THURSDAY Oct. 3, 2013 — An experimental drug that lowers LDL “bad” cholesterol by helping sweep it from the bloodstream appears to be both safe and effective in its first human trial.
The drug known as ALN-PCS reduced cholesterol an average of 40 percent in the small, early study, and, if proven to work in large trials, potentially could replace or complement statins, the researchers said.
Currently, statin drugs such as Lipitor, Crestor and Zocor are widely used to control cholesterol. One heart doctor not involved with the new study said another class of drugs might be useful.
“Cardiovascular disease remains the leading cause of death of men and women globally and reduction of LDL cholesterol with statin medications has been demonstrated to substantially reduce the risk of first or recurrent cardiovascular events,” said Dr. Gregg Fonarow, a professor of cardiology at the University of California, Los Angeles.
However, while statin therapy is very effective for heart risk reduction and generally well tolerated, a substantial number of people cannot achieve ideal LDL cholesterol levels despite high statin dosing, he said. And others can’t take statins at all.
“As such there is an important need to develop addition therapies to lower LDL cholesterol,” Fonarow said.
The new trial demonstrated dramatic reductions in LDL cholesterol on top of statin therapy, he said, and “these agents are being further evaluated in very large randomized controlled clinical outcome trials.”
The report was published Oct. 3 in the online edition of The Lancet.
In this early, phase I trial, researchers tried the drug on 32 healthy patients with mild to moderate raised low-density lipoprotein (LDL) cholesterol. Patients were randomly assigned to one of six doses of ALN-PCS or an inactive placebo.
The drug, which is given intravenously, significantly reduced cholesterol. Those given the highest dose saw an average 40 percent reduction in LDL cholesterol, the researchers found.
ALN-PCS was well tolerated, and a similar number of patients in both groups had mild to moderate side effects (79 percent compared to 88 percent), such as a temporary rash. In addition, the drug didn’t cause any significant changes in liver function or inflammation, the researchers said.
The investigational drug works by blocking the production of a protein called PCSK9 that regulates cholesterol. This protein destroys LDL receptors that clear the artery-clogging cholesterol from the blood, the researchers explained.
Prior studies have shown that gene mutations that cause an increase in PCSK9 lead to increased LDL cholesterol, while gene mutations causing less PCSK9 appear to lower cholesterol. In addition, statins may actually boost levels of PCSK9, which could reduce their effectiveness, the researchers noted.
RNA interference is a process of gene “silencing” using small molecules of RNA to shut off particular genes — for example, PCSK9.
“The next step will be larger, multi-dose studies to address the long-term safety and tolerability of ALN-PCS in various patient populations, including those on statins and those who are statin-intolerant,” said study co-author Kevin Fitzgerald, senior director for research at Alnylam Pharmaceuticals, which helped develop the drug and funded the new study.
“Statins work for some patients but not for everyone,” he added, and new medicines are needed “to lower LDL-cholesterol and reduce the risk of coronary artery disease.”