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In Cholesterol Drug Price Fight, Real Message Is “Wait Til Next Year”

Xconomy National — 

The authors of a study published Tuesday in the Journal of the American Medical Association argue that the new wave of cholesterol-fighting drugs, hailed as a big medical step forward when they launched last year, should cost 70 percent less than their current list price to be worth the trouble prescribing them.

The drugs’ owners, Amgen (NASDAQ: AMGN) and Regeneron Pharmaceuticals (NASDAQ: REGN), immediately contested the findings, noting, for example, that the list price—over $14,000 per year for each —isn’t actually what anyone pays for the drugs. Regeneron blamed the study and others like it for dampening demand for the drugs. They were approved in the summer of 2015 for high risk patients who can’t lower their dangerous cholesterol levels with the standard of care, drugs called statins, and by other means.

Drug pricing should be top of mind for many Americans in the fall. The issue has come up time and again in the presidential campaign, and California voters will consider a state initiative to control prices. A similar measure in Ohio just suffered a setback at the hands of the state’s Supreme Court.

Statins are seemingly everywhere, but heart disease remains the leading cause of death in the U.S., according to the Centers for Disease Control and Prevention.

Still, early demand for the new drugs, known as PCSK9 inhibitors, is dismal. In the first six months of 2016, evolocumab (Repatha), from Amgen, and alirocumab (Praluent), from Regeneron and its partner Sanofi, have combined for less than $100 million in revenues, a far cry from the blockbuster sales that many analysts predicted the drugs would ring up. (They are called PCSK9 inhibitors because they block a protein, proprotein convertase subtilisin/kexin type 9, which interferes with the body’s ability to clear so-called bad cholesterol from the bloodstream.)

PCSK9 blockers could still prove popular and necessary, but doctors, insurance companies, and their agents will need convincing through long-term studies that show the drugs reduce heart attacks and strokes. Data from those studies, with more than 50,000 patients involved, are expected next year from Amgen, Regeneron-Sanofi, and Pfizer (NYSE: PFE), whose anti-PCSK9 drug bococizumab is still experimental.

In clinical trials, the drugs led to dramatic reductions of so-called bad cholesterol, LDL-c, which was good enough for U.S. and European approval last year, with limitations, because of decades of evidence linking cholesterol levels to heart disease. But there is no direct connection yet between the new drugs and better health.

Even if the upcoming studies make that connection, the JAMA study’s lead author says his study’s message is unlikely to change. “We don’t expect these drugs to magically become cost-effective based on new data,” says Dhruv Kazi, a cardiologist and biostatistician at the University of California, San Francisco. “This conversation is happening because we think these drugs work and are safe. The challenge is not the effectiveness. It’s the cost.”

“Our existing prevention therapies for cardiovascular disease are fairly effective, so it’s unlikely the findings from these studies will change health outcomes so dramatically that these drugs become cost-effective at these price tags,” Kazi says.

The study says the price needs to come down to $4,536 a year to be worth prescribing, based on a complicated formula that measures quality of life, known in shorthand as QALY. (For those who need additional help beyond statins, the drug ezetimibe (Zetia) was more cost effective, according to the study.)

Both drugs must be taken in perpetuity, making their price tags particularly prohibitive. But measuring their cost-effectiveness at those prices and at this time is wrong-headed, say Amgen and Regeneron spokespeople. The list price isn’t the actual price, because of secret discounts and rebates the drug makers negotiate with insurers and their agents, like Express Scripts (NYSE: ESRX).

The spokespeople also criticize the study’s QALY definition, but they also refuse to divulge the real-world price of the drugs that the authors should instead have used in their calculations. (It’s unlikely that the real-world prices are anywhere close to the 70 percent reduction recommended in the study.)

Another point of contention: it’s premature to calculate the drugs’ value before data arrive from the massive outcome studies. It’s because of “misleading analyses” like Kazi’s that payers have put “unprecedented restrictions” on the PCSK9 drugs, says Regeneron spokeswoman Hala Mirza. Three quarters of patients who have been prescribed alirocumab have been denied coverage, she says.
Amgen spokeswoman Kristen Davis sent a statement to Xconomy that read, in part, “We remain concerned that these types of assessments are focused on ringing alarm bells from a payer perspective, rather than focusing on a rigorous analysis that fully reflects the patient perspective of value.” (Davis offered an alternative: a study funded and conducted by Amgen that concluded evolocumab “may be” cost effective.)

Alirocumab and evolocumab are approved for people at high risk of heart attack or stroke who can’t reduce their dangerous cholesterol levels with statins, or who can’t tolerate statins. There are roughly 9 million Americans who fit those criteria.

One restriction: Insurers are demanding proof that patients seeking anti-PCSK9 medication in fact have bad reactions, such as muscle pain, to statins. “When our clients have denied coverage, it is most frequently due to a lack of documentation and lab results from a physician demonstrating that the patient does in fact meet the clinical criteria for this drug,” says Express Scripts spokesman David Whitrap. His company’s insurance-industry clients cover 25 million Americans.

Whitrap declined to say how many people have been denied coverage for a PCSK9-blocking drug. He did not comment on Regeneron’s claim that 75 percent of alirocumab prescriptions are denied coverage.

The drug companies can’t complain about all the restrictions. In fact, since it launched alirocumab Regeneron has advocated patients on statins should first explore higher doses before turning to a prescription of the new drugs. “We definitely believe that patients should be evaluated” for a maximum statin dose, says Mirza.

The new JAMA study also estimated that the drugs at current list prices, if prescribed to everyone eligible, would run up health care costs of more than half a trillion dollars the next five years. (Total U.S. retail prescription sales were $287 billion in 2015.)

Given that roughly half of all people eligible for statins—which have gone generic, are easy-to-take pills rather than injectable antibody drugs, and are widely available—are not on statins, it’s hard to imagine everyone eligible for PCSK9 inhibitors taking PCSK9 inhibitors. Kazi acknowledges that real-world costs will be lower, but he argues that even with fewer people taking the drugs, the cost effectiveness, at current prices, would remain unacceptable.

One twist that bears watching as part of the larger drug-price debate: Some insurers, such as Cigna and Harvard Pilgrim, have agreed to pay on a sliding scale for the drugs’ performance. If they don’t lower cholesterol as much as they did in clinical trials—a fairly high bar—the price goes down. (Express Scripts has not negotiated pay-for-performance, says Witrap, “because there is very little question that these drugs effectively lower LDL.”)

The formulas for performance pricing are as secret as the list-price discounts. So it’s unclear if these pay-for-performance arrangements are significant or just window dressing. Either way, UCSF’s Kazi dismisses them as a “bad idea.” “It has to be linked to real performance, that is, fewer heart attacks and strokes,” he says.

It’s another reason why three of the biggest buzzwords in the medical world next year will be FOURIER, SPIRE-2, and ODYSSEY OUTCOMES—the names of the massive studies soon to wrap up.

Heart images courtesy of the National Library of Medicine.