UPDATED: PCSK9 Inhibitor Evolocumab Passes Test in Two Phase 3 Studies

December 17, 2013

THOUSAND OAKS, CA (updated December 19, 2013) — In a phase 3 study of the investigational cholesterol-lowering evolocumab (Amgen, Thousand Oaks, CA), the human monoclonal antibody for proprotein convertase subtilisin-kexin type 9 (PCSK9) met both of its co–primary end points, according to the top-line results of MENDEL-2 released this week [1] .

In addition, the company announced topline results from the DESCARTES study, a larger and longer study that tested evolocumab in patients for 52 weeks. Like the MENDEL-2 study, Amgen said the DESCARTES trial met its primary end point, which was the percent reduction from baseline in LDL cholesterol.

In MENDEL-2, evolocumab was tested at two doses, a subcutaneous injection of 140 mg every two weeks and a 420-mg injection once monthly, and both doses significantly lowered LDL-cholesterol levels from baseline after 10 and 12 weeks of treatment. The mean percent reductions in LDL cholesterol when compared with both placebo and ezetimibe (Zetia, Merck) were consistent with results observed in phase 2 studies, according to Amgen.

In a previous phase 2 study, a trial led by Dr Michael Koren (Jacksonville Center for Clinical Research, FL) and published late last year in the Lancet, treatment with the twice-monthly 140-mg dose lowered LDL-cholesterol levels by 50.9% after 12 weeks of treatment. The once-monthly 420-mg dose reduced LDL-cholesterol levels by 48.0%. Comparatively, treatment with ezetimibe reduced LDL-cholesterol levels 14.7% from baseline.

In the MENDEL-2 phase 3 study, which was also led by Koren, investigators included 614 patients with LDL-cholesterol levels>100 mg/dL and <190 mg/dL who were not currently receiving drug therapy. The primary outcome measures included the mean percent change from baseline in LDL cholesterol at weeks 10 and 12.

Patients were randomized to one of six experimental arms, including the two doses of subcutaneous evolocumab. In addition, the active comparator arms included patients randomized to subcutaneous placebo every two weeks or monthly in addition to 10 mg of ezetimibe. The placebo comparator arms randomized patients to subcutaneous placebo every two weeks or monthly and daily oral placebo.

The most commonly reported adverse events included headache, diarrhea, nausea, and urinary-tract infection. These events were balanced across the treatment groups.

With the phase 3 DESCARTES study, a safety and efficacy study of 901 individuals with elevated LDL-cholesterol levels, patients were treated with one of four background lipid-lowering strategies: dietary changes alone, dietary changes plus atorvastatin 10 mg, dietary changes plus atorvastatin 80 mg, and dietary changes plus atorvastatin 80 mg and ezetimibe 10 mg. For individuals who still had LDL-cholesterol levels >75 mg/dL, they were then randomized to monthly treatment with placebo or subcutaneous evolocumab 420 mg.

Regarding the 52-week reduction in LDL cholesterol, Amgen said the reduction was in line with that observed in the phase 2 Open-Label Study of Long-term Evaluation against LDL Cholesterol (OSLER) trial. In that study, as reported by heartwire , the once-monthly injections of evolocumab consistently suppressed LDL-cholesterol levels by about 50% compared with a standard-care approach.

Amgen plans to present the full results of MENDEL-2 and DESCARTES at a cardiology conference but where and when are currently unknown. The top-line results were disclosed to comply with US financial regulations.

As reported by heartwire , monoclonal antibodies are a busy research area, with several pharmaceutical companies developing drugs. Pfizer and Sanofi/Regeneron are also working on PCSK9 inhibitors, which are in various stages of development and in general have shown LDL-lowering prowess similar to evolocumab. Sanofi and Regeneron announced today that they are collaborating with the American College of Cardiology (ACC) in a manner that will help identify eligible patients for the upcoming phase 3 ODYSSEY OUTCOMES trial with alirocumab. The ACC will identify candidates for PSCK9 treatment through its PINNACLE registry. It is the first time the registry will be used for clinical-trial recruitment.

Amgen sponsored the MENDEL-2 and DESCARTES studies.

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