New Cholesterol-Lowering Drugs Shows Exciting Promise
Taking a different path, PCSK9 inhibitors reduce LDL levels in statin-intolerant patients.
For patients who are unable to reap cholesterol-lowering benefits from the drugs known as statins due to intolerable side effects, technology may soon offer an alternative and effective treatment.
While statins, including the most commonly used atorvastatin (Lipitor), simvastatin (Zocor,) and rosuvastatin (Crestor) are the first line of treatment for reducing levels of the artery-clogging fatty deposits that increase “bad” cholesterol (LDL) levels, a new class of drugs may provide an unmet need in cholesterol-lowering alternatives, according to Michael Rocco, MD, Medical Director of Cardiac Rehabilitation and Stress Testing and staff cardiologist at Cleveland Clinic.
Known as PCKS9 inhibitors, the drugs have shown to lower LDL cholesterol by more than 40 to 60 percent in small Phase 2 studies released by Amgen Inc. and Pfizer Inc. at the annual scientific meeting of the American Heart Association (November 2012).
The experimental PCKS9 inhibitor drugs targets a protein (PCKS9) that reduces the ability of the liver to remove artery-blocking cholesterol from the bloodstream. Using a novel approach, PCKS9 inhibitors are given by injection every two or four weeks. Amgen’s drug AMG 145 showed it can reduce LDL levels by as much as 55 percent even when combined with statins in patients genetically predisposed to high cholesterol.
The cholesterol-lowering benefits offered by PCKS9 inhibitors is welcome news to the roughly one million U.S. patients who are intolerant to statins and another 11 million whose cholesterol is not managed effectively by the drugs. “The most common side effects from statins include muscle pain, liver damage, digestive problems and for some, memory loss,” says Dr. Rocco. “Patients who cannot take statins and are at risk of heart disease or recurrent heart attacks have few effective alternatives proven to reduce adverse events.”
How it works
Statins lower cholesterol by blocking a key enzyme linked to the liver’s ability to produce cholesterol. By increasing the number of LDL receptors on the surface of liver cells, statins result in more cholesterol being removed form the bloodstream and a reduction in risk for high-cholesterol related diseases.
Alternatively, the fully human monoclonal antibody PCSK9 inhibitors lower bad cholesterol by preventing PCKS9 from binding to and degrading the LDL receptors in the liver resulting in more available to remove excess LDL cholesterol. Without PCKS9 bound to them, the LDL receptors are able to remove LDL-cholesterol from the blood, recycle and remain available for binding additional LDL-cholesterol.
“In many patients, increasing the level of statin therapy may be limited by worsening side effects or may not add sufficient further lowering of LDL cholesterol to achieve goals of treatment,” explains Dr. Rocco. “While we prefer to try two or more different types of statins before deciding if patients are intolerant to the drugs, often the side effects prevent us from continuing use.”
To help determine the possible future use of PCKS9 inhibitors in patients who are in tolerant to or are only able to take the lowest dose of the statins Cleveland Clinic is participating as a Phase III clinical trial site for Amgen’s drug AMG 145. As part of a worldwide effort to review the use of AMG 145 in 300 statin intolerant patients, Cleveland Clinic’s will follow six to eight patients throughout a 12-week period. The subcutaneous injections will be given every two or four weeks, with the goal of patients being instructed on how to administer the drug at home.
“The reduction in LDL cholesterol with the product from AMG 145 and other PCSK9 inhibitors is impressive, but we now need to determine if there are any safety issues due to long-term use and if there are the benefts of risk reduction seen with statins,” Dr. Rocco says. “The common side effects seen so far from AMG 145 are similar to statins, including muscle pain and nausea and fatigue. Further trials will determine if the benefits outweigh the risks.”