70% Repatha Cut? Amgen Counters With Own Study To Justify Price

Xconomy National — 

Writing in the Journal of the American Medical Association, researchers at the University of California, San Francisco argued this week that the price of the cholesterol-fighting drug evolocumab (Repatha) should come down 70 percent, to $4,215 a year, to be cost-effective.

But a separate study, published today in JAMA Cardiology and funded by the drug’s owner, Amgen (NASDAQ: AMGN), says that evolocumab is worth its current costs, or slightly less, in patients with sky-high cholesterol levels. As those levels drop, the cost-effectiveness of prescribing evolocumab drops, too—but not nearly as low as the independent assessment recommends.

Not surprisingly, each side takes issue with the other’s study design and data. They question each other’s assumptions about the risk of heart attacks, strokes, and other cardiac events—a key figure that gets plugged into their computer simulations—and they use different thresholds for the proper value of a year’s worth of “quality of life.”

Dhruv Kazi, a cardiologist and statistician who led the UCSF study, says his group’s “event rate”—assuming roughly 3 percent of the nearly 10 million people in its simulation would have a cardiac emergency every year—is not just sound, but lines up with the actual rate found in Amgen’s massive, 27,000-patient study of evolocumab use, called FOURIER.

The new Amgen-funded value study, which is separate from FOURIER, was led by cardiologist Gregg Fonarow at the University of California, Los Angeles Medical Center. Amgen contributed data and was the sole funder, but company officials say they had no say over the final analysis. It pegs the event rate two to three times higher, reflecting the fact that the researchers combined FOURIER data with data from higher-risk patients who have been prescribed evolocumab in the “real world”—that is, outside of controlled clinical trials. They found the data in commercial and public health databases. Kazi says their rate is not realistic; Joshua Ofman, Amgen’s senior vice president, Global Value, Access and Policy, says the UCSF approach is “terribly flawed.”

Out of the statistical tangle comes a clear message, however. The higher a patient’s potential risk of a cardiac event, with all the associated follow-on medical costs, the higher Amgen can justify its asking price for preventing those events with its drug. “We’re confident that at its prices today Repatha is cost effective,” says Ofman.

Evolocumab is a next-generation cholesterol-lowering drug that was approved by the FDA in 2015, as was rival drug alirocumab (Praluent), from Regeneron Pharmaceuticals (NASDAQ: REGN) and partner Sanofi. They are called PCSK9 inhibitors because they block an enzyme (proprotein convertase subtilisin/kexin type 9) that hinders the body’s ability to clear LDL-C, or “bad” cholesterol, from the blood stream.

Despite clear evidence that they lower dangerous cholesterol levels more effectively than the current standard of care, called statins, the two PCSK9 inhibitors have become a running point of contention in the national debate over drug prices. Both drugs have generated paltry sales: $141 million in 2016 for evolocumab, $116 million for alirocumab. They are meant to be taken once or twice a month via self-injection for a lifetime. (There is not yet a long-term analysis for alirocumab. Sanofi and Regeneron plan to release theirs near the end of this year.)

The FDA approved the two drugs for certain patients who aren’t helped by statins, such as people who have a genetic predisposition to high cholesterol or who have bad reactions to statins. There could be as many as 9 or 10 million Americans who fit that profile. But very few of them have received a PCSK9 inhibitor. In the face of the two drugs’ roughly $14,000 list price—“the most expensive preventive therapies by far in the history of cardiovascular medicine,” according to a JAMA Cardiology editorial accompanying the Amgen-funded study—insurers have refused to cover most prescriptions at first blush, demanding proof a patient truly needs the next-generation drugs instead of a low-cost generic statin.

Amgen published FOURIER data in March that showed a reduction in cardiac events over two years. But the study didn’t last long enough to show that people taking evolocumab were living longer—a so-called survival benefit. As Xconomy reported at the time, cardiologists reviewing FOURIER data acknowledged evolocumab’s benefit reducing cardiac events but were skeptical that the data could nudge payers to widen their coverage.

In the JAMA Cardiology editorial, however, the authors say that lack of a survival benefit in FOURIER casts a shadow on the new study’s assumptions. The model assumes a long-term survival benefit because of evolocumab’s record of lowering cholesterol and reducing cardiac events. Not so fast, say the researchers: “Late emergence of survival benefit has been observed in a number of large statin trials. It is also possible that, unlike statins, PCSK9i therapy does not improve survival despite lowering LDL cholesterol levels.” A disconnect between lower cholesterol and improved survival has emerged in other cardiac drug studies, they write. “If long term benefits have in fact been overestimated in the current model (as they clearly were in an earlier version of this model), huge price reductions would be necessary for PCSK9i therapy to provide acceptable value by conventional benchmarks of cost-effectiveness.”

The authors of the editorial are Daniel Mark of Duke University Clinical Research Institute, Ilana Richman of the Yale University School of Medicine, and Mark Hlatky of Stanford University School of Medicine.

Amgen’s Ofman defended the assumption that preventing cardiac events, as recorded in FOURIER, should translate into survival, saying that the Fonarow study made “conservative assumptions.”

There is another point of divergence in the Fonarow and Kazi studies. When they modeled cost savings from evolocumab, the former factored in productivity—the economic cost of a heart attack victim not going to work, for example. Kazi says his group’s study sticks to just the medical costs saved—the hospital stay, the follow-on procedures—by avoiding a cardiac event.

The Fonarow study acknowledges that the current annual list price ($14,523) is not cost-effective for people with less elevated cholesterol levels. FOURIER, for example, accepted people with cholesterol levels all the way down to 70 mg/dl. For them, evolocumab should come in at just under $10,000 a year to be worth prescribing, the study says.

It might already do that. The problem is, no one beyond Amgen and the companies paying for the drug actually know. Amgen has said, as drug companies often do, that the list price is not a real-world price because of rebates and discounts negotiated in secret with insurance companies and their agents. The evolocumab discounts that Amgen has negotiated are undisclosed; the Fonarow study, to which Amgen contributed industry data, tabbed the average industry rebate at 29 percent.

Amgen has also said it would refund costs if a patient suffers a heart attack or stroke while on evolocumab. Ofman said “several” of its more than 20 contracts with insurers have refunds built in. He said that all patients under those contracts, regardless of individual cholesterol level or risk, would qualify for refunds.

Correction: A previous version of this article misidentified a scientific journal.