Treatment with a monoclonal antibody designed to reduce low-density lipoprotein (LDL) cholesterol in at-risk patients who were statin intolerant lowered lipid levels and improved adherence compared with statins in a study presented Nov. 17 at the American Heart Association scientific session in Chicago.

“I don’t think people realize how complex these patients are,” lead investigator and study presenter Patrick M. Moriarty, MD, told Cardiovascular Business. As director of clinical pharmacology at the University of Kansas Medical Center in Kansas City, Moriarty said as many as half of the patients who present at his clinic are statin intolerant. In other studies, 10 percent to 25 percent of patients report being statin intolerant, making the need for an alternative treatment acute.

“I call them delicate flowers,” he continued. These patients are at risk of cardiovascular events but statin-related complications such as muscle pain make it difficult for them to adhere to treatment. The mechanisms behind this side effect are not clearly understood and even the definition of statin intolerance may be murky.

ODYSSEY ALTERNATIVE, one of 14 trials in the ODYSSEY phase III clinical program, was designed to overcome some of the limitations of previous studies involving statin-intolerant patients. Moriarty presented safety and efficacy results for alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, during the late-breaking clinical trial session.

The international, randomized, double-blind, double-dummy placebo-controlled study required several stages. The study enrolled patients who were very high-, high- or moderate-risk who had a history of statin intolerance, which was defined as the inability to tolerate at least two different statins because of skeletal-muscle symptoms, with one of the statins at the lowest approved starting dose.

During a single-blind run-in period, all patients received placebo subcutaneous injections and placebo pills. Those who reported muscle-related adverse events were excluded. The remaining 314 patients were randomized to alirocumab 75 mg and a daily oral placebo (126 patients); a placebo subcutaneous injection and daily oral ezetimibe 10 mg, a recommended option for statin-intolerant patients (125 patients); or a placebo subcutaneous injection and daily oral atorvastatin 20 mg (63 patients). Alirocumab dose could be increased at week 12, depending on baseline risk and lipid levels at week eight.

The study also included a three-year open label treatment period after the 24-month double-blind treatment period.

The primary efficacy endpoint was the change in LDL cholesterol between baseline and week 24 for the alirocumab and ezetimibe groups. The safety analysis assessed treatment-emergent adverse events and adherence.

At 24 weeks, the alirocumab group experienced a greater change in LDL cholesterol from baseline compared with the ezetimibe group, at a reduction of 45 percent vs. 14.6 percent. More patients in the alirocumab group reached target lipid levels, at 42 percent vs. 4 percent for the ezetimibe group.

For safety, fewer patients in alirocumab group reported skeletal-muscle-related treatment-emergent adverse events than in the ezetimibe group and the atorvastatin group (32.5 percent vs. 41.1 percent vs. 46 percent, respectiely) and fewer discontinued treatment as a result (15.9 percent vs. 20.2 percent vs. 22.2 percent, respectively).

Almost 90 percent of patients continued on the open-label study. Discontinuation due to skeletal-muscle-related treatment-emergent adverse events dropped to 1.4 percent in the open-label period.

“[Alirocumab] is safer, more efficacious than ezetimibe and more potent,” Moriarty said. He called it a win-win for patients with the potential to dramatically change treatment for statin-intolerant patients.