Experimental Drug Cuts Arterial Plaque
Preliminary results from a small study reported in the Nov. 5 Journal of the American Medical Association (JAMA) could have important ramifications for the treatment of atherosclerosis.
The 47-patient study, led by Cleveland Clinic Foundation cardiologist Steven E. Nissen, examined the effect of five once-weekly infusions of recombinant apolipoprotein A-I (ApoA-I) Milanoactually, a complex of a naturally occurring phospholipid and a synthetic version of a variant apolipoprotein in high-density lipoprotein (HDL) cholesterolon the amount of arterial plaque in patients who had suffered an acute coronary event.
ApoA-I Milano corresponds to a naturally occurring form of ApoA-I discovered decades ago in a small population living in northern Italy. A mutation in the gene coding for ApoA-I Milano results in the expression of a form of HDL cholesterol that confers protection from atherosclerosis. People who express the protein have very low levels of HDL cholesterol but are not at increased risk for coronary disease.
According to the report, atheroma volume had decreased by 4.2 percent, on average, six weeks after patients received the first ApoA-I infusion. In contrast, plaque volume remained the same in patients in a placebo group.
Nissen expressed his surprise at the study participants' rapid response to the drug: "I really thought this was the longest of the longshots in the world, because we thought of [atherosclerosis], for a long time, as this kind of chronic, indolent, slowly advancing disease that didn't change by very much." Nissen made the comment during a Nov. 9 investors' conference hosted by Esperion Therapeutics of Ann Arbor, Mich., which funded the study and has licensed the ApoA-I Milano complex.
"We were just completely wrong," Nissen said. "We now know that coronary disease is more dynamic than previously realized and can be rapidly affected by agents that augment reverse cholesterol transport."
Reverse cholesterol transport is the movement of cholesterol from arterial plaques to the liver, which processes cholesterol for excretion in the bile. The ApoA-I component of HDL is thought to mediate the reverse transport process.
Patients were eligible for the study if diagnostic angiography performed within two weeks after a myocardial infarction or an episode of unstable angina showed atherosclerosis resulting in a 20 percent or greater narrowing of the luminal diameter in a major heart vessel. At baseline, the researchers examined the narrowed vessel using intravascular ultrasound, or IVUS. Within two weeks of each patient's receipt of the last dose of ApoA-I Milano complex or placebo, the vessel was examined again and the before-and-after IVUS images compared for changes in the atheroma burden.
Patients were randomized into three treatment groups and received once-weekly infusions consisting of 15 mg/kg of ApoA-I Milano complex, 45 mg/kg of the experimental drug, or 0.9 percent sodium chloride, the placebo treatment.
No difference in atheroma reduction was reported between the two ApoA-I Milano dosage groups, a finding that Nissen attributed to the drug's full activation of the reverse-cholesterol transport process at the lower dose.
Nissen said that the JAMA report included one particularly striking IVUS cross-section showing a reduction in atheroma diameter from 8.1 mm to 5.35 mm after treatment with the recombinant HDL.
"That plaque is 34 percent smaller at the end of five weeks," Nissen said. "When I saw that, I fell over. For a disease that's considered a chronic disease, to see a third of the plaque erased in five weeks, that was very exciting" news about the therapy's potential.
Nissen and his coauthors stressed the need for confirmation of the study's findings in a larger patient population and with a longer follow-up period.