Effects of RG7652, a Monoclonal Antibody Against PCSK9, on LDL-C, LDL-C Subfractions, and inflammatory Biomarkers in Patients at High Risk of or With Established Coronary Heart Disease

Literature - Baruch A, Mosesova S, Davis JD, et al. - Am J Cardiol. 2017 Mar 1, Epub ahead of print

Background

Atherosclerosis has, additional to the role of LDL-c, a strong inflammatory component that can affect vascular health and plaque stability [1-4]. Therefore, this multicenter, randomized, double-blind, placebo-controlled phase 2 study, called EQUATOR, assessed the LDL-c lowering and the impact on inflammatory biomarkers by RG7652, a fully human PCSK9 antibody, when added to standard-of-care therapy for 6 months, in patients with a high risk for, or with established coronary heart disease (CHD). Patients were randomized to placebo (n=57 completed), RG7652 200 mg subcutaneously every 8 weeks (200 q8w, n=23 completed), 400 mg every 4 (400 q4w, n=52 completed) or 8 weeks (400 q8w, n=28 completed), 800 mg every 8 (800 q8w, n=46 completed) or 12 weeks (800 q12w, n=23 completed).

Main results

• Of the 248 patients randomized, 7.7% discontinued the study.
• Mean LDL-c at baseline was 125.8 mg/dL and the proportion of patients with baseline LDL-c <120 and ≥120 mg/dL were comparable in each group.
• Mean reductions LDL-c at day 167 were -7.7%, -10.7% (P=0.54), -58.7% (P<0.001), -23.3% (P=0.0013), -16.1% (P=0.029) and -44.3% (P<0.001) for placebo, 200 mg q8w, 200 mg q4w, 400 mg q8w, 800 mg q12w and 800 mg q8w, respectively. P values were compared to placebo.
• Results were similar between statin-treated and statin-intolerant patients and between diabetic and nondiabetic patients.
• Levels of ApoB were reduced with RG7652 with -5%, -5.3% (P=0.96), -46.7% (P<0.001), -16.6% (P=0.0023), -13.3% (P=0.038) and -35.6% (P<0.001), respectively. P values were compared to placebo.
• Levels of Lp(a) were changed with 4.6%, -3.7% (P=0.38), -25.5% (P<0.001), -14.9% (P=0.0058), -8.8% (P=0.034) and -22.5% (P<0.001), respectively. P values were compared to placebo.
• Characterization of lipoprotein variables focused on the 400 q4w and 800 q8w groups only. Both large and small LDL-c particles were significantly reduced in both groups on day 15, 85 and 169. Throughout treatment, large LDL-c was more reduced than small LDL-c (from baseline to day 169, -38% and -26% for small LDL in 400 q4w and 800 q8w respectively and -63% and -44% for large LDL in 400 q4w and 800 q8w respectively).
• Levels or inflammatory markers hsCRP or effector cytokines IL-6 and TNF-α were not significantly changed by RG7652.
• Adverse events (AEs) were observed in 86.3% of patients of all RG7652 treatment arms combined and in 87.5% of placebo patients. No apparent dose-related trend in AEs was observed. Most AEs were mild or moderately and the incidence of severe AEs were 9.3% and 10.9% in combined RG7652 arms and placebo arm respectively.
• Treatment-related AEs were more often experienced in RG7652-treated patients (34.4%) compared to placebo (25%).
• Cardiac AEs were noticed in 8.2% of RG7652 patients (4.4% serious) and in 7.8% of placebo patients (6.3% serious).
• Hypertension was more often experienced in RG7652-treated patients.

Conclusion

References

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