European drug market entries 2015 with new mechanisms of action

Mechanism

Alirocumab and evolocumab are recombinant human IgG1 monoclonal antibodies that target PCSK9.^2,3 PCSK9 binds to low-density lipoprotein (LDL) receptors on hepatocytic cell membranes, locking the receptors in an open conformation that targets them for lysosomal degradation instead of recycling (Fig 1). As the number of LDL receptors decreases, lipoprotein internalisation is reduced and plasma LDL levels concomitantly increase.⁴ Alirocumab and evolocumab bind PCSK9, rendering it unable to interact with LDL receptors. As a result, LDL receptors are upregulated and plasma LDL-C levels decrease.

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Fig 1.

Effect of alirocumab and evolocumab on PCSK9-mediated degradation of LDL-R. A – PCSK9 binds to LDL-R, locking it in an open conformation; B – the resulting complex is transported from the cell membrane into the cell by clathrin-mediated endocytosis; C – the open conformation of LDL-R causes the complex to be targeted for lysosomal degradation instead of recycling; D – alirocumab and evolocumab bind to PCSK9, precluding it from binding to LDL-R and resulting in increased net LDL-R recycling (E). LDL-R = low-density lipoprotein receptor; PCSK9 = proprotein convertase subtilisin/kexin type 9. Reproduced from the Teaching Resource ­Centre Pharmacology.

Indication

Alirocumab and evolocumab are authorised for the treatment of primary hypercholesterolaemia (non-familial and heterozygous familial) or mixed dyslipidaemia in adults as an adjunct to diet either (a) in combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C targets with the maximum tolerated dose of a statin or (b) alone or in combination with other lipid-lowering therapies in patients who do not tolerate statins or for whom a statin is contraindicated.^2,3

Evolocumab is also authorised for the treatment of homozygous familial hypercholesterolaemia in patients aged 12 years and older in combination with other lipid-lowering therapies.³

Clinical application

Lipiniski et al recently carried out a meta-analysis of 17 clinical trials in which patients were randomised to PCSK9 inhibitors, placebo, ezetimibe, or PCSK9 inhibitors and ezetimibe.⁵ They found that monotherapy with PCSK9 inhibitors led to a 57% reduction in LDL-C and 36% reduction in total cholesterol. The largest reductions in serum lipid levels were achieved when PCSK9 inhibitors were combined with ezetimibe: LDL-C was reduced by 69% and total cholesterol by 46%; statins commonly reduce LDL-C by 30–64%. Mortality and cardiovascular events were not primary endpoints in any of the studies but are currently under investigation. It remains to be seen whether these compounds will produce further reductions in cardiovascular events compared with statins, as they are more expensive and less convenient to administer.

Alirocumab and evolocumab are administered by subcutaneous injection every 2 weeks (starting dose 75 mg and 140 mg, respectively); evolocumab may also be administered once a month at a dose of 420 mg. Common adverse effects (1–10%) include local injection site reactions, nasopharyngitis and upper respiratory tract infections.^2,3

Mechanism

Neprilysin, a neutral endopeptidase, breaks down a number of vasoactive peptides with beneficial haemodynamic effects, including atrial natriuretic peptide, bradykinin and adrenomedullin. Inhibition of neprilysin by sacubutril leads to increased levels of these peptides, countering the vasoconstriction, sodium retention and other maladaptive neurohumoral overcompensation responses characteristic of heart failure, as depicted in Fig 2.⁷

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Fig 2.

Effect of sacubutril/valsartan on the events of neuro-humoral remodelling events associated with heart failure. ANP and BNP have a vasodilative effect. The endogenous enzyme neprilysin breaks these down, inhibiting vasodilation. Sacubitril prevents neprilysin from degrading ANP and BNP. Valsartan acts on the RAAS system by inhibiting the angiotensin II type 1 receptor. ANP = atrial natriuretic peptide; BNP = brain natriuretic peptide; EF = ejection fraction. Reproduced from the Teaching Resource Centre Pharmacology.

Indication

Sacubutril/valsartan is approved for the treatment of symptomatic chronic heart failure with reduced ejection fraction,⁶ referred to in National Institute for Health and Care Excellence guidelines as heart failure due to left ventricular systolic dysfunction.⁹

Clinical application

In the PARADIGM-HF (prospective comparison of ARNi with an ACE inhibitor to determine impact on global mortality and morbidity in heart failure) study, patients were randomised to treatment with either sacubitril/valsartan or the ACE inhibitor enalapril. The primary outcome measure was a composite of death from cardiovascular causes and hospitalisation for heart failure.¹⁰ Significantly fewer patients in the sacubutril/valsartan group experienced the primary outcome (hazard ratio 0.80, 95% CI 0.73–0.87) or death from any cause (hazard ratio 0.84, 95% CI 0.76–0.93).¹⁰

Treatment with sacubutril/valsartan is normally started with one tablet of 49 mg/51 mg twice daily. After 2–4 weeks, the dose is doubled to one tablet of 97 mg/103 mg twice daily, if tolerated by the patient.⁶

Contraindications include concomitant treatment with ACE inhibitors (which can cause serious angioedema), aliskiren-containing medicines, hereditary or idiopathic angioedema, liver disease and pregnancy in the second or third trimester.⁶ Like ACE inhibitors, sacubutril/valsartan very commonly (≥10%) causes hyperkalaemia and hypotension; the former less commonly than with ACE inhibitors, the latter more so. Other adverse effects include renal impairment (≥10%) and, commonly (1–10%), renal failure, hypokalaemia, hypoglycaemia, dizziness, cough, gastrointestinal disorders and fatigue.^6,10

Mechanism

Some forms of severe asthma are associated with elevated blood and sputum eosinophil levels.¹¹ IL-5 is a key mediator of pulmonary eosinophilia;^12,13 it supports the proliferation and differentiation of precursor cells into mature eosinophils in bone marrow and stimulates chemotaxis and adhesion of eosinophils in lung tissue (Fig 3). Mepolizumab is a recombinant IgG1 monoclonal antibody that targets IL-5, preventing it from binding to the IL-5 receptor on eosinophil precursors.

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Fig 3.

Mepoluzimab and IL-5-mediated signal transduction in eosinophils. IL-5 binds to the IL-5-receptor on the plasma membrane, stimulating a number of signal transduction pathways. The MAPK pathway promotes eosinophil differentiation, cytokine production, and degranulation. STAT1, STAT3 and STAT5 pathways stimulate the expression of genes involved in eosinophil survival. Activation of PI3K and NF-κB pathways result in eosinophil adhesion and chemotaxis. IL-5R = interleukin 5 receptor; MAPK = mitogen-activated protein kinases; NF-κB = nuclear factor kappa B; PI3K = phosphoinositide 3-kinase; STAT = signal transducer and activator of transcription. Reproduced from the Teaching Resource Centre Pharmacology.

Indication

Mepolizumab is indicated for severe refractory eosinophilic asthma in adults, as an add-on to inhalation or systemic glucocorticoid therapy.¹⁴

Clinical application

Mepolizumab is a new treatment for patients with severe eosinophilic refractory asthma. In two clinical trials, patients receiving mepolizumab experienced roughly half as many clinically significant asthma exacerbations per year compared with patients taking placebo.^15,16 In another study, mepolizumab use was associated with a significant reduction in oral glucocorticoid use compared with placebo (odds ratio 2.39, 95% CI 1.25–4.56).¹⁷

Mepolizumab is administered by subcutaneous injection of 100 mg every 4 weeks.

Headache is a very common (>10%) adverse effect of mepolizumab. Common (1–10%) adverse reactions include urinary and lower respiratory tract infections, abdominal pain, eczema, back pain and local injection site reactions.