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Heart & Vascular Institute Physician eNewsletter - Fall 2013

Cleveland Clinic studies focus on PCSK9 inhibition

While statin therapy is an effective first-line treatment for patients diagnosed with high cholesterol and with coronary artery disease (CAD), many patients fail to achieve adequate LDL-C reduction despite maximally tolerated statin treatment, and others are intolerant to statins.

Current drug development research seeking to solve these problems is focused on an unexpected area: biologics. Ongoing clinical studies — including those led by Cleveland Clinic — are evaluating monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, or PCSK9.

“These are promising drugs, but it’s still early in the testing process,” says Steven Nissen, MD, chairman of the Department of Cardiovascular Medicine in Cleveland Clinic’s Miller Family Heart & Vascular Institute. “If PCSK9 inhibitors prove to be both safe and effective, it’s worth getting excited about. It means virtually anybody will be able to reach their LDL-cholesterol target.”

PCSK9 inhibition is being studied in a broad group of patients with hyperlipidemia and mixed dyslipidemia. Three groups of special interest, since they often are unable to see the full benefits of current LDL-C lowering goals, include those with familial heterozygous hypercholesterolemia, patients prescribed statin therapy but unable to achieve treatment goals, and individuals unable to tolerate statins.

How PCSK9 inhibitors work

PCSK9 inhibitors increase liver surface LDL receptors and cholesterol clearance by preventing the newly identified PCSK9 protein from degrading LDL receptors. These biologics, which are administered subcutaneously every two to four weeks, have the potential to lower LDL-C more effectively than the highest doses of the most powerful statins, Dr. Nissen says.

Study results presented at the American Heart Association Scientific Sessions in 2012 and at major cardiology conferences in 2013 found PCSK9 inhibitors can lower LDL-C between 40 and 70 percent when used alone or combined with a statin with or without ezetimibe.

While optimal dosing regimens for these investigational agents are still being evaluated, their effects appear to be long lasting.

Cleveland Clinic-led research

Cleveland Clinic, with Dr. Nissen serving as principal investigator, is leading a multi-center international trial (GLAGOV) focused on the effect of the PCSK9 inhibitor AMG145 on the regression of CAD. Additional phase 3 clinical trials of the agent, guided by Cleveland Clinic site principal investigator Michael Rocco, MD, are examining the use of the drug in patients intolerant to statins (GAUSS-2) and assessing longer-term safety in an open-label study (OSLER-2).

“If these studies and others demonstrate long-term safety and tolerability along with continued efficacy, this class of drug may offer an alternative for the up to 10 percent of individuals unable to tolerate adequate doses of statins,” says Dr. Rocco, Medical Director of Cardiac Rehabilitation and Stress Testing, Section of Preventive Cardiology at Cleveland Clinic.

In the GLAGOV trial, the agent’s effect on plaque growth in coronary arteries is being measured by intravascular ultrasound (IVUS). Results are expected in two to three years.

“Long-term phase 3 studies such as the intracoronary ultrasound study we are conducting will allow us to better assess safety and the impact of these drugs on the development of atherosclerosis,” Dr. Rocco says. “These drugs so far appear to be safe and effective at reducing LDL-cholesterol. What remains to be shown is whether the very low LDL-C levels achievable with them will have an impact on reducing heart attack and cardiac-related death.”

Tremendous potential

Overall, the ability of PCSK9 inhibitors to dramatically lower LDL-C levels in various populations of patients with dyslipidemia holds tremendous potential for reducing heart-disease risk in patients who cannot benefit maximally from statins.

However, not everyone has responded to PCSK9 inhibitors. People with certain genetically driven types of dyslipidemia with few or no functioning LDL receptors may not benefit.

So far, few serious side effects have been reported in short-term studies; the ongoing phase 3 trials will assess longer-term safety and tolerability. Some studies have reported irritation at the injection site and there have been limited reports of myalgia and creatinine-kinase elevation signals.

For information or to inquire about possible patient enrollment, please contact: Nurse coordinator Christine Shin, RN, at 216.445.6397 or

Reviewed: 09/13

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This information is provided by Cleveland Clinic and is not intended to replace the medical advice of your doctor or health care provider. Please consult your health care provider for advice about a specific medical condition.

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