With New Data, Amgen Promises Refund If Cholesterol Drug Doesn’t Work

Xconomy San Francisco — 

Stung by slow sales of its next-generation anti-cholesterol drug, Amgen hopes new clinical data, released this morning, will spur doctors to boost prescriptions and—perhaps more important—drive insurers to loosen their restrictions.

The data, from a massive study of more than 27,000 patients, come at a time when drug and healthcare prices are a top U.S. political issue, and pricey new cholesterol drugs have been a key battleground.

With the data, Amgen (NASDAQ: AMGN) is providing the first significant evidence that evolocumab (Repatha), part of a new wave of drugs called PCSK9 inhibitors, can reduce the rates of heart attacks and strokes. In 2015, the FDA approved evolocumab as well as a rival PCSK9 inhibitor based on evidence that they lowered cholesterol.

Sekar Kathiresan, director of preventative cardiology at Massachusetts General Hospital in Boston, called the results “practice-changing.” But he nonetheless added there “will still be a vigorous debate about cost-effectiveness.”

No one disputes that heart disease is a major medical problem. The current standard of care, a class of drugs called 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.

But how much society is willing to pay for better treatments has become a key national issue. The data from Amgen’s “Fourier” study are meant to prove to insurers and clinicians that evolocumab is worth its $14,000 per month list price, which was met with major resistance. Evolocumab generated $141 million in revenue in 2016, well short of initial expectations. The rival drug, alirocumab (Praluent), fared about as badly, with $116 million in 2016 sales.

(Alirocumab’s owners, Sanofi and Regeneron Pharmaceuticals, are supposed to present their own long-term data later this year.)

Amgen said today it would offer a refund to payers that “lower access barriers” if patients on their plans taking evolocumab suffer a heart attack or stroke. Specifically, for any patient who had a heart attack or stroke after taking evolocumab for at least six months, payers would get a refund in the form of an additional rebate, the details of which would be subject to negotiations with each payer.

The company hinted at price flexibility when evolocumab launched, and already uses payment schemes that link the drug’s net price to cholesterol reductions and “anticipated appropriate patient utilization.” But this is the first time the firm has linked refunds to health setbacks. Cardiologists are taking a wait and see approach for now.

“I’ve never really seen [alternative pricing models] pan out as a winner in the clinic,” said Eric Topol, a practicing cardiologist and the head of the Scripps Translational Science Institute. “I don’t hold a lot of hope.”

Amgen released the first and most important batch of Fourier data today at the American College of Cardiology’s annual meeting. The detailed results are being published simultaneously in the New England Journal of Medicine. Here are the headline numbers:

After a median of 2.2 years of treatment, 1,344 (or 9.8 percent) of the patients treated with a combination of statins and evolocumab suffered heart attacks, strokes, cardiovascular deaths, or were hospitalized for unstable angina or bypass surgery. By comparison, 1,563 patients (11.3 percent) of those on treatment with a statin alone suffered those events—a 15 percent difference in relative risk of such events between the two groups, and an absolute risk reduction of 1.5 percent for the combination treatment. Measuring the difference in all of these events was the study’s main goal.

A secondary measure only included patients who had suffered heart attacks, strokes, or cardiovascular deaths. By this measure, 816 (or 5.9 percent) of the patients treated with a combination of statins and evolocumab suffered heart attacks, strokes, or cardiovascular deaths, compared to 1,013 (7.4 percent) for those on treatment with a statin alone—a 20 percent difference in relative risk of such events between the two groups, and an absolute risk reduction of 1.5 percent, again, for the combination.

More data on safety and the restricted access to the drug are coming later this weekend, but Amgen reported, top-line, that no new safety problems cropped up during the trial. Cardiologists not associated with Amgen had flagged two key indicators to watch: rates of neurological side events (1.6 percent for evolocumab patients, 1.5 percent for statin-only), and the onset of diabetes (8.1 percent for evolocumab, 7.7 percent for statin-only).

While Amgen said in a statement that those differences weren’t notable, Topol disagreed, and said that the increase in instances of diabetes partially offsets evolocumab’s reduction in heart attacks. “The [diabetes] signal is there,” he said. “The study just isn’t powered enough to show that it’s statistically significant.”

Still, Elliott Levy, Amgen’s senior vice president of global development, said the study results were “about as good a result as you can get.”

“I can’t think of any intervention in cardiovascular medicine that had a treatment effect of 20 percent or more on major cardiovascular events with this kind of safety profile that has not been incorporated into guidelines or changed practice,” he said.

Levy noted that the treatment effect got better with time—a 16 percent reduction in heart attacks, strokes, and deaths climbed to 25 percent after one year. The implication, he said, is that larger benefit is “probably a true reflection of what patients will experience if they take the drug over time.”

“So we expect that this drug also will be embraced by the medical community” and incorporated into clinical guidelines, Levy said. “Then it will be up to the payers to accommodate the drug.”

At first blush, however, cardiologists were lukewarm on whether the new data would prompt more prescriptions or reimbursement. While the study was a success, “it’s not as striking as I would have hoped,” Topol said. “It falls short of the expectations for such an expensive injectable drug.” Topol added, for instance, that while evolocumab led to fewer heart attacks and strokes, it didn’t reduce the total number of deaths when compared to statin-only patients—444 patients (3.2 percent) on evolocumab died, compared to 426 (3.1 percent) of the statin-only patients.

Cardiologist Ethan Weiss at the University of California, San Francisco, was more blunt: “Overall I think this is pretty disappointing,” he said. “It is going to be hard to justify the cost of these medicines for the magnitude of risk reduction in all-comers.”

Amgen’s shares fell more than 6 percent Friday morning.

Close to 40 million Americans take statins, but they don’t work for everyone. There are roughly 9 million Americans who can’t reduce their dangerous cholesterol levels with statins, or who can’t tolerate statins because of side effects that range from muscle pain and damage to liver problems. Amgen would love to open up the market to more and more of these people, as would rival PCSK9 developers Sanofi (NYSE: SNY) and Regeneron Pharmaceuticals (NASDAQ: REGN), but that will take time, more testing, and more evidence of their benefit.

As Robin Dullaart, an endocrinologist at the University of Groningen wrote in an editorial to be published in the NEJM this morning, there were limitations to the Fourier findings. The duration of evolocumab treatment was “rather short.” More testing is needed to determine how effective PCSK9 blockers are in various categories of high risk patients, as well as those who start treatment just after a heart attack or stroke, Dullaart wrote.

For now, Topol said, patients typically have to have gotten bypass surgery or had a heart attack to have no issues getting a PCSK9 blocker covered by insurance. It’s much harder for others.

PCSK9 inhibitors are injectable antibodies administered once or twice a month. They block a protein, called proprotein convertase subtilisin/kexin type 9, which interferes with the body’s clearance of so-called bad cholesterol from the bloodstream. The drugs showed a striking ability to lower cholesterol levels in clinical studies and were hailed as a big medical advance.

The FDA approved both alirocumab and evolocumab for familial hypercholesterolemia (FH), a rare, inherited version of extremely high cholesterol that statins don’t alleviate, as well as for patients with a history of heart disease who aren’t being helped enough by statins.

Heading toward the launch of both drugs, Wall Street analysts revved up huge sales projections. Leerink Partners said in late 2014 that the market for PCSK9 inhibitors could reach nearly $11 billion at its peak, with alirocumab and evolocumab each nabbing 40 percent.

But insurers and their purchasing agents, called pharmacy benefit managers, began sounding alarms well before the approvals about the potential impact of PCSK9 costs on the U.S. healthcare system.

Those alarms, and doctors’ reticence, have effectively turned the launch of the two drugs into a disaster. Pfizer (NYSE: PFE) was developing a PCSK9 inhibitor as well but pulled the plug in late 2016.

Meanwhile, people who are approved for the drugs aren’t necessarily getting them, either.

Katherine Wilemon, president and CEO of the nonprofit FH Foundation, said just 4.6 percent of the 4,000 patients in the foundation’s registry are taking PCSK9 blockers. Access is “historically low,” she said, citing “restrictive prior authorization criteria” from payers. This is despite the fact that many patients and leaders in the FH field believe PCSK9 blockers are a “turning point for the management of the disease.”

Wilemon said patients and physicians have to prove what type of statin regimen is “max tolerated” first, a potentially laborious process, and even then, many payers require FH patients to first try and fail Merck’s ezetimibe (Zetia), as well, before getting a PCSK9 blocker. Beyond the FH population, several insurers have demanded proof that patients seeking anti-PCSK9 medication in fact have bad reactions, such as muscle pain, to statins.

Studies like an August article in the Journal of the American Medical Association called on Amgen and Regeneron to slash their prices to be worth the headaches of prescribing them, fanning the flames.

UCSF cardiologist Weiss, for instance, who hasn’t written a single prescription for a PCSK9 blocker, said: “I’ve had a couple of patients in whom we’ve had casual conversations about it, particularly people with statin intolerance, and we’ve mutually decided we’d wait to see what the effect is on outcomes before I used them.”

That’s what made Amgen’s Fourier trial, and Regeneron’s like-sized Odyssey Outcomes study (expected to produce data later this year), so important. Amgen in March said that the study had hit its main and secondary goals, but didn’t divulge the details, instead waiting for the ACC meeting. In the meantime, analysts guessed as to how big of a victory the study really was for Amgen. In a research note, Leerink analyst Geoffrey Porges expected a roughly 20 percent relative risk reduction in cardiovascular events, but noted that payers “may need to see 25 percent or more to start getting constructive and loosening PCSK9 access restrictions.” RBC Capital Markets’ Michael Yee was more optimistic. In a note earlier this week, He expected a 20 to 25 percent relative risk reduction, and maintained the PCSK9 drugs still have potential $5 billion to $7 billion worldwide revenue with positive outcomes studies.

That seems unlikely at this point, but Amgen will spend the ACC meeting using the Fourier data to make its case to doctors and payers for broader adoption. In the meantime, MGH’s Kathiresan said he’ll probably prescribe statins first for patients trying to get their LDL levels down to healthy levels following a heart attack or bypass surgery, then Merck’s ezetimibe (Zetia), and then PCSK9 blockers.

Weiss, meanwhile, called ezetimibe “the real winner” here because of its low cost, comparatively—the drug went generic last year and was shown, in 2014, to modestly reduce the risk of heart attacks and strokes when combined with a statin. How payers approach mandating the progression of one drug to the other “will be fascinating to watch,” he said.