Physicians' Academy for Cardiovascular Education

Novel anti-PCSK9 antibody gives robust and durable LDL-c lowering with less frequent dosing

Kastelein JJ et L., Eur Heart J. 2016

Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study

 
Kastelein JJ1, Nissen SE2, Rader DJ et al.,
Eur Heart J. 2016 Jan 12. pii: ehv707. [Epub ahead of print]
 

Background

Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) are being developed to address the residual cardiovascular disease (CVD) risk often seen despite statin treatment. PCSK9 plays a central role in LDL-c metabolism, because it inhibits recycling of the LDL-receptor.
Neutralisation of PCSK9 with antibodies, administered via subcutaneous injection appears safe and effective for reducing LDL-c in patients on standard-of-care lipid-lowering therapy. Several PCSK9 antibodies have been shown to lower LDL-c by at least 60% when administered every 2 or 4 weeks [1-3]. When administered at monthly doses, large dosages are required to sustain LDL-c reduction. Less frequent subcutaneous dosing would be preferable in the context of chronic administration.
LY3015014 (LY) is a humanised immunoglobulin G4 (IgG4) monoclonal antibody, which showed relatively long duration of action in preclinical studies [4,5]. Administration of LY every 8 weeks might suffice to lower LDL-c, and offer a dosing advantage as compared with other PCKS9 antibodies. This study therefore evaluated LDL-c lowering following 16-weeks of subcutaneous administration of LY every 4 (Q4W, 20, 120 or 300 mg) or 8 weeks (Q8W, 100 or 300 mg, alternating with placebo) in patients with primary hypercholesterolemia, when added to standard-of-care lipid-lowering therapy. 527 patients were randomised to treatment.
 

Main results

  • Significant and dose-dependent decreases in LDL-c by beta quantification were seen with LY. Least squares (LS) mean (95% CI) per cent reductions from baseline to week 16 were -14.9% (-19.6 to -10.2) with LY20 Q4W, -40.5% (-45.0 to -36.0) with LY120 Q4W, -50.5% (-55.0 to -46.0) with LY300 Q4W, -14.9% (-19.5 to -10.2) with LY100 Q8W, and -37.1% (-41.9 to -32.3) with LY300 Q8W, while with placebo an increase of 7.6% (3.2, 12.1) was seen.
  • Reductions in calculated LDL-c level were evident from 2 weeks following the initial dose, and were maintained during the whole treatment phase.
  • At all doses but LY20 Q4W, patients taking statins showed a larger decrease of LDL-c than those not taking statins. Male patients showed greater efficacy of LY than females, for all doses except LY100 Q8W.
  • Significant dose-dependent reductions in non-HDL-c, ApoB and triglycerides were seen with LY as compared with placebo. Lp(a) was significantly reduced in all Q4W groups and with LY300 Q8W.
  • No treatment-related serious adverse events (AEs) were reported. 21 patients (4.0%) discontinued study drug as a consequence of an AE; no difference was seen between treatment groups. Mild injection site reactions were the most commonly reported AEs, more often with LY than with placebo.
  • Anti-drug antibodies (ADA) were detected post-baseline in 6.5% of patients treated with LY and in 4.7% who received placebo. At the final follow-up visit 23 LY-treated patients and 0 placebo-patients showed greater than four-fold increase in titre from baseline.
  • Elevations >3ULN in aspartate aminotransferase or alanine aminotransferase were uncommon and not seen in the group receiving the highest LY dose.
 

Conclusion

Subcutaneous administration of the monoclonal anti-PCSK9-antibody LY every 4 or 8 weeks yielded significant and durable reductions of LDL-c, non-HDL-c, ApoB and Lp(a). LDL-c reductions were maintained over the dosing interval for the Q4W dosing groups, while about two-thirds of the maximal effect remained at the end of the dosing interval in the LY300 Q8W treated group.  
Prolonged LDL-c lowering and reductions in atherogenic lipoproteins were seen with this PCSK9 inhibitor, when dosed every 4 of 8 weeks. The short-term safety profile of LY was comparable to that reported for other PCSK9 antibodies.
 
Find this article online at Eur Heart J
 

References

1. Giugliano RP, Desai NR, Kohli P, et al; LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007–2017.
2. Raal FJ, Stein EA, Dufour R, et al; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015;385:331–340.
3. Robinson JG, Nedergaard BS, Rogers WJ, et al, for the LAPLACE-2 Investigators. Effect of evolocumab or ezetimibe added to moderate or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomised clinical trial. JAMA 2014;311:1870–1882.
4. Beyer TP, Eacho PI, Schroeder KM, et al. A PCSK9 antibody that blocks binding to LDLR while allowing normal PCSK9 inactivation by furin is afforded a reduced clearance rate and a longer
duration of effect in mice. ATVB 2015;35:A538. Abstract 538.
5. Schroeder KM, Beyer TP, Hansen RJ, et al. Proteolytic cleavage of antigen extends the durability
of an anti-PCSK9 monoclonal antibody. J Lipid Res 2015;56:2124–2132.