Praluent Cuts Deaths by 29% for Those With Highest Cholesterol Levels, ODYSSEY Finds

Waiting paid off for Sanofi and Regeneron, as a new study shows the PCSK9 inhibitor alirocumab, sold as Praluent, cut deaths by 29% among patients whose low-density lipoprotein (LDL) or “bad” cholesterol is at least 100 mg/dL, compared with placebo.

Findings of the 18,924-patient ODYSSEY Outcomes trial, presented this morning at the 67th Scientific Session of the American College of Cardiology (ACC) in Orlando, Florida, give Sanofi-Regeneron’s alirocumab a benefit not seen a year ago in FOURIER, the cardiovascular outcomes trial for Amgen’s evolocumab (Repatha), the only other proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor with FDA approval.

“The longer the follow up, the greater the magnitude of the effect,” said Philippe Gabriel Steg, MD, chief of cardiology at Hôpital Bichat in Paris, the co-chair of the study, who presented the results. FOURIER, which opened ACC a year ago, had a follow-up period of 26 months vs 34 months for ODYSSEY Outcomes, and Steg said it was a key difference between the 2 trials.

For payers, the data support protocols that have limited PCSK9 inhibitors to high-risk patients, but they also show a clear benefit that physicians say payers must now recognize: the positive findings were largely driven by patients who started the trial with LDL cholesterol levels above 100 mg/dL. Valentin Fuster, MD, of Mount Sinai, editor in chief of the Journal of the American College of Cardiology, said having criteria is no justification for the barriers that physicians and patients have tolerated since PCSK9 inhibitors were approved 3 years ago. In light of these new results, these problems must end, he said at a press conference.

Fuster described mountains of paperwork support staff must complete, and “back and forth” questions that consume too much of a physician’s time. “They try to make the patient ineligible, “ he said “It’s very, very hard.”

In response to these complaints, Sanofi and Regeneron also announced an accessibilty program that will leverage results of an updated analysis from the Institute for Clinical Economic Review (ICER), which previously calculated that PCSK9 inhibitors were not cost effective. The pharmaceutical companies privately shared early data from ODYSSEY Outcomes with ICER, and today the group released 2 preliminary updated value-based price benchmarks, after netting out rebates and discounts: (1) for patients with a recent acute coronary event, alirocumab should cost $2,300-$3,400 per year for all patients who meet trial eligibility criteria, and (2) alirocumab should cost $4,500-$8,000 per year if used to treat higher-risk patients with LDL cholesterol ≥100 mg/dL despite intensive statin therapy.

Steg emphasized that no adverse events were seen over 3 years, except for injection site reactions. “We were really pleased to see the treatment was effective and associated with a reduction in mortality. It is remarkable that such a potent intervention is also so safe,” he said in a statement. “Because the treatment effect was so much more marked in the patients with the highest LDL cholesterol, we believe that these patients are the optimal candidates for therapy.”

PSCK9 inhibitors seemed a sure hit when results for evolocumab were presented at ACC in 2014—this entirely new mechanism blocked the PCSK9 enzyme, preventing its ability to stymie the liver from filtering LDL cholesterol out of the blood. PCSK9 inhibitors could reduce LDL cholesterol by up to 60% when used with metformin, but the question was: would that translate into fewer cardiovascular events?

FDA approved both monoclonal antibodies in 2015, but limited them to high-risk patients and those with genetic conditions that cause high cholesterol. Regulators would wait to see cardiovascular outcomes trials before expanding indications. Notably, the FDA declined to approve them for low-risk patients who claimed statin intolerance.

A year ago, FOURIER showed evolocumab produced an overall reduction in cardiac events, especially heart attacks, and that benefit increased after the first year. But there was a slight, nonsignificant increase in all-cause death, and payers were not impressed with the results. The day the results were announced, Amgen offered a money-back guarantee to payers if any patient had a heart attack while taking the drug. There have been some takers, but there have also been analyses that question the offer.

Because FOURIER studied a larger and different population for a shorter period, researchers will no doubt pore over the data to glean whether today’s results show a class effect for patients with the highest LDL cholesterol levels and the greatest risk profile. FOURIER studied 27,564 stable patients with atherosclerotic cardiovascular disease (ASCVD), of which only 20% had an acute coronary syndrome (ACS) in the prior year. All patients in ODYSSEY had an ACS. On average, ODYSSEY patients were 5 years younger (mean age 58), and there was a more complex dosing scheme.

Overall, ODYSSEY Outcomes found a 15% reduction in major adverse cardiovascular events (MACE), which included heart attack, stroke, unstable angina, and coronary heart disease deaths. FOURIER also showed a 15% reduction in its MACE, which was defined slightly differently (heart attack, stroke, unstable angina, cardiovascular deaths, and coronary revascularization).

In ODYSSEY, however, subgroup results showed that the outcomes for patients who started with the highest LDL cholesterol (LDL-C) levels (above 100 mg/dL) accounted for the results, both for the all-cause death rates and for the MACE. The results showed:

• Time to the first all-cause death: overall hazard ratio (HR), 0.85; those with LDL-C ≥100 mg/dL, HR 0.71.
• Beyond 12 months, time to the first all-cause death: all patients, HR 0.79; those with LDL-C ≥100 mg/dL, HR 0.67.
• MACE: those with LDL-C <100 mg/dL, HR 0.91; those with LDL-C ≥100 mg/dL 0.76.

While overall ODYSSEY Outcomes results showed a lower rate of strokes among patients taking alirocumab, the overall FOURER results showed a lower rate of heart attacks among patients taking evolocumab.

With prices set above $14,000 a year, PCSK9 inhibitors have never met the lofty sales expectations analysts forecast in 2015. Payers interpreted the FDA label strictly and ensured that the only patients who would receive the drugs were those with familial hypercholesterolemia or high-risk patients with established ASCVD and whose LDL cholesterol did not meet goals with maximally tolerated statins. As Fuster noted, cardiologists and other physicians have complained that they cannot get their patients through prior authorization even when they meet the criteria, and studies support these claims.

In recent months, FOURIER researchers have released additional results showing stronger benefits among the highest-risk patients: at the American Heart Association meeting in November 2017, analyses showed evolocumab produced substantial benefits for patients with peripheral artery disease, for those with a history of myocardial infarction and those with residual coronary artery disease.

In a statement, ACC said the data will help researchers evaluate the cost-effectiveness of alirocumab, because “PCSK9 inhibitors cost tens of thousands of dollars per year and are often not covered by insurers.

“Now that we have two trials that consistently show benefits from PCSK9 inhibitors, and given the mortality benefit that we are reporting here for the first time, I think these results may change the equation for these drugs,” Steg said. “We’re not just talking about preventing nonfatal events such as heart attacks but actually preserving life.”