In addition to the GAUSS-2 and LAPLACE-2 trials that were presented as late breaking clinical trials, three more studies that evaluated PCSK9 inhibition with evolocumab (AMG 145) were presented at ACC 2014.

MENDEL-2 was a phase 3 study that investigated the relative efficacy of biweekly (Q2W) and monthly (Q4W) subcutaneous (SC) evolocumab therapy over 12 weeks, in comparison to placebo and oral ezetimibe in patients with hypercholesterolaemia currently not receiving statins. 614 Patients with LDL-c>100 and <190 mg/dL and Framingham risk scores <10% were randomised to different combinations of placebo (SC and/or oral) with evolocumab 140 mg biweekly or 420 mg monthly or ezetimibe. 
Evolocumab monotherapy yielded on average  55-57% decrease of LDL-c from baseline, as compared to placebo, and a 38-40% reduction relative to ezetimibe. Other lipoproteins were also favourably altered.

DESCARTES is the longest study thus far evaluating evolocumab treatment (420 mg Q4W) for 52 weeks, against placebo in 901 patients with hyperlipidaemia (>75 mg/dL or >1.9 mmol/L). Patients had a run-in period of 4-12 weeks with background lipid-lowering therapy with diet alone, or diet plus different statin dosing regimes, with or without ezetimibe.
Evolocumab showed a mean (+SE) reduction in LDL-c from baseline of 57.0 +2.1%, as compared with placebo. A strong reduction was seen in patients on lipid-lowering background therapy, as well as in those on statins, with or without ezetimibe. Consistent reductions were seen at week 12 and week 52. The vast majority of patients on evolocumab, but not the other treatment regimes, achieved target LDL-c < 70 mg/dL at week 52. Levels of apolipoprotein B, non-HDL cholesterol, lipoprotein (a) and triglycerides also diminished with evolocumab treatment.
Thus, evolocumab added to diet alone, or high- or low-dose statins, with or without ezetimibe, significantly reduces LDL-c in patients with a wide range of CV risks, with a durable effect up to 52 weeks.

The RUTHERFORD-2 study focussed on 331 patients with Heterozygous Familial Hypercholesterolaemia Disorder who did not manage to achieve LDL-c<100 mg/dL despite statins and ezetimibe. This study evaluated LDL-c reduction with evolocumab (Q2W or Q4w) for 12 weeks, in comparison to statin treatment with or without ezetimibe. Both Q2W and Q4W gave around 60% LDL-c reduction as compared to placebo. The vast majority (>60%) of patients on evolocumab achieved LDL-c target of <70 mg/dL, as compared to 2% with placebo and statins and ezetimibe. Clear reductions of ApoB, triglycerides and LP(a) were seen, while HDL-c and ApoA1 increased.
Thus, also in patients with heterozygous familial hypercholesterolaemia, evolocumab importantly reduces LDL-c and improves lipid profiles.

Evolocumab was generally well-tolerated, and treatment-emergent adverse effects were consistently similar across treatment groups. The Q2W and Q4W dosing schemes are clinically equivalent.

PCSK9 inhibition with the human monoclonal antibody evolocumab thus appears to be an attractive and effective strategy to further reduce LDL-c and improve lipid profiles, in addition to statin and ezetimibe treatment, in a broad range of patients. The ongoing FOURIER trial studies the effect of evolocumab treatment on cardiovascular outcomes.

-Blom DJ, Hala T, Bolognese M, et al., on behalf of the DESCARTES Investigators. A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia. N Engl J Med 2014;Mar 29
-Koren MJ; Lundqvist P; Bolognese D et al. Anti-PCSK9 Monotherapy for Hypercholesterolemia – The MENDEL-2 Randomized, Controlled Phase 3 Clinical Trial of Evolocumab.J Am Coll Cardiol. March 29, 2014. doi:10.1016/j.jacc.2014.03.018.
-RUTHERFORD-2: The Addition of Evolocumab (AMG 145) Allows the Majority of Heterozygous Familial Hypercholesterolemic Patients to Achieve Low-density Lipoprotein Cholesterol Goals - Results from the Phase 3 Randomized, Double-blind, Placebo-controlled Study. Presented at ACC 2014, 29 March 2014.