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In July 2015, the FDA approved alirocumab as a second line treatment to lower [[LDL cholesterol]] for adults who have [[familial hypercholesterolemia|hereditary high cholesterol]] and people with [[atherosclerosis]] who require additional lowering of LDL cholesterol when diet and [[statin]] treatment have not worked.<ref name=FDA2014>FDA. July 24, 2015 [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm FDA Press release: FDA approves Praluent to treat certain patients with high cholesterol]</ref> This was the first approval of a [[PCSK9]] inhibitor.<ref name=FDA2014/>
In July 2015, the FDA approved alirocumab as a second line treatment to lower [[LDL cholesterol]] for adults who have [[familial hypercholesterolemia|hereditary high cholesterol]] and people with [[atherosclerosis]] who require additional lowering of LDL cholesterol when diet and [[statin]] treatment have not worked.<ref name=FDA2014>FDA. July 24, 2015 [http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm FDA Press release: FDA approves Praluent to treat certain patients with high cholesterol]</ref> This was the first approval of a [[PCSK9]] inhibitor.<ref name=FDA2014/>

==Society and culture==
In 2014 as PCSK9 inhibitors approached regulatory approval, market analysts estimated that that overall market for these drugs could be $10B per year, with each of alirocumab and Amgen's competing drug 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.<ref name=Staton>Tracy Staton for FiercePharmaMarketing. May 7, 2014 [http://www.fiercepharmamarketing.com/story/payers-already-fretting-about-next-pharm-apocalypse-pricey-pcsk9-cholestero/2014-05-07 Payers fret about the next drug doomsday: Pricey PCSK9 cholesterol meds]</ref> 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 [[biotherapeutics]] 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.<ref name=Staton/>

When the drug was approved in Ju;y 2015, the announced price was higher than analysts had predicted: $14,600 a year.<ref name=Szabo>Liz Szabo for USA Today July 24, 2015 [http://www.msn.com/en-us/news/us/fda-approves-new-cholesterol-drug-at-dollar14600-a-year/ar-AAdsOdi 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 that the FDA approval was based on lowering cholesterol alone, and not on better health outcomes, such as fewer heart attacks or longer life.<ref name=Szabo/>


== References ==
== References ==

Revision as of 01:51, 26 July 2015

Alirocumab
Monoclonal antibody
Type?
SourceHuman
TargetProprotein convertase subtilisin/kexin type 9 (PCSK9)
Clinical data
Trade namesPraluent
Routes of
administration		Subcutaneous injection
ATC code
  • none
Legal status
Legal status
  • FDA approved
Identifiers
CAS Number
ChemSpider
Chemical and physical data
FormulaC6472H9996N1736O2032S42
Molar mass146.0 kDa g·mol−1

Alirocumab (trade name Praluent)[1] is a biopharmaceutical drug approved by the FDA in July 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.

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.[2] It is administered by subcutaneous injection.[2]

Side effects

Side effects that occurred in more than 2% of people treated with 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.[2]

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.[2]

Pharmacology

Main article: PCSK9

Alirocumab works by inhibiting the PCSK9 protein. PCSK9 binds to the low-density lipoprotein receptor (LDLR), which leads to the receptor being degraded, and thus less LDL cholesterol being removed from circulation. Inhibiting PCSK9 prevents the receptor from being degraded, and thus promotes removal of LDL cholesterol from circulation.[3]

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.[2]

Physical and chemical properties

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.[2]

It is produced using Chinese hamster ovary cells transfected with recombinant DNA, that are grown in tanks.[2]

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.[4]

The discovery and validation of the target set off a race among pharmaceutical and biotech companies.[5][6]

Alirocumab was discovered by Regeneron Pharmaceuticals using its "VelocImmune" mouse, in which many of the genes coding for antibodies have been replaced with human genes.[7][8]: 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.[9]: Slide 26  Alirocumab was co-developed with Sanofi under a deal made in 2007.[10] Before it received its international nonproprietary name it was known as REGN727 and SAR236553.[11]

Phase 1 trial results were reported in 2012 in the New England Journal of Medicine.[7][12] A phase 3 trial of statin intolerant patients called ODYSSEY ran for 65 weeks.[13] Results were presented at the 2014 European Society of Cardiology meeting.[14] 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.[15]

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.[16][17]

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.[18] This was the first approval of a PCSK9 inhibitor.[18]

Society and culture

In 2014 as PCSK9 inhibitors approached regulatory approval, market analysts estimated that that overall market for these drugs could be $10B per year, with each of alirocumab and Amgen's competing drug 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.[19] 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 biotherapeutics 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.[19]

When the drug was approved in Ju;y 2015, the announced price was higher than analysts had predicted: $14,600 a year.[20] Pharmacy benefit managers continued expressing their concerns, as did insurance companies and some doctors, who were especially concerned that the FDA approval was based on lowering cholesterol alone, and not on better health outcomes, such as fewer heart attacks or longer life.[20]

References

  1. ^ a b International Nonproprietary Names for Pharmaceutical Substances (INN), World Health Organization
  2. ^ a b c d e f g Alirocumab label Label revised, July 2015. Page accessed July 25, 2015
  3. ^ *"The Evolving Role of PCSK9 Modulation in the Regulation of LDL-Cholesterol". Retrieved 13 May 2015.
  4. ^ 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.
  5. ^ Abifadel M, et al. Living the PCSK9 adventure: from the identification of a new gene in familial hypercholesterolemia towards a potential new class of anticholesterol drugs Curr Atheroscler Rep. 2014 Sep;16(9):439. Review. PMID 25052769
  6. ^ Desai NR, Sabatine MS. PCSK9 inhibition in patients with hypercholesterolemia. Trends Cardiovasc Med. 2015 Feb 11. pii: S1050-1738(15)00030-4. Review. PMID 25771732
  7. ^ a b BiotechDaily International staff writers. Apr 17, 2012 LDL-Lowering Monoclonal Antibody Shines in Early Clinical Trials
  8. ^ 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
  9. ^ Regeneron. Presentation to Credit Suisse 2013 Antibody Day on Friday, May 10, 2013 Regeneron: Science to Medicine
  10. ^ 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. {{cite news}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)Open access icon
  11. ^ Attention: This template ({{cite pmid}}) is deprecated. To cite the publication identified by PMID 24316621, please use {{cite journal}} with |pmid=24316621 instead.
  12. ^ Stein EA, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012 Mar 22;366(12):1108-18. PMID 22435370
  13. ^ "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: 554–61. Nov–Dec 2014. doi:10.1016/j.jacl.2014.09.007. PMID 25499937.
  14. ^ "Huge Decreases in LDL Cholesterol With Alirocumab: ODYSSEY".
  15. ^ Robinson, Jennifer G.; Farnier, Michel; Krempf, Michel; Bergeron, Jean; Luc, Gérald; Averna, Maurizio; Stroes, Erik S.; Langslet, Gisle; Raal, Frederick J. (April 16, 2015). "Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events". New England Journal of Medicine. 372 (16): 1489–1499. doi:10.1056/NEJMoa1501031. ISSN 0028-4793. PMID 25773378.
  16. ^ John Carroll for FierceBiotech. July 30, 2014 Sanofi, Regeneron pay $67M for a shortcut in the blockbuster PCSK9 race with Amgen
  17. ^ Ron Winslow and Joseph Walker for the Wall Street Journal. July 30, 2014 Drug Firms Buy $67.5 Million Voucher to Speed FDA Review
  18. ^ a b FDA. July 24, 2015 FDA Press release: FDA approves Praluent to treat certain patients with high cholesterol
  19. ^ a b Tracy Staton for FiercePharmaMarketing. May 7, 2014 Payers fret about the next drug doomsday: Pricey PCSK9 cholesterol meds
  20. ^ a b Liz Szabo for USA Today July 24, 2015 FDA approves new cholesterol drug - at $14,600 a year
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