Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: A Phase II pooled analysis.

BACKGROUND: Alirocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is in Phase III development for the treatment of hypercholesterolemia. In Phase II studies, 150 mg every 2 weeks (Q2W) was the highest Q2W dose studied, and it is currently the highest Q2W dose under development. To better assess the safety and efficacy of this dose, data across three Phase II studies were pooled. METHODS: We analyzed data from three double-blind, randomized, placebo-controlled Phase II studies of 8 or 12 weeks' duration. In the current analysis, 77 patients were randomized to the control group and 108 were randomized to alirocumab 150 mg Q2W administered via a single 1 mL subcutaneous injection. RESULTS: Adverse events (AEs) occurred in 58.3% of alirocumab patients compared with 54.5% of placebo-controlled patients. The most common AE was mild, transient injection-site reactions. No signal for muscle symptoms such as myalgia and no cases of neurocognitive effects were reported or observed. One alirocumab patient, also receiving atorvastatin 80 mg/day, had an increase in aspartate transaminase 3 to 5 times the upper limit of normal. Alirocumab 150 mg Q2W reduced low-density lipoprotein cholesterol (LDL-C) from baseline by 68.4% compared with 10.5% for the control group. More than 90% of patients achieved an LDL-C target of < 70 mg/dL with alirocumab versus 8% with control. Marked reductions in other atherogenic lipids and modest increases in high-density lipoprotein cholesterol were also observed. CONCLUSION: At the highest Q2W dose under development (150 mg), alirocumab appears well tolerated and produces robust LDL-C reductions. These data suggest that alirocumab 150 mg Q2W is an appropriate dose for further evaluation in Phase III trials.

Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials).

Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipid-lowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (-30.3% vs -0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.

Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy.

OBJECTIVES: The primary objective of this study was to evaluate the low-density lipoprotein cholesterol (LDL-C)-lowering efficacy of 5 SAR236553/REGN727 (SAR236553) dosing regimens versus placebo at week 12 in patients with LDL-C ≥100 mg/dl on stable atorvastatin therapy. Secondary objectives included evaluation of effects on other lipid parameters and the attainment of LDL-C treatment goals of <100 mg/dl (2.59 mmol/l) and <70 mg/dl (1.81 mmol/l). BACKGROUND: Serum proprotein convertase subtilisin kexin 9 (PCSK9) binds to low-density lipoprotein receptors, increasing serum LDL-C. SAR236553 is a fully human monoclonal antibody to PCSK9. METHODS: This double-blind, parallel-group, placebo-controlled trial randomized 183 patients with LDL-C ≥100 mg/dl (2.59 mmol/l) on stable-dose atorvastatin 10, 20, or 40 mg for ≥6 weeks to: subcutaneous placebo every 2 weeks (Q2W); SAR236553 50, 100, or 150 mg Q2W; or SAR236553 200 or 300 mg every 4 weeks (Q4W), alternating with placebo for a total treatment period of 12 weeks. RESULTS: SAR236553 demonstrated a clear dose-response relationship with respect to percentage LDL-C lowering for both Q2W and Q4W administration: 40%, 64%, and 72% with 50, 100, and 150 mg Q2W, respectively, and 43% and 48% with 200 and 300 mg Q4W. LDL-C reduction with placebo at week 12 was 5%. SAR236553 also substantially reduced non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). SAR236553 was generally well tolerated. One patient on SAR236553 experienced a serious adverse event of leukocytoclastic vasculitis. CONCLUSIONS: When added to atorvastatin, PCSK9 inhibition with SAR236553 further reduces LDL-C by 40% to 72%. These additional reductions are both dose- and dosing frequency-dependent. (Efficacy and Safety Evaluation of SAR236553 [REGN727] in Patients With Primary Hypercholesterolemia and LDL-cholesterol on Stable Atorvastatin Therapy; NCT01288443).