Munich, Germany—A total of 16 novel classes of drugs are under development for the management of lipoprotein metabolism toward the prevention of cardiovascular disease (CVD), according to John J.P. Kastelein, MD, PhD, Academic Medical Center, University of Amsterdam, the Netherlands. Dr Kastelein reviewed several of these approaches at the 2012 European Society of Cardiology (ESC) Congress.
New Approaches to LDL-C Reduction
Apolipoprotein (apo)-B mRNA antisense drugs, microsomal triglyceride transfer protein (MTP) inhibitors, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are promising new approaches to reducing low-density lipoprotein cholesterol (LDL-C), according to Dr Kastelein.
ApoB mRNA Antisense Drugs
Mipomersen (Kynamro; Genzyme/Sanofi, Isis Pharmaceuticals) is an apoB mRNA antisense drug that has been studied in a trial of patients with familial hypercholesterolemia. In addition to statin therapy and ezetimibe, a once-weekly subcutaneous injection of 200 mg mipomersen reduced LDL-C by 28% compared with 5.2% with placebo at 28 weeks (2 weeks after the final dose). The LDL-C reduction continued to increase over time.
“This is the beginning of personalized therapy,” according to Dr Kastelein. Applying the approach of personalized medicine in CVD, drugs such as mipomersen have the potential to be used for the highest-risk patients, which are expected to prove cost-effective and confer a positive risk-benefit ratio in this patient population.
ApoB mRNA antisense drugs work by decreasing the synthesis of apoB, a component of atherogenic lipoproteins and a central player in the pathogenesis of atherosclerosis. ApoB synthesis is inhibited by destroying the RNA for apoB in the liver cell. In contrast, currently available drugs lower the concentration of apoB by increasing its clearance.
MTP Inhibitors
The inhibition of the MTP limits the secretion of cholesterol and triglycerides from the intestine and the liver. This results in lower levels of chylomicrons and very-low-density liproprotein, and leads to lower levels of LDL-C, total cholesterol, and triglycerides.
BMS-201038/AEGR-733. In a phase 2, open-label study in patients with familial hypercholesterolemia and high LDL-C levels, in addition to optimal lipid-lowering therapy, the use of 1-mg/kg dose of BMS-201038/ AEGR-733 reduced LDL-C by approximately 50%, triglycerides by approximately 65%, and non–high-density lipoprotein cholesterol (HDL-C) by 60% (Cuchel M, et al. N Engl J Med. 2007;356:148-156). Despite the proof of concept, a limiting factor to be addressed is the side effect of diarrhea that results from blocking chylomicrons in the intestine. Other studies with this compound are under way or were recently completed.
PCSK9 Inhibitors
A 20-week study of SAR236553 (also known as REGN727; Sanofi) showed a rapid reduction in LDL-C of approximately 60% at week 2 and sustained at week 12, with a 150-mg subcutaneous injection of SAR236553 every 2 weeks in patients with familial hypercholesterolemia. Further study with this compound is ongoing.
AMG 145 (Amgen) is an investigational monoclonal inhibitor of PCSK9 currently in phase 2 clinical trials. The inhibitor compound binds to PCSK9, a circulating protein produced by the liver, and prevents it from binding to LDL receptors in the liver, allowing the LDL receptors to take up and remove LDL-C.
Some trials, including Treating to New Targets and the ongoing ILLUMINATE trial, are now measuring PCSK9 levels in the population with familial hypercholesterolemia, Dr Kastelein noted; they also investigate the suitability of PCSK9 inhibitors in patients with acute coronary syndromes because of the rapid reduction of LDL-C levels with these agents.
New Approaches to HDL
CETP Inhibitors
Anacetrapib (Merck) and evacetrapib (Eli Lilly) are 2 cholesterol ester transfer protein (CETP) inhibitors under development. These potent CETP inhibitors modify nearly all lipoproteins in the right direction, reducing LDL (by approximately 40%), non-HDL, apoB, lipoprotein(a), and particle numbers, and raising HDL (by approximately 138%).
No increase in cardiovascular events was seen with anacetrapib in the long-term Determining the Efficacy and Tolerability of CETP Inhibition with Anacetrapib (DEFINE) safety trial.
The Randomized Evaluation of the Effects of Anacetrapib Through Lipid- Modification (REVEAL) Heart Protection Study (HPS)-3 Thrombolysis In Myocardial Infarction (TIMI)-55 trial, which includes approximately 30,000 patients in the United States, Europe, and Asia with occlusive arterial disease, is comparing anacetrapib 100 mg versus placebo, in addition to atorvastatin, to determine its effect on the primary outcome of coronary death, myocardial infarction, or coronary revascularization. Results are expected to be reported in late 2016 or early 2017.
With evacetrapib, similar LDL reductions were seen (approximately 36% with the 500-mg dose and approximately 22% with the 100-mg dose), as well as increases in HDL (129% with the 500-mg dose and 95% with the 100-mg dose).
ApoA1-Based Strategies
A number of apoA1-based therapies are currently being developed. APL-180 (Novartis) is an apoA1 mimetic, which is an artificially constructed part of apoA1.
A full-length ApoA1 (Cerenis Therapeutics) is another drug in this class currently under development.
A delipidation approach to create pre-beta HDL (HDL Therapeutics) is generated by removing lipids from mature HDL to create immature HDL to be infused back into the patient with familial hypercholesterolemia. A small proof-of-concept study showed that this approach reduced total atheroma volume as assessed by intravascular ultrasound imaging. “Selective delipidation removes the cholesterol and restores it to pre-beta HDL,” said Dr Kastelein; he anticipates this approach will be tested in larger trials.
The SUSTAIN trial is a phase 2b clinical study of RVX-208, an apoA1-inducer (Resverlogix). Results from this trial of 176 patients were announced by the company just after the ESC Congress. At 24 weeks, RVX-208 increased HDL-C levels, the study primary end point, and increased apoA1 and large HDL particles, the secondary end points.
“In the next 5 years, we will prove or disprove that additional LDL-lowering with agents other than statins is effective, and whether or not the HDL hypothesis [with the infusion of HDL] is true,” said Dr Kastelein, referring to trials including IMPROVE IT with ezetimibe; HPS-2, with nicotinic acid; and REVEAL, with CETP inhibitors.