Pharma Phantasy: The $30 Billion PCSK9 Inhibitor Market

–Drug company dreams up a study showing all the benefits and none of the costs or risks of PCSK9 inhibitors.

Here’s a pro tip for pushing a drug (or, indeed, any aggressive treatment or screening strategy): focus exclusively on the benefits, even if they are modest at best, and completely ignore side effects and costs. If you do this I can guarantee that even the most mildly effective treatment will look great.

A perfect example is a study published last week in JAMA Cardiology. Chris Cannon and coauthors used sophisticated modelling techniques to estimate the percentage of people with atherosclerotic cardiovascular disease (ASCVD) who would require a PCSK9 inhibitor after first undergoing intensive lipid-lowering therapy (LLT) with statins and ezetimibe. Here’s their conclusion (emphasis added):

“In a large and representative US population with ASCVD, 53.2% received statins at baseline and only 25.2% achieved LDL-C levels of less than 70 mg/dL. Our study suggests that, under maximal treatment intensification with LLT, assuming full compliance and no tolerability issues, roughly 86% of patients would achieve LDL-C levels of less than 70 mg/dL with statins and ezetimibe only. Adding a PCSK9 inhibitor to the regimen for the remaining 14% of patients with LDL-C levels of at least 70 mg/dL would result in more than 99% of the population with ASCVD achieving LDL-C levels of less than 70 mg/dL. These data help identify the therapies that could be used to maximize lowering of LDL-C levels in patients with ASCVD.”

Notice that this estimate assumes “full compliance and no tolerability issues” and, of equal importance, there is no mention of cost. Further, the goal of the strategy under examination is simply to get as many people as possible to a low cholesterol level. There is no attempt to calculate what clinical benefits that might result in, or, of course, at what cost, either economic or medical, this would be achieved.

Pharma Phantasy

This is a paper where all drugs are effective and no one thinks about costs or side effects.

If that sounds like a pharmaceutical company fantasy that’s because that is exactly what this paper is. All the authors have received money from Sanofi and Regeneron (which makes the PCSK9 inhibitor Praluent (alirocumab)) or actually work for those companies or for companies hired by Sanofi and Regeneron. Cannon and Matthew R. Reynolds are the only two academic authors. They are affiliated with Harvard Hospitals and have both received funding from Sanofi. The study itself was funded by Sanofi and Regeneron.

The other four authors work for Sanofi or Regeneron or a company hired by them called Axtria. Here is how Axtria comes up in a Google search:

In addition to the named Axtria co-author, the fine print at the end of the article acknowledges two additional Axtria employees who “contributed to the development of the simulation, execution of the statistical analyses, and development of manuscript drafts.”

The paper also acknowledges the role of “Rachel Wright, PhD, Prime [a large medical communications company], provided editorial and administrative support for later drafts.”

The links to Sanofi and Regeneron run even deeper and include an editor of the journal. One of Cannon’s colleagues at Brigham and Women’s Hospital is Marc Sabatine. Sabatine succeeded Eugene Braunwald as the chairman of the TIMI Study Group and was the co-chair of a major PCSK9 inhibitor trial, FOURIER. Sabatine is a deputy editor of JAMA Cardiology.

There’s more. The Cannon article has an accompanying viewpoint written by… yes, Sabatine and another Brigham colleague of Cannon’s, Robert Giugliano. Giugliano was also on the FOURIER executive committee and has also received money from Sanofi. I imagine it will again come as no surprise that the article argues in favor of expanded use of PCSK9 inhibitors, not only in people with heart disease but as primary prevention in high risk people without heart disease. In their article Sabatine and Giugliano briefly mention, and quickly brush aside, the issue of side effects, and make no effort to explore in any detail the vitally important question of cost effectiveness.

Just to recap the COI highlights: Sanofi and Regeneron develop, write and pay for an article that only looks at the benefits of their product. The only two academic authors on the paper who don’t work for the company or its affiliates have also received funding from the manufacturers. The article is published in JAMA Cardiology, whose deputy editor is a colleague of the first author at the Brigham and who has also performed research on the same class of drugs. That editor joins with another Brigham colleague, who also has conflicts, to write a viewpoint supporting the study and arguing for expanded use of PCSK9 inhibitors.

I asked Howard Bauchner, the editor-in-chief of the JAMA family journals, to respond to questions about the article and viewpoint. He said that the role of the authors was fully disclosed in the article and that the JAMA journals “provide more information than most journals in this regard.” He expressed no concern about Sabatine’s viewpoint. He said that it is not the policy of the JAMA journals “that no one with a potential COI should write an opinion piece…” He said that “it is certainly a consideration during the review process, but more importantly is the content of the opinion piece. All articles are reviewed with respect to potential financial COI and bias. We certainly expect full-disclosure with respect to potential COI.” He also said that “we do not exclude editorial members from writing” opinion pieces. “They are reviewed in the same manner as all other articles.” Finally, Bauchner also stated that he had no idea how many, if any, reprints were purchased for these articles. “I am never provided that information, nor should I be.”

The Real World Costs of PCSK9 Inhibitors

A short research letter published in JAMA Internal Medicine presents an entirely different perspective on the role of PCSK9 inhibitors in the real world. Rather than ignoring the cost, as in the Cannon paper and the accompanying viewpoint by Sabatine and Giugliano, this paper tries to assess the actual cost of PCSK9 inhibitors in the real world.

The paper was written in response to an innovative pricing strategy developed by Amgen, the manufacturer of another PCSK9 inhibitor, Repatha (evolocumab). In an attempt to quell fierce resistance against the high cost of Repatha, Amgen said that it would return the price of the drug to some payers when a patient taking the drug had a stroke or MI.

The new analysis by Inmaculada Hernandez (University of Pittsburgh) makes clear that this strategy will not have a significant impact on the overall cost of the drugs in the real world. She estimates that the price of evolocumab, which is now listed at $14,000/year but is generally discounted to around $9,100, would be reduced by about 2.15% to about $8,904. This, obviously would have little effect on the cost effectiveness equation of the drug, since previous studies have found that the price of PCSK9 inhibitors would have to drop by more than half to be cost-effective. (See also this analysis by Rod Hayward in the Incidental Economist showing that this strategy could never have a serious impact on the cost-effectiveness equation.)

Even with discounts, Hernandez calculates that it would cost over $1.5 million to prevent an acute MI and $5 million to prevent a stroke. In response to email questions she said that it is “important for guidelines to consider cost-effectiveness of the available therapeutic alternatives. Otherwise, we have the risk of ending up with unsustainable guidelines that… do not translate into acceptable value for money.”

Hernandez pointed out that even in the high risk subgroup, identified by Sabatine and Giugliano as those who would benefit most from PCSK9 inhibitors, the drugs are still far from cost-effective.

I asked Hernandez to give a rough estimate of the cost for PCSK9 inhibitors if the drugs were prescribed along the lines suggested by Cannon et al in their paper. In the Cannon model 14% of people with heart disease need a PCSK9 inhibitor to effectively lower their LDL levels. Hernandez said that this means that 3.29 million people (out of a total of 23.5 million people with heart disease) would need a PCSK9 inhibitor. This would cost more than $29 billion each year– though Hernandez reminds us that this is “after rebates and refunds for those who have strokes or heart attacks.”

It’s easy to see how this scenario represents a dream-come-true for pharmaceutical companies. For the rest of us it would be a nightmare.