Preparing for a novel era in CV prevention

Three PCSK9 inhibitors are currently under clinical development: evolocumab, alirocumab and bococizumab. In all PCSK9 clinical trials, basically three indications are currently pursued, which include high CV risk or CV event/LDL-c levels above 70 or 100 mg/dL, genetic dyslipidaemiaeand statin intolerance. John Kastelein focussed his lecture on genetic dyslipidaemia, such as familiar hypercholesterolaemia(FH). FH is very prevalent in Western society and is estimated to occur in 1 in 200 people.

The attention for FH has increased enormously over thepast years; the number of publications doubled compared to 2009. Kastelein highlighted the most recently published papers which describe that FH individuals are at greater risk from their LDL-c than other individuals with similar LDL-c levels, that also recurrent event risk is much higher in FH patients, that FH is hardly diagnosed in Norway before the first coronary event at age 44, that only 75% of patients are on high-dose statins and seldom reach the LDL-c guideline target and at last, that the mean average of death for FH patients is now 60 years, predominantly as a result of a CV event (all discussed in7).

“Current management of HeFH is too little and too late (….) but the future looks a lot brighter”

When combining all clinical trials with alirocumab, bococizumab and evolocumab, we now have safety and efficacy data for 1634 FH patients. Although outcome data of bococizumab have not been published yet, some data of the alirocumab and evolocumab trials have been published. For example, the RUTHERFORD-2 placebo-controlled phase 3 study in which the efficacy and safety of evolocumab was evaluated during a 12-week period in a large cohort of heterozygous FH (heFH) patients8. In this trial, 111 patients received evolocumab 140 mg every 2 weeks, 110 patients received 420 mg every month, 110 patients received either placebo every 2 weeks or once a month (1:1). In both treatment arms, around 60% difference in LDL-c reduction from baseline was noticed, compared to placebo. As a result, around 70% of patients reached the LDL-c goal of <70 mg/dL, which was, according to Kastelein, probably only around 20% for high-dose statins plus ezetimibe. Encouraging numbers achieved with evolocumab, have never been seen before with any other drug in heFH patients.

In the other PCSK9 trial, the ODYSSEY programme, the efficacy and safety of alirocumab (75/150 mg every 2 weeks) was evaluated in even a larger number of heFH patients9. In this programme, four studies were included: FHI, FHII, LONG TERM and HIGH FH, all with a duration of 78 weeks. All studies showed similar results; like the evolocumab trial, patients received an LDL-c reduction of around 60% from baseline, which already occurred after 4 weeks (first measured time point). This corresponded to an LDL-c goal achievement of 65-75% of patients.

Exploring the achievement of LDL-c goals over the last decades retrospectively, one can appreciate that this tremendously improved over the last 30 years; 30 years ago the average LDL-c levels were around 350 mg/dL. Still, progress is too little and too late. However, now, the future looks a lot brighter; both evolocumab and alirocumab, on top of statins/ezetimibe, offer a level of goal achievement that was thus far impossible.