Alirocumab is a human monoclonal antibody to PCSK9 (proprotein convertase subtilisin/kexin type 9), a circulating protein that modulates the activity of the LDL cholesterol receptor in the liver. The monoclonal antibody lowers serum LDL cholesterol and is used to treat severe hypercholesterolemia. Alirocumab therapy has been associated with a low rate of serum aminotransferase elevations and has yet to be linked to instances of clinically apparent acute liver injury.
Alirocumab (al" i rok' ue mab) is a human IgG1 monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), a serine protease that decreases the activity of the LDL cholesterol receptor in the liver. Inhibition of PCSK9 increases the low density lipoprotein (LDL) cholesterol receptor, leading to an increased uptake of LDL particles and a decrease in serum LDL cholesterol. Patients with a genetic deficiency in PCSK9 have low levels of LDL cholesterol, and inhibition of the protein activity with monoclonal antibody leads to a marked lowering of LDL cholesterol. In several controlled trials, alirocumab was shown to lower LDL cholesterol in persons with heterozygosity for familial hypercholesterolemia and in persons at risk for atherosclerosis who have been unable to achieve adequate cholesterol lowering with standard lipid lowering agents (statins). Alirocumab was approved for use in the United States in 2015. The current indications are limited to patients with severe hypercholesterolemia who are heterozygous for familial hypercholesterolemia or who have had clinical complications of atherosclerosis and an inadequate response to standard therapies. Alirocumab should be given in combination with advice on diet and exercise and is usually used in combination with oral lipid lowering agents such as statins. Alirocumab is available in solution in single use syringes or pens of 75 or 150 mg/mL under the brand name Praluent. The recommended initial dose is 75 mg administered subcutaneously every two weeks, which can be raised to 150 mg every two weeks based upon tolerance and response. Side effects are uncommon and rarely serious, but include injection site reactions (7%) and myalgia (4%). Rare, but potentially serious side effects may include memory impairment, neurocognitive defects, confusion and hypersensitivity reactions.
In premarketing studies, liver test abnormalities were uncommon in patients taking alirocumab and rates of abnormalities were only slightly higher than in patients receiving placebo injections. Some degree of ALT elevation was reported in 2.5% with alirocumab vs 1.7% with placebo injections. ALT or AST values greater than 3 times the upper limit of normal (ULN) occurred in 1.7% of persons on alirocumab vs 1.4% on placebo. No instances of acute, clinically apparent liver injury attributed to alirocumab were reported during the prelicensure evaluation and none have been reported since. However, alirocumab has had limited use and has been available commercially for a short time only.
Likelihood score: E (unlikely cause of clinically apparent liver injury).
Mechanism of Injury
Alirocumab is a human monoclonal antibody and is metabolized in many tissues to polypeptides and amino acids which are unlikely to be toxic. Monoclonal antibody therapy sometimes causes immune mediated liver injury, but such events have not been described in alirocumab or evolocumab.
with alirocumab and other monoclonal antibodies to PCSK9 have been well
tolerated with rates of adverse events similar to those with placebo or
comparator treatments. Local injection site reactions occur with these agents,
but are generally mild and improve with continued therapy. Monoclonal
antibodies to PCSK9 has not been linked to significant elevations in serum
enzymes or bilirubin or to clinically apparent liver injury. Patients who
develop serum aminotransferase elevations above 3 times the upper limit of
normal should be evaluated for other causes of liver injury including
drug-induced injury from another antilipemic agent.
Other Drugs in the Class: Evolocumab
REPRESENTATIVE TRADE NAMES
Alirocumab – Praluent®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 19 February 2018
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Kereiakes DJ, Robinson JG, Cannon CP, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: The ODYSSEY COMBO I study. Am Heart J 2015 169: 906-915.e13. PubMed Citation (Among 316 patients with coronary artery disease and hypercholesterolemia, despite high doses of statins, who were treated with alirocumab [75 mg] or placebo injections every 2 weeks, LDL cholesterol levels decreased by 48% and adverse events including laboratory test abnormalities were similar between groups).
Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, et al.; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372: 1489-99. PubMed Citation (Among 2341 patients at high or moderate risk for cardiovascular events and hypercholesterolemia, despite high doses of statins, who were treated with alirocumab [150 mg] or placebo injections every two weeks, adverse events more common with alirocumab included injection site reactions [5.9% vs 4.2%], myalgia [5.4% vs 2.9%], neurocognitive events [1.2% vs 0.5%] and ophthalmologic events [2.9% vs 1.9%], but ALT elevations above 3 times ULN occurred at similar rates [1.8% vs 2.1%]).
Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, et al.; ODYSSEY COMBO II Investigators. 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 Heart J 2015; 36: 1186-94. PubMed Citation (Among 720 patients with hypercholesterolemia, despite high doses of statins, treated with either alirocumab or ezetimibe for up to 104 weeks, rates of side effects were similar in the two groups and ALT elevations above 3 times ULN occurred in 1.7% on alirocumab vs 0.4% on ezetimibe, but there were no episodes of clinically apparent liver injury).
Koren MJ, Roth EM, McKenney JM, Gipe D, Hanotin C, Ferrand AC, Wu R, et al. Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis. Postgrad Med 2015; 127: 125-32. PubMed Citation (Pooled analysis of 3 phase II trials of alirocumab [n=108] vs placebo [n=77] for 8-12 weeks, found no significant difference in rates of adverse events and no instance of ALT elevations above 3 times ULN in either group).
Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52. PubMed Citation (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 41 cases were attributed to lipid lowering agents including 31 to statins, 5 to niacin and 5 to fibrates, but none to alirocumab or evolocumab).
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Stroes E, Guyton JR, Lepor N, Civeira F, Gaudet D, Watts GF, Baccara-Dinet MT, et al.; ODYSSEY CHOICE II Investigators. Efficacy and safety of alirocumab 150 mg every 4 weeks in patients with hypercholesterolemia not on a statin therapy: the ODYSSEY CHOICE II Study. J Am Heart Assoc 2016; 5. pii: e003421. PubMed Citation (Among 233 patients with hypercholesterolemia, not on statin therapy, who were treated with one of two doses of alirocumab or placebo injections for 24 weeks, adverse event rates were similar except for injection site reactions [13.8% vs 3.5% vs none with placebo], and ALT elevations above 3 times ULN occurred in only 1 alirocumab [0.6%] vs no placebo recipient).
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Bays HE, Leiter LA, Colhoun HM, Thompson D, Bessac L, Pordy R, Toth PP. Alirocumab treatment and achievement of non-high-density lipoprotein cholesterol and apolipoprotein B goals in patients with hypercholesterolemia. J Am Heart Assoc 2017; 6. pii: e005639. PubMed Citation (Among 4983 patients with hypercholesterolemia enrolled in 10 controlled trials of alirocumab, total and serious adverse event rates were similar in all groups except for injection site reactions which were greater with alirocumab; no mention of ALT elevations or hepatotoxicity).
El Shahawy M, Cannon CP, Blom DJ, McKenney JM, Cariou B, Lecorps G, Pordy R, Chaudhari U, Colhoun HM et al. Efficacy and safety of alirocumab versus ezetimibe over 2 years (from ODYSSEY COMBO II). Am J Cardio 2017; 120: 931-9. PubMed Citation (Among 720 patients with inadequate control of cholesterol levels with maximal doses of statins who were treated with alirocumab or ezetimibe for up to 2 years, adverse event rates were similar, ALT elevations above 3 times ULN occurred in 2.1% on alirocumab vs 0.8% on ezetimibe, but the abnormalities were usually a single value and no patient developed clinically apparent liver injury).
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