Alirocumab – a PCSK9 inhibitor

Alirocumab – a PCSK9 inhibitor

Alirocumab is a human monoclonal antibody to proprotein convertase subtilisin–kexin type 9 (PCSK9). It is used to treat high cholesterol which is not controlled by diet and statin therapy. Those with statin intolerance will also benefit from this drug. It may be noted that several patients treated with currently available oral lipid lowering agents do not reach target low density lipoprotein cholesterol (LDL-C) levels recommended by clinical guidelines. The cardiovascular risk of these patients remain significantly high. Earlier, these patients had only one option – LDL apheresis. Now there is an additional option: PCSK9 inhibitors, though the currently available agents have to be given parenterally.

Mechanism of action of PCSK9 inhibitors

The function of PCSK9 is to bind to LDL receptors on hepatocytes and promote their degradation in endosomes and lysosomes. The reduction of LDL receptors leads to increase in levels of LDL cholesterol. Hence inhibition of PCSK9 by drugs like alirocumab can produce marked reduction of LDL cholesterol levels [1].

Indications and dosage

Those who with high cardiovascular risk from atherosclerotic disease or heterozygous familial hypercholesterolemia and unable to reach target LDL-C targets with maximally tolerated doses of statins alone or in combination with other lipid lowering agents [2].

The medication is available as prefilled syringes or pens containing 75 mg or 150 mg, to be given once in two weeks as subcutaneous injections. The drug has to be stored in refrigerator [3].

Effectiveness of the drug

Injections of 75 mg given once in two weeks produced 44.2% reduction of LDL-C at 8th week. The reduction was sustained at 96th week with 47.9% reduction [4].

In addition alirocumab reduced levels of lipoprotein (a) and ApoB. Lp(a) is an independent risk factor for cardiovascular disease and we know that statins have hardly any effect on lowering Lp(a). Lp(a) possibly accounts for the residual cardiovascular risk after reaching target LDL-C levels.

A meta-analysis of 24 randomized controlled trials [5] totalling over ten thousand patients showed suggested 50% reduction in cardiovascular events [6].

Important downsides of alirocumab

  1. High cost
  2. Parenteral route of administration with a small percentage of injection site reactions

Though anti drug antibody and reduced effectiveness was noted in studies with bococizumab which was a humanized antibody, immunogenicity was low for alirocumab which is a fully human antibody.

Other adverse events noted were nasopharyngitis, flu like illness and occasional myalgia.

Safety of alirocumab

Short term studies have documented a good safety profile for the drug. But some long term concerns about neurocognitive events and developing diabetes mellitus has been raised [2].

A pooled analysis of 9 ODYSSEY Phase 3 trials having nearly thousand patient with diabetes mellitus and atherosclerotic cardiovascular disease showed that the drug did not appear to affect glycemia over a 78-104 week period [6].

Neurocognitive events were amnesia, memory impairment, and confusional state. But these events were rare [3].

References

  1. Zhang J, Tecson KM, Rocha NA, McCullough PA. Usefulness of alirocumab and evolocumab for the treatment of patients with diabetic dyslipidemia. Proc (Bayl Univ Med Cent). 2018 Apr 11;31(2):180-184.
  2. Tomlinson B, Hu M, Zhang Y, Chan P, Liu ZM. Alirocumab for the treatment of hypercholesterolemia. Expert Opin Biol Ther. 2017 May;17(5):633-643.
  3. Turner PL, Barry KA. Alirocumab (Praluent) for Treatment of Hyperlipidemia. Am Fam Physician. 2016 Aug 15;94(4):310-1.
  4. Farnier M, Hovingh GK, Langslet G, Dufour R, Baccara-Dinet MT, Din-Bell C, Manvelian G, Guyton JR. Long-term safety and efficacy of alirocumab in patients with heterozygous familial  hypercholesterolemia: An open-label extension of the ODYSSEY program. Atherosclerosis. 2018 Nov;278:307-314.
  5. Navarese EP, Kolodziejczak M, Schulze V, Gurbel PA, Tantry U, Lin Y, Brockmeyer M, Kandzari DE, Kubica JM, D’Agostino RB Sr, Kubica J, Volpe M, Agewall S, Kereiakes DJ, Kelm M. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Jul 7;163(1):40-51.
  6. Hlatky MA, Kazi DS. PCSK9 Inhibitors: Economics and Policy. J Am Coll Cardiol. 2017 Nov 28;70(21):2677-2687.
  7. Ganda OP, Plutzky J, Sanganalmath SK, Bujas-Bobanovic M, Koren A, Mandel J, Letierce A, Leiter LA. Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials. Diabetes Obes Metab. 2018 Oct;20(10):2389-2398.

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