Injection to Lower LDL-C Shows Promise

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Alirocumab, an investigational, injectable PCSK9 inhibitor, appeared to effectively and safely lower LDL cholesterol when given once every 2 weeks, according to results from multiple trials.

Among patients already taking a maximally-tolerated statin, those assigned to treatment with alirocumab achieved a 50.6% change in baseline LDL cholesterol at week 24 compared with a 20.7% reduction among patients on ezetimibe (P<0.0001), reported Christopher Cannon, MD, of Brigham and Women's Hospital in Boston, and colleagues at the European Society of Cardiology meeting.

Cannon's group also reported that 77% of the high-risk cardiovascular disease patients in the study achieved an LDL goal of less than 70 mg/dL at week 24 in the trial named ODYSSEY COMBO II.

The trial enrolled 479 patients who were randomly assigned to alirocumab and daily placebo, and 241 patients who were assigned oral ezetimibe (Zetia) plus placebo injections.

Of the patients in the study on alirocumab, about 80% who achieved their goal did not require up-titration from the 75 mg dose of the drug (maximum of 150 mg every 2 weeks).

The most common adverse events were:

• Upper respiratory tract infection: 6.5% among alirocumab patients and 6% among ezetimibe patients
• Accidental overdose: 6% and 7%
• Myalgia: 4% and 5%
• Dizziness: 5% in both arms

In the separate ODYSSEY LONG-TERM trial, Jennifer Robinson, MD, MPH, from the University of Iowa in Iowa City, and colleagues, reported that patients treated from onset with 150 mg dose of alirocumab achieved a 61.9% reduction in LDL cholesterol compared with a 0.8% increase in LDL cholesterol among patients on placebo (P<0.0001). All the patients were also on maximally-tolerated statin therapy.

In addition, Robinson said that 81% of patients treated with alirocumab achieved their LDL goal of 70 mg/dL for very-high-risk patients or 100 mg/dL for high-risk patients, compared with 9% of those patients on placebo (P<0.0001).

The study enrolled 1,553 patients who were assigned to the self-injected alirocumab and 788 patients on placebo. While the patients were seen every 3 months, they did not receive regular reminders to administer the injections, Robinson told MedPage Today.

The ongoing, double-blind trial is designed to evaluate the long-term safety and efficacy of 150 mg alirocumab among patients with very-high cardiovascular risk, including patients with heterozygous familial hypercholesterolemia.

At 52 weeks, there was a 57% reduction from baseline in LDL cholesterol levels in the alirocumab group versus a 4% increase in the placebo group, representing a 61% reduction in alirocumab group compared with placebo (P<0.0001).

In a post hoc safety analysis, Robinson reported an approximately 50% lower rate of adjudicated major cardiovascular events -- 1.4% in the alirocumab patients and 3% in the placebo patients (P<0.01).

"ODYSSEY LONG TERM is the first PCSK9 inhibitor study to show a lower rate of major cardiovascular events," she said, but cautioned that this post hoc analysis required confirmation in a prospective outcomes trial.

Two other trials, ODYSSEY FH I and ODYSSEY FH II, that enrolled heterozygous familial hypercholesterolemia patients also on maximally-tolerated statins showed efficacy of treatment with alirocumab, said Michel Farnier, MD, from Point Medical in Dijon, France, and colleagues.

For the primary endpoint of the trials at 24 weeks, there was an average reduction of 48% with alirocumab from baseline LDL compared with placebo (P<0.0001) and that reduction was durable at 52 weeks.

Between 72% and 81% of patients in the alirocumab groups achieved their prespecified LDL cholesterol goal at 24 weeks compared with 2% and 11% of patients in the placebo groups (P<0.0001). Approximately 50% of patients in the alirocumab groups achieved target LDL cholesterol level, while remaining on the 75 mg dose.

In the ongoing trials, 323 patients diagnosed with familial hypercholesterolemia were assigned to alirocumab in the FH I trial, and 163 patients were assigned to placebo. In the FH II trial, 167 patients were assigned to alirocumab and 82 patients were randomized to the placebo arm of the trial.

"Alirocumab really is a very exciting innovation," Ian Graham, MB, BCh, professor of medicine at Trinity College in Dublin, told MedPage Today, "But we have to temper our enthusiasm with a little bit of caution because sometimes -- as we have found with the drugs that are supposed to raise HDL -- expectation doesn't turn out as good as we hoped. So far it is looking good."

Graham noted that "alirocumab started out in familial hypercholesterolemia because that is the biggest therapeutic challenge. I think what people are hopeful for is that it will be helpful in other hypercholesterolemia patients. There may be 40%, 50%, 60% of patients -- apart from those with familial hypercholesterolemia -- who cannot get to goal. But we have to see the outcome data; we have to see the safety data to be absolutely convinced of this."

From the American Heart Association:

• AHA Science News from ESC 2014