Pharmacokinetics, pharmacodynamics, and safety of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, in healthy subjects when administered in co-mixture with recombinant human hyaluronidase: A phase 1 randomized trial

Almasa Bass, Anna Plotka, Khurshid Mridha, Catherine Sattler, Albert M Kim, David R Plowchalk, Almasa Bass, Anna Plotka, Khurshid Mridha, Catherine Sattler, Albert M Kim, David R Plowchalk

Abstract

Aim: Prior to the discontinuation of bococizumab's clinical development, it was considered advantageous to develop an infrequent dosing regimen (eg, monthly). Therefore, we conducted a phase 1 study to evaluate the pharmacokinetics, pharmacodynamics, and safety of bococizumab when administered in co-mixture with recombinant human hyaluronidase (rHuPH20).

Method: Healthy subjects (N = 60) were randomized equally among 4 groups that received a single subcutaneous dose of either bococizumab 150, 300, or 450 mg co-mixed with rHuPH20 or bococizumab 300 mg alone. Bioavailability and lipid-lowering effect of bococizumab were evaluated by using ANCOVA models.

Results: In the groups administered bococizumab co-mixed with rHuPH20, dose-normalized C max and AUCinf were 26.6 to 39.1% and 18.3 to 36.6% greater, respectively, compared with bococizumab 300 mg alone. Despite these increases, mean percent reductions from baseline in low-density lipoprotein cholesterol were smaller in the bococizumab 300 mg + rHuPH20 group than in the bococizumab 300-mg group at Day 21 (52.2% and 59.5%, respectively) and were similar at Day 29 (51.7% and 49.6%, respectively). Compared with the group administered bococizumab 300 mg alone, the bococizumab 300 mg + rHuPH20 group did not show a significantly altered AUEC85 (ratio of adjusted means: 102.5%, 90% confidence interval: 96.1-109.3%) but did show a higher MaxELDL-C (ratio of adjusted means: 125.4%, 90% confidence interval: 103.3-152.2%), indicating diminution of efficacy. The most frequent adverse events were injection-site erythema, injection-site bruising, and nasopharyngitis; all injection-site adverse events were mild.

Conclusion: Co-mixture with rHuPH20 increased the bioavailability of bococizumab without proportional increase in pharmacodynamic effect.

Trial registration: ClinicalTrials.gov, NCT02667223.

Keywords: PCSK9 inhibitor; bococizumab; hyaluronidase; hypercholesterolemia; pharmacodynamics; pharmacokinetics.

Figures

Figure 1
Figure 1
Linear and semilogarithmic (inset) concentration‐time profiles of bococizumab following a single subcutaneous dose of bococizumab alone or in co‐mixture with rHuPH20. rHuPH20, recombinant human hyaluronidase
Figure 2
Figure 2
Time course of percent change in LDL‐C from baseline following a single subcutaneous dose of bococizumab alone or in co‐mixture with rHuPH20. LDL‐C, low‐density lipoprotein cholesterol; rHuPH20, recombinant human hyaluronidase; SEM, standard error of the mean

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