Alirocumab (trade name Precedent ) is an FDA-approved biopharmaceutical drug on July 24, 2015 as second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. These are human monoclonal antibodies that belong to a new class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it is the first agent to receive FDA approval. FDA approval relies on the completion of further clinical trials to further determine efficacy and safety.
The 2015 cost is estimated at $ 14,300 per year, making alirocumab significantly more cost-effective than other lipid-lowering therapies.
Video Alirocumab
Medical use
Alirocumab is used as second-line treatment to lower LDL cholesterol for adults who have severe forms of high cholesterol and people with atherosclerosis who require an additional decrease in LDL cholesterol when diet and statin treatment do not work. This is managed by subcutaneous injection. In July 2015, it was not known whether alirocumab prevented premature death from cardiovascular disease or prevented a heart attack; Clinical trials to determine outcomes are ongoing at that time, the results expected in 2017.
Maps Alirocumab
Side effects
Side effects occur in more than 2% of people treated with alirocumab in clinical trials and that occur more frequently than with placebo, including nasal and throat irritations, injection and bruising reactions, flu-like symptoms, urinary tract infections, diarrhea, bronchitis and cough, and muscle pain, pain, and seizures.
There is no data available on the use of alirocumab in pregnant women to assess the risk to the fetus, nor is there data used in children.
Pharmacology
Alirocumab works by inhibiting PCSK9 protein. PCSK9 binds to low-density lipoprotein (LDLR) receptors (which take cholesterol from the circulation), and that binding causes degraded receptors, and less LDL cholesterol is excluded from circulation. Inhibiting PCSK9 prevents receptors from degrading, and promotes the elimination of LDL cholesterol from circulation.
After subcutaneous alirocumab administration, PCSK9 free maximum suppression occurs within 4 to 8 hours and has a clear half-life of 17 to 20 days. Dose-dependent inhibition. Antibodies are distributed through the circulation, and are removed at low concentrations by binding to their targets, and at higher concentrations via proteolytic pathways.
Chemistry
Alirocumab is a human monoclonal antibody of IgG1 isotype. It is made of two heavy human chains connected with disulfide, each disulfide-related to the human light chain. It has an approximate molecular weight of 146 kDa.
It is produced using Chinese hamster ovary cells that are transfected with recombinant DNA, which grows in the tank.
History
The importance of PCSK9 as a biological target for drug discovery emerged in 2003, when a series of findings led to the identification of proteins and genes, its role in causing some cases of family hypercholesterolaemia when multiple mutations were present, and its role in causing very low levels of LDL cholesterol when there were other mutations.
Target discovery and validation sparked a race between pharmaceutical and biotech companies.
Alirocumab was discovered by Regeneron Pharmaceuticals using the mouse "VelocImmune", in which many genes that encode antibodies have been replaced by human genes. In an investor presentation, Regeneron claimed that with their system, it only took about 19 months from the time they first immunized mice with PCSK9 until they filed IND. Alirocumab was developed in conjunction with Sanofi under an agreement made in 2007. Before accepting its international non-base name, it is known as REGN727 and SAR236553.
Phase 1 trial results are reported in 2012 in the New England Journal of Medicine. Phase 3 trials of statin intolerance patients called ODYSSEY lasted 65 weeks. The results were presented at a meeting of the European Society of Cardiology 2014. A 78-week study of alirocumab in 2,341 people using statins at high risk for cardiovascular events and having high LDL cholesterol levels was published in April 2015.
In July 2014, Regeneron and Sanofi announced that they had purchased a priority review voucher that BioMarin had won for a recent approval of a rare illness drug of $ 67.5 million; vouchers were cut four months from the time of regulatory review to alirocumab and were part of their strategy to defeat Amgen to market with the first approval of PCSK9 inhibitors.
In July 2015, the FDA approved alirocumab as a second-line treatment for lowering LDL cholesterol for adults who had high hereditary cholesterol and those with atherosclerosis who needed an additional decrease in LDL cholesterol when diet and statin treatment did not work. This is the first approval of PCSK9 inhibitors. FDA approval relies on the completion of further clinical trials to further determine efficacy and safety.
Regeneron and Amgen have each filed patent protection on their monoclonal antibodies and the company ends up in patent litigation in the US. In March 2016 the district court found that alirocumab violated the Amgen patent; Amgen then requested a directive banning Regeneron and Sanofi from alirocumab marketing, which was granted in January 2017. The judge gave Regeneron and Sanofi 30 days to file an appeal before the order came into effect. In October 2017, the US Court of Appeals canceled the ban and ordered a new trial after finding the jury given incorrect instructions and evidence of detention. Regeneron and Sanofi were allowed to resume alirocumab marketing during the appeals process.
Society and culture
In 2014 as a PCSK9 inhibitor approached regulator approval, market analysts estimated that the overall market for these drugs could be $ 10B per year, with each alirocumab and competing drug Amgen having $ 3B sales per year, and other competitors dividing the remaining $ 4B, based on the estimated annual price for alirocumab $ 10,000 per year. At the same time, pharmaceutical benefits managers such as Express Scripts and CVS Caremark, while recognizing that new drugs can help patients who do not have uncontrolled cholesterol levels, and recognize that injecting biopharmaceuticals will always be more expensive than pills, and especially more expensive than generic pills, expressed concerns about the new cost burden on health care systems.
When the drug was approved in July 2015, the published price was higher than analysts had expected: $ 14,600 a year. Pharmaceutical benefits managers continue to express their concerns, as do insurance companies and some doctors, who are especially concerned over prices, given the fact that FDA approval is based on cholesterol reduction alone, and not on better health outcomes, such as fewer heart attacks or more life long.
The current treatment for people with very high cholesterol that can not be controlled with diet or statins is apheresis, which is similar to dialysis in which a person visits the clinic every month and his blood is mechanically screened, in this case to remove LDL cholesterol.. The maintenance fee is $ 8000 per month, or $ 96,000 per year. The price of alirocumab is determined in part by the production of apheresis which is no longer needed.
References
Source of the article : Wikipedia
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