Don't believe the PCSK9 hype. While we continue to get bombarded by headlines about how well this new class of cholesterol lowering drugs performs, I believe that investors (and consumers) would be best suited to perform their own due diligence. My path down this road started in late 2014 as I started performing research on Esperion Therapeutics (NASDAQ:ESPR), which ultimately led to my startling conclusions about how wrong that we - as a society - have been in regards to cholesterol.
My research was then validated, at least to a certain extent, when Amgen's (NASDAQ:AMGN) Repatha and Regeneron's (NASDAQ:REGN)/Sanofi's (NYSE:SNY) Praluent were approved with a very limited label in the summer of 2015. Much to the surprise of many analysts and professionals in the medical field, the FDA decided that a cardiovascular outcomes trial (CVOT) would be needed before the label is expanded beyond patients with a genetic condition for extremely high LDL-C or those at high-risk. With top line results of Amgen's FOURIER CVOT expected in the second half of 2016, this article details my rationale as to why I believe the results will disappoint.
The debate over cholesterol has been going on for quite some time. Most literature I've seen points to the early 1900s and a Russian scientist named Anitschkow as being the first to show a link between cholesterol and atherosclerosis by feeding rabbits cholesterol. I'll leave the debate as to whether an herbivore is an appropriate test subject to another day, but the cholesterol hypothesis really started to ramp up in 1948 with the commencement of the Framingham study.
The government funded Framingham study ultimately found that the build-up of plaque led to atherosclerosis and heart disease. And since plaque is formed by a combination of fat and cholesterol, researchers thought there was an easy fix. Lower consumption of fat and cholesterol, and voila, risk for heart disease should be mitigated. I'm not quite sure how this logic made sense at the time; wouldn't the same logic mean that by eating animal muscle (protein), we should also automatically develop more muscle and get stronger?
Nevertheless, this was the basic premise up until early this year when the 2015 Dietary Guidelines for Americans was released, and cholesterol is no longer listed as a concern for over consumption. Since the purpose of this article is not to discuss what a "healthy" diet actually is, however, I'm going to instead focus on the factors that I believe are most important to CVOTs (given that the diet aspect should wash out in such large trials).
Inflammation Is The Real Culprit
My research indicates that high levels of LDL-C are not the cause of atherosclerosis, but rather a part of the puzzle. For this reason, I ignore the headlines about "percent reduction of LDL" and the "lower is better" mantra, and instead focus on the details provided about the reduction of inflammation. So when reviewing the results from the different PCSK9 trials, I was astounded to find what was missing from the results; anything about inflammation. That's a major red flag for me, and here's why.
As a natural part of the aging process, humans start losing some of their anti-inflammatory nutrients. In addition, oxidative stress becomes more pronounced as antioxidants are stripped away and leave us more susceptible to persistent organic pollutants. Without sufficient antioxidants, LDL becomes inflamed, which is where the problems begin. Macrophages attempt to combat the inflammation by engulfing the oxidized LDL through a process known as endocytosis. This ultimately leads to the formation of foam cells, which is a direct indication of plaque build-up. Unfortunately, this all occurs at the microscopic level and is hard to detect, but it gives us an idea as to why persistently high levels of LDL are associated with atherosclerosis and heart disease.
Given this knowledge about how plaque is formed, the key to stopping the whole process is to avoid inflammation. A very common measure for inflammation is C-reactive protein (CRP). According to WebMD:
The body produces CRP during the general process of inflammation. Therefore, CRP is a "marker" for inflammation, meaning its presence indicates an increased state of inflammation in the body.
Given that statins have been shown to reduce CRP, it's not surprising that statins have produced good results in CVOTs. As further stated on WebMD:
In studies involving large numbers of patients, CRP levels seem to be correlated with levels of heart disease risk. In fact, CRP seems to predict cardiovascular risk at least as well as cholesterol levels do. Data from the Physicians Health Study, a clinical trial involving 18,000 apparently healthy male doctors, found that elevated levels of CRP were associated with a threefold increase in the risk of heart attack.
In the Harvard Women's Health Study, results of the CRP test were more accurate than cholesterol levels in predicting heart problems. Twelve different markers of inflammation were studied in healthy, postmenopausal women. After three years, CRP was the strongest predictor of risk. Women in the group with the highest CRP levels were more than four times as likely to have died from coronary disease, or to have suffered a nonfatal heart attack or stroke compared to those with the lowest levels.
The typical test to measure CRP is referred to as high-sensitivity CRP ((hs-CRP)), and most doctors will refer to levels over 3.0 mg/L as being "high risk" for cardiovascular disease. This is extremely important to understand as it relates to the CVOTs for the PCSK9 drugs, so I'll have more on this later.
There's a lot more evidence that points to inflammation and not just LDL levels as to the real culprit of heart disease. A 2011 paper titled Stabilisation of Atherosclerotic Plaques found that statins stabilized atheromatous plaques by mechanisms largely independent of LDL lowering. And this coincides with the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), which found that lovastatin reduced CV events in patients with low LDL and high CRP levels, but showed no clinical benefit in patients with both low LDL and low CRP levels. Additionally, as stated in this Medscape article, only high risk patients should even be given statins:
What was equally striking was that of the total deaths (157) in both the treatment and placebo groups, more than two-thirds (115) were from noncardiovascular causes. This emphasizes the point that in a group of people not at high risk of coronary deaths, therapy to lower cholesterol cannot do very much to lower mortality as the patients are more likely to succumb to noncardiovascular causes.
Despite having shown beneficial results in CVOTs, there is a major bit of irony related to statins. Statins reduce Coenzyme Q10, or CoQ10 for short, which is a powerful antioxidant. According to the Mayo Clinic:
Coenzyme Q10 (CoQ10) is an antioxidant that is made in the human body. CoQ10 is needed for basic cell function. CoQ10 levels decrease with age and may be low in people with cancer, certain genetic disorders, diabetes, heart conditions, HIV/AIDS, muscular dystrophies, and Parkinson's disease.
So CoQ10 is often low in people with heart conditions and muscular dystrophies. A common side effect noted by patients taking statins is muscle weakness and fatigue, which sometimes leads to these patients being designated "statin intolerant." While the debate over exactly what causes statin intolerance will surely continue to rage on, there is overwhelming evidence in my eyes that it is largely related to decreased levels of CoQ10.
So with Amgen's new data about the efficacy of Repatha compared to ezetimibe (NYSE:MRK) in statin intolerant patients, it's important to note that muscle related side effects were still reported in 20.7% and 28.8% for Repatha and ezetimibe patients, respectively. Does this mean that muscle weakness is simply a function of all cholesterol lowering drugs? The answer to this question will likely have a big impact on the market potential to the future of all non-statin cholesterol lowering drugs.
Along with muscle impacts, statins are also reported to have major cognitive impacts. This was the topic of Duane Graveline's book that was published in 2004 titled Lipitor Thief of Memory. And a simple scan of previous trial results and medical literature seems to back-up the memory loss claims.
Firstly, it's important to remember that 25% of the cholesterol in your body is actually found in your brain. Also, cholesterol serves as the raw material for the production of progesterone, estrogen, cortisol, testosterone, and even vitamin D. So from this perspective, artificially lowering cholesterol is bound to have some negative consequences.
Secondly, even Amgen's OSLER-1 study reported neurocognitive impacts that look scary to my untrained eyes. After only 1 year of dosing, the evolocumab group had a neurocognitive event rate that was 3 times higher than the standard therapy group (0.9% vs. 0.3%). And this matches up with interim results from the ODYSSEY trial, which found that the alirocumbab group had over 2 times higher neurocognitive event rate than the placebo group (1.2% vs. 0.5%).
Therefore, it's my belief that long-term studies will show an even larger increase in neurocognitive events the longer cholesterol is artificially lowered, and that's not just my opinion. The FDA has also previously acknowledged concerns about neurocognitive impacts from the PCSK9 drugs, so this will certainly be a key data point when CVOT results are released.
Amgen has indicated that it expects top line results from its FOURIER CVOT in the second half of 2016. So as we start to approach that time frame, investors will start placing their bets. The primary endpoint for the trial is the time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke or coronary revascularization. Treatment will be randomized between Repatha in combination with statin therapy or placebo plus statin therapy. The inclusion criteria are for LDL-C to be greater than 70 mg/dL and clinically evident cardiovascular disease.
Now that we know that inflammation is the real cardiovascular threat, as opposed to LDL, is it easy to assume the trial will fail given that PCSK9s have not been reported to reduce inflammation? Not necessarily. With an inclusion criterion of "clinically evident cardiovascular disease at high risk for a recurrent event" (per clinicaltrials.gov), the trial appears to be limiting its patients to those that would likely have higher CRP levels, and thus would be at high risk for a recurrent event.
Higher CRP levels mean higher inflammation, which as we now know, means that the LDL is susceptible to oxidation and will eventually become a foam cell. This can result in additional plaque formation, which obviously puts the patient at a higher risk for a cardiovascular event. So by limiting the amount of LDL that can ultimately end up causing plaque, the trial could yield positive results. Thus, in this vein, the "lower is better" thesis for LDL will appear to be validated, even if it's confounding the real issue. The byproduct might be, however, increased muscular and cognitive side effects that would need to be seriously considered before long-term use.
Conversely, if enough patients in the trial have low enough levels of inflammation, the lower levels of LDL from PCSK9 treatment will not yield beneficial effects due to the lack of foam cell formation. In this case, the serious side effects will be for naught. Caveat emptor.
What does my crystal ball say? The FOURIER trial will ultimately be headlined with "successful" and "groundbreaking" results where the primary endpoint is barely met and scary safety results are initially pushed aside. Then, as the public is able to dig more fully into the data, it will become evident that the devil is in the details and that the drug label(s) should not be expanded to a wider population. The risk/benefit/cost analysis will just simply not be good enough without a further reduction in inflammation.
The readout from the FOURIER CVOT will obviously have an immediate impact to the whole class of cholesterol lowering drugs. I suspect that the whole class will initially trade in the same direction - with little differentiation for mechanism of action - until the reverberations are fully digested. Despite all the progress that's recently been made toward understanding cholesterol's real role in cardiovascular health, the "lower is better" mantra still seems to be the prevalent theme within the public. This means all investors in the space should be prepared for an "unexpected" bout of volatility during the second half of 2016. Related stocks include Sanofi, Regeneron, Esperion, Alnylam (NASDAQ:ALNY), The Medicines Company (NASDAQ:MDCO), Pfizer (NYSE:PFE), AstraZenca (NYSE:AZN), Merck , Eli Lilly (NYSE:LLY), Catabasis (NASDAQ:CATB).
Disclosure: I am/we are long CATB.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
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