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A Novel Cholesterol Lowering Drug Candidate: the PCSK9-inhibitor REGN727

An ongoing Phase I clinical trial for a new, experimental cholesterol-fighting drug is displaying very encouraging results.1 Researchers have known for some time that PCSK9 (proprotein convertase substilisin/kexin type 9) is a protein that binds to the Low-Density Lipoprotein Receptor (LDLR), which prevents LDLR from binding to LDL and removes it from circulation.2-4 Too much LDL (bad) cholesterol circulating in the blood can lead to the thickening of artery walls, which makes them less flexible and therefore impairs their function and increases the risk of heart disease.


Schematic diagram of A) normal artery and B) artery displaying plaque buildup and narrowing of the artery.
Figure 1. Schematic diagram of A) normal artery and B) artery displaying plaque buildup and narrowing of the artery.

 

In this phase one clinical trial, which is designed to determine if a drug is safe, researchers found that by using a monoclonal antibody called REGN727, that it was not only safe, but it also effectively blocked PCSK9 and therefore significantly reduced bad cholesterol in healthy patients as well as those also taking the popular cholesterol-lowering drug Lipitor. If these initial results continue in larger trials, the drug could prove to be more effective than statins, the widely prescribed drugs that have been very successful in lowering levels of LDL.

The REGN727 study included three trial arms. Two arms used 72 healthy volunteers who were either injected with a single dose of the drug in increasing amounts to test for side effects. A third arm included 21 people with a family history of high cholesterol, and 30 people with nonfamilial high cholesterol. All of those subjects were also receiving treatment with the statin Lipitor. A control group of subjects with nonfamilial high cholesterol was treated only with a special diet. None of the subjects who received REGN727 discontinued the study because of adverse effects, and the subjects who received REGN727 had a striking reduction of 60-65% in LDL cholesterol.1

 

Heart Disease and Cholesterol
Cardiovascular or heart disease, mainly atherosclerosis, remains the leading cause of death in the United States and throughout the world. Elevated levels of LDL cholesterol and/or reduced levels of HDL cholesterol in human plasma are major risk factors for heart disease.

Cholesterol is a fatty substance that is an important part of the outer lining of cells in the body of animals. Cholesterol in the blood originates from dietary intake and liver production. Dietary cholesterol comes primarily from animal sources including meat, poultry, fish, and dairy products. LDL (low density lipoprotein) cholesterol is called "bad" cholesterol, because elevated levels of LDL cholesterol are associated with an increased risk of coronary artery disease. HDL (high density lipoprotein) cholesterol is called the "good cholesterol" because HDL cholesterol particles prevent atherosclerosis by extracting cholesterol from artery walls and disposing of them through liver metabolism. Research has shown that lowering LDL cholesterol reduces the risk of heart attacks, strokes, and peripheral artery disease.

Because elevated LDL cholesterol levels are a definite risk for developing heart disease, there are treatment options for this early warning sign. Adopting a healthy lifestyle can help prevent high cholesterol levels, but sometimes adding a prescription medication is necessary to lower cholesterol levels.

The most frequently used cholesterol lowering medication is the family of statin drugs.5 Statins work by inhibiting the enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is a major enzyme involved in synthesizing cholesterol in the liver. This results in reduced cholesterol levels in liver cells, which then meet their cholesterol requirements by taking up cholesterol circulating in the blood, via a protein on the liver cell surface called an LDL receptor. LDL receptors break down the circulating cholesterol, which results in reduced levels of LDL cholesterol in the blood. Evidence exists to suggest that statins increase the number of liver cell LDL receptors.5

The drug candidate being studied in the phase I trial is based on another avenue to lower cholesterol levels. PCSK9 (proprotein convertase substilisin/kexin type 9) is a protein that binds to LDLR, which prevents LDLR from binding to LDL and removes it from circulation. People who have a mutation that reduces the activity of PCSK9 have lower levels of LDL, as well as a reduced risk of cardiovascular events.


REGN727
PCSK9 is a protein that binds to LDLR, which prevents LDLR from binding to LDL and removes it from circulation. Regeneron and Sanofi have prepared a humanized monoclonal antibody to PCSK9.1 As a PCSK9 inhibitor, the monoclonal antibody called REGN727, is designed to bind to PCSK9 and prevent it from inhibiting LDLR. This PCSK9 inhibitor may offer advantages over the statin cholesterol lowering drugs in that it is not potentially toxic and it does not also increase blood glucose levels in the patient.  

Schematic of antibody structure showing variable and constant regions.
Figure 2: Schematic of antibody structure showing variable and constant regions.

REGN727 as a monoclonal antibody is unique as a drug candidate because antibodies produced in species other than human can be antigenic themselves and thus only able to be given as a dose one single time. Regeneron has used their VelocImmune® technology to derive a fully human monoclonal therapeutic antibody.6 Unlike other technological platforms, VelocImmune mice take advantage of the normal murine humoral response to create high affinity therapeutic antibodies. VelociGene technology, is a proprietary, high-throughput process using automated systems to make virtually any genetic modification in mouse Embryonic Stem (ES) cells. Therefore, the resulting antibodies possess fully human variable regions linked to murine constant regions utilizing the genuine murine expression control mechanisms. Despite the fact that the antibodies produced by VelocImmune mice possess mouse constant regions, Regeneron scientists have developed high-throughput methods to join the desired variable regions to human constant regions of any type, and followed by subsequent insertion into mammalian production lines to create fully human antibodies.6

 

The therapeutic monoclonal antibody directed against PCSK9, produced in this way, is showing strong results at this early stage of clinical trials. Other pharmaceutical companies are also developing antibodies against PCSK9 in an aim to reduce LDL cholesterol levels to prevent heart disease.3,4,7,8

 

References:

  1. Stein, E.A. et al., (2012) N Engl J Med (2012) 366:1108-1118.
  2. Costet, P. et al., (2008) Trends in Biochemical Sciences, 33; 426-434.
  3. Cao, G. et al., (2008) Endocrine, Metabolic and Immune Disorders – Drug Targets 8; 238-243.
  4. Kwon, H.J. et al., (2008) PNAS 105: 1820-1825.
  5. Statin Answers, http://www.statinanswers.com/science1.htm
  6. Stevens, S. (2011) Pharma Focus Asia http://www.pharmafocusasia.com/clinical_trials/human_antibody_discovery.htm (velocimmune-regeneron)
  7. Zhang, L., et al., Int J Biol Sci. (2012) 8: 310–327.
  8. Amgen's PCSK9 Inhibitor Reduced LDL Cholesterol up to 81 Percent in Phase 1b Study, http://www.amgen.com/media/media_pr_detail.jsp?releaseID=1676152
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