PCSK9 inhibitor studies show benefit for patients with high LDL

PHILADELPHIA — Numerous studies on PCSK9 inhibitors have been completed that establish their efficacy and safety in patients with high LDL, according to a presentation at National Lipid Association Scientific Sessions.

“For those of us who have been in this field, it’s an example of what happens when you combine genetics with biotechnology,” Christie M. Ballantyne, MD, FNLA, professor of medicine, chief of the section of cardiovascular research and director of the Center for Cardiovascular Disease Prevention at Baylor College of Medicine in Houston, and diplomate for the American Board of Clinical Lipidology, said in a presentation. “We’ll be seeing a lot more of this, as you’ve heard about a lot of the new targets identified by human genetics and then with the ability to make [monoclonal antibodies], … [small interfering] RNA, other approaches to make inhibitors quite straightforward.”

Christie M. Ballantyne

FOURIER trial

One of the completed trials, FOURIER, was a randomized, double blind study of 22,500 patients who were high-risk or stable with established CVD and prior stroke, MI or symptomatic peripheral artery disease. The patient population had LDL above 70 mg/dL or non-HDL above 100 mg/dL. Patients were assigned to receive 140 mg of evolocumab (Repatha, Amgen) once every 2 weeks, 420 mg of evolocumab once per month or placebo. Follow-up took place every 12 weeks.

The primary endpoint was MI, CV death, hospitalization for unstable angina, stroke or coronary revascularization. The key secondary endpoint was MI, CV death or stroke.

At 48 weeks, patients assigned evolocumab saw a 59% mean reduction in LDL cholesterol (95% CI, 58-60, P < .00001) and an absolute reduction of 56 mg/dL (95% CI, 55-57) compared with those assigned placebo. Median LDL for the evolocumab group was 30 mg/dL (interquartile range, 19-46).

“Notice that this is a sustained reduction in LDL, and in fact, if you take away the people who quit taking the therapy, it was completely flat, so it showed both the efficacy and durability of the treatment evolocumab, which is a fully human PCSK9 inhibitor,” Ballantyne said in the presentation.

The primary endpoint occurred more in patients assigned placebo (14.6%) vs. those assigned evolocumab (12.6%) at 36 weeks (HR = 0.85; 95% CI, 0.79-0.92). Similar findings occurred for the secondary endpoint for the evolocumab (7.9%) and placebo groups (9.9%; HR = 0.8; 95% CI, 0.73-0.88).

“There was no effect on unstable angina, and one of the things that’s happened is that with the high-sensitivity assays, people who come in who really have unstable angina usually rule in for a non-STEMI,” Ballantyne said in the presentation.

Researchers performed a landmark analysis, which determined that the secondary endpoint increased more in the placebo group vs. the evolocumab group at 12 months (HR = 0.84; 95% CI, 0.74-0.96) and 36 months (HR = 0.75; 95% CI, 0.66-0.85).

The risk for fatal or nonfatal stroke or MI increased in the placebo group at 12 months (HR = 0.81; 95% CI, 0.7-0.93) and 36 months (HR = 0.67; 95% CI, 0.59-0.77) compared with the evolocumab group.

“What was very interesting was that the group with prior stroke, they had benefit,” Ballantyne said during the presentation. “One of the things that I was looking for very carefully is, we’ve all heard about the pleiotropic effect of statins, and there’s effects on the nitric oxide, inflammation, C-reactive protein. The association between LDL and stroke is much weaker than with [MI], and one of the things I was looking for is in fact, would these drugs reduce stroke, because it wasn’t clear to me whether that was truly a lipid effect or a pleiotropic effect of statins, and what we saw was that the stroke reduction in this study was just as good as the reduction of [MI].”

SPIRE-1 and SPIRE-2

Researchers in the SPIRE-1 and SPIRE-2 trials compared the effects of bococizumab with placebo. In SPIRE-1, 12,000 patients had LDL above 70 and less than 100 mg/dL, and SPIRE-2 included 6,300 patients with an LDL above 100 mg/dL. Both trials were discontinued in November 2016. Absolute risk in the SPIRE-1 trial was 3.02 per 100 person-years and 4.19 per 100 person-years in the SPIRE-2 trial.

“In fact, bococizumab compared to the two approved therapies, which are alirocumab (Praluent, Sanofi/Regeneron) and evolocumab, which are both fully human, this agent had much higher frequency of antidrug antibodies, including neutralizing antibodies, and unfortunately what ended up happening, if you look at the curves for on-treatment LDL, there was a loss of efficacy,” Ballantyne said in the presentation.

In SPIRE-1, patients assigned placebo had a mean LDL of 94.1 mg/dL vs. 57.1 mg/dL in patients assigned bococizumab at 28 months. The placebo group (143.2 mg/dL) also had higher LDL in the SPIRE-2 trial compared with the bococizumab group (89.5 mg/dL) at 28 months.

The primary endpoint in the SPIRE-2 trial, nonfatal stroke, nonfatal MI, CV death or unstable angina requiring urgent revascularization, occurred more in the placebo group (224 events) than the bococizumab group (179 events; HR = 0.79; 95% CI, 0.65-0.97) at a median follow-up of 12 months.

Ballantyne said the conclusions to draw from the completed studies are that lower LDL is linked to improved CV outcomes, therapy for a longer period of time contributed to better outcomes, there was no safety signal for LDL below 20 mg/dL at 2 years, and to predict absolute benefit of any therapy, the amount of LDL reduction and absolute risk of the patient can prove to be helpful.

ODYSSEY Outcomes trial

ODYSSEY Outcomes is an ongoing randomized trial of alirocumab vs. placebo with an estimated 18,600 patients aged 40 years and older with ACS and an MI within 52 weeks, which is estimated to be completed in December 2017. Patients were assigned 75 mg titrated to 150 mg of alirocumab or placebo. Primary efficacy measures included nonfatal MI, time to first occurrence of CHD death, hospitalization for unstable angina and fatal or nonfatal ischemic stroke. The study is scheduled to continue for 64 months, with patient follow-ups occurring for at least 2 years, Ballantyne said.

GLAGOV study

Researchers of the GLAGOV study reviewed 970 patients with CAD who underwent coronary catherization and took lipid-lowering therapy. Patients were assigned evolocumab or placebo once monthly for 78 weeks. The primary endpoint was change in percent atheroma volume up to 78 weeks. Those assigned evolocumab saw a 0.95% reduction (P < .0001) in atheroma volume vs. a 0.05% increase in patients assigned placebo.

The lipid parameters for GLAGOV were similar to the other outcomes trials that were performed, where LDL went down and HDL went up, but there was no effect on high-sensitivity C-reactive protein, Ballantyne said.

“If there’s no effect on [high-sensitivity C-reactive protein], can you say that there’s no effect on inflammation? I think this is one of the things we get and as we move forward, [high-sensitivity C-reactive protein] is a marker of systemic inflammation,” Ballantyne said in the presentation. “Before you say PSCK9 inhibitors don’t have anti-inflammatory effects, it’s important to look that there in fact are data that they do have effects on white blood cell activation in patients who have hyperlipidemia. This obviously needs more investigation and more studies, but the world of inflammation is more complex than just C-reactive protein.” – by Darlene Dobkowski

Reference:

Ballantyne CM. PCSK9 Outcomes Studies. Presented at: National Lipid Association Scientific Sessions; May 18-21, 2017; Philadelphia.

Disclosure: Ballantyne is a board member of the National Lipid Association and reports receiving grant or research support or consultant fees from Abbott Diagnostics, Amarin, Amgen, Astra Zeneca, Eli Lilly, Esperion, Genzyme, Ionis, Matinas BioPharma, Merck, Novartis, Pfizer, Otsuka, Regeneron, Roche Diagnostics, Sanofi and Takeda.