Evolocumab

Last updated

Evolocumab
Monoclonal antibody
Type Whole antibody
Source Human
Target PCSK9
Clinical data
PronunciationEE-voh-lock-yoo-mab
Trade names Repatha
Other namesAMG-145 [1]
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • AU:B1
Routes of
administration 		Subcutaneous
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [2]
  • US: ℞-only [3]
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
ChemSpider
  • none
UNII
KEGG
Chemical and physical data
Formula C6242H9648N1668O1996S56
Molar mass 141790.89 g·mol−1

Evolocumab, [4] sold under the brand name Repatha, is a monoclonal antibody that is an immunotherapy medication for the treatment of hyperlipidemia.

Contents

Evolocumab is a fully human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 is a protein that targets LDL receptors for degradation; its inhibition thereby enhances the liver's ability to remove LDL-C, often colloquially referred to as "bad" cholesterol, from the blood. [5] [6]

Mechanism

Evolocumab is designed to bind to PCSK9 and inhibit PCSK9 from binding to LDL receptors on the liver surface. In the absence of PCSK9, there are more LDL receptors on the surface of liver cells to remove LDL-C from the blood. [7]

Adverse effects

Injection site reactions such as redness and pain are common and are reported in approximately 2.1–4.3% of cases. [8] [9] Concerns about mortality rate underreporting in the FOURIER study have attracted some controversy in the media. [10]

History

Amgen submitted a biologics license application (BLA) for evolocumab to the FDA in August 2014. [11] The FDA approved evolocumab injection on 27 August 2015, for some patients who are unable to get their LDL cholesterol under control with current treatment options. [12] The European Commission approved it in July 2015. [13] Evolocumab received approval from Health Canada on September 10, 2015. [14] Amgen reported approval by Health Canada in a press release on September 15, 2015. [15]

Results of the FOURIER trial were published in March 2017. [16]

Regeneron Pharmaceuticals and Amgen had each filed for patent protection on their monoclonal antibodies against PCSK9 and the companies ended up in patent litigation in the U.S. In March 2016 a district court found that Regeneron's drug alirocumab infringed Amgen's patents; Amgen then requested an injunction 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. [17] After several years of litigation, the patent dispute between Regeneron and Amgen was docketed by the SCOTUS for March-April 2023 [18] Numerous legal commentators were surprised by the SCOTUS decision, considering the existing trend not to review patent cases from the United States Court of Appeals for the Federal Circuit, since this court was created in 1982 to assure uniformity in patent law among all federal courts. The question before the US Supreme Court is "Whether enablement is governed by the statutory requirement, that the specification teach those skilled in the art to “make and use” the claimed invention, or whether it must instead enable those skilled in the art “to reach the full scope of claimed embodiments” without undue experimentation—i.e., to cumulatively identify and make all or nearly all embodiments of the invention without substantial “time and effort.” [18] Other commentators believe, that the SCOTUS took the case, because of the significance of the legal question, which is deemed comparable to the impact of KSR v. Teleflex.

Issued Amgen's patents have a so-called “functional genus claim,” which defines an antibody by its epitope, the specific target against which it binds. Although, Amgen did discover the target antigen, the antigen itself cannot be patented, because it is a product of nature (i.e. it was discovered rather than invented). However, Amgen was able to convince the USPTO to issue a patent, that broadly claims yet-unmade antibodies with a high affinity to the discovered antigen. Although there are many potential problems with such "functional genus" claims, the lower courts invalidated broad Amgen's claims based on the patent requirements for sufficiency of disclosure. The purposivism justification for disallowing such broad poorly-enabled claims is to allow other pharmaceutical companies to develop other (and potentially better) drugs, that target the same receptor. However, the drawback of such narrow interpretation, is the resulting reluctance of the antigen discoverers to share their finding with the World, because such early disclosure would prevent them from reaping the maximum profits from their discovery, which they could obtain by developing multiple medications, and keeping them secret for many years. [19] However, such dilemma is not unique to biologics or to pharmaceuticals, since the purpose of the patent system is to provide an incentive for earlier disclosure in the gambling game from-discovery-to-market, that does not necessarily reward every participant according to their contribution, but encourages discovers and inventors to play the gambling game nevertheless. [20]

Society and culture

Economics

In 2015 it cost about US$14,100 per year. One article calculated this to be about $400,000 to $500,000 per quality-adjusted life year (QALY), which did not meet "generally accepted" cost-benefit thresholds. The authors calculated that an annual cost of $4,500 would meet an acceptable $100,000 per QALY standard. [21] On October 26, 2018, the maker of the drug, Amgen, announced a 60% cut in price and the drug at that date cost $5,850 per year. [22]

Related Research Articles

<span class="mw-page-title-main">Low-density lipoprotein</span> One of the five major groups of lipoprotein

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, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL). LDL delivers fat molecules to cells. LDL is involved in atherosclerosis, a process in which it is oxidized within the walls of arteries.

<span class="mw-page-title-main">Statin</span> Class of drugs used to lower cholesterol levels

Statins are a class of medications that reduce illness and mortality in people who are at high risk of cardiovascular disease. They are the most commonly prescribed cholesterol-lowering drugs, and are also known as HMG-CoA reductase inhibitors.

Lipid-lowering agents, also sometimes referred to as hypolipidemic agents, cholesterol-lowering drugs, or antihyperlipidemic agents are a diverse group of pharmaceuticals that are used to lower the level of lipids and lipoproteins such as cholesterol, in the blood (hyperlipidemia). The American Heart Association recommends the descriptor 'lipid lowering agent' be used for this class of drugs rather than the term 'hypolipidemic'.

Dyslipidemia is a metabolic disorder characterized by abnormally high or low amounts of any or all lipids or lipoproteins in the blood. Dyslipidemia is a risk factor for the development of atherosclerotic cardiovascular diseases (ASCVD), which include coronary artery disease, cerebrovascular disease, and peripheral artery disease. Although dyslipidemia is a risk factor for ASCVD, abnormal levels don't mean that lipid lowering agents need to be started. Other factors, such as comorbid conditions and lifestyle in addition to dyslipidemia, is considered in a cardiovascular risk assessment. In developed countries, most dyslipidemias are hyperlipidemias; that is, an elevation of lipids in the blood. This is often due to diet and lifestyle. Prolonged elevation of insulin resistance can also lead to dyslipidemia. Likewise, increased levels of O-GlcNAc transferase (OGT) may cause dyslipidemia.

<span class="mw-page-title-main">Simvastatin</span> Lipid-lowering medication

Simvastatin, sold under the brand name Zocor among others, is a statin, a type of lipid-lowering medication. It is used along with exercise, diet, and weight loss to decrease elevated lipid levels. It is also used to decrease the risk of heart problems in those at high risk. It is taken by mouth.

<span class="mw-page-title-main">Rosuvastatin</span> Statin medication

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<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology and a growing subspecialty of oncology.

<span class="mw-page-title-main">Epitope mapping</span> Identifying the binding site of an antibody on its target antigen

In immunology, epitope mapping is the process of experimentally identifying the binding site, or epitope, of an antibody on its target antigen. Identification and characterization of antibody binding sites aid in the discovery and development of new therapeutics, vaccines, and diagnostics. Epitope characterization can also help elucidate the binding mechanism of an antibody and can strengthen intellectual property (patent) protection. Experimental epitope mapping data can be incorporated into robust algorithms to facilitate in silico prediction of B-cell epitopes based on sequence and/or structural data.

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<span class="mw-page-title-main">Familial hypercholesterolemia</span> Genetic disorder characterized by high cholesterol levels

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<span class="mw-page-title-main">PCSK9</span> Mammalian protein found in humans

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 (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.

Alirocumab, sold under the brand name Praluent, is a medication used as a second-line treatment for high cholesterol for adults whose cholesterol is not controlled by diet and statin treatment. It is a human monoclonal antibody that belongs to a novel class of anti-cholesterol drugs, known as PCSK9 inhibitors, and it was the first such agent to receive FDA approval. The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.

<span class="mw-page-title-main">Dupilumab</span> Drug used to treat allergic diseases

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Amgen Inc. v. Sanofi, 598 U.S. 594 (2023), is a United States Supreme Court case in which the Court held that Amgen's two patent applications on cholesterol-lower drugs failed to satisfy the enablement clause of §112 of the Patent Act, 35 U.S.C. § 112(a).

References

  1. ↑ Sheridan C (December 2013). "Phase 3 data for PCSK9 inhibitor wows". Nature Biotechnology. 31 (12): 1057–1058. doi:10.1038/nbt1213-1057. PMID   24316621. S2CID   34214247.
  2. ↑ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 10 April 2023.
  3. ↑ "Repatha- evolocumab injection, solution Repatha- evolocumab kit". DailyMed. U.S. National Library of Medicine. 6 May 2020. Retrieved 20 October 2020.
  4. ↑ World Health Organization (2013). "International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 70". WHO Drug Information. 27 (3). hdl: 10665/331167 .
  5. ↑ Coppinger C, Movahed MR, Azemawah V, Peyton L, Gregory J, Hashemzadeh M (20 May 2022). "A Comprehensive Review of PCSK9 Inhibitors". Journal of Cardiovascular Pharmacology and Therapeutics. 27: 10742484221100107. doi: 10.1177/10742484221100107 . PMID   35593194. S2CID   248918656.
  6. ↑ Weinreich M, Frishman WH (2014). "Antihyperlipidemic therapies targeting PCSK9". Cardiology in Review. 22 (3): 140–146. doi:10.1097/CRD.0000000000000014. PMID   24407047. S2CID   2201087.
  7. ↑ "PCSK9 инхибитори – нов клас медикаменти за лечение на дислипидемия" [PCSK9 inhibitors – a new class of drugs for the treatment of dyslipidemia]. Списание МД[MD Journal] (in Bulgarian). November 2016. Retrieved 28 October 2018– via spisaniemd.bg.
  8. ↑ Choi JY, Na JO (September 2019). "Pharmacological Strategies beyond Statins: Ezetimibe and PCSK9 Inhibitors". Journal of Lipid and Atherosclerosis. 8 (2): 183–191. doi:10.12997/jla.2019.8.2.183. PMC   7379114 . PMID   32821708.
  9. ↑ Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. (May 2017). "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease". The New England Journal of Medicine. 376 (18): 1713–1722. doi: 10.1056/NEJMoa1615664 . hdl: 10536/DRO/DU:30157496 . PMID   28304224. S2CID   1972937.
  10. ↑ "Altmetric – Restoring mortality data in the FOURIER cardiovascular outcomes trial of evolocumab in patients with cardiovascular disease: a reanalysis based on regulatory data". bmj.altmetric.com.
  11. ↑ "Amgen Submits Biologics License Application For Novel Investigational LDL Cholesterol-Lowering Medication Evolocumab To The FDA". Amgen. 28 August 2014.
  12. ↑ "FDA approves Repatha to treat certain patients with high cholesterol". FDA News Release. U.S. Food and Drug Administration. U.S. Food and Drug Administration. 27 August 2015. Retrieved 30 August 2015.
  13. ↑ "European Commission Approves Amgen's New Cholesterol-Lowering Medication Repatha™ (evolocumab), The First PCSK9 Inhibitor To Be Approved In The World, For Treatment Of High Cholesterol". Amgen. 21 July 2015. Archived from the original on 22 July 2015. Retrieved 11 January 2020.
  14. ↑ "Regulatory Decision Summary (SBD): REPATHA - 2015 - Health Canada". www.hc-sc.gc.ca. Archived from the original on 7 October 2015. Retrieved 6 October 2015.
  15. ↑ "Amgen - Media - In The News". www.amgen.ca. Archived from the original on 4 March 2016. Retrieved 17 September 2015.
  16. ↑ Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. (May 2017). "Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease". The New England Journal of Medicine. 376 (18): 1713–1722. doi: 10.1056/nejmoa1615664 . hdl: 10536/DRO/DU:30157496 . PMID   28304224. S2CID   1972937.
  17. ↑ Feeley J, Bloomfield D, Decker S (5 January 2017). "Amgen Wins Ban on Sanofi's Praluent Cholesterol Drug Sales". Bloomberg News.
  18. 1 2 "Amgen Inc. V. Sanofi". SCOTUSblog.
  19. ↑ Holman CM (2022). "Amgen v. Sanofi: The Supreme Court Takes up the Enablement Requirement in the Context of Therapeutic Monoclonal Antibodies". Biotechnology Law Report. 41 (6): 269–282. doi:10.1089/blr.2022.29293.cmh. S2CID   254435116.
  20. ↑ Tu SS, Nagar S, Van de Wiele VL (May 2023). "Broad Patent Claims Come Before the Supreme Court in Amgen v Sanofi". JAMA. 329 (19): 1641–1642. doi: 10.1001/jama.2023.5638 . PMID   36972066. S2CID   257765649.
  21. ↑ Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD, et al. (August 2016). "Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease". JAMA. 316 (7): 743–753. doi: 10.1001/jama.2016.11004 . PMID   27533159.
  22. ↑ Goldman D. "The bigger message behind Amgen's decision to slash cost of its Repatha cholesterol drug". MarketWatch. Retrieved 28 October 2018.
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