Alirocumab

Mechanism of action: Alirocumab is a human IgG1 monoclonal antibody that binds with high affinity and specificity to proprotein convertase subtilisin kexin type 9 (PCSK9).

This reduces the activity of PCSK9 and prevents PCSK9 from binding to LDL-C receptors on the cell surface of hepatocytes and LDL-C receptors from being degraded. This increases the number of LDL-C receptors on the cell surface and allows more LDL-C to be taken up from the bloodstream into the hepatocytes, thereby lowering serum LDL-C levels.

ODYSSEY LONG TERM study: RCT Phase III (≥18J) Efficacy and safety 2341 patients with high cardiovascular risk; with max. tolerated statin therapy possibly additional lipid-lowering medication LDL-C≥70 mg/dl over 78 weeks alirocumab (150mg every 2 weeks) versus placebo. Additional LDL-C reduction 62% (mean LDL-C 48mg/dl alirocumab, 119mg/dl placebo), sustained over 72 weeks, additional reduction in ApoB 54%, triglycerides 17.3%, Lp(a) 25.6%, slight increase in HDL 4.6%. Reduction in Lp(a) cannot be explained by reduction in PCSK9 activity and increase in LDL receptor count and has therefore not yet been clarified (Robinson JG et al 2015).

ODYSSEY OUTCOME study: Phase III cardiovascular outcome study in 18924 patients; effect of alirocumab in addition to maximally tolerated statins in patients who have had an acute coronary syndrome (ACS) (acute MI, unstable angina): alirocumab reduces the relative risk of major adverse cardiovascular events (MACE) by 15% in patients who have recently suffered an ACS (Schwartz GG et al 2018).

ODYSSEY KIDS study: Phase III, RCT, 153 patients with HeFH (8-17Y, mean 12Y); good efficacy and safety comparable to results in adults (Santos RD et al 2024). Approval for children in the EU 2023 in the USA 2024.

An open-label phase III study on the applicability of alirocumab as an additional treatment option for children with homozygous familial hypercholesterolemia (hoFH) in children (8-17Y) (Bruckert E et al 2022)

The approval of alirocumab is based on data from a total of 10 Phase III ODYSSEY studies (comparison with placebo, ezetimibe).

Absorption: after sc application 3-7 days to maximum serum concentration (_tmax) for all doses; absolute bioavailability 85%; approximately the same exposure with application of 150mg every 2 weeks or 300mg once every 4 weeks but greater variation _Cmax to _Cthrough for once every 4 weeks.

Distribution: mainly in the bloodstream.

Metabolism: as expected, degradation as with other proteins by cleavage into peptides and individual amino acids.

Elimination: at low concentrations by saturable binding to the target protein PCSK9, at higher concentrations also by non-saturable proteolytic degradation (cleavage into peptides and amino acids); mean half-life: 14 days (75mg) up to 20 days (150mg).

Concentration-dependent reduction of PCSK9 and LDL-C up to saturation, no further reduction thereafter but longer duration of action.

No clinically relevant differences for gender, ethnicity or older patients.

for further details see the technical info.

^Praluent® 75mg, 150mg, 300mg solution for injection in prefilled pen (Sanofi)

^Praluent® 75mg, 150mg solution for injection in prefilled syringe (Sanofi)

Bruckert E, Caprio S, Wiegman A, et al (2022). Efficacy and Safety of Alirocumab in Children and Adolescents With Homozygous Familial Hypercholesterolemia: Phase 3, Multinational Open-Label Study. Arterioscler Thromb Vasc Biol. 42(12):1447-1457. doi/10.1161/ATVBAHA.122.317793.

Robinson JG, Farnier M, Krempf M, et al. for the ODYSSEY LONG TERM Investigators (2015). Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1489-99. doi/full/10.1056/NEJMoa1501031.

Santos RD, Wiegman A, Caprio S et al (2024). Alirocumab in Pediatric Patients With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial. JAMA Pediatr. 178(3):283-293. doi:10.1001/jamapediatrics.2023.6477.

Schwartz GG, Steg PG, Szarek M et al for the ODYSSEY OUTCOME Investigators (2018). Outcome Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med. 379:2097-2107. doi/full/10.1056/NEJMoa1801174.

Alirocumab ^Praluent® (Sanofi)