Evolocumab

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Evolocumab
Mass / length primary structure 141.8 kDa
Identifier
External IDs
Drug information
Drug class PCSK9 inhibitor

Evolocumab (trade name Repatha ; manufacturer Amgen ) is a human monoclonal antibody , and drug from a new group of PCSK9 - inhibitors (inhibitors). Evolocumab is the first PCSK9 inhibitor to be approved in the EU (“first-in-class”) and is used to treat hypercholesterolemia ( high cholesterol levels ). It was approved in the USA in August 2015.

properties

Evolocumab works as an inhibitor of the human enzyme PCSK9 (proprotein convertase subtilisin / kexin type 9), which is involved in the regulation of cholesterol metabolism . It was developed by Amgen and approved for use in the treatment of familial hypercholesterolemia in July 2015. It is also approved if statins are not tolerated or if they are insufficient. The PCSK9 antibody can also be combined with statins or other lipid lowering agents.

Repatha is the only PCSK9 inhibitor approved in the EU for lowering the cardiovascular risk ( heart attack / stroke ) for patients with hypercholesterolemia in secondary prevention .

(Familial) hypercholesterolemia

Independent risk factors for coronary artery disease (CHD) are increased LDL cholesterol and lipoprotein (a) as well as decreased HDL cholesterol . The exposure time is decisive, so that genetic (i.e. familial) forms of hypercholesterolemia are particularly important for the development of atherosclerosis . In milder forms, treatment takes the form of lifestyle measures (exercise, diet, etc.). If the overall cardiovascular risk is increased and the LDL target value is not achieved through lifestyle measures, statin therapy is usually necessary. According to guidelines, an LDL cholesterol value of less than 70 mg / dl should be aimed for in patients at particularly high risk. In patients with proven atherosclerosis, the use of a statin is advisable, even if the initial LDL level is below 100 mg / dl. For many patients with familial hypercholesterolemia, these target values ​​remain difficult to achieve despite drug therapy. Familial hypercholesterolemia is an autosomal dominant disease characterized by elevated plasma LDL levels, xanthomas, and early coronary artery disease. So far, mutations in three genes have been discovered as causes, all three of which influence the function of the LDL receptor: mutations of the LDL receptor gene, the apoB100 gene and the PCSK9 gene .

regulation

PCSK9 and LDL receptors are both mainly regulated by the intracellular cholesterol level: if this level falls, then gene expression of the LDL receptor and PCSK9 is induced. The mechanism of action of statins consists in the inhibition of a key enzyme ( HMG-CoA reductase , SREBP ) and leads to a lowering of intracellular cholesterol in the liver cells. They are therefore also known as HMG-CoA reductase inhibitors. The effect via the SREBP leads to a regulatory increase in the production (and secretion) of PCSK9, so statins increase the PCSK9 levels and thus attenuate their actual LDL lowering potential somewhat. This can explain why statins can hardly lower LDL cholesterol by more than 50%. A combination of statins with PCSK9 inhibitors is expected to have an additive effect.

Mechanism of action

PCSK9 binds to the LDL receptor (LDL-R) and is taken up by liver cells with it . PCSK9 binding promotes endocytosis and the degradation of the LDL receptor in endosomes . As a result, fewer LDL receptors are available for recirculation to the cell surface, which reduces the binding of LDL cholesterol. Evolocumab specifically binds serum PCSK9, thereby preventing the formation of LDL receptor PCSK9 complexes and the intracellular degradation of the LDL receptor. More LDL cholesterol can be absorbed by the LDL receptors and broken down in the cell.

Clinical development

As part of the PROFICIO study program initiated by Amgen, 20 studies with the inclusion of 30,000 patients are planned for evolocumab. PRoFicio represents P rogram to R educe LDL-C and Cardiovascular O utcomes F ollowing I nhibition of P C SK9 I n Different P O pupations . The results of u. a. Phase 3 studies were presented at the American College of Cardiology's 63rd Annual Scientific Sessions (ACC.14) in March 2014.

The phase 3 program examines evolocumab administered every two weeks and monthly in different patient groups in 14 studies, including in combination with statins in patients with hyperlipidaemia (LAPLACE-2 and YUKAWA-2); in patients with hyperlipidemia who cannot tolerate statins (GAUSS-2 and GAUSS-3); as monotherapy in patients with hyperlipidemia (MENDEL-2); in patients with familial hypercholesterolemia (RUTHERFORD-2 and TAUSSIG) and homozygous familial hypercholesterolemia (TESLA and TAUSSIG) and the administration of evolocumab (THOMAS-1 and THOMAS-2).

Five other studies evolocumab are intended to provide long-term security and -Wirksamkeits data: These include Fourier ( F urther Cardiovascular OU tcomes R esearch with PCSK9 I nhibition in Subjects with E levated R isk ), Descartes ( D urable e ffect of PC S K9 Antibody C omp AR ed wi T h Plac E bo S tudy ), OSLER-2 ( O pen Label S tudy of L ong T ER m Evaluation Against LDL-C Trial-2 ), GLAGOV ( GL obal A ssessment of Plaque Re G ression with a PCSK9 Antib O dy as Measured by intra V ascular Ultrasound ) and TAUSSIG ( T rial A ssessing Long term US e of PC S K9 I nhibition in Subjects with G Enetic LDL Disorders ).

FOURIER study

The results of the Repatha Outcome Study (FOURIER), in which 27,564 patients were included, showed that the additional administration of evolocumab to optimized lipid-lowering therapy led to a strong and sustained reduction in LDL-C by 59% over the average total study duration of 2, 2 years ago. In addition, a significant reduction in cardiovascular events (MACE) of 20% in the secondary combined endpoint, made up of cardiovascular death, myocardial infarction or stroke, was found (p <0.001). In the primary composite endpoint, consisting of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina pectoris, or coronary revascularization (the first of the above events was counted), a significant reduction in cardiovascular events of 15% was found (p <0.001).

OSLER studies

In April 2015, another randomized, multicenter phase III study was published that included 4465 patients and had a median follow-up of 11.1 months. Study participants were recruited on their last control visit as part of a previous study and randomized centrally in a 2: 1 rate. However, no placebo was given, so the study was not blinded . Patients who were transferred from one of five phase II studies were included in the OSLER-1 study (1324 patients), those from one of seven phase III studies in the OSLER-2 study (3141 patients). In the OSLER-1 study , patients received evolocumab 420 mg once a month as a subcutaneous injection for continued standard therapy; in the OSLER-2 study , they received 420 mg once a month or 140 mg every two weeks, as they choose. The control group (1489 patients in total) only continued the standard therapy. The two sub-studies were evaluated in summary form. After 12 weeks, there was a significant decrease in the LDL cholesterol level in the blood, which was 73.4 mg / dl lower (-60.9%) and remained so over time. After 48 weeks, the reduction in the LDL value was a mean of 70.5 mg / dl (−58.4%). Serious adverse drug reactions were observed in 7.5% of both groups ; however, in a post hoc analysis, the risk of cardiovascular events such as myocardial infarction, stroke or the like was significantly reduced with 2.18% in the control group and 0.95% in the evolocumab group ( hazard ratio 0.47).

These results are largely congruent with a concurrently published placebo-controlled phase III study of another PCSK9 antibody, alirocumab . Comparative studies between the individual PCSK9 antibodies do not yet exist. The number of patients and the follow-up period are not yet sufficient to identify rare, severe adverse effects.

Studies

  • DESCARTES: Blom DJ, et al .: A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia . In: New England Journal of Medicine . March 2014, doi : 10.1056 / NEJMoa1316222 .
  • GAUSS-2: Stroes E, et al .: Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: The GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab . In: J Am Coll Cardiol . tape 63 , no. 23 , 2014, p. 2541-2548 , doi : 10.1016 / j.jacc.2014.03.019 .
  • LAPLACE-2:
    • Robinson JG, et al .: Rationale and Design of LAPLACE-2: A Phase 3, Randomized, Double-Blind, Placebo- and Ezetimibe-Controlled Trial Evaluating the Efficacy and Safety of Evolocumab in Subjects With Hypercholesterolemia on Background Statin Therapy . In: Clinical Cardiology . 2014, doi : 10.1002 / clc.22252 .
    • Robinson JG, et al .: Effect of Evolocumab or Ezetimibe Added to Moderate- or High-Intensity Statin Therapy on LDL-C Lowering in Patients With Hypercholesterolemia The LAPLACE-2 Randomized Clinical Trial . In: JAMA . tape 311 , no. 18 , 2014, p. 1870–1882 , doi : 10.1001 / jama.2014.4030 .
  • MENDEL-2: Koren MG, et al .: Anti-PCSK9 Monotherapy for Hypercholesterolemia - The MENDEL-2 Randomized, Controlled Phase 3 Clinical Trial of Evolocumab . In: J Am Coll Cardiol . tape 63 , no. 23 , 2014, p. 2531-2540 , doi : 10.1016 / j.jacc.2014.03.018 .
  • OSLER: Koren MJ, et al .: Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial . In: Circulation . tape 129 , no. 2 , 2014, p. 234-43 , doi : 10.1161 / CIRCULATIONAHA.113.007012 , PMID 24255061 .
  • Raal F, et al: Reduction in Lipoprotein (a) With PCSK9 Monoclonal Antibody Evolocumab (AMG 145) . In: J Am Coll Cardiol . tape 63 , no. 13 , April 2014, p. 1278-1288 , doi : 10.1016 / j.jacc.2014.01.006 .
  • Raal F, et al .: The addition of evolocumab (amg 145) allows the majority of heterozygous familial hypercholesterolemic patients to achieve low-density lipoprotein cholesterol goals - results from the phase 3 randomized, double-blind, placebo-controlled study , ACC 2014 .

literature

  • Wolfgang Koenig, Nikolaus Marx, Joachim Thiery, Gerald Klose: Pocket guideline: Diagnosis and therapy of dyslipidemias . Ed .: German Society for Cardiology - Heart and Circulatory Research eV 3rd edition. 2012 ( dgk.org [PDF]).
  • Željko Reiner, Alberico L. Catapano, et al .: ESC / EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) . In: European Heart Journal . tape 32 , no. 14 , 2011, p. 1769–1818 , doi : 10.1093 / eurheartj / ehr158 .

Web links

Individual evidence

  1. ↑ Statement On A Nonproprietary Name Adopted By The USAN Council - Evolocumab ( February 19, 2014 memento in the Internet Archive ), American Medical Association .
  2. ^ Reichert JM .: Antibodies to watch in 2014. In: mAbs . tape 6 , no. 1 , 2014, p. 5-14 , doi : 10.4161 / mabs.27333 , PMID 24284914 .
  3. ↑ a b c d Data From Phase 3 Pivotal Studies Show Amgen's Novel Investigational Cholesterol-Lowering Medication Evolocumab Significantly Reduced LDL Cholesterol In Statin Intolerant Patients And In Patients On Statins , Amgen PM on March 30, 2014, accessed April 2, 2014
  4. ↑ a b 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 ( Memento from July 22, 2015 in the web archive archive.today ), PM by Amgen on July 21, 2015, accessed July 22, 2015
  5. ↑ FDA Approves Amgen's New Cholesterol-Lowering Medication Repatha ™ (evolocumab) , Amgen PM, August 27, 2015, accessed March 21, 2020
  6. ↑ Summary of the European public assessment report (EPAR) for Repatha , der EMA, accessed on December 30, 2015
  7. ↑ Summary of the EPAR for the public of the EMA (German), accessed on December 30, 2015
  8. ↑ Amgen Receives European Commission Approval For Repatha® (Evolocumab) To Prevent Heart Attack And Stroke In Adults With Established Cardiovascular Disease , PM Amgen, May 16, 2018, accessed on March 21, 2020
  9. ↑ Evan A. Stein et al: Effect of a Monoclonal Antibody to PCSK9 on LDL Cholesterol . In: New England Journal of Medicine . tape 366 , no. 12 , 2012, p. 1108-1118 , doi : 10.1056 / NEJMoa1105803 , PMID 22435370 .
  10. ↑ Clinical study (phase III): Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) at Clinicaltrials.gov of the NIH .
  11. ↑ Sabatine MS: Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease In: New England Journal of Medicine . Volume 376, 2017, pages 1713-1722, doi: 10.1056 / NEJMoa1615664 .
  12. ↑ Marc S. Sabatine, Robert P. Giugliano, Stephen D. Wiviott, Frederick J. Raal, Dirk J. Blom, Jennifer Robinson, Christie M. Ballantyne, Ransi Somaratne, Jason Legg, Scott M. Wasserman, Robert Scott, Michael J. Koren, Evan A. Stein: Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. In: New England Journal of Medicine . Volume 372, No. 16, 2015, pages 1500–1509, doi: 10.1056 / NEJMoa1500858 .