A piece of the PCSK9 pie

The science of genomics has grown exponentially in recentyears, and one of the fields in which it's making the biggest waves is incholesterol management.

The interest started in 2003 when Abifadel, et al., noted in Nature Genetics the existence of a mutation in the gene proteinconvertase subtilisin-like/kexin type 9 (PCSK9). While the function of the genewas unknown, the mutation slowed the body's ability to get rid of LDLcholesterol. Dr. Jonathan Cohen, director of the McDermott Center for HumanGrowth and Development at University of Texas Southwestern and investigator atthe Howard Hughes Medical Institute at UT Southwestern, and Dr. Helen Hobbs, aprofessor in the UT Southwestern Department of Medicine Department of MolecularGenetics at the University of Texas Southwestern Medical Center, thenhypothesized that if one mutation could lead to high LDL levels, other similarmutations might exist that could instead result in very low LDL levels.

Cohen and Hobbs then located a study that revealed 2.5percent of black individuals in the study possessed a mutated PCSK9 gene thatno longer functioned, and those with one copy of a disabled gene presented withlower-than-normal LDL levels and a high resistance to heart disease, even inthe presence of risk factors such as high blood pressure, diabetes and/orsmoking. The potential of such a mechanism is easy to see.

Their work hasn't stopped there, as the main focus of theHobbs-Cohen Laboratory, as noted on their website, is "how dysregulation oflipid uptake and trafficking contributes to human diseases. A major focus ofour research effort is to elucidate the role of PCSK9, PNPLA3 and the ANGPTLproteins in the trafficking and processing of lipids and lipoproteins."

In related research, a team of scientists for the Cohortsfor Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortiumpublished a paper in Nature Genetics inwhich they cover "initial steps for interrogating whole-genome sequence data tocharacterize the genetic architecture of a complex trait, levels ofhigh-density lipoprotein cholesterol." Based on sequencing data from CHARGEstudies, the researchers "estimate that common variation contributes more toheritability of HDL-C levels than rare variation, and screening for Mendelianvariants for dyslipidemia identified individuals with extreme HDL-C levels.Whole-genome sequencing analyses highlight the value of regulatory and non-protein-codingregions of the genome in addition to protein-coding regions."

The traditional approach to treating high cholesterolgenerally seeks to block the body's ability to absorb cholesterol, encouragingit to burn it up instead. The most common drugs are statins, which block theproduction of cholesterol in the liver, helping to lower LDL cholesterol andtriglycerides. Lipitor, Pfizer's blockbuster cholesterol drug, falls in thecategory of statins, as do Zocor, Pravachol and Crestor.

But with the publication of this research on the effects ofPCSK9, several companies are racing to get drug candidates to market thatharness this genomics approach instead. Amgen is advancing AMG 145, a Phase IIIhuman monoclonal antibody that inhibits PCSK9 for the treatment ofhyperlipidemia. In November 2012, Amgen reported that AMG 145, in combinationwith statin therapy (with or without ezetimibe) lowered LDL cholesterol by upto 56 percent in patients with heterozygous familial hypercholesterolemia.

Sanofi and Regeneron Pharmaceuticals Inc. are advancingREGN727/SAR236553 for the treatment of hypercholesterolemia, announcing inNovember 2011 that patients in their Phase II study saw mean reductions in LDLcholesterol in the range of 30 percent to more than 65 percent. A Phase IIIprogram for the drug candidate was launched in July 2012. Pfizer also has itshat in the game, no doubt seeking a comeback after its Lipitor earningsatrophied in the face of generic competition; its version of a PCSK9 drug is RN316, currently in Phase II development for the treatment ofhypercholesterolemia.

There's no shortage of market potential for cholesterolmanagement, as the current market for cholesterol drugs is close to $40billion. According to the Centers for Disease Control and Prevention (CDC), 71million Americans have high LDL (or "bad") cholesterol, representing roughly33.5 percent of the population. Only one out of every three adults with highcholesterol have it under control, and less than half get treatment. Inaddition, those with high total cholesterol face approximately twice the riskof heart disease, which remains the leading cause of death in the UnitedStates. The CDC also reports that the average total cholesterol level forAmerican adults is 200 mg/dL, which is borderline high risk.