Huge Decreases in LDL Cholesterol With Alirocumab: ODYSSEY

August 31, 2014

BARCELONA, SPAIN — Treatment with alirocumab (Sanofi/Regeneron Pharmaceuticals), an investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, resulted in significant reductions in LDL cholesterol in various groups of patients who received the drug, including individuals at high risk for cardiovascular events currently taking a maximally tolerated statin dose.

In one analysis of the ODYSSEY Long-Term Study , a study consisting of 2341 patients at high risk for cardiovascular events, investigators conducted a post hoc analysis to investigate the effect of alirocumab on major cardiovascular events, the same end point being tested in the major morbidity and mortality ODYSSEY OUTCOMES study. After 65 weeks of treatment, the results suggested alirocumab significantly reduced the risk of major events compared with those who received placebo and a maximally tolerated statin.

Dr Jennifer Robinson

Speaking with heartwire , Dr Jennifer Robinson (University of Iowa, Iowa City), the lead investigator of the ODYSSEY Long-Term Study, said the post hoc analysis should be interpreted cautiously but the data at least suggest the researchers are on the right track. "This is an agent that is doing what we want it to do," said Robinson. "It's very encouraging."

Dr John Harold (Cedars-Sinai Medical Center, Los Angeles, CA), who was not affiliated with the ODYSSEY studies, said the reductions in LDL cholesterol observed in the studies were very dramatic, and while the PCSK9 inhibitor drug class has the potential to alter the field of lipid management, more data are still needed. "In the cohorts studied, particularly in patients with familial hypercholesterolemia, we don't really have too many other agents to use," Harold told heartwire . "So, in those patients, it could be a game-changer. But the role of alirocumab in other patients still needs to be seen. We are still following guideline recommendations."

Those guidelines at present recommend either a high-dose or moderate-dose statin depending on a patient's baseline risk. In fact, the recent US guidelines did away with LDL cholesterol as a treatment target, instead asking physicians to first assess risk and then prescribe a statin accordingly. In fact, the new guidelines almost completely abandon other lipid-lowering agents, pushing them way down the treatment algorithm unless patients are unable to take a statin.

Harold told heartwire there are also patients who are truly intolerant to statins and these individuals remain at high cardiovascular risk. "We don't often have a lot of choice," said Harold referring to the statin-intolerant patients.

The Results So Far (So Good?)

The results of ODYSSEY Long-Term, ODYSSEY FH I and II , and ODYSSEY COMBO were presented today here at the European Society of Cardiology (ESC) 2014 Congress during a media briefing and hot-line session. Briefly, the three studies are summarized as follows:

  • ODYSSEY COMBO II : Testing the efficacy and safety of alirocumab in 720 patients at high risk for cardiovascular events despite treatment with a maximally tolerated statin. Patients received a 75-mg injection of alirocumab every two weeks, and the dose was increased to 150 mg every two weeks if their LDL-cholesterol levels remained >70 mg/dL at week 8. Patients in the control arm received a maximally tolerated statin, ezetimibe 10 mg/day, and a placebo injection.

  • ODYSSEY FH I and I: In total, 735 heterozygous familial hypercholesterolemia (FH) patients treated with a maximally tolerated statin who were not at the recommended LDL-cholesterol goal of <70 mg/dL (history of cardiovascular disease) or <100 mg/dL (no history of cardiovascular disease) were randomized to alirocumab 75 mg every two weeks or to placebo. Like the COMBO study, the dose was increased to 150 mg every two weeks if the patient's LDL-cholesterol level remained above 70 mg/dL at week eight.

  • ODYSSEY Long-Term: Evaluated the safety and efficacy of alirocumab in 2341 patients with heterozygous FH or at high risk for cardiovascular events who were receiving a maximally tolerated dose of statin but who had an LDL-cholesterol level >70 mg/dL. Patients were randomized to alirocumab 150 mg every two weeks or to placebo. The primary efficacy end point was the reduction in LDL-cholesterol levels at 24 weeks, but the study will continue to evaluate patients beyond one year.

In the ODYSSEY COMBO study, treatment with alirocumab reduced LDL-cholesterol levels 50.6% from baseline compared with a 20.7% reduction among those who received ezetimibe (p<0.0001). At 24 weeks and 52 weeks, the mean LDL cholesterol achieved in the alirocumab arm was 51.6 mg/dL and 53.3 mg/dL, respectively. Overall, 18.4% of patients treated with alirocumab were uptitrated to the 150-mg dose.

Dr Michel Farnier

In the FH I and II studies, which were presented by Dr Michel Farnier (Point Médical, Dijon, France), the reduction in LDL cholesterol was nearly 49% from baseline, with approximately 40% of heterozygous FH patients requiring the 150-mg dose of alirocumab. The mean LDL-cholesterol level achieved at 24 and 52 weeks was approximately 70 mg/dL.

And finally, in the ODYSSEY Long-Term Study, which included 1530 patients treated with alirocumab, the mean LDL-cholesterol reduction was 61.0% from baseline. For those at high risk or very high risk of cardiovascular events, 81% achieved the previously recommended LDL-cholesterol targets of <100 mg/dL (high-risk patients) or <70 mg/dL (very high-risk patients). Regardless of baseline risk, 79% of study participants achieved an LDL- cholesterol level of <70 mg/dL after 24 weeks of alirocumab treatment.

As noted, the long-term study also evaluated major cardiovascular events at 65 weeks. Using the same end point as that used in the alirocumab outcomes study, which was the time to first coronary heart disease death, nonfatal MI, fatal and nonfatal ischemic stroke, or unstable angina requiring hospitalization, there was a benefit to treatment with the PCSK9 inhibitor. The absolute event rate of major cardiovascular events was 1.4% in the alirocumab arm and 3.0% in the placebo arm, a difference that translated into a relative risk reduction of 54%.

The ODYSSEY OUTCOMES study is still enrolling patients, and full results are not expected until 2018. Up to 18 000 individuals with acute coronary syndrome will be randomized to optimal medical therapy or optimal medical therapy plus alirocumab and followed for as long as 64 months.

Putting the Results in Perspective

Discussing the results of ODYSSEY in a media briefing, Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA), who led the ODYSSEY COMBO study, commented on LDL cholesterol as a surrogate end point, noting that LDL is one of the best surrogates in cardiovascular medicine. Of hundreds of thousands patients randomized in clinical trials, the lower LDL cholesterol goes, the better the reduction in cardiovascular event rates, he said. The new clinical guidelines recently deemphasized LDL cholesterol as a target, however, and instead chose to emphasize an approach to using high-dose statin therapy.

Dr Christopher Cannon

The evidence from the ODYSSEY studies thus far shows that the drug is able to reduce "sky-high" LDL-cholesterol levels, particularly in those with genetic lipid abnormalities such as FH. "Ultimately, we're going to need to see the cardiovascular outcomes with this class of drugs, or with any class of drug, but both are important, both the LDL level and the outcomes," said Cannon.

To heartwire , Harold said that he is reassured by the side-effect profile of alirocumab. In the data presented from ODYSSEY, there did not appear to be any adverse events associated with alirocumab despite the low LDL-cholesterol levels achieved. On balance, the neurocognitive side effects, an issue raised by the Food and Drug Administration (FDA) in March 2014 when the agency asked Regeneron and Sanofi to monitor for this potential concern in their clinical trials, were balanced across treatment arms. Injection-site reactions were more common among those who received alirocumab.

On Thursday, Amgen, the maker of evolocumab , another PCSK9 inhibitor, announced it has applied to the US FDA for approval on the basis of LDL lowering observed in its clinical-trial program. Regeneron and Sanofi are also expected to submit their data to the FDA and will receive an expedited review after paying $67.5 million to acquire a voucher from another pharmaceutical company. The voucher allows alirocumab to undergo a six-month regulatory review instead of the usual 10-month process.

Speaking with heartwire , Dr Christie Ballantyne (Baylor University, Houston, TX) said that he expects the approval process to be not unlike the approval process for diabetes drugs—specifically, that the companies will have to show that the PCSK9 inhibitors are effective in lowering LDL cholesterol and that they are also safe. He speculates the large outcomes studies can follow afterward as long as the regulatory bodies in the US and Europe are convinced of safety, he said.

Asked about repeating history with another version of ezetimibe, that being the approval of alirocumab, evolocumab, or bococizumab (Pfizer) based on surrogate end points without any idea if the drugs reduce hard clinical end points, Ballantyne said the two scenarios are very different. When ezetimibe was approved based on LDL lowering, an outcomes study wasn't even in the works (the IMPROVE-IT study will finally be presented this November at the American Heart Association meeting, 12 years after the drug was approved by the FDA). With the PCSK9 inhibitors, the sponsors have all initiated outcomes studies, and enrollment has already begun in these large morbidity and mortality trials, he said.

Robinson reports research grants and consulting fees from Amarin, Amgen, AstraZeneca, Daiichi-Sankyo, Genentech/Hoffman-La Roche, GlaxoSmithKline, Merck, Regeneron/Sanofi, and Zinfandel/Takeda; Cannon reports grants and consulting fees from Accumetrics, Arisaph, AstraZeneca, Boehringer-Ingelheim, Janssen, GlaxoSmithKline, Merck, Takeda, Bristol-Myers Squibb, CSL Behring, Essentialis, Lipimedix, Pfizer, Regeneron, and Sanofi; and Farnier reports grants, consulting fees, and/or honoraria from Abbott, Amgen, Boehringer-Ingelheim, Genzyme, Kowa, Merck, Novartis, Recordati, Roche, Sanofi, and SMB.

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