PCSK9 inhibitors

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PCSK9 inhibitors are drugs that are used in the therapy of high cholesterol levels when other lipid-lowering therapies are not sufficiently effective or not possible. The available for therapy PCSK9 inhibitors is monoclonal antibodies , the subcutaneously injected be.

Mode of action

PCSK9 inhibitors are inhibitors ( inhibitors ) of the proprotein convertase PCSK9 . PCSK9 reduces the number of LDL receptors on the cell membrane of the liver cells . PCSK9 inhibitors bind to the circulating PCSK9 and prevent them from binding to the LDL receptors; This increases the number of LDL receptors on the cell membrane. The breakdown of LDL cholesterol via these receptors is increased accordingly . As a resultant drug effect, PCSK9 inhibitors achieve a considerable lowering of the LDL cholesterol level in the blood.

Medicinal substances

In 2015 the following PCSK9 inhibitors were approved as drugs in the European Union :

  • The monoclonal antibody alirocumab as a praluent from Sanofi , approved in September 2015.
  • The monoclonal antibody evolocumab as a repatha from Amgen , approved July 2015.

In Bococizumab it was another PCSK9 inhibitors, which the company Pfizer investigated. In November 2016, Pfizer announced that further development had been discontinued.

Other substances targeting PCSK9 are in clinical development, such as: B .:

indication

PCSK9 inhibitors may be indicated as a treatment option in familial hypercholesterolaemia or in mixed dyslipidaemia in the event that statin therapy is insufficiently effective .

According to the approval, PCSK9 inhibitors can be used alongside a diet "in adults with primary hypercholesterolemia [...] or mixed dyslipidemia [...] in combination with statin [...] or a statin together with other blood lipid-lowering drugs in patients who do not respond adequately to the." Respond to the maximum dose of the statin […]. ”In the case of statin intolerance, therapy with PCSK9 inhibitors may be indicated.

The annual therapy costs are extremely high at around € 9,500 to € 13,000 (as of 2016). In its guidelines from 2016, the German Society for Cardiology only mentions PCSK9 inhibitors as a reserve option for patients with a very high cardiovascular risk who do not respond to the standard drugs even in combination and in the highest tolerated dose (recommendation grade IIb, evidence level C).

Side effects

Side effects of therapy with PCSK9 inhibitors are to be expected in up to 10% of the treated patients. The side effect profiles for alirocumab and evolocumab appear to be very similar. Most of these are allergic reactions and irritations around the injection site. Memory disorders and muscle damage ( rhabdomyolysis ) have also been described; a diabetes- promoting effect and favoring pancreatitis is discussed. Serious undesirable effects have not yet been described. However, the number of patients treated so far and the duration of the treatments are not yet sufficient to identify possible rare serious side effects (as of June 2016).

Individual evidence

  1. ↑ European Medicines Agency EMA .
  2. ↑ a b Red List 2016, drug directory for Germany (including EU approvals and certain medical devices) , ISBN 978-3-946057-00-0 .
  3. ↑ Bococizumab is being investigated by Pfizer in phase II studies: Bococizumab (RN316) significantly reduced LDL cholesterol in statin-treated adults with high cholesterol in a phase 2b study1 , Pfizer press release of March 27, 2014, accessed on March 22, 2014 May 2016.
  4. ↑ Pfizer Discontinues Global Development of Bococizumab, Its Investigational PCSK9 Inhibitor , Pfizer PM November 1, 2016, accessed November 2, 2016
  5. ↑ Vaccine that lowers cholesterol in mice offers hope of immunizing against cardiovascular disease ( Memento of September 9, 2017 in the Internet Archive ), PM Affiris of June 20, 2017, accessed on June 22, 2017
  6. ↑ The AT04A vaccine against proprotein convertase subtilisin / kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE * 3Leiden.CETP mice , European Heart Journal of June 19, 2017, doi : 10.1093 / eurheartj / ehx260
  7. ↑ The approval of alirocumab relates to heterozygous forms of hypercholesterolemia, the approval of evolocumab to both heterozygous and homozygous forms of hypercholesterolemia.
  8. ↑ Landmesser U et al .: “2017 Update of ESC / EAS Task Force on practical clinical guidance for proprotein convertase subtilisin / kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia.” In: “Eur Heart J.” 2017: Oct 18 Epub ahead of print. doi: 10.1093 / eurheartj / ehx549
  9. ↑ European Medicines Agency EPAR summary for the public - Repatha - Evolocumab EPAR .
  10. ↑ A similar formulation can be found in the corresponding evaluation of the European Medicines Agency in the evaluation of Praluent - Alirocumab: European Medicines Agency (EMA) Assessment report Praluent (alirocumab) , as of July 2015, EPAR , accessed on June 10, 2016.
  11. ^ Technical information from Amgen on Repatha.
  12. ^ Specialist information from Sanofi on Praluent.
  13. ↑ After: New on the market - PCSK9 inhibitor evolocumab (Repatha) , arznei-Telegram 2015, 46, 109-110.
  14. ↑ a b PCSK9 inhibitor alirocumab (Praluent) , arznei-Telegram 2016, 47, ea-t on the Internet .
  15. ↑ German Cardiac Society - Heart and Circulatory Research eV (2017): ESC Pocket Guidelines. Diagnosis and therapy of dyslipidemias, version 2016. Börm Bruckmeier Verlag GmbH, Grünwald. Abstract of the "ESC / EAS Guidelines for the Management of Dyslipidaemias", European Heart Journal 2016; doi : 10.1093 / eurheartj / ehw272
  16. ↑ European Medicines Agency (EMA) Assessment report Praluent (alirocumab) , as of July 2015, EPAR , accessed on June 10, 2016.
  17. ↑ European Medicines Agency (EMA) European Assessment Report (EPAR) Repatha (evolocumab), as of May 2015, EPAR , accessed on June 10, 2016.
  18. ↑ 4.3% local allergic reactions with evolocumab: Marc S. Sabatine et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular effects. New England Journal of Medicine 2015, 372, 1500-1509.
  19. ↑ 5.9% local allergic reactions to alirocumab: Jennifer G. Robinson et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events New England Journal of Medicine 2015, 372, 1489-1499.
  20. ↑ Specialist information from Sanofi on Praluent: general allergic reactions 8.1%, irritation in the area of ​​the injection site 6.1%.
  21. ↑ Amgen specialist information on Repatha: general allergic reactions below 10%, irritation in the area of ​​the injection site below 10% (no detailed information).