What is low-density lipoprotein (LDL) cholesterol and how does it differ from high-density lipoprotein (HDL)?
Lipids, primarily cholesterol and triglycerides, come from two sources: what is naturally manufactured in the liver and what comes from the intestines through the diet.
These lipids are transported to various parts of the body through particles known as lipoproteins.
There are three types of lipoproteins that carry lipids throughout the body:
- Very low-density lipoproteins (VLDL) - the primary carrier of triglycerides from the liver to the body;
- Low-density lipoproteins (LDL) - carriers of cholesterol to other parts of the body and;
- High-density lipoproteins (HDL) - carriers of cholesterol from other parts of the body back to the liver and other cholesterol-utilizing organs.
LDL-cholesterol (LDL-C) is considered “bad” cholesterol due to its ability to enter the walls of the arteries and cause the initiation and progression of atherosclerotic plaques. Over time, these plaques can become the source of heart attacks and strokes.
By contrast, HDL-cholesterol (HDL-C) is thought to be “good” cholesterol due to its ability to transport cholesterol from arterial plaques to the liver.
How do lipid-lowering medications work?
Statins are the most widely used LDL-C-lowering medication. They work by inhibiting a key step in the synthesis of cholesterol (HMG CoA reductase), which takes place in liver cells. This inhibition results in an increase of LDL receptors on the surface of the liver cells, which bind and pull LDL-C out of the bloodstream, resulting in lower levels of cholesterol.
In general, statins can reduce LDL-C levels by 20-55 percent, depending on the drug and dosing regimen. It is important to note that some patients may have a less efficacious response to statins compared to others, and that some patients may experience side effects that make them intolerant to statins.
An additional lipid-lowering medication is ezetimibe. This product works by inhibiting a key protein involved in the absorption of cholesterol from the intestines (that comes via diet). It typically reduces cholesterol by 15-20 percent.
Numerous studies (primarily using statins) have demonstrated the benefits of lipid-lowering therapy, specifically the reduction of LDL-C and its role in reducing the incidence of heart attack and stroke in patients.
By contrast, there is little data that suggests an increase in HDL-C will result in the reduction of cardiovascular events.
How many people are unable to satisfactorily control their LDL levels and why don’t lipid-lowering therapies work for everyone?
Lowering LDL-C is the primary treatment objective in patients with high cholesterol (hypercholesterolemia), regardless of cardiovascular disease history. In developed countries, 60 percent of heart disease and 40 percent of strokes are in large part due to high levels of LDL-C. Despite treatment with current standard of care (SoC), an estimated 66 percent of all treated U.S. adults do not achieve their LDL-C goal. In particular, we feel there are three patient populations that experience unsatisfactory LDL-C treatment:
- Patients with high cardiovascular risk (such as those who have already suffered a heart attack or stroke) – because of their high risk level, treatment guidelines recommend more intensive therapy and treatment goals for these patients. Even with statins and other therapies, many of these patients cannot achieve the desired treatment levels.
- Patients that are intolerant to statins – statins represent the main foundation of treatment for LDL-C reduction. If a patient cannot tolerate a statin due to side effects, it is often difficult for them to reach treatment goals, as the available remaining therapies are less efficacious. It has been estimated that 5-10 percent of patients may ultimately be intolerant to statins.
- Patients with familial hypercholesterolemia (FH) – these are patients that have a single genetic mutation that results in extremely high levels of LDL-C. Untreated, these patients are at extremely high risk for premature cardiovascular disease. Patients with FH will typically respond well to existing therapies, but because their LDL-C levels are so high, they often cannot achieve their treatment goal.
In the U.S. and the large five countries in Europe, there are an estimated 21 million patients in need of LDL-C reduction within these three categories.
What role does proprotein convertase subtilisin/kexin type 9 (PCSK9) play in cholesterol homeostasis?
The discovery of PCSK9 in 2003 was a significant advance in the science and research of LDL-C management since the first statin was discovered more than 40 years ago.
PCSK9 is a protein secreted by the liver cells; it binds to and regulates the number of LDL receptors on liver cells, thereby playing a natural role in the clearance of LDL-C.
The PCSK9 protein lowers the number of available LDL receptors to remove excess LDL-C from the bloodstream. The result is less LDL-C being bound and higher levels of LDL-C in the blood.
Moreover, statins increase the level of circulating PCSK9, which in turn limits the maximum number of LDL receptors available to clear LDL-C from circulation.
The PCSK9 pathway is therefore a potentially novel mechanism for lowering LDL-C, either alone or in combination with statins or other lipid lowering therapies.
A new class of lipid-lowering therapies, PCSK9 inhibitors, are believed to target and inhibit PCSK9, increasing the availability of LDL receptors on liver cells and helping to lower LDL-C levels in the body.
Please can you outline the recent Phase 3 studies into an investigational monoclonal antibody targeting PCSK9?
Regeneron’s U.S.-based scientific heritage in collaboration with Sanofi’s global leadership in injectable and cardiovascular health provides a prolific collaboration to discover, develop, manufacture, and commercialize fully human monoclonal antibodies (MAbs).
Alirocumab is an investigational MAb that targets and blocks PCSK9, and is administered via subcutaneous injection. By inhibiting PCSK9, alirocumab has been shown to increase the number of LDL receptors on hepatocytes, thereby lowering LDL-C.
Overall, our Phase 3 ODYSSEY program is designed to evaluate safety and efficacy of alirocumab, with 14 global studies at more than 2,000 study centers, enrolling more than 23,500 patients.
Within the program, 13 of the 14 studies are focused on LDL-C lowering and will make up our initial regulatory filings for alirocumab. These trials will enroll more than 5,000 patients and by the time of their completion provide over 5,000 patient-years of double-blind assessment of safety and efficacy in patients on alirocumab.
In addition to this, we have initiated a global cardiovascular outcomes study in 18,000 patients that will look to demonstrate the addition of alirocumab on top of statin therapy on the occurrence of major cardiovascular events.
Our comprehensive Phase 3 ODYSSEY program has been specifically designed to allow physicians to target therapy to treat individual patient needs. As a result, we are studying alirocumab in three different patient types: high cardiovascular risk, statin intolerant and heterozygous familial hypercholesterolemia (HeFH).
We are also studying alirocumab in a variety of schedules (two- and four-week), starting doses (low 75 mg starting dose with ability to up-titrate to 150 mg if needed and higher 150 mg starting dose if LDL-C goal warrants it), administration sites (arm, leg or abdomen), combinations (monotherapy or in combination with standard of care [SoC]) and timeframes (ranging from 24 weeks to two years).
What data was recently presented at the American College of Cardiology's (ACC) 63rd Annual Scientific Session?
At ACC, Sanofi and Regeneron presented five abstracts from the investigational alirocumab program, including 24-week results from the Phase 3 ODYSSEY MONO trial. The MONO study compared the LDL-C-lowering efficacy and safety of alirocumab versus ezetimibe in hypercholesterolemic patients not receiving statin or other lipid-lowering therapies.
The study met its primary efficacy endpoint, demonstrating percent change in LDL-C from baseline to week 24. The most common class of adverse events was infections, which included nasopharyngitis and influenza, and upper respiratory tract infection.
What impact will these results have?
The 24-week results from the ODYSSEY MONO trial extend the safety observations from the Phase 2 trials. Robust data from nine additional Phase 3 studies, in addition to the ODYSEEY MONO data, will be coming out through the course of the year, and we look forward to sharing those results at future scientific venues.
What are Sanofi’s plans for the future?
We expect to submit an application for alirocumab for regulatory approval in 2015 for most regions worldwide. The ODYSSEY trials will continue in a double-blinded fashion through 12 months, 18 months and 24 months, creating approximately 5,000 total patient years of exposure (exclusive of cardiovascular outcomes trials).
Where can readers find more information?
Readers can find more information by visiting the Sanofi U.S. (www.sanofi.us) and Regeneron (www.regeneron.com) websites. You can also follow Sanofi U.S. on Twitter (@SanofiUS) and visit us on Facebook (www.facebook.com/sanofiUS).
About Jay Edelberg, M.D., and Bill Sasiela, Ph.D.
Jay Edelberg, M.D., Head, PCSK9 Development and Launch Unit, Sanofi
Jay Edelberg has been the head of the PCSK9 development and launch unit since April of 2012. He previously worked as the Group Director at Bristol-Myers Squibb and served as a director for GlaxoSmithKline. He has been a member of the board of directors for the American Federation for Aging Research since June 2007. Prior to joining GlaxoSmithKline, Edelberg was an Associate Professor of Medicine at Weil Cornell Medical College. He received his medical degree from Duke University in 1992. He served his general residency at Massachusetts General Hospital and was a cardiology fellow at Beth Israel Deaconess Medical Center.
Bill Sasiela, Ph.D., VP, Program Direction, Regeneron
William J. Sasiela, Ph.D., is Vice President of Program Direction, Cardiovascular Metabolism, at Regeneron Pharmaceuticals in New York, USA. Dr. Sasiela has worked with pharmaceutical companies including Parke-Davis, now a subsidiary of Pfizer Inc., and Aegerion Pharmaceuticals, Inc. before joining Regeneron in 2010. At Pfizer, Dr. Sasiela was responsible for the world-wide Lipitor (atorvastatin) medical program and involved in the development of atherosclerosis products within the company. At Aegerion, Dr. Sasiela oversaw the development of lomitapide. Dr. Sasiela holds a B.S. in biochemistry from Virginia Tech and a Ph.D. from the University of South Carolina School of Medicine, and also conducted post-doctoral research at the University of North Carolina, Chapel Hill.