelines.
• And regular monitoring of blood cholesterol levels is not necessary. The effects of treatment should not be based on how much cholesterol-lowering takes place.

It has been estimated that implementing these guidelines would result in 70 million people in the US being on statins.

It was pointed out immediately by some of the top cardiologists in the land that the guidelines overestimated risk by a significant percentage, so that a great many people who did not need statins would be taking them. In particular, the algorithm overweighted age, so that many older persons with no risk factors at all would be prescribed statins.

And, because LDL-C goals were not part of the guidelines and regular cholesterol monitoring is not part of the drill, there’s no way for doctors or patients to have any idea of whether the statin treatment is actually doing them any good. Patients would have to take it on faith, and this would likely lead to poor patient adherence to treatment.

A nod to the cholesterol skeptics …

There are among us those who are doubtful whether cholesterol is really the source of the cardiac problems. Instead, they point to a number of other related factors: inflammation, endothelial dysfunction, oxidative stress.

These are indeed real. But cholesterol is involved with all of them.
If you already know all about cholesterol, you can skip this – and I’ll try to keep it short. But here are some basics that a lot of people don’t know about.

Cholesterol is a simple molecule, solid at body temperature, and not soluble in water. In itself, cholesterol is neither “good” nor “bad”– the distinction is between the little bundles of lipids and proteins that carry cholesterol in our circulatory system. The larger, looser ones – low-density lipoproteins – are the ones called “bad” cholesterol (i.e., LDL-cholesterol), because they are more apt to shed cholesterol molecules, which can be deposited in the walls of our arteries. The smaller, denser ones – high-density lipoproteins (i.e., HDL-cholesterol) – convey the cholesterol molecules back to the liver, where they are taken up by the bile and carried in the bile duct to the colon, where they are eliminated in feces. Therefore, HDL-C is “good” cholesterol.

But remember that cholesterol is absolutely essential to life. It is present in all our tissues, providing structural integrity. And cholesterol is essential to the synthesis of every hormone in our bodies. We synthesize about 80% to 90% of our cholesterol; only a small fraction enters our bodies as cholesterol. You may read somewhere that cholesterol is only synthesized from animal sources. This is entirely untrue. Vegans make cholesterol just fine; if they didn’t, they would be dead.

LDL-C particles are not all the same size. It now appears that the smaller LDL-C particles are more susceptible to oxidative damage, and may also inhibit the synthesis of nitric oxide, which is thought to be one of the body’s natural mechanisms to combat atherosclerosis. The larger LDL-C particles are comparatively benign. And HDL-C has another decidedly beneficial effect. Its principal lipoprotein, apo A-1, plays a part in preventing particles involved in atherosclerosis from adhering to arterial walls.

So, indeed, those other factors play an important part in coronary artery disease and heart disease in general. But it’s hard to get away from the basic fact that what gets deposited in the arterial walls is cholesterol. That has been known for over a hundred years. What we’re beginning to understand better is how it gets there and how it causes damage.

What’s this about the “innocence” of saturated fats?

Recent evidence points to further complications in the cholesterol story. The accepted wisdom, up until recently, has been that the arch-villain in our diets is saturated fat. Now, at least some data seems to exonerate saturated fat as a principal cause in heart disease.

In a December piece (“Tidings: Mostly Glad”), Doc Gumshoe referred to a 2009 analysis of 21 studies in almost 350,000 subjects, observed for up to 21 years, which found that the persons who consumed the highest amounts of saturated fats did not have any increased risk of cardiovascular disease, compared with the persons who consumed the smallest amounts of saturated fats. (Siri-Taurino PW, Am J Clin Nutr 2009)

And in March of this year, another analysis was published, this one looking at 72 studies in more than 600,000 subjects. Again, these the results were that people who consumed the most saturated fats did not have more heart disease than people who consumed less saturated fats. And people who consumed more mono- or polyunsaturated fats, (e.g., olive oil or corn oil) did not have less heart disease. (Chowdhury R, Ann Int Med 2014)

Different types of fat were associated with varying levels of cardiovascular risk. Omega-3 fats, mostly found in fish, appeared to be protective, as did some fats found in dairy products. (Note: this doesn’t apply to omega-3 supplements, which have not been found to deliver cardiac benefit.) On the other hand, omega-6 fats, found in some vegetable oils and processed foods, were related to elevated risks.

Saturated fats do increase the levels of some LDL-cholesterol, but not of the smaller, denser LDL-C particles that deposit plaque in the arteries. These more dangerous LDL-C particles are linked to high carbohydrate diets and foods with a high glycemic index – i.e., “sugary” or high-fructose . This finding reinforced the conclusions of a Danish study that found that persons who substituted low-fat, sweet foods for higher fat foods experienced more cardiovascular events. (Astrup A, Am J Clin Nutr 2011)

So, what does all this have to do with PCSK9 agents?

As of now, Doc Gumshoe’s prognostication is that at least Amgen’s and Regeneron’s drugs will get fairly prompt FDA approval. What happens after that remains to be seen. There was a flurry of worry about possible cognitive side effects in connection with evolocumab, but careful analysis of the data did not reveal any increased risk. They do lower LDL-C by big margins, and, at least in the short term, the side effects profiles seem to be benign.

To get comparable LDL-C reductions with statins, high doses have to be employed, with an elevated risk of side effects. Statin side effects, particularly the muscle aches – and in the most severe cases, destruction of muscle tissue – are by now very well known, statins having been on the market for more than 20 years. There certainly may be side effects with the PCSK9 agents. It may just be too early for them to emerge.

There is likely to be considerable resistance from the payers. Statins now are inexpensive, and in most cases it would be difficult to justify substituting an expensive drug, given by injection, for a cheap oral drug. The response from the insurance companies will be, “You need to justify to us, on a case-by-case basis, why you need this expensive new drug.”

Compliance may also be a big deal. For the PCSK9 inhibitors to attain blockbuster status, it’s going to be necessary to get a lot of new patients on those drugs – not just the ones who aren’t getting satisfactory results on statins. Many of those new patients will have to be people who don’t currently know they’re supposed to be on cholesterol-lowering medications – the ones who get swept in under the new ACC/AHA guidelines. Most of those patients have no current symptoms – they’re merely “at risk” based on the numbers in the new algorithm. How many physicians are going to prescribe an expensive new drug to those patients? And how many patients, with no symptoms to remind them that they have a condition that needs treatment, are going to stick with the treatment plan?

And there’s yet another body of inconvenient data that does not bode well for the PCSK9s. The studies showing that the evils of saturated fats are greatly overestimated are only part of a trend that goes back to the Exoneration of the Egg. (Remember when the Evil Egg was the embodiment of what we had to avoid in order to keep out cholesterol?) Saturated fats were to be avoided not only because they cause us to gain weight, and there’s no doubt that obesity contributes to ill health in lots of ways. But when we’re considering heart health, the link was always between saturated fats and elevated levels of LDL-cholesterol.

Now, there’s evidence that what saturated fats do is increase the levels of the larger LDL-C particles, which don’t appear to be particularly harmful. It’s the smaller, denser LDL-C that most contributes to atherosclerosis, and those are more related to sugars and carbohydrates – not to saturated fats.

But cholesterol-lowering drugs, whether statins or PCSK9s, don’t discriminate between the “innocent” LDL-C and the “guilty” LDL-C. It seems possible, and even likely, that people who are not specifically at high risk for heart disease can manage their risk quite adequately by following a diet, and a not-particularly-stringent diet at that.

The benefits of cholesterol-lowering drugs for the high-risk population are very well established, and Doc Gumshoe doesn’t anticipate any change in that perception.

But for the rest of the population, not at high risk based on clinical evidence, but only on statistical modeling, this new class of drugs, the PCSK9 inhibitors, may be swimming against the tide.

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Please keep the comments coming! Doc Gumshoe got a couple of demerits for the HRT blog, including one for just referring to hormone replacement therapy in the title as HRT, which looked like a stock symbol to some folks. But I want to know what people are interested/curious about, as well as when I hit or miss the mark with these pieces. Miss Truesdell didn’t shrink from telling me, “Michael, you made a mistake on line 3 of that proof – fix it!” I (eventually!) was grateful to her, and I’ll be grateful to you for correcting any goofs. Thanks again, Michael Jorrin (aka Doc Gumshoe)