Alirocumab | Monoclonal Antibody | Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitor | Management of High Cholesterol

Alirocumab is a fully human monoclonal antibody (IgG1) targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). It is developed as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with hyperlipidaemia, including hypercholesterolaemia and heterozygous familial hypercholesterolaemia (HeFH) [1, 2].

Alirocumab is a human monoclonal antibody of the IgG1 isotype. Chemically, it is made of two disulfide-linked human heavy chains, each disulfide-linked to a human light chain. It has an approximate molecular weight of 146 kDa. It is produced using Chinese hamster ovary cells transfected with recombinant DNA.

PCSK9 is a negative regulator of low-density lipoprotein (LDL) receptors in the liver and reduces the ability of liver to remove LDL-cholesterol (LDLC) from the blood. Alirocumab prevents PCSK9-mediated degradation of LDL receptors, thereby increasing the expression of LDL receptors on the liver surface and improving its capacity to bind LDL-C.

Alirocumab prevents PCSK9-mediated degradation of LDL receptors, thereby increasing the expression of LDL receptors on the liver surface and improving its capacity to bind LDL-C. It is administered as a subcutaneous (SC) injection and is being investigated as a single agent and also in combination with statin therapy.

Alirocumab was approved by the US-FDA in July 2015 as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with HeFH or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL-C. In the EU, it has received a positive opinion from the European Medicines Agency Committee for Medicinal Products for Human Use.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) as Drug Target

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that plays a central role in cholesterol homeostasis. Circulating PCSK9 molecules reduce the number LDL receptors (LDLRs) on the surface of hepatocytes, which limits hepatic cholesterol uptake and increases serum LDL-C levels. Inhibition of the PCSK9-LDLR interaction may reduce CV risk in patients with hypercholesterolemia by reducing serum LDL-C. PCSK9 was first discovered to be involved with lipid metabolism in 2003. A case of autosomal dominant hypercholesterolemia was determined to be related to a defect in the gene encoding PCSK9. Additional investigation confirmed that the defect was related to a gain-of-function mutation causing increased levels of the protein. Animal studies showed that PCSK9 was involved in lipid metabolism and suggested that a loss of function would result in decreased levels of LDL-C [3].

PCSK9 is a serine protease and is the ninth member of the proprotein convertase family. PCSK9 was originally called NARC-1. It is found primarily in the liver, intestine and kidney and is formed in the endoplasmic reticulum, modified in the Golgi and released into the vascular space. PCSK9 transcription is controlled by SREBP-2, the identical transcription factor that controls LDL receptor (LDLR) transcription. Statins and other LDL-C lowering drugs that decrease intracellular cholesterol cause an increase in SREBP-2 signaling. Increased SREBP-2 causes increased LDLR production and results in increased transport of circulating LDL into the cell. The same increase in SREBP-2 signaling also causes an increase in PCSK9 production.

It is believed that normal LDLR function is to bind a LDL particle on the cell surface, endocytose the LDL particle and LDLR together, then release the LDLR to recirculate to the cell surface, while the LDL particle is transported into a lysosome for degradation. It has been shown that PCSK9 binds to the LDLR and directs the LDL particle - receptor complex to the lysosome, preventing recirculation of the LDLR, thus leading to degradation of both the LDL particle and LDLR. By targeting the LDLR for degradation and preventing receptor recycling, PCSK9 decreases the available cell surface LDLRs and causes an increase in the serum LDL-C.

An unmet need of the market is the ability to sufficiently reduce LDL cholesterol (LDL-C) levels in the full spectrum of high-risk and challenging patients with primary hypercholesterolemia and familial hypercholesterolemia (FH). Patients who are intolerant to statins and other current therapies also pose a significant challenge to treatment. Monoclonal antibodies to proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce low-density lipoprotein (LDL) cholesterol levels in patients who are being treated with statins. There are theoretically three ways to decrease PCSK9 levels in the circulation, either by inhibiting synthesis, by binding free PCSK9 or increasing PCSK9 clearance from the bloodstream. The first two methods of inhibiting synthesis or binding free PCSK9 are currently under investigation.

Mechanism of Action in Alirocumab

Alirocumab is a fully human IgG1 monoclonal antibody that has high affinity and specificity to proprotein convertase subtilisin/kexin type 9 (PCSK9). Inhibition of circulating PCSK9 by Alirocumab prevents PCSK9-mediated degradation of LDLRs, thereby increasing the number of LDLRs at the cell surface and decreasing serum LDL-C levels. As LDLRs also bind triglyceride (TG)-rich remnant lipoproteins, Alirocumab can decrease serum levels of apolipoprotein B (apoB), non-high-density lipoproteincholesterol (non-HDL-C), and TGs [1].

Despite LDLRs having low affinity for lipoprotein (a) [Lp(a)], Alirocumab can also reduce serum Lp(a) levels but the exact mechanism by which alirocumab exerts its effect on Lp(a) levels is not fully understood.

Administration of single subcutaneous (SC) 50, 100 and 150 mg doses of Alirocumab to patients with hypercholesterolaemia produced maximal reductions in free PCSK9 levels on the third day after administration, with nadirs of 87.6, 98.7, and 98.8 %, respectively. The greatest mean reductions in LDL-C were observed on day 8 (50 and 100 mg doses) or day 15 (150 mg dose) [2, 3].

Dosages and Approvals:

Alirocumab (Tradename: Praluent), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), is a product of the collaboration between Regeneron and Sanofi. Since 2007, Regeneron and Sanofi are in agreement to expand and extend the discovery, development and commercialisation of fully-human therapeutic antibodies utilising Regeneron’s proprietary VelociSuite of technologies (including VelocImmune).

In September 2015, Alirocumab was approved as an adjunct to diet for the treatment of primary hypercholesterolemia [heterozygous FH (heFH) and nonfamilial hypercholesterolemia (nonFH)] or mixed dyslipidemia in the EU, and on July 2015, as an adjunct to diet and maximally tolerated statins for the treatment of heFH or clinical atherosclerotic CVD (ASCVD) in the USA.

Alirocumab is the first proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to receive FDA approval.

The usual starting dose for Alirocumab is 75 mg administered subcutaneously once every 2 weeks. Patients requiring larger LDL-C reduction (>60%) may be started on 150 mg once every 2 weeks, or 300 mg once every 4 weeks (monthly), administered subcutaneously. The dose of Alirocumab can be individualised based on patient characteristics such as baseline LDL-C level, goal of therapy, and response. Lipid levels can be assessed 4 to 8 weeks after treatment initiation or titration, and dose adjusted accordingly (up-titration or down-titration). If additional LDL-C reduction is needed in patients treated with 75 mg once every 2 weeks or 300 mg once every 4 weeks (monthly), the dosage may be adjusted to the maximum dosage of 150 mg once every 2 weeks.

Alirocumab is injected as a subcutaneous injection into the thigh, abdomen or upper arm. To administer the 300 mg dose, give two 150 mg injections consecutively at two different injection sites. It is recommended to rotate the injection site with each injection.

Reported Activities for Alirocumab:

Alirocumab is a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) that is administered via subcutaneous injection every 2 weeks.

In a well-established mouse model of hyperlipidemia and atherosclerosis (APOE*3Leiden.CETP mice), subcutaneous Alirocumab 3 or 10 mg/kg weekly for 18 weeks reduced total cholesterol (TC) and triglycerides (TGs), and decreased atherosclerosis development in a dose-dependent manner. Moreover, Alirocumab significantly reduces LDL-C levels in patients with heFH or nonFH (including those with statin intolerance), whether used as monotherapy or added to statin or non-statin lipid-lowering therapies (LLT).

Alirocumab does not affect the concentrations of statins as it is not involved in the cytochrome P450 enzyme pathway. The estimated half-life of Alirocumab is 17-20 days.

Summary

Common name: REGN-727; REGN727; REGN 727; SAR-236553; SAR236553; SAR236553; ALI; Anti-PCSK9 monoclonal antibody; Anti-proprotein convertase subtilisin kexin type 9 monoclonal antibody

Trademarks: Praluent

Molecular Formula: -

CAS Registry Number: 1245916-14-6

CAS Name: -

Molecular Weight: -

SMILES: -

InChI Key: -

InChI: -

Mechanism of Action: Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) Inhibitors; PCSK9 Protein Inhibitors

Activity: Antihyperlipidaemics; Treatment for High Cholesterol; Treatment for Hyperlipidaemia

Status: Launched 2015 (US, EU)

Chemical Class: Monoclonal Antibodies; mAbs

Originator: Regeneron Pharmaceuticals / Sanofi

Alirocumab Synthesis

US8062640B2: The patent reports synthesis and activities for various human antibody (including Alirocumab) or antigen-binding fragment of a human antibody that specifically binds and inhibits human proprotein convertase subtilisin/kexin type 9 (hPCSK9) characterized by the ability to reduce serum LDL cholesterol by 40-80% over a 24, 60 or 90 day period relative to predose levels, with little or no reduction in serum HDL cholesterol and/or with little or no measurable effect on liver function, as determined by ALT and AST measurements.

US8795669B2: The patent provides pharmaceutical formulations comprising a human antibody (including Alirocumab) that specifically binds to human proprotein convertase subtilisin/kexin type 9 (PCSK9). The formulations may contain, in addition to an anti-PCSK9 antibody, at least one amino acid, at least one sugar, or at least one non-ionic surfactant. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability after storage for several months.

Sideeffects: Alirocumab appears well-tolerated overall. The incidence of serious adverse events (AE) has been comparable between Alirocumab-treated and nonalirocumab-treated groups in clinical trials. The most common treatment related adverse events (AEs) observed include nasopharyngitis, injection site reactions, influenza, diarrhea, upper respiratory tract infections and urinary tract infections [3].

There is a potential for immunogenicity with Alirocumab as it is a monoclonal antibody with approximately 5% of patients developing antidrug antibodies of unclear significance compared with a rate of 0.6% in the control group.

Other adverse events of interest with Alirocumab included neurologic events (3.5 vs. 3.5 % with placebo), treatment emergent or worsening of pre-existing diabetes (3.4 vs. 3.1 %), increases in liver enzymes to the upper limit of normal (ULN) (1.7 vs. 1.4 %), and neurocognitive events (0.8 vs. 0.7 %).

Others:

1. Alirocumab significantly reduced LDL-C levels by up to 72% and had a favorable effect on lowering Lp(a), apoB, non-HDL-C and triglycerides (TG) as well in patients with HeFH. Alirocumab reduced LDL-C levels to less than 70 mg/dl in 79% of patients, with the reduction in LDL-C being maintained over time.

2. The association between PCSK9 inhibition and reducing atherosclerosis development and cardiovascular (CVD) events is an area of deep interest going forward. Alirocumab seems to have an anti-inflammatory component as it reduces monocyte recruitment by decreasing macrophage composition and necrotic core content, thereby inhibiting plaque development. This may be driven by reduced infiltration of LDL into the artery wall or other anti-inflammatory factors [3].

3. The bioavailability of Alirocumab as a subcutaneous injection is approximately 85%. Alirocumab does not affect the concentrations of statins as it is not involved in the cytochrome P450 enzyme pathway. The estimated half-life of alirocumab is 17 - 20 days.

References:

1. Markham, A. Alirocumab: First Global Approval. Drugs 2015, 75(14), 1699 - 1705. (FMO)

2. Greig, S. L.; et. al. Alirocumab: A Review in Hypercholesterolemia. Am J Cardiovasc Drugs 2016, 16(2), 141 - 152. (FMO)

3. Dahagam, C.; et. al. PCSK9 inhibitors and their role in high-risk patients in reducing LDL cholesterol levels: alirocumab. Future Cardiol 2016, 12(2), 149 – 157. (FMO)

4. Walsh, S.; et. al. Stabilized formulations containing anti-PCSK9 antibodies. US8795669B2

5. Sleeman, M. W.; et. al. High affinity human antibodies to PCSK9. US8062640B2

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