Evolocumab Not Cost-Effective at Current List Price

Once again, two new analyses are calling into question the cost-effectiveness of adding the PCSK9 inhibitor evolocumab to statin therapy in patients with atherosclerotic cardiovascular disease, at least at its current price.

At $14,500 per year, treatment with evolocumab (Repatha, Amgen) results in an incremental cost-effectiveness ratio (ICER) of $268,637 per quality-adjusted life-year (QALY) gained, a number that far exceeds generally accepted thresholds. In order to achieve an ICER of $150,000, which is the upper limit of what is considered cost-effective therapy, the price of evolocumab would have to be reduced by approximately one-third.

“At the current list price, we find the drug exceeds current cost-effectiveness thresholds,” lead investigator of one of the studies, Gregg Fonarow, MD (Ronald Reagan University of California, Los Angeles), told TCTMD. “However, with what we feel is a fair reflection of the current discounted price, it gets closer. At a net price at or below $9,669 per year, that would result in the drug meeting the cost-effectiveness threshold and offer reasonable value and all of the clinical benefits.”

Fonarow et al’s study was published today in JAMA Cardiology.

In an accompanying editorial, Daniel Mark, MD (Duke Clinical Research Institute, Durham, NC), Ilana Richman, MD (Yale University School of Medicine, New Haven, CT), and Mark Hlatky, MD (Stanford University School of Medicine, CA), note that the LDL-lowering PCSK9 inhibitors “have achieved the dubious distinction of being the most expensive preventive therapies by far in the history of cardiovascular medicine.”

For the editorialists, given that routine use is not affordable for healthcare systems or insurance companies, the solution is to either drastically lower the price or radically restrict the therapy to patients at a significantly increased risk of cardiovascular disease.

“We must also not lose sight of the fact that money spent on PCSK9 inhibitor therapy could be invested by health systems to make better use of the affordable drugs we already have (eg, improving adherence to statins and prescribing the most effective doses of statins),” write Mark, Richman, and Hlatky.

Cost-Effectiveness Analysis: Some Assumptions

In March, as reported by TCTMD, the FOURIER trial was published and showed for the first time that treatment with a PCSK9 inhibitor reduced the risk of major cardiovascular events. Although there was no effect on all-cause or cardiovascular mortality, MI and stroke were reduced 27% and 21%, respectively, when evolocumab was added to maximally tolerated statin therapy.

The price of evolocumab, as well alirocumab (Praluent, Sanofi/Regeneron), remains the “elephant in the room,” as the editorialists point out, and several previous analyses have suggested the drugs are not cost-effective. In one analysis, researchers argued the drugs would only be worth the cost if the price was reduced to no more than $4,500 per year. The nonprofit Institute for Clinical Economic Review recommends an annual price of approximately $2,500 in the secondary-prevention setting.

“Certainly, clinical outcomes, as well as safety, matters to clinicians, patients, and their families,” said Fonarow. “That said, cost is a major issue from all perspectives.”

The World Health Organization has suggested that the upper threshold of an acceptable level of cost-effectiveness is roughly three times the GDP per capita, which in the US translates to an ICER of approximately $150,000 per QALY. The American College of Cardiology and American Heart Association use a similar threshold for determining value, defining a low-value therapy as one with an ICER ≥ $150,000 per QALY gained. A high-value treatment is defined as one costing less than $50,000 per QALY gained.  

Fonorow et al’s evolocumab cost-effectiveness study, which includes several Amgen employees as co-authors, adopts a “societal perspective,” which incorporates all the indirect costs of cardiovascular events borne by patients, their family members, and society over a lifetime horizon. Patients were selected from the National Health and Nutrition Examination Survey (NHANES) and included individuals 18 years and older (mean age 66 years) with atherosclerotic cardiovascular disease and LDL cholesterol 70 mg/dL or greater (mean 104 mg/dL) treated with statin therapy.

The treatment effects of evolocumab were based on individual endpoints in FOURIER and researchers assumed no reduction in cardiovascular mortality for the first 5 years of treatment. After 5 years, they modelled the reduction in cardiovascular mortality to match the reduction observed in the Cholesterol Treatment Trialists’ Collaboration meta-analysis of more versus less intensive statin therapy (risk reduction of 9.5% per 38.67 mg/dL reduction in LDL cholesterol).

In their analysis, the researchers included several different scenarios but concluded that at the current price of $14,523, evolocumab is not a cost-effective treatment option. If evolocumab was discounted 29% to $10,311, the ICER is $165,689 per QALY gained, which is still above the threshold considered cost-effective. To achieve an ICER of $150,000, $100,000, and $50,000 per QALY gained, evolocumab would need to be priced at $9,669, $7,623, and $5,578, respectively.

For FOURIER trial participants, the ICER would be $413,579 per QALY gained at its full list price. In these patients, evolocumab would need to be priced at $6,780 per year to be cost-effective. If the drug was limited to patients with LDL cholesterol levels ≥ 100 mg/dL, the ICER is $172,194 per QALY gained, making it cost-effective at $13,225.  

‘It Offers Substantial Clinical Benefit’

To TCTMD, Fonarow said that if there are no discounts and the true list price is being paid, use of evolocumab would be very selective and confined to the highest-risk patients alone. However, he believes that at a discount of 30% to 35%, which puts the drug close to its value-based price of $10,000 per year and is a typical discount for similar biologic medications, “it offers substantial clinical benefit.”  

In the second paper published this week, this one in the Journal of the American Medical Association, Dhruv Kazi, MD (Zuckerberg San Francisco General Hospital, CA), and colleagues also take a crack at analyzing the cost-effectiveness of PCSK9 inhibitor therapy. In their assessment of the data, though, adding PCSK9 inhibitors to statins is estimated to prevent 2,893,500 more major adverse cardiovascular events compared with ezetimibe (Zetia, Merck/Schering-Plough) but at a cost-effectiveness ratio of $450,000 per QALY gained. For them, the price of PCSK9 inhibitors would need to be reduced by 71% to be cost-effective (assuming a threshold of $100,000 per QALY gained).

Inmaculada Hernandez, PhD (University of Pittsburgh, PA), who has also conducted analyses looking at the cost of evolocumab, told TCTMD the results aren’t surprising, noting they are in line with previous studies showing the drug isn’t cost-effective at its current price.

“Having said that, I acknowledge these studies are simulations and are not following patients to see how much they spend on healthcare, so I know there are assumptions that have to be made,” she said. “It’s not whether it’s right or wrong, but what you think is reasonable in the model.”

Hernandez, who was not involved in either of the new studies, noted that while there is a wide discrepancy between the two papers—the ICER per QALY gained is almost $200,000 higher in the Kazi et al analysis—the conclusions are the same, that being the drug’s cost “is way above what we usually considered cost-effective in this country.” She added that there is no formalized definition of cost-effective in the US and this measure also varies between countries. While an ICER of $150,000 per QALY gained is used in the US, treatments that don’t meet this threshold have been covered by payers previously.

Amgen, for their part, issued a statement accompanying the Fonarow et al analysis, stating the study “affirms the clinical benefit and economic value of delivering [evolocumab] to the right high-risk patients,” such as MI/stroke patients with high LDL levels despite statin therapy. They took issue with the Kazi et al paper, though, telling TCTMD that it may not adequately reflect the drug’s value. They worry that such analyses may become a tool for blocking access to the drug.        

Favorable Assumptions

In their editorial, Mark, Richman, and Hlatky point out that real-world use of evolocumab might be less favorable than the modelling used by Fonarow and colleagues.

Specifically, they note that the magnitude of a mortality reduction “has a profound effect on the estimated cost-effectiveness.” If no late survival benefit occurs, the ICER skyrockets to $483,800 per QALY gained and the drug would need to be priced at $7,246 to be cost-effective. In the Kazi et al analysis that assumes no survival advantage, the cost-effectiveness ratio for PCSK9 inhibitor therapy is $1.8 million per QALY gained.

“Cost-effectiveness considerations are not the only factor in deciding if and when to use a new therapy,” state the editorialists. “However, they do suggest we should carefully consider the efficiency of using PCSK9 inhibitors and the opportunity cost of allocating resources to this drug rather than investing in other effective prevention strategies.”

Commenting on the mortality benefit, Fonarow said that assuming a cardiovascular mortality reduction beyond 5 years is justified. As nonfatal MIs and strokes are prevented with treatment, this should translate into a later reduction on cardiovascular mortality over time. “Certainly, with statin therapy, it takes time for the mortality benefit to emerge,” he said. “It’s not surprising in a short-term study like FOURIER with just 2 years of follow-up that there wouldn’t be a benefit seen.”

From a clinical perspective, Fonarow said physicians do feel “some sense of responsibility” in that the therapies they’re prescribing are reasonably cost-effective and offer value. More importantly, though, if a patient can’t get access medications, either because of denials from the insurance company or pharmacy-benefits manager, or if the copayment is so high the out-of-pocket costs are prohibitive, this ultimately has a larger impact on their clinical decision making, he said.