[Sciences/Stroke] PCSK9-FOURIER trial and why newer drug is not always better

You may have heard about the FOURIER trial making the news…..or maybe not. What you have maybe heard was this new published clinical trial that has created a divide in the news: In one hand it sounds evolocumab (a PCSK9 inhibitor) is the next cholesterol lowering blockbuster that would put statins into the category of “old drugs”, in the other hand it was raised how this new treatment provide little benefits for a hefty added price ($14’100/year price tag according to this article) compared to statins ($1’409/year price tag for a branded form).

So what is about this study, how does it fare and does it really have such a beneficial value that worth paying the extra $$$? Lets go through together. For this post, I will base my comments on two articles: the FOURIER clinical trial  (Ray, Landmesser et al. 2017) and a recent meta-analysis on the benefits of statins on cardiovascular events (Chou, Dana et al. 2016) .

How does statins and PCSK9 work?

You have heard about statins as a cholesterol-lowering drug, heard about the LDL/HDL ratio with one being “bad” (LDL) and the other being “good” (HDL). Cholesterol is part of our normal functioning. We need cholesterol for our cells and our tissues. Cholesterol is an important component of our cell membrane allowing it to have a certain “fluidity”. Cholesterol is also the precursor of any steroid hormones and it is the source for essential groups of steroid hormones such as glucocorticoids (anti-inflammatory), mineralocorticoids (blood pressure), androgens (male sexual hormones) or estrogens (female sexual hormones).

Cholesterol can come from two sources: diet (by consuming animal products) and by de novo synthesis by the liver from acetyl-coenzyme A (acetyl-coA, through a very long and complex biochemical pathway).

346px-hmg-coa_reductase_pathway

Our liver can produce the amount of cholesterol we need daily, therefore the cholesterol obtained from the diet is an extra amount that is pooled with our endogenous cholesterol. Cholesterol is a fatty acid, it is a lipophilic compound (like fat) that is poorly dissolving in water. One biological adaptation in our evolution was to combine these cholesterol on some proteins called “lipoproteins”, allowing cholesterol to piggy-back and therefore be “soluble” in blood and in interstitial fluids. You have different flavors of these “lipoproteins” based on their physico-chemical properties as observed by ultra-centrifugation. We have the light form called “low-density lipoproteins” (LDL) and the heavier form called “high-density lipoproteins” (HDL).

ng0208-129-f1

LDLs are taken up by cells through a particular receptor called “LDL receptors” (LDLR). These receptors are expressed on the cell surface, in particular by liver cells and endothelial cells (cell lining the inner side of blood vessels). LDLs are the one found mostly in atherosclerotic plaques that are responsible for myocardial infarction (MI or heart attack) and cerebral ischemia (ischemic stroke).

Therefore, it is important to keep these LDL levels within normal range. You have two possible actions: either you reduce your dietary intake and/or use medication aimed to block the endogenous cholesterol production.

This is where statins and PCSK9 inhibitors come into action.
Statins target the enzyme called HMG-coA reductase that is involved in the early step of cholesterol biosynthesis.

Proprotein convertase substilisin/kexin 9 (PSCK9) inhibitors in the other hand block the interaction of PSCK9 with LDLRs. PSCK9 is produced by most of our cells and have an affinity to LDLRs. Therefore PCSK9 can compete with LDL for binding to LDLRs and therefore increase the amount of circulating LDL. Worse, once bound to its receptor, PCSK9 forces the internalization of LDLR and block its recycling, further accentuating the amount of circulating LDLs. By blocking PCSK9 ability to bind to LDLR, you can free more LDLR to bind circulating LDLs and therefore decrease your LDL levels.


What is evolocumab?

One compound have been approved by the FDA in this matter, its name is evolocumab (Repatha®, Amgen). It is a biologic, an antibody that will bind to PCSK9 and impeach its binding to LDLR. Because it is a biologic, it is very expensive to produce because it is a high molecular weight protein that cannot be synthesized by chemistry. We have genetically-modified yeasts or mammalian cells that know how to synthesize it if you give them the right gene. Yet, synthesis is only one problem solved, the other problem is protein folding.
It is like an origami folding, a very tortuous and complicated series of step to achieve a desired shape. Like an origami, fail to properly fold and you will have a far cry of a desired finished product.
Yeast and mammalian cells may not fully be efficient at this task and therefore you have to deal with small amount of biologically active product at the end of the manufacturing process. Evolocumab has been approved by the FDA in 2015 for the use in people that cannot use statins and that failed to control their cholesterol levels by dietary intervention. Because it showed interesting outcomes, it was tempting to consider the added benefit of this biologic over statins. We have a good idea on statins risks and benefits and one major advantage of statins are their price. We have generic forms that are very cheap, much more cheaper than evolocumab (at least 10 times cheaper, considering the full price before coupons and insurance plans).

The FOURIER trial
This is the clinical trial that is at the epicenter of the news. In this trial, they assess how evolocumab (EVO) stood against statins and possibility outperformed statins. Statins have been shown their added benefits for patients with high cholesterol compared to placebo treated.

Because it is unethical to assess EVO versus non-treated individuals, you have to compare groups taking their statins with EVO versus groups taking their statins without (refered here as placebo). This is also a method to show that EVO outperforms statins.

We have two groups of reasonable sample sizes: EVO (N=13’784) and placebo (N=13’780) with matched parameters (age, sex, ethnicity, condition, medication……) to ensure the effect you observe are mostly due to EVO and nothing else.
The striking data here is the lowering of the LDL. In placebo, this level is about 90 mg/dL. In EVO group, we are going down to 30mg/L. That’s fairly impressive. But at the end, you want to see the outcome right?

In our case, our outcomes are how many cases of heart attack and stroke we are dealing with.

This is were the results are becoming more contrasted and less exciting.
If we look at secondary endpoint (death by cardiovascular event, heart attack or stroke), EVO fared a bit better than placebo (5.9% versus 7.4%).

For 2000 persons suffering, EVO saved the life of one person death by cardiovascular death. For 200 patients, it saved one person from an heart attack and one person to stroke injury compared to placebo (statins) group.

Considering the possible side effects reported to the medication, the lack of pharmacovigilance and foremost the price of the drug, you have to weight the benefits over risk and costs. This is where things are less shiny. This study fails to show us how EVO will replace statins.

Statins are the devil we know, they are doing their job well, we know their risks and associated side effects fairly well and they are very affordable. EVO is certainly great for patients that cannot rely on statins to control their cholesterol. But the benefit of EVO over statin is marginal and not worth the risk and costs.

References:
Chou, R., T. Dana, I. Blazina, M. Daeges and T. L. Jeanne (2016). “Statins for Prevention of Cardiovascular Disease in Adults: Evidence Report and Systematic Review for the US Preventive Services Task Force.” JAMA 316(19): 2008-2024.

Ray, K. K., U. Landmesser, L. A. Leiter, D. Kallend, R. Dufour, M. Karakas, T. Hall, R. P. Troquay, T. Turner, F. L. Visseren, P. Wijngaard, R. S. Wright and J. J. Kastelein (2017). “Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol.” N Engl J Med.

 

Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s