Amgen’s PCSK9 inhibitor, evolucumab (AMG145) met its co-primary endpoints in a phase 3 trial: the percent reduction from baseline in low-density lipoprotein cholesterol (LDL-C) at week 12, and the mean percent reduction from baseline in LDL-C at weeks 10 and 12. The mean percent reductions in LDL-C, or “bad” cholesterol, compared to placebo and ezetimibe were consistent with results observed in the MENDEL Phase 2 study.
Amgen (AMGN) announced the findings of the MENDEL-2 trial, which evaluated safety, tolerability and efficacy of evolocumab in 614 patients with high cholesterol. The full findings will be presented at a future medical conference. The trial looked at AMG145 as a standalone treatment. In November, Amgen announced positive results for OSLER-2, which looked at AMG-145 in conjunction with standard of care (statin) treatments.
While we do not have detailed results yet, the top-line results are noteworthy. As in the OSLER-2 trial, AMG145 worked to lower cholesterol when combined with a statin, but did not appear to do so as a standalone treatment.
According to the American Heart Association, an estimated 71 million Americans have high cholesterol, which is considered a significant risk in heart attacks, strokes and other coronary diseases.
Statin drugs such as Pfizer’s (PFE) atorvastatin (Lipitor), Merck’s (MRK) simvastatin (Zocor), AstraZeneca’s (AZE) rosuvastatin (Crestor) and generic equivalents, block an enzyme called HMG-CoA reductase, which controls cholesterol production in the liver. When the liver senses that HMG-CoA reductase levels are too low, the liver responds by creating a protein that leads to an increase in the production of LDL (low density lipoprotein, or “bad” cholesterol) receptors.
The liver helps to clear LDL from the body; however, in some patients, the PCSK9 protein inhibits the liver’s ability to clear LDL from the patient’s blood. Amgen’s Evolucumab (AMG145) inhibits the PCSK9 protein, enabling the liver to remove LDL more effectively.
MENDEL-2 is a phase 3 randomized, multi-center, double-blind, double-dummy, stratified, placebo and ezetimibe/Zetia-controlled parallel group study designed to evaluate the efficacy and safety of evolocumab in 614 patients with high cholesterol with a 10-year Framingham risk score of 10 percent or less who were not receiving lipid-lowering therapy.
Ezetimibe (Zetia) lowers plasma cholesterol levels by decreasing cholesterol absorption in the small intestine. It may be used alone when other cholesterol-lowering medications are not tolerated, or together with when statins alone do not control cholesterol.
Patients were randomized to one of six treatment groups to compare two dosing regimens of evolocumab/AMG145 (140 mg every two weeks or 420 mg monthly) with placebo and ezetimibe/Zetia (10 mg daily). The co-primary endpoints were the percent reduction from baseline in LDL-C at week 12 and the mean percent reduction from baseline in LDL-C at weeks 10 and 12. Secondary efficacy endpoints included the absolute change from baseline in LDL-C at week 12 and the percentage changes from baseline at week 12 in non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), total cholesterol (TC)/HDL-C, ApoB/apolipoprotein A1 (ApoA1) ratio, lipoprotein(a), triglycerides, HDL-C and very LDL-C (VLDL-C).
Recently the FDA commented that companies working on a new class of cholesterol-lowering drugs known as PCSK9 inhibitors, may not have to prove they also reduce the risks or heart attacks and strokes. If this holds, AMGN and other companies with PCSK9 inhibitors could see a reduction in the cost and time to market for their new products. Two medical groups altered their guidelines suggesting doctors focus on drugs that have been proven to reduce risk for heart attack and stroke and not just help patients reach targets for lowering their LDL cholesterol.
