Amgen's PCSK9 inhibitor Repatha significantly cuts risk for cardiovascular events in outcomes study, but falls short of expectations

Amgen on Friday unveiled detailed results from the late-stage FOURIER trial at the American College of Cardiology (ACC) annual scientific session, showing that Repatha (evolocumab) led to a significant 15-percent reduction on a combined measure consisting of hospitalisation for unstable angina, coronary revascularisation, heart attack, stroke or cardiovascular death, although some analysts had been hoping that the PCSK9 inhibitor would lead to as much as a 30-percent reduction. The study also found a significant 20-percent reduction in the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death. Further, the company noted that "consistent with recent trials of more intensive LDL lowering, there was no observed effect on cardiovascular mortality."

In light of the FOURIER results, Amgen said it plans on offering a refund to payers that are "willing to remove access barriers" if patients on their plans taking Repatha for at least six months suffer a heart attack or stroke. Insurers have been reluctant to pay for Repatha, which has a list price of $14 523 a year, with sales falling short of expectations in 2016 at only $141 million, while revenue for Sanofi and Regeneron Pharmaceuticals' similar PCSK9 inhibitor Praluent (alirocumab) have also disappointed at $116 million last year. "These robust data...validate that the net prices of Repatha in the market today are value-based," remarked Joshua Ofman, senior vice president of Global Value, Access and Policy at Amgen, adding "now that Repatha has proven a meaningful reduction in cardiovascular events, we expect payers to remove onerous barriers and help appropriate patients get access to Repatha." He said the company would be working with payers to discuss "innovative contracting options over the coming months."

For related analysis, see KOL Views: Rapid reaction to the detailed FOURIER data – where does anti-PCSK9 class go from here?

In February, Amgen reported that the FOURIER study met its main goal, with Repatha significantly cutting the risk of cardiovascular events in patients with clinically evident atherosclerotic cardiovascular disease (ASCVD). The trial consisted of 27 564 patients who had a heart attack, ischaemic stroke or symptomatic peripheral artery disease, as well as an LDL cholesterol level of at least 70 mg/dL or a non-HDL cholesterol level of at least 100 mg/dL despite optimised statin therapy. Patients were randomised to receive subcutaneous Repatha or placebo, both combined with statin therapy. The primary endpoint was time to cardiovascular death, heart attack, stroke, hospitalisation for unstable angina, or coronary revascularisation, while the key secondary goal was the time to cardiovascular death, myocardial infarction or stroke. The trial continued until at least 1630 patients experienced a key secondary major adverse cardiac event.

According to the latest data, which were also published in the NEJM, Repatha's benefit in the hard MACE composite endpoint increased over the median 2.2 years of the study, from a relative risk reduction of 16 percent in the first year to 25 percent beyond the first year. Further, results showed that patients on Repatha saw their heart attack risk fall by 27 percent, while the risk for stroke and coronary revascularisation were cut by 21 percent and 22 percent, respectively, compared with placebo. In addition to there being no observed effect on cardiovascular death, there was no observed effect on hospitalisation for unstable angina, the company said.

Amgen's head of R&D Sean Harper, who anticipated that there might be some negative investor reaction to the FOURIER results, said "there is no legitimate criticism you can make about the efficacy outcome, though you do have to be able to interpret the data." He noted that evidence from an exploratory analysis, which was adjusted for what he called a "treatment lag," showed that Repatha's relative risk reduction for fatal and non-fatal heart attack or stroke was 19 percent in the first year and 33 percent beyond the first year. However, shares in Amgen fell as much as 6 percent on the data.

Meanwhile, Elliott Levy, Amgen's senior vice president of global development, suggested that since the treatment effect improved with time, the larger benefit is "probably a true reflection of what patients will experience if they take the drug over time." Levy predicted that Repatha "will be embraced by the medical community" and incorporated into clinical guidelines, and "then it will be up to the payers to accommodate the drug," while Harper noted that "the prices that are actually being paid by payers in the US marketplace today, after the rather large rebating that goes on, are right in the middle of the value range for a product like this."

In regards to whether the FOURIER results are good enough to drive higher sales, CVS Caremark CEO Troyen Brennan remarked "if we sense the consensus is that this demonstrates there's a substantial decrease in cardiac outcomes, it will increase the number of people receiving PCSK9 inhibitors." Meanwhile, Steven Miller, chief medical officer at Express Scripts, said "getting the patients approved [for coverage of PCSK9 inhibitors] had been difficult, and because there was no endpoint data many practitioners didn't push very hard." However, he expects "now that there is endpoint data, they are going to be pushing a lot harder to write these scripts."

Commenting on the reimbursement issue, Mizuho Securities analyst Salim Syed said he thought the minimum level of risk reduction would need to be about 20 percent for insurers to start reimbursing the drug more widely, and said the number "could be higher" still. Meanwhile, RBC Capital Markets analyst Michael Yee estimated that the PCSK9 inhibitor class "is likely to grow to at least a $3-billion to $5-billion worldwide market over the next five plus years."

Repatha was approved by the FDA in 2015 for the treatment of adults with heterozygous familial hypercholesterolaemia (HeFH), homozygous familial hypercholesterolaemia or clinical ASCVD who need additional lowering of LDL cholesterol. The approval came shortly after the US regulator cleared Praluent for patients with HeFH and those with ASCVD needing additional lowering of LDL cholesterol. Sanofi and Regeneron are currently evaluating the potential cardiovascular benefits of Praluent in the 18 000-patient ODYSSEY OUTCOMES study, with results expected later this year.

For related analysis, read Physician Views Poll Results: Cardiologists suggest magnitude of benefit seen with PCSK9s will be key to driving broader adoption of drug class.

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