PCSK9 is a determinant of circulating LDL-C levels
.1 PCSK9 binds to LDL receptors present on the surface of hepatocytes (liver cells). When PCSK9 binds an LDL receptor, the latter is taken into the cell and degraded. This in turn leaves fewer LDL receptors available on hepatocytes to remove
excess LDL-C from the blood.4 People with natural loss-of-function mutations in PCSK9 have significantly reduced LDL-C and a low incidence of coronary heart disease,5 while conversely gain-of-function mutations in PCSK9 result in significant elevations of LDL-C and increased cardiovascular (CV) risk.6
The PCSK9 pathway is one of the best examples of how genetics has led to identification of a new target for cholesterol management. It began when genetics researchers took DNA samples from patients with low cholesterol levels and found that, although very rare in Caucasians, 2% of patients of native African descent had one of two mutations that were associated with a 40% reduction in LDL-C.7 In a subsequent study researchers found that people bearing this mutation had 28% lower LDL-C levels than people with PCSK9 function.2 Moreover, this reduction corresponded to an 88% lower incidence of coronary artery disease (CAD) in this population.5 CAD remains a leading cause of morbidity and mortality worldwide.8
A new class of investigational drugs: PCSK9 inhibitors
Thanks to this genetic discovery, targeting the PCSK9 pathway is now a novel mechanism under investigation for lowering LDL-C. By inhibiting PCSK9, PCSK9 inhibitors are believed to increase the number of LDL receptors on hepatocytes and facilitate LDL clearance from the blood, ultimately leading to LDL-C reduction. PCSK9 normally binds to LDL receptors on the surface of hepatocytes and targets them for destruction; by blocking this binding, PCSK9 inhibitors help protect the LDL receptors from being destroyed.1 The PCSK9 inhibitors in late-stage development are monoclonal antibodies. Monoclonal antibodies are designed to bind to a specific target, while avoiding other targets.
Traditional LDL-C lowering therapies, such as statins, lead to higher levels of PCSK9.1 This leads to a reduction in LDL receptors on the cell surface, which leads to higher levels of LDL-C.9 As statins act to up-
.1 PCSK9 binds to LDL receptors present on the surface of hepatocytes (liver cells). When PCSK9 binds an LDL receptor, the latter is taken into the cell and degraded. This in turn leaves fewer LDL receptors available on hepatocytes to remove
excess LDL-C from the blood.4 People with natural loss-of-function mutations in PCSK9 have significantly reduced LDL-C and a low incidence of coronary heart disease,5 while conversely gain-of-function mutations in PCSK9 result in significant elevations of LDL-C and increased cardiovascular (CV) risk.6
The PCSK9 pathway is one of the best examples of how genetics has led to identification of a new target for cholesterol management. It began when genetics researchers took DNA samples from patients with low cholesterol levels and found that, although very rare in Caucasians, 2% of patients of native African descent had one of two mutations that were associated with a 40% reduction in LDL-C.7 In a subsequent study researchers found that people bearing this mutation had 28% lower LDL-C levels than people with PCSK9 function.2 Moreover, this reduction corresponded to an 88% lower incidence of coronary artery disease (CAD) in this population.5 CAD remains a leading cause of morbidity and mortality worldwide.8
A new class of investigational drugs: PCSK9 inhibitors
Thanks to this genetic discovery, targeting the PCSK9 pathway is now a novel mechanism under investigation for lowering LDL-C. By inhibiting PCSK9, PCSK9 inhibitors are believed to increase the number of LDL receptors on hepatocytes and facilitate LDL clearance from the blood, ultimately leading to LDL-C reduction. PCSK9 normally binds to LDL receptors on the surface of hepatocytes and targets them for destruction; by blocking this binding, PCSK9 inhibitors help protect the LDL receptors from being destroyed.1 The PCSK9 inhibitors in late-stage development are monoclonal antibodies. Monoclonal antibodies are designed to bind to a specific target, while avoiding other targets.
Traditional LDL-C lowering therapies, such as statins, lead to higher levels of PCSK9.1 This leads to a reduction in LDL receptors on the cell surface, which leads to higher levels of LDL-C.9 As statins act to up-
Proprotein convertase subtilisin kexin type 9 (PCSK9) is an enzyme that impairs low‐density lipoprotein
cholesterol (LDL‐C) clearance from the plasma by promoting LDL receptor degradation regulate levels of PCSK9, the protein target for PCSK9 inhibitors, these two treatments may prove synergistic
and achieve additional lipid-lowering effects when used in combination.2
An estimated 59% and 45% of treated patients in the U.S. and Europe, respectively, do not reach their target
LDL-C goal.10,11 In patients who do not achieve their LDL-C goal on a statin, PCSK9 inhibitors may lead to a
further reduction in LDL-C. This new investigational drug class may also be a much-needed therapeutic
option for the 5-10% of the population who cannot tolerate statins due to side effects.12 An additional group
of patients that may benefit are those with Heterozygous Familial Hypercholesterolemia (HeFH), an
inherited disease that is characterized by elevated LDL-C levels, the vast majority of whom are not at goal
with current treatment options.13 As a result, people with HeFH experience a much higher death rate from
cardiovascular disease than the general population.14
Alirocumab: a PCSK9 antibody
Fewer than 5 years after PCSK9 was initially identified as a target for drug development, Regeneron and Sanofi commenced human clinical trials of SAR236553/REGN727, now known as alirocumab, a fully human monoclonal antibody directed against PCSK9.1,3 Alirocumab was created using Regeneron’s pioneering VelocImmune® technology, and is being developed in collaboration with Sanofi, a company with a strong heritage in cardiovascular disease.
Alirocumab is administered via subcutaneous injection, which means a needle is inserted just under the skin; on delivery, the antibody moves into small blood vessels and then into the bloodstream.
Alirocumab: a PCSK9 antibody
Fewer than 5 years after PCSK9 was initially identified as a target for drug development, Regeneron and Sanofi commenced human clinical trials of SAR236553/REGN727, now known as alirocumab, a fully human monoclonal antibody directed against PCSK9.1,3 Alirocumab was created using Regeneron’s pioneering VelocImmune® technology, and is being developed in collaboration with Sanofi, a company with a strong heritage in cardiovascular disease.
Alirocumab is administered via subcutaneous injection, which means a needle is inserted just under the skin; on delivery, the antibody moves into small blood vessels and then into the bloodstream.
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