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In The Debate About Cost And Efficacy, PCSK9 Inhibitors May Be
The Biggest Challenge Yet
Posted By William Shrank On February 17, 2015 @ 9:00 am In Costs and Spending,Drugs and
Medical Technology,Organization and Delivery | 10 Comments
The American health care system is far and away the most costly in the world. Health care reform
is intended to lower costs, but they are still rising, albeit less steeply than in the past. Moderation
is not however the case in the area of specialty pharmacy. The medications to treat Hepatitis C are
the most cited examples of a general inflationary trend, but the pipeline of expensive medications
is extensive.
Yet, policymakers and payers appear unwilling to undertake significant cost controls on medication
pricing. Indeed the controversy over the $84,000 price tag for Sovaldi (sofosbuvir) has largely
faded, suggesting a certain resiliency in our system’s ability to absorb costs.
We believe that resiliency is about to be challenged in a manner unlike we have seen in the past,
at least in the area of pharmaceuticals. A number of pharmaceutical manufacturers are developing
a new class of medication to manage high cholesterol — the PCSK9 (proprotein convertase
subtilisin/kexin 9) enzyme inhibitors.
PCSK9 Inhibitors
The medication is injected, generally once or twice a month, and evidence from randomized
controlled trials suggests that they are well­tolerated and highly effective in reducing low­density
lipoprotein cholesterol (LDL­C). While prospective outcomes studies are not yet available to assess
their efficacy in reducing adverse cardiovascular events, the scientific community is preparing for
likely approval of these medications to manage familial hypercholesterolemia, and there is growing
interest in additional subgroups where treatment may be appropriate.
While this class of medications will no doubt lead to substantial clinical improvements in some
patients, those improvements will be costly. The PCSK9 inhibitors will be specialty medications and
likely priced as such. While we will not know exact pricing until the first generation of these
medications is approved for use by the Food and Drug Administration sometime in mid­2015,
estimates of annual pricing for these injectable drugs are in the range of $7,000 – $12,000 [1] .
Given the number of people potentially eligible for treatment with the PCSK9 inhibitors will
number in the millions, the potential overall expenditures by payers are huge.
The controversy surrounding the introduction of Sovaldi is instructive in preparing for the PCSK9
inhibitors. While the outcry centered over the price of these treatments—approximately $1,000 a
pill—the real issue was what happens when you multiply that price by the size of the eligible
population, up to 3 million infected Hepatitis C patients in the U.S. The price tag of curing all of the
1.5 million people currently known to be infected with Hepatitis C in the United States could be as
high as $150 billion, likely spread out over more than ten years. Screening and treatment of those
not yet diagnosed could double that total.
Ongoing Maintenance Therapy
The PCSK9 inhibitors pose a similar, but in many ways more compelling and complex, set of
problems. Their target, hyperlipidemia, is one of the most prevalent conditions in the developed
world. And the PCSK9 inhibitors do not provide a cure; they will be prescribed for ongoing
maintenance therapy — decades for patients who survive that long. Moreover, they in some ways
represent a silver bullet — injected once a month with few side effects, and they reduce LDL
cholesterol dramatically.
Existing trial data evaluating the effects of PCSK9 inhibitors [2] on lowering LDL­C have been
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Health Affairs Blog » In The Debate About Cost And Efficacy, PCSK9 Inhibitors May Be The Biggest Challenge Yet » Print
striking. For example, Phase III data for Amgen’s evolocumab demonstrated LDL­C reductions of
46–64 percent from baseline at week 12 [3] in various patient populations with hyperlipidemia.
PCSK9’s have also been associated with positive effects on other components of the lipid profile,
both increasing high­density lipoprotein (HDL) and lowering triglycerides. In studies to date, the
medications have been well­tolerated. The main area of concern has to do with neuro­cognitive
side effects, but to date, there are not sufficient safety data to definitively understand this risk.
The major rub with the class though is that while there is evidence to show that this class reduces
intermediate outcomes (LDL), we have limited information to date about how this class of
medications will affect clinical outcomes (primarily cardiovascular events).
Outcomes studies for each drug candidate are in the field today, but may not be available until as
late as 2018. However, the recent successes in improving cardiovascular outcomes [4] using
ezetimibe (Zetia) plus a statin adds support to the proposition that the lower the LDL cholesterol,
the better the outcomes.
The Target Population
This controversy in cardiology is critically important for the eventual target population for the
PCSK9 inhibitors, and their long­terms costs to the health care system. The initial label may be
limited to familial hypercholesterolemia, but some might argue that all statin intolerant or
inadequately responsive hyperlipidemic patients should be treated. As well, off­label use of
medications is a fact of clinical life. At the outset, expert endocrinologists and cardiologists will do
most of the prescribing, but utilization will spread.
How much will it spread? The prevalence of familial hypercholesterolemia is 1 in 300 to 500, so
there are approximately 620,000 patients with this disorder currently living in the United States.
A related group will be those whose genetic status is unknown, but have LDL greater than 190,
and are unlikely to get to goal with a statin. The number of individuals in this category is
conservatively estimated at one million Americans.
Then there are those who are statin intolerant. It is estimated that approximately 5­15 percent of
patients with hypercholesterolemia experience side effects with statins [5] , representing one to
three million people in the U.S. Thus as many as 3.5 million Americans may qualify initially for
PCSK9 inhibitor therapy.
Pharmacy benefit managers will attempt to limit that number, based on clinical guidelines and
expert opinion. They will likely require laboratory tests to show evidence of muscle inflammation or
liver damage before allowing treatment for those with statin intolerance. Patients and their
doctors claiming subject symptoms of muscle ache or fatigue will have to re­challenge patients.
But it is unclear how much these medical management efforts will limit utilization.
And a much broader potential patient population awaits, as the recent set of debates around
cholesterol management guidelines indicates. The American Heart Association and American
College of Cardiology recently decided that management to a specific LDL cholesterol goal is not
appropriate. The new guidelines suggest that those patients who have had a previous cardiac
event should be treated initially with high dose statins to lower the cholesterol as much as
possible.
It is clear that PCSK9 inhibitors are as, or more, potent than statins. So the argument might even
be to treat everyone with a history of coronary artery disease (up to 15 million people) with PCSK9
inhibitors. As noted above, the ezetimibe trials support the proposition that lower LDL leads to
better outcomes.
Health Care Cost Implications
So, with this potential patient population, how much is the bill for the health care system? The
math is simple. If we assume costs of $10,000 per year, familial hypercholesterolemia and severe
hypercholesteremia alone would represent a $16 billion market, dwarfing initial Sovaldi costs.
Statin intolerant patients would add an additional $20 billion set of costs. And those with a history
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of coronary disease could add as much as $150 billion annually.
Even if we limit this latter group to those for whom statins are ineffective (patients who do not
reach LDL goals from previous guidelines) the price tag would be somewhere between $50 and
$100 billion. And this leaves aside what is likely the eventual target for the manufacturers,
primary prevention.
As this is chronic therapy, PCSK9 sales could be expected to persist and grow over time, and will
likely be the highest selling class of medications in history. Plus, as a biologic agent, there will not
be a simple pathway to cheaper generics in a 10­15 year timeframe. Even in a system that costs
$4 trillion per year, a single therapy adding $100­200 billion in costs annually is extraordinary.
Managed pharmacy care, indeed the health care system, has never seen a challenge like this to
our resilience in absorbing costs. Payors, the employers, and health insurers, will first be shocked,
then expect action. Action will take the form of compliance with clinical guidelines, and careful
managed care oversight.
But in addition, perhaps the costs of PCSK9 inhibitors will push us to develop some consensus
about the pricing of new specialty medications, as part of a more thoughtful discussion about the
use of scarce resources on behalf of patients.
Article printed from Health Affairs Blog: http://healthaffairs.org/blog
URL to article: http://healthaffairs.org/blog/2015/02/17/in­the­debate­about­cost­and­
efficacy­pcsk9­inhibitors­may­be­the­biggest­challenge­yet/
URLs in this post:
[1] $7,000 – $12,000: http://www.fiercepharmamarketing.com/story/payers­already­
fretting­about­next­pharm­apocalypse­pricey­pcsk9­cholestero/2014­05­07
[2] the effects of PCSK9 inhibitors: http://www.ncbi.nlm.nih.gov/pubmed/24691094
[3] baseline at week 12: http://www.ncbi.nlm.nih.gov/pubmed/24694531
[4] cardiovascular outcomes: http://finance.yahoo.com/news/vytorin­ezetimibe­
simvastatin­significantly­reduced­164500123.html
[5] side effects with statins: http://archinte.jamanetwork.com/article.aspx?
articleid=215232
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