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No, The New Cholesterol Drugs From Sanofi And Amgen Aren't Going To Cost $150 Billion A Year

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In an article on the Health Affairs blog 4 CVS executives speculate that the new cholesterol lowering PCSK9 inhibitors from Amgen and Sanofi might achieve yearly sales of $150 billion or even higher. I think these numbers are a bit silly. But first let's take a look at their extremely bullish case:

Simple Math...

The CVS authors calculate that 3.5 million people in the US may qualify for PCSK9 inhibitors when they are first approved. This includes about 620,000 people in the US who have familial hypercholesterolemia, a group that will likely be the first to receive the drug. Then there are probably another million people "whose genetic status is unknown, but have LDL greater than 190, and are unlikely to get to goal with a statin." Finally there are somewhere between 1 to 3 million people who are "statin intolerant." Further down the road, if large outcomes studies now underway provide compelling evidence, the indication for the drugs could conceivably expand into the entire population of people with coronary artery disease and even into the high risk primary prevention population.

"The math" they write, "is simple. If we assume costs of $10,000 per year, familial hypercholesterolemia and severe hypercholesteremia alone would represent a $16 billion market... Statin intolerant patients would add an additional $20 billion set of costs. And those with a history of coronary disease could add as much as $150 billion annually."

...Complicated World

The math may indeed be simple but the real world is far more complicated. So let's tale a closer look at some of the obstacles to these sky-high numbers. The authors themselves point out that pharmacy benefit managers will attempt to limit usage by demanding laboratory tests and other measures before authorizing reimbursement. This strikes me as at least one key point of resistance that the authors don't fully explore.

But I think we can expect significant resistance from other quarters as well.

So far nearly the entire discussion about PCSK9 inhibitors has stemmed from the companies developing the drugs and the researchers and KOLs (key opinion leaders, in pharmaspeak) who have much to gain, financially and otherwise, from the success of the PCSK9 inhibitors. Already the market preparation CME programs funded by the companies have become a virtual full employment act for many lipid experts. (It might be easier and simpler if Sanofi and Amgen just established a college scholarship program for the children of these experts.)

But remember: in many cases these are the same experts and KOLs who a decade ago were arguing passionately in favor of nearly universal use of statins not only for secondary prevention but for primary prevention. They were only partly joking when they proposed putting statins in the water supply. They brushed aside questions of statin side effects and statin intolerance. Now, with the incentives on the other side, they have suddenly discovered that millions of people can't take statins and that millions of people who are taking statins aren't getting enough benefit from them.

Outside of the small KOL circle there may well surface a whole  lot more resistance than than we have seen so far. The "statin wars" and the nearly unending string of pharma scandals have had a significant impact on physicians and patients alike. They will raise questions and objections. An expensive monoclonal antibody delivered through an injection and with no outcomes evidence will be a ripe target for this skepticism.

The patient population for PCSK9 inhibitors is quite different from the populations that have made the new and ultra-expensive hepatitis C and cancer drugs successful. Many of these patients don't feel sick or think of themselves as being ill, and the prospect of a lifetime of treatment will meet resistance. There is growing recognition (see these discussions by Darrel Francis and Lisa Rosenbaum) that many people don't want to take pills even if there is strong evidence that they can prolong life. The level of resistance for an injected medication will undoubtedly be even higher.

In addition to the benefit managers I suspect that the FDA will play an important restraining role. At least at first, until the outcomes trials are completed, I think the label for the PCSK9 inhibitors will be quite strict. The indications will be quite limited and the FDA may well establish a severe Risk Evaluation and Mitigation Strategy-(REMS) that will throttle down the so far unencumbered marketing efforts of Sanofi and Amgen.

One other caveat: even if everything goes right for the PCSK9 inhibitors their ultimate success might be limited by competition. It's still way too early to predict but one contender, Esperion's ETC-1002, an entirely novel oral drug, has attracted a lot of interest. Because it is an oral drug that may have similar LDL-lowering efficacy plus other potentially beneficial metabolic effects, it could conceivably put a halt to the PCSK9 inhibitor parade. The drug is scheduled to enter phase III trials later this year.

I don't make financial projections. My guess is that these drugs will only be moderately successful, at least at first, until the results of the outcomes studies become known, perhaps in 2018. A big win in these trials could indeed mean a huge market for these drugs. $150 billion still sounds crazy to me, but if things go well it is reasonable to speculate that they might become some of the the best selling drugs of all time. Again, however, caution is necessary. A big outcomes win needs to be carefully defined. A statistically significant reduction in the relative risk reduction of a composite endpoint won't be enough. For these drugs to reach the stratosphere would require large absolute reductions in mortality with big reductions in absolute risk as well as relative risk. Both the NNT (number needed to treat) and the cost effectiveness calculations would need to be quite impressive.

One other very important point: so far the PCSK9s appear to be safe. But the prospect of millions of users spending billions of dollars will invite extremely close scrutiny. And when you go looking for trouble you never know what you're going to find.

I suspect that the CVS authors themselves are aware that their projections are rather far fetched. Perhaps, in the interest of their employer and other payers, they are hoping to get people to ask tough questions about these drugs.