New Treatments in Pipeline Raise HDL in Short, Long Term
NEW YORK — Drug treatments that raise serum HDL cholesterol are already available, but several potentially better, more targeted treatments are moving through the development pipeline, H. Bryan Brewer Jr., M.D., said at an international symposium on triglycerides and HDL.
The new treatments are in a range of development stages, from preclinical animal studies to phase III clinical trials, said Dr. Brewer, director of lipoprotein and atherosclerosis research at the Washington Hospital Center.
Short-term treatments to raise HDL are geared to treating patients with acute coronary syndrome (ACS) who need rapid plaque stabilization. This approach includes infusion of exogenous apolipoprotein A1, the main protein component of HDL cholesterol, delipidation of HDL, or infusion of an apo A1 mimetic peptide.
Long-term treatments designed to lower cardiovascular risk are also in the works. The strategies include oral treatment with an apo A1 mimetic peptide or treatment with an agent that inhibits the cholesterol ester transfer protein (CETP), which is involved in regulating the size of cholesterol particles. Reduced CETP activity is antiatherogenic.
Speaking at the symposium, sponsored by the Giovanni Lorenzini Medical Foundation, Dr. Brewer summarized the progress to date on these treatments:
▸ Apo A1 infusion. The first of the new wave of HDL cholesterol treatments used a recombinant, variant apo A1 protein, apo A1 Milano. Five weekly infusions of apo A1 Milano given to 36 patients with ACS led to an average drop in atheroma volume of about 1%, a significantly better reversal of atherosclerosis than was seen in a control group of 11 patients (JAMA 2003;290:2292–300). The results of this “landmark” study showed that rapid regression of atherosclerosis was possible and that acute apo A1 infusions could be given to patients with ACS, Dr. Brewer said. Clinical testing is ongoing.
▸ HDL delipidation. In this process, a patient undergoes plasmapheresis to remove cholesterol from existing HDL particles using an organic solvent. The delipidated HDL is then returned to the patient. This 4-hour treatment can increase cholesterol efflux about 20-fold, said Dr. Brewer. It is scheduled to start clinical testing in late 2005. Dr. Brewer is also chief scientific director for Lipid Sciences Inc., the company that is developing this treatment.
▸ Synthetic apo A1 mimetic peptide. Researchers have produced an 18-amino-acid peptide that mimics the structure of a portion of the amphipathic, helical peptide that forms apo A1. In vitro and animal studies indicate that the 18-amino-acid peptide can remove cholesterol from cells without cytotoxicity. Animal studies are continuing with this intravenous agent.
▸ CETP inhibitors. The most advanced of these agents is torcetrapib. In a pilot, uncontrolled study with 19 patients, 120 mg torcetrapib daily for 4 weeks boosted serum HDL by about 50% (N. Engl. J. Med. 2004;350:1505–15). Torcetrapib's clinical efficacy is being tested in a study that will follow atherosclerosis regression using intravascular ultrasound. But, in a controversial move, Pfizer, which is developing torcetrapib, is now studying it clinically only in combination with atorvastatin. Another CETP inhibitor, JTT-705, is being developed by Roche and is also in clinical studies.
▸ Oral synthetic apo A1 mimetic peptide. The D-4F peptide is similar in concept to the other synthetic apo A1 mimetic peptide under study, except it is made exclusively from D-amino acids, is not digested, and is orally active. The D-4F peptide is in early-phase human testing.
