ODYSSEY Delivers a Win for Alirocumab in ACS, With a Signal of Survival Benefit

ORLANDO, FL—ODYSSEY, the large cardiovascular morbidity and mortality trial testing alirocumab (Praluent, Regeneron/Sanofi), has come up with a significant win for the PCSK9 inhibitor.

Although the reduction in major adverse cardiovascular events was relatively modest among ACS patients, and in line with the benefit seen with the other commercially available PCSK9 inhibitor evolocumab (Repatha, Amgen), treatment with alirocumab was also associated with a reduction in the risk of all-cause mortality when compared with placebo.

Lead investigator Philippe Gabriel Steg, MD (Hôpital Bichat, Paris, France), who presented the results during a “showcase” late-breaking clinical trial session here at the American College of Cardiology 2018 Scientific Session, was cautious in interpreting the all-cause mortality observation. Still, the overall benefit should move the needle in terms of getting more patients treatment with this notoriously hard-to-access drug class.

“I think further improving event rates in post-ACS patients for those who remain at high risk, and having an impact on all-cause mortality, is really important for patients and physicians,” said Steg. “I assume it will sway both patients and physicians, and hopefully payers and regulators to give greater access to these drugs. This is not a minimal improvement in the care of these patients. A 15% reduction in MACE is in the range of what aspirin achieves. I also would point out that even statins have not shown a mortality benefit in the post-ACS setting.”

Valentin Fuster, MD (Icahn School of Medicine at Mount Sinai, New York, NY), who spoke with the media during a press conference where the results were announced, believes “the study is going to change practice.”

I hope this particular study is a trigger, is a catalyzer, for making this drug much more available today for people who [need to] use it. Valentin Fuster

Like Steg, Fuster said the reduction in the primary endpoint is “not trivial,” nor is the 15% relative reduction in all-cause mortality. However, the prohibitively high drug costs remain a key barrier, at $14,000 per year, that limits use in clinical practice.

“I hope this particular study is a trigger, is a catalyzer, for making this drug much more available today for people who [need to] use it,” said Fuster.

For James de Lemos, MD (University of Texas Southwestern Medical Center, Dallas, TX), who was not involved in the study, the “unsurprising” ODYSSEY results are reassuring in that the observed benefit lines up with the 15% reduction in cardiovascular death, MI, stroke, hospitalization for unstable angina, and revascularization seen in FOURIER with evolocumab. The mortality benefit, he said, is a “nice bonus.”  

“Anytime something replicates in science is great news,” de Lemos told TCTMD. “Scientifically, it’s a magnificent study. From a practical standpoint, it’s very similar to FOURIER in that the magnitude of benefit in the overall study is modest and when you think about the expense of the drug, you still have a problem.”

Regeneron and Sanofi announced today they are willing to further reduce the price of alirocumab if insurance companies reduce the barriers patients and physicians frequently encounter when trying to access the drug. The manufacturers said they plan to price alirocumab based on input from the nonprofit Institute for Clinical and Economic Review (ICER), which would reduce the price of alirocumab to $4,500 to $8,000 per year.   

The ODYSSEY Trial

The ODYSSEY trial included patients with a recent ACS and inadequate control of lipid levels, which was defined as LDL cholesterol 70 mg/dL or higher, non-HDL cholesterol 100 mg/dL or greater, or apolipoprotein B 80 mg/dL or greater. The majority of patients qualified on the basis of “elevated” LDL cholesterol levels. Prior to randomization, all patients were treated with high-intensity atorvastatin (40 to 80 mg) or rosuvastatin (20 to 40 mg), or the maximum tolerated dose of one of the drugs, for a run-in period of 2 to 16 weeks. 

Importantly, investigators aimed to treat patients to an LDL cholesterol target range of 25 to 50 mg/dL. Treatment with alirocumab reduced LDL cholesterol levels from approximately 90 to 37.6 mg/dL at 4 weeks. Over time, there was a “creep” in LDL cholesterol levels, increasing to 53.3 mg/dL at 48 weeks, which investigators attributed to patients stopping statin therapy. In the placebo arm, the median LDL cholesterol levels were 101.4 mg/dL at 48 weeks.

After a median follow-up of 2.8 years, there was a significant reduction in the risk of coronary heart disease death, nonfatal MI, ischemic stroke, or unstable angina requiring hospitalization, the study’s primary composite endpoint, in the alirocumab-treated patients compared with placebo.

The benefit was driven by a significant reduction in the risk of nonfatal MI, ischemic stroke, and unstable angina requiring hospitalization. Although there was no reduction in the risk of CHD or cardiovascular death, investigators did observe a statistically significant reduction in the risk of all-cause mortality. The ODYSSEY trial is first clinical trial to show a mortality benefit with a PCSK9 inhibitor—there was no such reduction observed in the FOURIER trial.

ODYSSEY: Primary Outcomes

ODYSSEY: Secondary Outcomes

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In a post hoc analysis stratifying patients by prespecified baseline LDL cholesterol levels, those with LDL cholesterol ≥ 100 mg/dL had an absolute 3.4% reduction in the primary endpoint, as well significant reductions in CHD and cardiovascular mortality. In this post analysis, those with LDL cholesterol levels of 100 mg/dL or greater treated with alirocumab had an absolute 1.7% reduction in all-cause mortality compared with placebo, whereas the mortality benefit was not seen in those with lower LDL levels.

Consistent Findings With FOURIER

To TCTMD, James Underberg, MD (NYU Langone Medical Center, New York, NY), and Seth Martin, MD (Johns Hopkins Medicine, Baltimore, MD), said the overall findings were “no surprise.” Both pointed out that the modest treatment effect might have been minimized given that the trial design had physicians back off alirocumab if LDL cholesterol levels went too low.

For example, 7.7% of patients treated with alirocumab were switched over to placebo in a blinded fashion because LDL cholesterol levels fell to less than 15 mg/dL.

Steg, for his part, was even-keeled in his presentation of the data, pointing out the reduction was of borderline statistical significance (nominal P value = 0.026), what with the bar set in the trial’s statistical design and that investigators prioritized CHD and cardiovascular mortality in their prespecified analysis. In the overall study, neither CHD nor cardiovascular mortality was reduced in the alirocumab-treated patients. 

“All-cause mortality is certainly the ultimate outcome of interest to patients and physicians,” said Steg. While trial investigators are not making a “formal claim” for the mortality reduction, they believe the finding is legitimate, particularly since they observed a significant reduction in the risk of CHD, cardiovascular, and all-cause mortality in patients with the highest baseline LDL cholesterol levels.

It’s ‘lifesaving’ with a very small L. James de Lemos

“The fact we have this consistency in the higher-risk subgroup buttresses the credibility of a 15% lower risk of death,” Steg said.

Regarding the mortality reduction with alirocumab, but not evolocumab, Martin speculated that the different patient populations played a role. In ODYSSEY, patients were randomized relatively early after an ACS event, while those in FOURIER had chronic coronary artery disease. The ODYSSEY trial follow-up was also longer in duration by approximately 7 to 8 months.

“Many people felt that FOURIER was just too short to see a mortality reduction,” said Martin. However, he suspects the mortality benefit observed with alirocumab is a class effect. “I don’t think there’s a mechanism to say why alirocumab would reduce mortality but evolocumab wouldn’t.” 

For de Lemos, the mortality reduction is an important finding, but he pointed out the absolute difference between the placebo- and alirocumab-treated patients was just 0.6% over nearly 3 years. “It’s ‘lifesaving’ with a very small L,” he said.

In contrast, Underberg, as well as Andrew Foy (Penn State Health, Hershey, PA), questioned the clinical applicability of the mortality benefit, with Foy somewhat underwhelmed by the absolute risk reduction. Underberg said the ODYSSEY presentation at ACC is simply a first look at important data and predicted greater attention will turn to the study paper and its details when published.

Biggest Bang for the Buck in High-Risk Patients

For Underberg, a critical finding from ODYSSEY is that the patients who gained the most from treatment were those at highest risk, those being patients with LDL cholesterol levels ≥ 100 mg/dL despite intensive statin therapy.

“It reminds us over and over again in situations where we’re trying to reduce cardiovascular events with lipid agents, the benefit is accrued in the highest-risk patient and the ones who have the greatest absolute change in LDL cholesterol,” said Underberg.

It makes sense that people far away from that goal are the ones you target with the expensive therapy. James Underberg

de Lemos said the post hoc analysis is provocative in that it suggests a means to reduce the number of ACS patients who might be treated with such an expensive therapy. That said, he believes future clinical guidelines will recommend clinicians aim to reduce LDL cholesterol levels in post-ACS patients to less than 50 mg/dL. “It makes sense that people far away from that goal are the ones you target with the expensive therapy,” he said.

For Foy, the subgroup analysis suggests a potential niche where the drug might have a role. “The interesting thing in terms of applicability to clinical practice is that it’s not really that hard to get a patient below 100 [mg/dL] by starting statin therapy, unless they have intolerance and need to be on a low dose,” he said.

From a clinical perspective, Foy suggested post-ACS treatment would include high-intensity statin therapy followed by ezetimibe (Zetia, Merck/Schering-Plough), with use of a PCSK9 inhibitor reserved for patients with elevated LDL cholesterol levels. “You don’t want to fit this to just make it work in those patients,” he said, “but it’s nice that it does.” 

Martin suggested such an approach could make sense, particularly as a means to identify those with the most to gain from alirocumab or evolocumab. With intensive statin therapy followed by ezetimibe, “physicians could then see where the patient is to decide if they then need a PCSK9 inhibitor versus more intensive upfront therapy where you get the PCSK9 inhibitor onboard right at the time of an ACS event,” said Martin.

Speaking with the media, Steg stressed that he and his co-investigators are “not trying to spin a negative trial into a positive” with their LDL-cholesterol subgroup analysis. The trial is positive, he said, but given the economic data to date showing the agents are far from cost-effective, they wanted to tease out where the biggest bang for the buck might lie. “I’m still convinced, and the data shows an overall benefit in the trial, but as a clinician, given the cost-conscious environment we’re in we have to select patients in whom to start if we’re restricted,” said Steg.

A “back of the envelope” calculation in ODYSSEY suggests that 64 patients need to be treated to prevent one MACE and 163 patients to prevent one death, said Steg. Among patients with LDL cholesterol levels ≥ 100 mg/dL, the number needed to treat to prevent one MACE is 29 and to prevent one death is 60.