Physicians' Academy for Cardiovascular Education

Unanticipated attenuation of LDL-c lowering response to humanised PCSK9 antibody over time

Safety and Cardiovascular Event Efficacy of Bococizumab Among 27,000 High Risk Patients

Presented at ACC.17 by Paul M. Ridker

Mar. 16, 2017 - news

Background

The SPIRE bococizumab clinical development program consisted of 6 SPIRE Lipid-lowering trials (n=4449, SPIRE HR, SPIRE LDL, SPIRE FH, SPIRE LL, SPIRE SI and SPIRE AI) and two SPIRE CV outcomes trials SPIRE-1 (n=16817) and SPIRE-2 (n=10621). The difference between SPIRE-1 and SPIRE-2 was the minimally required LDL-c level for inclusion: ≥70 mg/dL for SPIRE-1 and LDL-c ≥100 mg/dL for SPIRE-2.

In the SPIRE trials, patients on maximally tolerated statins and at high CV risk were randomised to bococizumab 150 mg SC Q2W or placebo. Bococizumab is a humanised antibody (over 90% human) directed against PCSK9.

Main results

SPIRE lipid-lowering trials

Based on the completed SPIRE lipid-lowering trials, it was decided on November 1, 2016 to discontinue further development of bococizumab. Consequently, the SPIRE-1 and SPIRE-2 outcome trials were discontinued prematurely.

SPIRE-1 and SPIRE-2 outcome trials

Conclusion

These data show that the PCSK9 antibody bococizumab lowers LDL-c by 55-60% when given in addition to statin therapy. An unanticipated attenuation of this effect was seen over time due to the development of anti-drug antibodies. This higher immunogenicity also explains the higher rate of injection site reactions observed with bococizumab, as compared with fully human monoclonal PCSK9 antibodies.

The wide individual variability in LDL-c response to bococizumab, even in those without ADAs, suggests that on-treatment LDL-c measurement is important in clinical practice. During the press conference, when the individual variability in lipid-lowering response was discussed, dr. Paul Ridker mentioned that ‘measuring LDL-c on-treatment is what our guidelines ought to say'. It is unknown whether other PCSK9 antibodies show similar individual variability.

Despite the anti-drug antibody production and the individual response and early trial termination, bococizumab significantly reduced CV event rates in the higher-risk SPIRE-2 trial, but not in the lower-risk SPIRE-1 trial. Consistent with the ‘lower the better for longer’ hypothesis, clinical benefits were greater in those who achieved and sustained greater absolute and relative reductions in LDL-c. Thus, these data support the use of PCSK9 inhibitors in selected patients in addition to aggressive statin therapy.

Disclosures

Our coverage of ACC.17 is based on the information provided during the congress.

The SPIRE lipid-lowering trials results were published today in NEJM The SPIRE-1 and SPIRE-2 results were published today in NEJM