PCSK9 Drugs Are Overhyped

Summary

PCSK9 drugs have limited use and will likely show substantial side effects in long-term studies.

The real culprit of cardiovascular risk is discussed.

My rationale as to why the FOURIER Cadiovascular Outcomes Trial will disappoint is laid out.

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.

Some Background

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?

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More on this from Zoe Harcombe ...

PCSK9 Inhibitors & Statins

Statin side effects pave the way for son of statins…  

Introduction

In May 2014, two doctors were maliciously attacked by a researcher. The researcher heads up the Clinical Trial Service Unit (CTSU) at Oxford University.

The doctors’ crimes (they were independent, but the same) were to mention that statin side effects might affect approximately 18-20% of takers. Both doctors referenced a peer reviewed article, which said that “the rate of reported statin-related events to statins was nearly 18%.” (The researcher demanded a retraction of both articles and continues to want the journal editor’s head on a plate, so to speak.

The journal commissioned an independent investigation to see if the articles should be consigned to Orwellian thought police archives. The best thing about the investigation was that it emerged that the researcher’s unit had received £268 million from pharmaceutical companies/interested parties. (Are you thinking what I’m thinking?!)

Wind forward to 4th April 2016 and an astonishing paper was published in The Journal of the American Medical Association (JAMA). The paper opened with the words: “Muscle-related statin intolerance is reported by 5% to 20% of patients.”

That’s just muscle-related statin side effects – what do the numbers become when mind, mood, memory, mo-jo and more side effects are added in?!

The study reported in the JAMA paper was funded by Amgen (remember that name). The combined conflicts of the authors covered most drug companies that make cholesterol lowering medications (I couldn’t see any not represented). Even more interesting was the fact that one of the authors, David Preiss, is a member of the CTSU. The same CTSU headed up by the researcher demanding the retractions for even mentioning that statin side effects could be as high as 20%.

What’s going on?

What’s going on is that it has become strategic to attack statins. Statins are now off patent – pharma speak for not being worth as much money any more. In preparation for the end of the gravy train, researchers have been working on other ways to lower cholesterol. The fact that higher cholesterol is associated with lower deaths (for men and women, from heart disease and all-causes) seems to have conveniently escaped their notice.

The powers that be have tried all sorts to find the next blockbuster cholesterol-impairment drug. Most notably they have tried, and failed, to raise HDL, which they think is good cholesterol when it is a lipoprotein. Maybe that’s why they failed.

The one that they have managed to get past drug approval bodies (which is sadly not difficult when most of those are conflicted) is called a PCSK9 inhibitor. (It spell checks to “pesky”, which amuses me).

PCSK9 Inhibitors

If I told you that a drug went on sale on 1st September 2015, which involved fortnightly injections at a cost of £4,000 a year and for which trials on incidents or deaths had not even started, you might be shocked. That’s exactly what happened. A drug named “Repatha” went on sale, having been “granted marketing authorisation” (note marketing authorisation, not drug approval) by the European Medicines agency on 21st May 2015.

Repatha is a PCSK9 inhibitor. One of a human’s estimated 20,000-25,000 protein coding genes is PCSK9. The PCSK9 gene provides instructions for making a protein that helps to regulate the amount of cholesterol in the blood stream. The PCSK9 protein controls the number of low-density lipoprotein (LDL) receptors on the surface of cells. LDL receptors are particularly plentiful in the liver, enabling the liver to remove cholesterol from the blood stream as needed. This is how the body is designed to work.

The company that makes Repatha, Amgen, describes its drug as follows: “Repatha is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of the liver to remove LDL cholesterol from the blood”. Repatha is thus designed to stop the body from working in the way it is designed to work.

Statins were also designed to stop the body doing what it was designed to do. Statins block a vital pathway in the body – the mevalonate pathway. PCSK9 inhibitors impair a genetic/protein production pathway in the body.

My fundamental objection to all drugs that are designed to stop the body doing what it is designed to do, is that I don’t like money-motivated, share-holder driven, pharmaceutical companies ‘playing God’. I trust evolution more than Pfizer and Amgen.

What we need to know about Repatha/PCSK9 inhibitors

There are probably only two key things to know:

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