Evolocumab

Patients with mutations in their LDL receptors have very high concentrations of LDL cholesterol and therefore an increased risk of cardiovascular disease. The TESLA Part B trial randomised 33 patients to add evolocumab and 17 patients to add placebo to their lipid-lowering therapy. At the start of the trial the mean LDL-cholesterol concentration was 9 mmol/L. After 12 weeks of injecting evolocumab 420 mg monthly this concentration fell by 23.1% while there was a 7.9% increase in the placebo group. There was also a significant reduction in apolipoprotein B.3

The RUTHERFORD-2 trial randomised 331 patients who had heterozygous familial hypercholesterolaemia with LDL-cholesterol concentrations of at least 2.6 mmol/L despite lipid-lowering therapy. Two groups of 110 patients injected evolocumab 420 mg monthly or 140 mg every two weeks while 109 patients injected a placebo. After 12 weeks the concentration of LDL cholesterol had declined from a mean of 4.0 mmol/L to 1.8 mmol/L with monthly injections and from 4.2 mmol/L to 1.7 mmol/L with two-weekly injections. Concentrations were largely unchanged with placebo. Both regimens of evolocumab were also associated with significant reductions in apolipoprotein B and triglycerides.⁴

Most patients who require drug treatment for raised cholesterol will be prescribed a statin. In some cases this treatment will not achieve the target concentration for cholesterol. The patients may then be given an additional drug such as ezetimibe. The LAPLACE-2 trial looked at adding evolocumab or ezetimibe to treatment with a statin. This trial used evolocumab 140 mg every two weeks or 420 mg monthly. It also used three different statins at different doses so the 2067 patients were randomised to 24 different treatment groups. At the start of the study the patients had LDL-cholesterol concentration around 2.82 mmol/L. After 12 weeks this had reduced to approximately 1.28 mmol/L in patients taking evolocumab with atorvastatin 10 mg. The combination of evolocumab and atorvastatin 80 mg reduced the concentration to approximately 0.93 mmol/L. A primary outcome was the mean percentage change in LDL cholesterol from baseline for weeks 10 and 12 of the trial. For evolocumab these reductions were around 59–66% with moderate or high doses of statins. These changes were greater than those seen in the ezetimibe groups. Combined with atorvastatin, ezetimibe reduced LDL cholesterol by approximately 17–24%. Evolocumab also reduced concentrations of apolipoprotein B and triglycerides.⁵

The DESCARTES trial investigated treatment with evolocumab over a year. There were 905 patients who had an LDL-cholesterol concentration above 1.94 mmol/L despite lipid-lowering therapy. The patients were allocated to be treated with diet alone, atorvastatin 10 mg, atorvastatin 80 mg or atorvastatin 80 mg plus ezetimibe. Within each of these groups the patients were given evolocumab 420 mg monthly or a placebo. After 52 weeks the mean LDL cholesterol fell from 2.69 mmol/L, across all groups, to 1.32 mmol/L with evolocumab, but was almost unchanged in the placebo groups. The largest percentage change (61.6%) was in the group treated with evolocumab and atorvastatin 10 mg in addition to diet. Treatment with evolocumab was also associated with reductions in apolipoprotein B and triglycerides.⁶

The MENDEL-2 trial assessed 615 patients who were not taking a statin. These patients had LDL-cholesterol concentrations averaging around 3.7 mmol/L. They were randomised to take evolocumab, ezetimibe or placebo. After 12 weeks patients injecting evolocumab every two weeks had reduced their LDL-cholesterol concentration by 57% compared with a 17.8% reduction with ezetimibe. The corresponding figures for monthly treatment were 56.1% and 18.6%. There was little change in the placebo groups.⁷

Evolocumab has also been investigated for patients with statin intolerance in the GAUSS placebocontrolled trials.⁸ The GAUSS-2 trial enrolled 307 patients who had been unable to tolerate at least two statins. They were randomised to take daily ezetimibe, evolocumab 140 mg every two weeks, or evolocumab 420 mg monthly. At the start of the trial the average concentration of LDL cholesterol was approximately 5 mmol/L. After 12 weeks this had reduced by 53–56% with evolocumab and 15–18% with ezetimibe.

At the time of its approval in Australia evolocumab had been taken by 5710 patients in clinical trials. There were eight deaths from cardiovascular causes compared with three in the control group. In the one-year trial, two patients taking evolocumab died. Adverse events led to 2.2% stopping treatment compared with 1% of the control group. Common adverse effects that occurred more frequently with evolocumab included upper respiratory infections, influenza, back pain, myalgia, hypertension and erythema at the injection sites. Elevations of creatine kinase were also more frequent than in the control group.⁶  

Injecting an antibody can cause allergic reactions. A small number (0.1%) of patients developed antibodies to evolocumab. 

There have been no drug interaction studies. The effects of evolocumab in human pregnancy and lactation are unknown.

There is no doubt that evolocumab lowers LDL cholesterol in a range of indications (see summary Table). However, this is a surrogate outcome and the drug’s benefits on clinical outcomes are still being studied. There were few deaths in the clinical trials, but the proportion due to cardiovascular causes was greater with evolocumab than in the control groups (0.14% vs 0.10%). A meta-analysis of the PCSK9 inhibitors suggests that the cardiovascular mortality rate for the class is 0.19% compared with 0.33% without treatment. However, this reduction in cardiovascular mortality is not statistically significant.⁹

Patients who completed the clinical trials of evolocumab could participate in the OSLER extension studies. In these open-label studies 2976 patients took evolocumab and 1489 took standard therapy. After a median follow-up of 11.1 months, 29 patients taking evolocumab had a cardiovascular event compared with 31 in the control group. The difference in event rates (0.95% vs 2.18%) was statistically significant.10

The long-term safety of the class also needs further study. This will include monitoring for any effects on glucose metabolism and neurocognitive function. Over a one-year period neurocognitive events were reported in 0.6% of the patients taking evolocumab and 0.2% of the control group.

When drug treatment is indicated for hypercholesterolaemia there is much more evidence to support treatment with statins. Injections of evolocumab will therefore be reserved for patients who cannot tolerate statins and when LDL-cholesterol concentrations remain significantly elevated despite treatment.2