written by reader Will PCSK9 Inhibitors Be the Next Blockbusters in Cardiovascular Disease?


By Michael Jorrin, "Doc Gumshoe", April 24, 2014

[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 ve