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Alirocumab

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Alirocumab
Monoclonal antibody
TypeWhole antibody
SourceHuman
TargetProprotein convertase subtilisin/kexin type 9 (PCSK9)
Clinical data
Trade namesPraluent
AHFS/Drugs.comMonograph
MedlinePlusa615035
License data
Routes of
administration		Subcutaneous injection
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
ChemSpider
  • none
KEGG
Chemical and physical data
FormulaC6472H9996N1736O2032S42
Molar mass145983.80 g·mol−1

Alirocumab (trade name Praluent)[1] is a biopharmaceutical drug approved by the FDA on July 24, 2015 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.[2]

2015 cost is estimated to be $14,300 USD per year, making alirocumab significantly less cost-effective than other lipid-lowering therapies.[3]

Medical uses

Alirocumab is used as a second-line treatment to lower LDL cholesterol for adults who have a severe form of hereditary high cholesterol and people with atherosclerosis who require additional lowering of LDL cholesterol when diet and statin treatment have not worked.[4] It is administered by subcutaneous injection.[4] As of July 2015, it is not known whether alirocumab prevents early death from cardiovascular disease or prevents heart attacks;[4] a clinical trial to determine outcomes was ongoing at that time,[5] the results of which were expected in 2017.[6] The New England journal of medicine published on the 7th of November 2018 positive results from a clinical trial with Alirocumab (Praluent). According to the study Praluent significantly reduced major adverse cardiovascular events by 15% and it was associated with a 15% lower risk of death from any cause (hazard ratio [HR] 0.85; 95% confidence interval [CI], 0.73 to 0.98) See [2]

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, 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.[4]

There are no available data on use of alirocumab in pregnant women to assess risks to the fetus, nor is there data on use in children.[4]

Pharmacology

Main article: PCSK9

Alirocumab works by inhibiting the PCSK9 protein.[7] PCSK9 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 being removed from circulation. Inhibiting PCSK9 prevents the receptor from being degraded, and promotes removal of LDL cholesterol from circulation.[8]

After subcutaneous administration of alirocumab, maximal suppression of free PCSK9 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 pathway.[4]

Chemistry

Alirocumab is a human monoclonal antibody of the IgG1 isotype.[1] 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.[4]

It is produced using Chinese hamster ovary cells transfected with recombinant DNA, that are grown in tanks.[4]

History

The importance of PCSK9 as a biological target for drug discovery 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 when some mutations are present, and its role in causing very low levels of LDL cholesterol when other mutations are present.[9]

The discovery and validation of the target set off a race among pharmaceutical and biotech companies.[10][11]

Alirocumab was discovered by Regeneron Pharmaceuticals using its "VelocImmune" mouse,[12] in which many of the genes coding for antibodies have been replaced with human genes.[13][14]: 255–258  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 IND.[15]: Slide 26  Alirocumab was co-developed with Sanofi under a deal made in 2007.[16] Before it received its international nonproprietary name it was known as REGN727 and SAR236553.[17]

Phase 1 trial results were reported in 2012 in the New England Journal of Medicine.[13][18] A phase 3 trial of statin intolerant patients called ODYSSEY ran for 65 weeks.[19] Results were presented at the 2014 European Society of Cardiology meeting.[20] 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.[21] Studies are ongoing to assess the effects of alirocumab in normocholesterolemic individuals.[22]

In July 2014, Regeneron and Sanofi announced that they had purchased a priority review voucher that BioMarin 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 to market with the first approval of a PCSK9 inhibitor.[23][24][25]

In July 2015, the FDA approved alirocumab as a second line treatment to lower LDL cholesterol for adults who have hereditary high cholesterol and people with atherosclerosis who require additional lowering of LDL cholesterol when diet and statin treatment have not worked.[5] This was the first approval of a PCSK9 inhibitor.[5] The FDA approval was contingent on the completion of further clinical trials to better determine efficacy and safety.[26]

Regeneron and Amgen had each filed for patent protection on their monoclonal antibodies and the companies ended up in patent litigation in the U.S. In March 2016 a district court found that 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.[27] 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.[28]

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'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.[29] At the same time, pharmacy benefit managers such as Express Scripts and CVS Caremark, while recognizing that the new drugs could help patients who were otherwise left with uncontrolled cholesterol levels, and recognizing that injectable biopharmaceuticals 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.[29]

When the drug was approved in July 2015, the announced price was higher than analysts had predicted: $14,600 a year.[6] 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 approval was based on lowering cholesterol alone, and not on better health outcomes, such as fewer heart attacks or longer life.[6]

The current treatment for people with very high cholesterol that cannot be controlled with diet or statins is apheresis, which is similar to dialysis 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.[2]

References

  1. ^ a b International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization
  2. ^ a b Gina Kolata for the New York Times. July 27, 2015 Praluent Looks Cheap to Those With Extreme Cholesterol
  3. ^ Kazi, Dhruv S.; Moran, Andrew E.; Coxson, Pamela G.; Penko, Joanne; Ollendorf, Daniel A.; Pearson, Steven D.; Tice, Jeffrey A.; Guzman, David; Bibbins-Domingo, Kirsten (16 August 2016). "Cost-effectiveness of PCSK9 Inhibitor Therapy in Patients With Heterozygous Familial Hypercholesterolemia or Atherosclerotic Cardiovascular Disease". JAMA. 316 (7): 743–53. doi:10.1001/jama.2016.11004. PMID 27533159.
  4. ^ a b c d e f g h "US Praluent label" (PDF). FDA. July 2015. See FDA index page for BLA 125559
  5. ^ a b c FDA. July 24, 2015 FDA Press release: FDA approves Praluent to treat certain patients with high cholesterol
  6. ^ a b c Liz Szabo for USA Today July 24, 2015 FDA approves new cholesterol drug - at $14,600 a year
  7. ^ Weinreich, M; Frishman, W (2014). "Antihyperlipidemic therapies targeting PCSK9". Cardiology in Review. 22 (3): 140–6. doi:10.1097/CRD.0000000000000014. PMID 24407047.
  8. ^ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". Archived from the original on 2015-05-18. Retrieved 13 May 2015.
  9. ^ Stephen S. Hall for Nature News. April 9, 2013 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.
  10. ^ Abifadel M, Elbitar S, El Khoury P, Ghaleb Y, Chémaly M, Moussalli ML, Rabès JP, Varret M, Boileau C (Sep 2014). "Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs". Current Atherosclerosis Reports. 16 (9): 439. doi:10.1007/s11883-014-0439-8. PMID 25052769.
  11. ^ Desai NR, Sabatine MS (Feb 2015). "PCSK9 inhibition in patients with hypercholesterolemia". Trends in Cardiovascular Medicine. 25 (7): 567–74. doi:10.1016/j.tcm.2015.01.009. PMID 25771732.
  12. ^ Regeneron website December 29, 2015 [1] Veloclmmune website
  13. ^ a b BiotechDaily International staff writers. Apr 17, 2012 LDL-Lowering Monoclonal Antibody Shines in Early Clinical Trials
  14. ^ Susana Magadán Mompó and África González-Fernández. Human Monoclonal Antibodies from Transgenic Mice. Chapter 13 in Human Monoclonal Antibodies: Methods and Protocols Ed. Michael Steinitz. Springer Science+Business Media, 2014. ISBN 978-1-62703-585-9
  15. ^ Regeneron. Presentation to Credit Suisse 2013 Antibody Day on Friday, May 10, 2013 Regeneron: Science to Medicine Archived 2016-03-04 at the Wayback Machine
  16. ^ Herper, Matthew (August 14, 2013). "How Two Guys From Queens Are Changing Drug Discovery". Forbes. United States. Archived from the original on March 16, 2014. Retrieved March 22, 2014.Open access icon
  17. ^ Sheridan C (Dec 2013). "Phase 3 data for PCSK9 inhibitor wows". Nature Biotechnology. 31 (12): 1057–8. doi:10.1038/nbt1213-1057. PMID 24316621.
  18. ^ Stein EA, Mellis S, Yancopoulos GD, Stahl N, Logan D, Smith WB, Lisbon E, Gutierrez M, Webb C, Wu R, Du Y, Kranz T, Gasparino E, Swergold GD (2012). "Effect of a monoclonal antibody to PCSK9 on LDL cholesterol". N. Engl. J. Med. 366 (12): 1108–18. doi:10.1056/NEJMoa1105803. PMID 22435370.
  19. ^ Moriarty PM, Jacobson TA, Bruckert E, Thompson PD, Guyton JR, Baccara-Dinet MT, Gipe D (Nov–Dec 2014). "Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial". Journal of Clinical Lipidology. 8 (6): 554–61. doi:10.1016/j.jacl.2014.09.007. PMID 25499937.
  20. ^ "Huge Decreases in LDL Cholesterol With Alirocumab: ODYSSEY".
  21. ^ Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ (Apr 2015). "Efficacy and safety of alirocumab in reducing lipids and cardiovascular events" (PDF). The New England Journal of Medicine. 372 (16): 1489–99. doi:10.1056/NEJMoa1501031. hdl:10447/127416. PMID 25773378.
  22. ^ Kostapanos, Michael S.; Cacciottolo, Paul J.; Hubsch, Annette; Pavey, Holly; Hurlock, James; Maki-Petaja, Kaisa; Wilkinson, Ian B.; Cheriyan, Joseph (24 October 2019). "vestigating the lowest hreshold of vascular b efits from LDL cholesterol lowering with a PC K9 mAb nhibi or (alirocumab) in health volunteers – a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale". Journal of Drug Assessment. 8 (1): 167–174. doi:10.1080/21556660.2019.1677673. PMC 6818119. PMID 31692938.
  23. ^ John Carroll (July 30, 2014), "Sanofi, Regeneron pay $67M for a shortcut in the blockbuster PCSK9 race with Amgen", FierceBiotech
  24. ^ Ron Winslow; Joseph Walker (July 30, 2014), "Drug Firms Buy $67.5 Million Voucher to Speed FDA Review", Wall Street Journal
  25. ^ Loftus, Peter (1 November 2015). "Drug Makers Buy Pricey Vouchers to Speed Products to Market". Wall Street Journal. Retrieved 19 November 2015.
  26. ^ New Alternatives to Statins Add to a Quandary on Cholesterol By GINA KOLATA, New York Times, AUG. 29, 2015
  27. ^ Feeley, Jef; Bloomfield, Doni; Decker, Susan (5 January 2017). "Amgen Wins Ban on Sanofi's Praluent Cholesterol Drug Sales". Bloomberg News.
  28. ^ "U.S. court reverses ban on sale of Regeneron, Sanofi cholesterol drug". Reuters. 5 October 2017.
  29. ^ a b Tracy Staton for FiercePharmaMarketing. May 7, 2014 Payers fret about the next drug doomsday: Pricey PCSK9 cholesterol meds
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