Antidrug-Antibody Formation: A Problem in PCSK9 Therapy?

Summary and Comment |
March 18, 2017

Antidrug-Antibody Formation: A Problem in PCSK9 Therapy?

  1. Karol E. Watson, MD, PhD, FACC

Immunogenicity, and its impact on effectiveness, differed greatly in two inhibitors of proprotein convertase subtilisin–kexin type 9.

  1. Karol E. Watson, MD, PhD, FACC

Therapy based on monoclonal antibodies (mAbs) might induce unwanted immunogenicity, which may lead to minor problems, such as injection-site reactions or flu-like symptoms, or to more serious problems, such as anaphylaxis or loss of drug efficacy. Two recent manufacturer-supported reports describe antidrug-antibody formation in patients exposed to mAb-based proprotein convertase subtilisin–kexin type 9 (PCSK9) therapies.

Ridker and colleagues reported data from six studies on approximately 4000 patients randomized to the experimental PCSK9 inhibitor bococizumab (a “humanized” mAb) or placebo. At 12 months, LDL cholesterol was significantly reduced with bococizumab (mean, −40%), but 48% of bococizumab patients had high-titer antidrug antibodies. This formation markedly diminished the magnitude and durability of LDL cholesterol reduction.

Roth and colleagues assessed antidrug antibodies in approximately 4700 patients enrolled in 10 placebo-controlled studies of the FDA-approved PCSK9 inhibitor alirocumab, a fully human mAb. Antidrug antibodies were observed in only 5.1% of the alirocumab group and 1.0% of the placebo group. Alirocumab recipients with antibodies still experienced significant LDL cholesterol reductions that persisted through the duration of the studies. No increase in adverse events was associated with antidrug-antibody status, although patients with antidrug antibodies had more frequent, mostly mild, injection-site reactions.


These two reports confirm that antidrug antibodies can develop in patients on PCSK9 mAb therapy. It must be emphasized that the reports are not head-to-head trials and are describing different study designs. Nonetheless, the articles describe antidrug-antibody development in a high percentage of bococizumab recipients and a low percentage of alirocumab recipients. One might wish to speculate that this difference occurred because the antibody in bococizumab is of murine origin (production of both mAbs involved mice, but for alirocumab, human immunological genes replaced the murine ones). Still, antidrug antibodies can develop in response to either fully human or humanized monoclonal antibodies. (The other FDA-approved PCSK9 inhibitor, evolocumab, is also a fully human mAb therapy.)

In November 2016, the makers of bococizumab discontinued further development, a decision based in part on the high immunogenicity rate and patients' widely varying LDL cholesterol response. Nevertheless, the lessons learned from bococizumab about immunogenicity and LDL response may provide insight into future lipid-lowering therapies.

Editor Disclosures at Time of Publication

  • Disclosures for Karol E. Watson, MD, PhD, FACC at time of publication Consultant / Advisory board: Lilly; Merck; Quest Editorial boards: Reviews in Cardiovascular Medicine; Circulation; Cardiology Today


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