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A piece of the PCSK9 pie
September 2013
by Kelsey Kaustinen  |  Email the author


The science of genomics has grown exponentially in recent years, and one of the fields in which it's making the biggest waves is in cholesterol management.  
The interest started in 2003 when Abifadel, et al., noted in Nature Genetics the existence of a mutation in the gene protein convertase subtilisin-like/kexin type 9 (PCSK9). While the function of the gene was unknown, the mutation slowed the body's ability to get rid of LDL cholesterol. Dr. Jonathan Cohen, director of the McDermott Center for Human Growth and Development at University of Texas Southwestern and investigator at the Howard Hughes Medical Institute at UT Southwestern, and Dr. Helen Hobbs, a professor in the UT Southwestern Department of Medicine Department of Molecular Genetics at the University of Texas Southwestern Medical Center, then hypothesized that if one mutation could lead to high LDL levels, other similar mutations might exist that could instead result in very low LDL levels.  
Cohen and Hobbs then located a study that revealed 2.5 percent of black individuals in the study possessed a mutated PCSK9 gene that no longer functioned, and those with one copy of a disabled gene presented with lower-than-normal LDL levels and a high resistance to heart disease, even in the presence of risk factors such as high blood pressure, diabetes and/or smoking. The potential of such a mechanism is easy to see.
Their work hasn't stopped there, as the main focus of the Hobbs-Cohen Laboratory, as noted on their website, is "how dysregulation of lipid uptake and trafficking contributes to human diseases. A major focus of our research effort is to elucidate the role of PCSK9, PNPLA3 and the ANGPTL proteins in the trafficking and processing of lipids and lipoproteins."
In related research, a team of scientists for the Cohorts for Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium published a paper in Nature Genetics in which they cover "initial steps for interrogating whole-genome sequence data to characterize the genetic architecture of a complex trait, levels of high-density lipoprotein cholesterol." Based on sequencing data from CHARGE studies, the researchers "estimate that common variation contributes more to heritability of HDL-C levels than rare variation, and screening for Mendelian variants for dyslipidemia identified individuals with extreme HDL-C levels. Whole-genome sequencing analyses highlight the value of regulatory and non-protein-coding regions of the genome in addition to protein-coding regions."
The traditional approach to treating high cholesterol generally seeks to block the body's ability to absorb cholesterol, encouraging it to burn it up instead. The most common drugs are statins, which block the production of cholesterol in the liver, helping to lower LDL cholesterol and triglycerides. Lipitor, Pfizer's blockbuster cholesterol drug, falls in the category of statins, as do Zocor, Pravachol and Crestor.
But with the publication of this research on the effects of PCSK9, several companies are racing to get drug candidates to market that harness this genomics approach instead. Amgen is advancing AMG 145, a Phase III human monoclonal antibody that inhibits PCSK9 for the treatment of hyperlipidemia. In November 2012, Amgen reported that AMG 145, in combination with statin therapy (with or without ezetimibe) lowered LDL cholesterol by up to 56 percent in patients with heterozygous familial hypercholesterolemia.  
Sanofi and Regeneron Pharmaceuticals Inc. are advancing REGN727/SAR236553 for the treatment of hypercholesterolemia, announcing in November 2011 that patients in their Phase II study saw mean reductions in LDL cholesterol in the range of 30 percent to more than 65 percent. A Phase III program for the drug candidate was launched in July 2012. Pfizer also has its hat in the game, no doubt seeking a comeback after its Lipitor earnings atrophied in the face of generic competition; its version of a PCSK9 drug is RN 316, currently in Phase II development for the treatment of hypercholesterolemia.  
There's no shortage of market potential for cholesterol management, as the current market for cholesterol drugs is close to $40 billion. According to the Centers for Disease Control and Prevention (CDC), 71 million Americans have high LDL (or "bad ") cholesterol, representing roughly 33.5 percent of the population. Only one out of every three adults with high cholesterol have it under control, and less than half get treatment. In addition, those with high total cholesterol face approximately twice the risk of heart disease, which remains the leading cause of death in the United States. The CDC also reports that the average total cholesterol level for American adults is 200 mg/dL, which is borderline high risk.
Code: E091319



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