Alirocumab

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Alirocumab
Mass / length primary structure 146.0 kDa
Identifier
External IDs
Drug information
ATC code C10 AX14
DrugBank DB09302
Drug class PCSK9 inhibitor

Alirocumab is a drug against hypercholesterolemia , which was approved in the USA by the American health authority FDA on July 24, 2015 and for the countries of the EU on September 23, 2015 under the trade name “Praluent”. Alirocumab is a human monoclonal antibody from a new group of drugs, the PCSK9 inhibitors ( inhibitors ).

properties

Alirocumab 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 has been studied by Regeneron Pharmaceuticals and Sanofi for use in the treatment of severe and familial hypercholesterolemia . Patients with familial hypercholesterolemia, patients with statin intolerance or high-risk cardiovascular patients often do not achieve the recommended LDL cholesterol target values ​​with the therapy options currently available, so there is a need for other therapies.

Mechanism of action

LDL receptors (LDL-R) on the surface of the liver cells are used to absorb circulating LDL cholesterol (LDL-C). PCSK9 binds to the LDL receptor and is taken up by liver cells with it . PCSK9 binding promotes endocytosis and the degradation of the LDL receptor in the endosomes . As a result, fewer LDL receptors are available for recirculation to the cell surface. Alirocumab is a fully human monoclonal antibody that specifically binds PCSK9. The binding of alirocumab to PCSK9 prevents 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. The LDL-C level in the blood drops.

Interestingly, PCSK9 inhibitors work synergistically with statin therapy. PCSK9 is formed to a greater extent through the use of statins, as a result of which fewer LDL-R are available for the uptake of the circulating LDL-C on the liver cell surface. By using a PCSK9 inhibitor, the effectiveness of the statins can be increased accordingly.

This mechanism of action is also the basis of the PCSK9-inhibiting agents such as evolocumab and bococizumab .

Clinical development

The development of the PCSK9 inhibitors is a prime example of how genetic research has led to the identification of a new therapeutic approach and the development of a new class of drugs in just a few years. The deciphering of the mechanism of action of PCSK9 began in 2003 with the discovery of very rare PCSK9 mutations. In early 2003, it was shown that gain-of-function mutations in the PCSK9 gene are associated with familial hypercholesterolemia and loss-of-function mutations are associated with low plasma LDL cholesterol levels and a low risk of coronary artery disease .

The ODYSSEY study program

The first phase I studies with alirocumab were initiated in 2011. This was followed by the establishment of the extensive ODYSSEY phase III study program. ODYSSEY consists of 15 Phase III studies with more than 23,500 patients worldwide. The study program examined patients with heterozygous familial hypercholesterolemia as well as patients with a very high cardiovascular risk (especially diabetics) and patients who cannot tolerate statins (statin intolerance). The majority of these ODYSSEY studies have already been completed. The results of ten Phase III studies, encompassing more than 5300 hypercholesterolemia patients, were submitted to the American and European Medicines Agency, i. H. FDA and EMA, submitted and form the basis of the approvals.

The results of the phase III study ODYSSEY LONG TERM were published in April 2015 at the same time as the similarly positive results of the phase III studies of another PCSK9 monoclonal antibody ( evolocumab ). The ODYSSEY LONG TERM study, a randomized, double-blind, placebo- controlled, multicenter study , included 2341 patients from 27 countries who had a high cardiovascular risk profile and, despite statin therapy at the highest tolerated dose, elevated LDL-C levels (over 70 mg / dl) exhibited. Patients received either alirocumab 150 mg or placebo as a subcutaneous injection every two weeks for 78 weeks in a 2: 1 assignment .

After just 24 weeks, the treatment with alirocumab reduced the LDL-C level by an average of 61% vs. Placebo + 0.8% baseline. The effect persisted over the entire duration of the study and was 52% reduction vs. Placebo + 3.6%.

A comparison of the PCSK9 antibodies (evolocumab / Repatha; Bococizumab) with one another does not yet exist.

In November 2018, the results of the ODYSSEY OUTCOMES study were presented and published at the AHA American Heart Association Congress. This study investigated the effect of alirocumab over a median of 2.8 years on the occurrence of cardiovascular events (myocardial infarction, death, stroke) in over 18,000 patients at increased cardiovascular risk due to an acute coronary event within the past 12 months and insufficiently controlled lipid parameters. The additional administration of alirocumab to the optimized lipid-lowering therapy led to a 15 percent reduction in the primary endpoint, consisting of the following cardiovascular events, myocardial infarction, ischemic stroke, coronary-related death or unstable angina-related hospitalization. In particular, patients with an initial LDL cholesterol value of over 100 mg / dL (> 2.0 mmol / l) benefited from alirocumab therapy and thus showed a statistically significant reduction of 24% in cardiovascular events with additional administration of alirocumab compared to sole optimized lipid-lowering therapy. A decrease in total deaths was also observed with alirocumab.

There were no increased rates of adverse effects with alirocumab.

Marketing authorization status

The American approval for alirocumab was granted in July 2015 for patients with hypercholesterolemia and mixed dyslipidemia who do not achieve their LDL cholesterol target values ​​despite the maximum tolerable statin dose. In the European Union, alirocumab is approved for the treatment of adult patients with primary hypercholesterolemia (heterozygous familial hypercholesterolemia [heFH] and non-familial) or mixed dyslipidemia accompanying a diet: a) in combination with a statin or with a statin and other lipid-lowering substances Therapy principles for patients who do not achieve the LDL-C target values ​​with a maximally tolerated statin therapy, or b) as monotherapy or in combination with other lipid-lowering therapy principles for patients with statin intolerance or when statins are contraindicated.

One year after evolocumab ( Repatha / Amgen ), alirocumab also received the approval extension "Reduction of cardiovascular events (heart attack and stroke) in patients with cardiovascular diseases" in the EU in March 2019.

Early benefit assessment

In Germany, since 2011, newly approved drugs with new active ingredients must be subjected to an " early benefit assessment " by the Federal Joint Committee (G-BA) in accordance with Section 35a SGB ​​V if the pharmaceutical manufacturer wants to achieve a higher sales price than just the fixed amount . Only if there is an additional benefit can the pharmaceutical manufacturer negotiate a price with the umbrella association of statutory health insurance companies. The dossier evaluations, on the basis of which the G-BA makes its decisions, are created by the Institute for Quality and Efficiency in Health Care (IQWiG) .

In the first assessment, carried out in 2016, the additional benefit of alirocumab in conjunction with a diet and possibly other lipid-lowering therapy principles in adults with primary (heterozygous familial or non-familial) hypercholesterolaemia or mixed dyslipidaemia was to be determined. If statins were still an option, the active ingredient was compared with the maximum tolerated drug and dietary therapy for lipid lowering. If statin therapy was out of the question due to contraindications or therapy-limiting side effects, it was compared with other lipid-lowering drugs as monotherapy and dietary therapy for lipid-lowering. For patients in whom drug and dietary options for lipid lowering had been exhausted, LDL apheresis was considered the “last resort” for therapy-refractory courses, possibly with accompanying drug-based lipid-lowering therapy. as ACT. For all three research questions, an additional benefit according to the G-BA decision was not proven.

Due to new scientific findings and the extension of the approval, the active ingredient was reassessed in 2019. A distinction was made not only between those affected, for whom statin therapy may or may not be an option, but also between adults with and without known atherosclerotic cardiovascular disease. According to the G-BA decision, an added benefit has not been proven for any of these patient groups. Patients who exhausted drug and dietary lipid lowering options were not the subject of this reassessment.

Individual evidence

  1. ↑ Statement On A Nonproprietary Name Adopted By The USAN Council - Alirocumab ( Memento March 27, 2014 in the Internet Archive ), American Medical Association .
  2. ↑ a b FDA approves Praluent to treat certain patients with high cholesterol PM FDA dated July 24, 2015, accessed on August 19, 2015.
  3. ↑ THE SECOND PCSK9 INHIBITOR Lipid-lowering drug alirocumab receives EU approval DAZ on September 28, 2015, accessed on September 29, 2015.
  4. ↑ Evan A. Stein et al. a .: 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 .
  5. ^ JM Reichert: Antibodies to watch in 2014. In: mAbs. 6, No. 1, 2013, pp. 5-14, doi: 10.4161 / mabs.27333 , PMID 24284914 .
  6. ↑ P. Stawowy, S. Kelle, E. Fleck: PCSK9 as a new target in the therapy of hypercholesterolemia . In: heart . S. 1-4 , doi : 10.1007 / s00059-013-3913-0 .
  7. ↑ Kereiakes DJ., Robinson JG., Cannon CP., Et al. Efficacy and safety of the proprotein convertase subtilisin / kexin type 9 inhibitor alirocumab among high cardiovascular rsik patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J 2015; 169: 906-915 doi: 10.1016 / y.ahj.2015.03.004
  8. ↑ Cannon CP., Cariou B. Blom D. et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur HJ 2015; 36: 1186-1194 doi: 10.1093 / eurheartj / ehv028
  9. ↑ Roth EM., Taskinen MR., Ginsberg HN. Et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolaemia: Results of a 24-week, double-blind, randomized phase 3 trial. International Journal of Cardiology 2014; 176: 55-61 doi: 10.1016 / j.ijcard.2014.06.049
  10. ↑ Moriatry PM., Jacobson TA., Bruckert E. et al. 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 2014; 8: 554-561 doi: 10.1016 / j.jacl.2014.09.007
  11. ↑ Bays H., Gaudet D., Weiss R. et al. Alirocumab as Add-on to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial. J Clin Endocrinol Metab. 2015; 100: 3140-3148 doi: 10.1210 / jc.2015-1520
  12. ↑ Gaudet D., Kereiakes DJ., McKenney JM., Et al. Effect of Alirocumab, a monoclonal Proprotein Convertase Subtilisin / Kexin 9 Antibody, on Lipoprotein (a) Concentratios (a Pooled Analysis of 150 mg Every Two Weeks Dosing from Phase 2 Trials). Am J Cardiol 2014; 114: 711-715 doi: 10.1016 / j.amjcard.2014.05.060
  13. ↑ a b Jennifer G. Robinson, Michel Farnier, Michel Krempf et al .: Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events. In: New England Journal of Medicine . Volume 372, No. 16, April 16, 2015, pp. 1489–1499, doi: 10.1056 / NEJMoa1501031 .
  14. ↑ Gregory G. Schwartz, P. Gabriel Steg a. a .: Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. In: New England Journal of Medicine. 379, 2018, p. 2097, doi : 10.1056 / NEJMoa1801174 .
  15. ↑ Sanofi: New England Journal of Medicine publishes positive detailed results from Praluent® (alirocumab) cardiovascular outcomes trial , press release, November 7, 2018.
  16. ↑ Sanofi: ODYSSEY OUTCOMES investigators highlight at AHA that Praluent® (alirocumab) was associated with fewer deaths from any cause , press release, November 11, 2018.
  17. ↑ Sanofi and Regeneron announce the approval of Praluent® (alirocumab) for the treatment of hypercholesterolemia in the European Union. Sanofi , September 28, 2015, archived from the original on January 16, 2016 ; accessed on October 7, 2015 .
  18. ↑ Praluent® (alirocumab) now approved in European Union to reduce the risk of cardiovascular events in patients with established cardiovascular disease , PM Sanofi from March 15, 2019, accessed on March 17, 2019
  19. ↑ A15-47 Alirocumab - Benefit assessment according to Section 35a SGB V; Accessed March 23, 2020.
  20. ↑ A16-16 Alirocumab - Addendum to Commission A15-47; Accessed March 23, 2020.
  21. ↑ Benefit assessment procedure for the active ingredient alirocumab (hypercholesterolaemia or mixed dyslipidaemia); Accessed March 23, 2020.
  22. ↑ A18-74 Alirocumab (primary hypercholesterolemia or mixed dyslipidemia) - benefit assessment according to Section 35a Social Code Book V (new scientific findings); Accessed March 23, 2020.
  23. ↑ Benefit assessment procedure for the active ingredient alirocumab (renewed benefit assessment § 14: hypercholesterolemia or mixed dyslipidemia); Accessed March 23, 2020.