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|Objective:||The primary objective of both studies was to evaluate the LDL-C lowering efficacy of PCSK9 moncolonal antibody therapy – either AMG 1451 or SAR236553/REGN727 (SAR236553)2 in patients with elevated LDL-C levels on stable atorvastatin therapy|
|Study design:||Multicentre, randomized, double-blind placebo-controlled, parallel group studies|
Study 1: Patients with hypercholesterolemia and fasting LDL-C levels >2·2 mmol/ L (85 mg/dL) while on a stable dose of atorvastatin (±ezetimibe) for ³4 weeks.
Study 2: Patients with LDL-C levels ³2.59 mmol/L (100 mg/dL) while on a stable dose of atorvastatin 10, 20, or 40 mg daily for ³6 weeks. Patients had a mean age of 56.7 years and 52% were female.
In both trials, concomitant treatment with other lipid-modifying therapy was prohibited.
|Other efficacy variables:||
|Safety variables:||Treatment-emergent adverse events; and LA PLACE TIMI 57 also evaluated the formation of antibody to treatment|
Study 1: After a screening phase (up to 6 weeks), eligible patients were randomized equally to one of the following groups:
The duration of treatment was 12 weeks.
The total duration of treatment was 12 weeks and there was an 8-week follow-up.
At 12 weeks, both treatments reduced LDL-C levels by more than 60%. Maximal LDL-C lowering efficacy was observed with AMG 145 140 mg every 2 weeks (Table 1) and SAR236553 150 mg every 2 weeks (Table 2). Both treatments also lowered triglycerides (by up to 33.7% with AMG 145 and 18.9% with SAR236553), and raised HDL-C. Neither treatment influenced apoA-I.
Table 1: Effect of AMG 145 140 mg every 2 weeks (Study 1)
Table 2. Effect of SAR236553 150 mg every 2 weeks (Study 2)
Study 1: The most common adverse events were nasopharyngitis (10% with AMG 145 vs 7% with placebo), cough (3% vs 2%], nausea (3% vs 0·6%) and injection site reactions (2% in each group). No patients developed anti-AMG 145 antibodies, neutropenia, or vasculitis.
Study 2: The profile of adverse events was similar in each group. Mild injection site reactions were most common. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis.
Understanding the role of PCSK9 in the regulation of LDL-C concentration has paved the way for the development of novel therapeutic approaches. PCSK9 binds the LDL receptor (LDLR) and promotes its degradation in the endosomal/lysosomal pathway.1 Thus, increased activity of PCSK9 leads to lower liver LDLR levels, reduction in LDL-uptake from the circulation, and hypercholesterolemia. In contrast, inhibiting PCSK9 would offer the possibility of lowering LDL-C concentration, a rationale which is now supported by clinical trials.2
Monoclonal antibody therapy targeting PCSK9 holds promise for improving achievement of LDL-C targets in statin-treated patients, a major unmet clinical need. Data from clinical trials, including those reported here, show that there is a reduction of >60% in LDL-C levels for at least 2 weeks after a single injection of a humanized PCSK9 monoclonal antibody therapy, with or without statin therapy.
While LDL-C is the primary treatment priority, there is clear evidence that targeting LDL-C still leaves a high residual cardiovascular risk. The Residual Risk Reduction Initiative (r3i) has emphasised the burden of residual cardiovascular risk associated with elevated atherogenic triglyceride-rich lipoproteins and low HDL-C.3
In the light of recent failed trials, such as AIM-HIGH4 and HPS2-THRIVE5 with niacin and continuing controversy about the role of cholesteryl ester transfer protein inhibition following termination of dalcetrapib, the second agent in this class,6 it is clear that additional treatments are needed. In the trials reported here, treatment with AMG-145 or SAR236553/REGN727 improved LDL-C goal achievement and also lowered triglycerides and raised HDL-C. SAR236553/REGN727 also reduced Lp(a) another atherogenic target. Both treatments appeared to be well tolerated. These findings support the ongoing development of this treatment modality in Phase-III trials to fully characterise their long-term efficacy and safety and effects on cardiovascular outcomes.
1. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism, Trends in Biochem Sci 2007;32:71-7.
|Key words||PCSK9; AMG 145; SAR236553/REGN727; atherogenic dyslipidemia; triglycerides; residual cardiovascular risk|