Researchers found that a human monoclonal antibody was well-tolerated in statin intolerant patients and reduced low density lipoprotein cholesterol (LDL-C) levels by 40.8 percent to 63 percent, depending on dosage. These findings were presented Nov. 5 at the American Heart Association scientific sessions in Los Angeles and were simultaneously published online in the Journal of the American Medical Association.

Statins are the standard treatment for therapeutic reduction of LDL-C, but of the estimated 20 million Americans who are annually treated with statins, between 10 and 20 percent are unable to tolerate the medication because of muscle-related side effects. The most widely used alternative for these patients is ezetimibe, a drug that inhibits cholesterol absorption and has been shown to reduce LDL-C levels by an average of 18 percent, which is not a sufficient reduction to be an effective treatment for most statin-intolerant patients.

A Phase 1 study has shown that a human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PKSK9) is effective in reducing LDL-C levels (J AM Coll Cardiol online Oct. 17). The monoclonal antibody, AMG145, interferes with LDL-C's ability to bind to cell receptors. David Sullivan, MD, of the Royal Prince Albert Hospital in Camperdown, Australia, and colleagues conducted this Phase 2 randomized, double-blind, placebo and ezetimibe-controlled, dose ranging study to assess the effectiveness and safety of AMG145 in patients who are not able to take statins. 

Between July 2011 and May 2012, the GAUSS (Goal Achievement after Utilizing an anti-PCSK9 anti-body in Statin-Intolerant subjects) investigators enrolled adults aged 18 to 75 at 33 sites in North America, Australia and Europe for 12 weeks of treatment with various doses of AMG145, AMG145 plus ezetimibe or placebo plus ezetimibe. Patients were eligible if they had LDL-C levels of 100mg/dL or greater with diagnosed coronary heart disease (CHD) or risk equivalent, or 130 mg/dL or greater without CHD or risk equivalent and two or more risk factors, or 160mg/dL without CHD or risk equivalent and with zero or one risk factor. Patients were considered statin-intolerant if standard doses of statins produced intolerable myalgia or myopathy and symptoms improved or resolved when they stopped taking statins.

Patients who met the study's inclusion and exclusion criteria and were evenly randomized and stratified by screening levels of LDL-C (less than 130mg/dL or 130 mg/dL or greater). Every four weeks over a 12-week period the participants received:

• AMG145 280mg, or
• AMG145 350mg, or
• AMG145 420mg, or
• AMG145 420 mg plus 10mg ezetimibe daily, taken orally, or
• Placebo plus 10 mg ezetimibe daily, taken orally.

The study included 157 patients who received at least one dose of investigational product; 155 patients completed the study through the final visit and 150 received all planned doses. Participant characteristics at baseline were similar among all groups. The mean age of participants was 62 years, 64 percent were female, and the mean baseline LDL-C level was 191mg/dL. All patients were statin-intolerant; 90 percent reported statin-induced myalgia and 9 percent reported myositis when treated with statins.

The primary endpoint was percentage change from baseline LDL-C levels measured at week 12. Safety endpoints were treatment-emergent adverse events, laboratory values, vital signs and electrocardiographic parameters and incidence of anti-AMG145 antibodies.

The researchers found a dose-dependent reduction in LDL-C levels among all participants who received AMG145 in their investigational product. At a 280mg dose, the mean reduction was 41 percent; at 350 mg, it was 43 percent, at 420 mg, a 51 percent reduction was found, and 63 percent reduction occurred among the group receiving 420mg AMG145 plus daily ezetimibe. In contrast, the group receiving placebo plus ezetimibe experienced a reduction of only 15 percent.

Sullivan et al reported that the reduction in LDL-C was significantly greater with every dose of AMG145. In groups taking AMG145 alone, 54 percent of the patients achieved LDL-C levels of less than 100mg/dL and 18 percent reached levels of less than 70mg/dL. Among the groups receiving placebo plus ezetimibe, 7 percent reached a level of less than 100mg/dL and none reached less than 70mg/dL. The most robust reductions were noted in the group treated with 420mg AMG145 plus ezetimibe: 90 percent of those patients achieved LDL-C levels of less than 100mg/dL and 62 percent reached less than 70mg/dL.

The authors reported that patients generally tolerated AMG145 well. Among patients receiving AMG145, 60 percent reported treatment-emergent adverse events, mainly myalgia, compared with 59 percent of the patients receiving placebo/ezetimibe. However, 94 percent of patients were able to complete the study.

"No relationship was apparent between the incidence of any single treatment-emergent AE and AMG145 dose, and the overall incidence of treatment-related AEs did not appear to be dose-related," the authors wrote. Four serious AEs occurred, all in patients receiving AMG145, but none were treatment-related.

The results achieved with AMG145 are "comparable with those achieved with maximal doses of the most efficacious statins," and these benefits occurred "without significant muscle-related side effects, in patients predisposed to such side effects," the authors wrote.

They added that the study used a short, 12-week period and that in a clinical setting the drug would be administered over a longer period. Also, ezetimibe administration was not blinded. The authors suggested larger studies with blinded ezitimibe are needed to adequately assess the effectiveness and safety of the AMG145/ezetimibe combination.