Opposite Day: Drug May Save Lives, So Drugmakers Offer To Cut Price
Praluent, a would-be breakthrough that targeted a heart attack gene, seemed doomed to go down in history as a pharmaceutical flop. But a new study — and an offer of discounts by its makers — may give it a second chance.
In a study being presented at the annual meeting of the American College of Cardiology in Orlando today, Praluent not only reduced the risk of heart attacks, strokes or chest pain by 15%, but also, more dramatically, appeared to reduce patients’ risk of dying. Seeing an opportunity, the drug’s makers — Regeneron, based in Tarrytown, NY., and the French drug giant Sanofi — are offering insurers a deal. For the highest-risk patients in the study, who had the highest cholesterol, they will cut the price from $14,000 to something in the range deemed cost-effective by the Institute for Clinical and Economic Review, or ICER, a group critical of high drug prices. ICER’s estimate, made possible by a rapid review of the new data? Between $4,500 and $8,000 a year, about a 50% discount to the list price.
“We’re hoping to break the gridlock,” says George Yancopoulos, the head of R&D at Regeneron and one of Praluent’s inventors. (He also takes the drug, paying out-of-pocket.) “Really, it’s not just a shame, it’s almost a crime to deny this drug to these patients who are at such high risk and will derive such a big benefit.”
Praluent and a rival drug, Amgen’s Repatha, were initially seen as a leap forward when they were approved in 2015. They target a protein called Proprotein convertase subtilisin/kexin type 9 (PCSK9). People who lack PCSK9 genes have super-low cholesterol and few heart attacks. The drugs, the logic went, should prevent heart attacks too (we now know they do). Insurers braced for an onslaught. CVS Health, the pharmacy benefit manager, estimated that the two medicines could have an annual cost of $150 billion.
Instead, the PCSK9 inhibitors drowned in paperwork. Less than half the patients prescribed the drug received insurance approval. Last year, the two medicines had combined sales of just $420 million, making them niche products from the perspective of the pharmaceutical business.
What went wrong? Everything. Everyone involved in the system seemed complicit in making the drugs unavailable to even the patients who needed them most. The $14,000 price pharmaceutical companies chose was quadruple what any previous cholesterol drug had cost. The Food and Drug Administration was skeptical of any claims that patients wouldn’t take the existing statin drugs – now cheap generics – because of side effects, closing off a lucrative market. And the first drug company trial to try and prove a benefit for the new cholesterol medicine, released by researchers working with Amgen last year, targeted patients at relatively low risk for heart attack and stroke, meaning, among other things, there was no benefit in preventing deaths.
Amgen’s study design had seemed to assume that insurers would, of course, give these drugs to the neediest patients. The study was aimed at quickly extending proof of benefit to healthier patients, and expanding the market. But the PCSK9 inhibitors were approved just after health insurers and pharmacy benefit managers were caught flat-footed by the soaring sales (and costs) of new hepatitis C drugs. “It was the first big ticket item that came out after the hepatitis C wave, so the payors were completely revved up,” says Steven Pearson, the founder and president of ICER, the cost-effectiveness group.
Instead, even patients who clearly needed the drugs had trouble getting them. Take those with familial hypercholesterolemia, FH, a rare genetic disease that causes very high cholesterol levels. Patients with the most serious form can have heart attacks in their twenties. Last year, I spoke to one patient whose insurer initially refused to move him from a $300,000 drug to a $14,000 PCSK9 inhibitor. Katherine Wilemon, an FH patient who runs the FH Foundation, was thrilled last year when the pharmacy benefit manager Express Scripts worked with her on removing barriers to the drugs after Amgen presented its data. (She gets her PCSK9 inhibitor as part of a clinical trial.)
She’s still grateful, but overall, she says patients who need the drugs are still not getting them. A recent case: a 36-year-old whose cholesterol levels are more than double healthy levels despite statin drugs. “We are getting more and more calls and hearing more and more from patients on Facebook, etcetera, that they are having difficulty getting their PCSK9 inhibitor prescriptions filled,” says Katherine Wilemon, the chief executive of the FH Foundation. “I think it’s about the same if not worse. And only 1% of the diagnosed FH patients are being prescribed PCSK9 inhibitors.”
Express Scripts and CVS were unable to comment in time for this story. But it seems that just as the U.S. healthcare system is unable to prevent cancer patients from getting expensive drugs with marginal benefits, it also fails to distinguish between patients who really need a drug and those who don’t. The question now is whether the new data from Regeneron and Sanofi is enough to move the needle.
The new study randomly assigned 18,000 patients who had either suffered a heart attack or had severe, sudden chest pain from heart blockages to receive either Praluent or placebo. On the surface, the results look similar to Amgen’s results with Repatha. There was a 15% reduction in the combination of deaths from heart disease, heart attacks, strokes caused by blood clots, and chest pain. Eleven point one percent of the patients in the placebo group had one of these problems, compared to 9.5% of those who received Repatha. Side effects were similar, with no signs of worries like problems thinking that were raised early on as a potential concern with these drugs.
“It certainly makes me consider it more than I do now, which is pretty much zero,” says Rita Redberg, a cardiologist at the University of California, San Francisco. “I’d like to see more data, but this certainly suggests a benefit for these patients.”
There were fewer deaths from heart disease, but this result was not statistically significant. But when all deaths were looked at, there was a 15% reduction, with a death rate of 4.1% in the placebo group and 3.5% in the Praluent group. Researchers think they may have simply misclassified some deaths that were caused by heart disease as having unknown cause.
The difference is striking (Initial response from Ethan Weiss, a cardiologist at UC San Francisco: “All cause mortality!!!!”). It isn’t statistically valid and “can’t be supported,” counters Sanjay Kaul of Cedars-Sinai Medical Center, because the researchers said they would test mortality from heart problems first. (This prevents chance findings from being accepted as true.) “It’s not going to be a formal claim with regulators, but I still think it’s a very important observation that will change people’s view of this treatment,” says Gabriel Steg, a professor of cardiology at Université Paris-Diderot who led the study for Sanofi-Regeneron.
Other problems with the study: patients were told to stop taking the drug if their cholesterol dropped too low and most patients got a low dose of Praluent, reducing its efficacy. (“You talk about shooting yourself in the foot,” says Yancopoulos.) But most of these would have made the drug look worse, and the study still succeeded.
The really interesting data may be in the patients whose blood levels of low-density lipoprotein (LDL, the “bad cholesterol”) were over 100 milligrams per deciliter at the start of the study. There were 5,629 of these patients, and they appeared to have a bigger benefit. Their risk of heart problems was reduced 24% –from 14.1% in the placebo group to 11.5% in those who got Praluent. The death rate in this group was cut from 5.7% to 4.1%, a 29% reduction in a patient’s risk of death.
“That’s who I treat with these drugs!” says Steven Nissen, the chairman of cardiology at the Cleveland Clinic and an investigator on Amgen’s studies. “I use them to get from 110 to something much lower.”
ICER says that for the general group tested in the study, Praluent wouldn’t be cost-effective unless the price were dropped to at most $3,400, about what statin drugs used to cost. But for the LDL above 100 group, the $4,500 to $8,000 range delivers a good cost-benefit. The reasons for that big spread? In part, ICER says, the uncertainty around the mortality benefit. If insurance companies and pharmacy benefit managers choose to believe it, the $8,000 number should work.
Regeneron and Sanofi say they will start negotiating with insurers and PBMs immediately. “This is the right thing to do for patients,” said Olivier Brandicourt, Sanofi’s chief executive, in an email. The companies will offer the new deal to insurers if they remove the barriers in place for patients getting the drugs. Ideally, the insurer would allow the physicians word that the patient met the criteria to be enough to prove a patient is high-risk. But they might consider reduction in paperwork, eliminating the need to submit detailed records of previous medication use, or show that patients are approved quickly and on their first request. Doctors told of the plan are hopeful.
“This is a powerful new option for LDL-lowering,” says Sekar Kethiresan, a cardiologist at Massachusetts General Hospital and one of the world’s top experts in the genetics of heart disease, about the new data. “Great science. Really consistent with all the human biology. And no side effects. None.
“I think the main issue is just the cost,” Kathiresan says. “And I hope, between the insurers and the companies, they’re able to get off this Mexican standoff and allow some kind of compromise that will allow greater access.”
Originally posted on forbes.com