Alirocumab
   HOME

TheInfoList



OR:

Alirocumab, sold under the brand name Praluent, is a
medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
used as a second-line treatment for
high cholesterol Hypercholesterolemia, also called high cholesterol, is the presence of high levels of cholesterol in the blood. It is a form of hyperlipidemia (high levels of lipids in the blood), hyperlipoproteinemia (high levels of lipoproteins in the blood), ...
for adults whose cholesterol is not controlled by diet and
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...
treatment. It is a human
monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...
that belongs to a novel class of anti-cholesterol drugs, known as
PCSK9 inhibitor Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
s, and it was the first such agent to receive
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
approval. The
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
approval was contingent on the completion of further clinical trials to better determine efficacy and safety. Common side effects include nasopharyngitis (cold), injection site reactions, and influenza. It was approved for medical use in the United States and in the European Union in 2015.


Medical uses

Alirocumab is used as a
second-line treatment A therapy or medical treatment (often abbreviated tx, Tx, or Tx) is the attempted remediation of a health problem, usually following a medical diagnosis. As a rule, each therapy has indications and contraindications. There are many different ...
to lower
LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
for adults who have a severe form of hereditary high cholesterol and people with
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
who require additional lowering of LDL cholesterol when diet and
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...
treatment have not worked. It is administered by subcutaneous injection. As of July 2015, it is not known whether alirocumab prevents early death from
cardiovascular disease Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, h ...
or prevents heart attacks; a
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...
to determine outcomes was ongoing at that time, the results of which were expected in 2017. In November 2018, ''
The New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. His ...
'' published positive results from a clinical trial with alirocumab. According to the study, alirocumab significantly reduced major adverse cardiovascular events by 15% and it was associated with a 15% lower risk of death from any cause (hazard ratio R0.85; 95% confidence interval I 0.73 to 0.98). In 2021, the U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) added an indication for alirocumab to treat adults with homozygous familial hypercholesterolemia (HoFH), a genetic condition that causes severely high cholesterol. It is not intended to be used alone but instead added to other treatments for HoFH.


Side effects

Side effects that occurred in more than 2% of people treated with alirocumab in clinical trials and that occurred more frequently than with
placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...
, included nose and throat irritation, injection site reactions and bruising, flu-like symptoms, urinary tract infection, diarrhea, bronchitis and cough, and muscle pain, soreness, and spasms. There are no available data on use of alirocumab in pregnant women to assess risks to the
fetus A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
, nor is there data on use in children.


Pharmacology

Alirocumab works by inhibiting the
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
protein.
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
binds to the low-density lipoprotein receptor (LDLR) (which takes cholesterol out of circulation), and that binding leads to the receptor being degraded, and less
LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
being removed from circulation. Inhibiting
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
prevents the receptor from being degraded, and promotes removal of LDL cholesterol from circulation.* After subcutaneous administration of alirocumab, maximal suppression of free
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
occurs within 4 to 8 hours and has an apparent half-life of 17 to 20 days. Inhibition is dose-dependent. The antibody is distributed through the circulation, and it is eliminated at low concentrations by binding to its target, and at higher concentrations through a
proteolytic Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
pathway.


Chemistry

Alirocumab is a human
monoclonal antibody A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a cell Lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Monoclonal antibodies ca ...
of the IgG1 isotype. 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 cell Chinese hamster ovary (CHO) cells are an epithelial cell line derived from the ovary of the Chinese hamster, often used in biological and medical research and commercially in the production of recombinant therapeutic proteins. They have foun ...
s transfected with
recombinant DNA Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning) that bring together genetic material from multiple sources, creating sequences that would not otherwise be foun ...
, that are grown in tanks.


History

The importance of PCSK9 as a
biological target A biological target is anything within a living organism to which some other entity (like an endogenous ligand or a drug) is directed and/or binds, resulting in a change in its behavior or function. Examples of common classes of biological targets ...
for
drug discovery In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which new candidate medications are discovered. Historically, drugs were discovered by identifying the active ingredient from traditional remedies or by ...
emerged in 2003, when a series of discoveries led to identification of the protein and its gene, its role in causing some cases of
familial hypercholesterolaemia Familial hypercholesterolemia (FH) is a genetic disorder characterized by high cholesterol levels, specifically very high levels of low-density lipoprotein (LDL cholesterol), in the blood and early cardiovascular disease. The most common mutatio ...
when some mutations are present, and its role in causing very low levels of LDL cholesterol when other mutations are present.Stephen S. Hall for Nature News. April 9, 201
Genetics: A gene of rare effect. A mutation that gives people rock-bottom cholesterol levels has led geneticists to what could be the next blockbuster heart drug.
/ref> The discovery and validation of the target set off a race among pharmaceutical and biotech companies. Alirocumab was discovered by
Regeneron Pharmaceuticals Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Westchester County, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities, giving rise to i ...
using its "VelocImmune" mouse,Regeneron website December 29, 201

Veloclmmune website
in which many of the genes coding for antibodies have been replaced with human genes.BiotechDaily International staff writers. Apr 17, 201
LDL-Lowering Monoclonal Antibody Shines in Early Clinical Trials
/ref> In an investor presentation, Regeneron claimed that with their system, it took only about 19 months from when they first immunized mice with PCSK9 until they filed their Investigational New Drug, IND. Alirocumab was co-developed with
Sanofi Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
under a deal made in 2007. Before it received its international nonproprietary name it was known as REGN727 and SAR236553. Phase 1 trial results were reported in 2012 in ''
The New England Journal of Medicine ''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one. His ...
''. A phase 3 trial of statin intolerant patients called ODYSSEY ran for 65 weeks. Results were presented at the 2014 European Society of Cardiology meeting. A 78-week study of alirocumab in 2341 people taking statins who were at high risk for cardiovascular events and had high LDL cholesterol levels was published in April 2015. This study showed a significant reduction of LDL cholesterol levels in patients taking both Alirocumab and oral statins compared to placebo patients solely taking oral statins. Studies are ongoing to assess the effects of alirocumab in normocholesterolemic individuals. In July 2014, Regeneron and Sanofi announced that they had purchased a
priority review voucher Priority review is a program of the United States Food and Drug Administration (FDA) to expedite the review process for drugs that are expected to have a particularly great impact on the treatment of a disease. The priority review voucher program ...
that
BioMarin BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme re ...
had won for a recent rare disease drug approval for $67.5 million; the voucher cut four months off the regulatory review time for alirocumab and was part of their strategy to beat
Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was esta ...
to market with the first approval of a PCSK9 inhibitor. In July 2015, the FDA approved alirocumab as a second-line treatment to lower
LDL cholesterol Low-density lipoprotein (LDL) is one of the five major groups of lipoprotein that transport all fat molecules around the body in extracellular water. These groups, from least dense to most dense, are chylomicrons (aka ULDL by the overall densit ...
for adults who have hereditary high cholesterol and people with
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
who require additional lowering of LDL cholesterol when diet and
statin Statins, also known as HMG-CoA reductase inhibitors, are a class of lipid-lowering medications that reduce illness and mortality in those who are at high risk of cardiovascular disease. They are the most common cholesterol-lowering drugs. Low- ...
treatment have not worked.FDA. July 24, 201
FDA Press release: FDA approves Praluent to treat certain patients with high cholesterol
/ref> This was the first approval of a
PCSK9 Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the ''PCSK9'' gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (ortholog ...
inhibitor. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety. Regeneron and Amgen had each filed for patent protection on their monoclonal antibodies and the companies ended up in
patent litigation Patent infringement is the commission of a prohibited act with respect to a patented invention without permission from the patent holder. Permission may typically be granted in the form of a license. The definition of patent infringement may va ...
in the U.S. In March 2016, a district court found that alirocumab infringed Amgen's patents; Amgen then requested an
injunction An injunction is a legal and equitable remedy in the form of a special court order that compels a party to do or refrain from specific acts. ("The court of appeals ... has exclusive jurisdiction to enjoin, set aside, suspend (in whole or in pa ...
barring Regeneron and Sanofi from marketing alirocumab, which was granted in January 2017. The judge gave Regeneron and Sanofi 30 days to appeal before the injunction went into effect. In October, 2017 the US Court of Appeals reversed the ban and ordered a new trial after finding the jury was given improper instructions and evidence was withheld. Regeneron and Sanofi were allowed to continue marketing alirocumab during the appeals process. The U.S.
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) granted approval of Praluent to Regeneron Pharmaceuticals, Inc.


Society and culture

In 2014 as PCSK9 inhibitors approached regulatory approval, market analysts estimated that the overall market for these drugs could be $10B per year, with each of alirocumab and
Amgen Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical Corporation, company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was esta ...
's competing drugs having sales of $3B per year, and other competitors dividing the remaining $4B, based on estimates of an annual price for alirocumab of $10,000 per year.Tracy Staton for FiercePharmaMarketing. May 7, 201
Payers fret about the next drug doomsday: Pricey PCSK9 cholesterol meds
/ref> At the same time,
pharmacy benefit managers In the United States, a pharmacy benefit manager (PBM) is a third-party administrator of prescription drug programs for commercial health plans, self-insured employer plans, Medicare Part D plans, the Federal Employees Health Benefits Program, ...
such as
Express Scripts Express Scripts Holding Company is a pharmacy benefit management (PBM) organization. In 2017 it was the 22nd-largest company in the United States by total revenue as well as the largest pharmacy benefit management (PBM) organization in the United ...
and
CVS Caremark CVS Caremark (formerly Caremark Rx) (stylized as , previously CVS/caremark) is the prescription benefit management subsidiary of CVS Health, headquartered in Woonsocket, Rhode Island. Company history Caremark was founded as a physician and ph ...
, while recognizing that the new drugs could help patients who were otherwise left with uncontrolled cholesterol levels, and recognizing that injectable
biopharmaceuticals A biopharmaceutical, also known as a biological medical product, or biologic, is any pharmaceutical drug product manufactured in, extracted from, or semisynthesized from biological sources. Different from totally synthesized pharmaceuticals, t ...
will always be more expensive than pills, and especially more expensive than generic pills, expressed concerns about the burden of the new costs on the health care system. When the drug was approved in July 2015, the announced price was higher than analysts had predicted: $14,600 a year.Liz Szabo for USA Today July 24, 201
FDA approves new cholesterol drug - at $14,600 a year
/ref> Pharmacy benefit managers continued expressing their concerns, as did insurance companies and some doctors, who were especially concerned over the price, in light of the fact that the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
approval was based on lowering cholesterol alone, and not on better health outcomes, such as fewer heart attacks or longer life. The treatment for people with very high cholesterol that cannot be controlled with diet or statins is
apheresis Apheresis ( ἀφαίρεσις (''aphairesis'', "a taking away")) is a medical technology in which the blood of a person is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation ...
, which is similar to
dialysis Dialysis may refer to: *Dialysis (chemistry), a process of separating molecules in solution **Electrodialysis, used to transport salt ions from one solution to another through an ion-exchange membrane under the influence of an applied electric pote ...
in that a person visits a clinic each month and his or her blood is mechanically filtered, in this case to remove LDL cholesterol. That treatment costs $8000 per month, or $96,000 per year. The price of alirocumab was determined based in part on making apheresis no longer necessary.Gina Kolata for the New York Times. July 27, 201
Praluent Looks Cheap to Those With Extreme Cholesterol
/ref>


Names

Alirocumab is the International nonproprietary name. International Nonproprietary Names for Pharmaceutical Substances (INN)
World Health Organization


References


External links

* {{Portal bar , Medicine Monoclonal antibodies PCSK9 inhibitors Sanofi