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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.

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.

SUBMITTER: Bass A

PROVIDER: S-EPMC6266420 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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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.

Bass Almasa A Plotka Anna A Mridha Khurshid K Sattler Catherine C Kim Albert M AM Plowchalk David R DR

Health science reports 20180718 9

<h4>Aim</h4>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).<h4>Method</h4>Healthy subjects (N = 60) were randomized equally among 4 groups that received a single subcutaneous dose of either bococi ...[more]

PMID: 30623096

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Project description:Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, combining genetic, transcriptomic and proteomic data from three vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms, with patient clinical parameters and immunohistochemistry of vascular biopsies. Apart from PCSK4, all PCSK family members lie in genetic regions containing variants associated with human cardiovascular traits. Transcriptomic analyses revealed that FURIN, PCSK5, MBTPS1 were downregulated, while PCSK6/7 were upregulated in plaques vs. control arteries. In abdominal aneurysms, FURIN, PCSK5, PCSK7, MBTPS1 were downregulated, while PCSK6 was enriched in diseased media. In thoracic aneurysms, only FURIN was significantly upregulated. Network analyses of the upstream and downstream pathways related to PCSKs were performed on the omics data from vascular biopsies, revealing mechanistic relationships between this protein family and disease. Cell type correlation analyses and immunohistochemistry showed that PCSK transcripts and protein levels parallel each other, except for PCSK9 where transcript was not detected, while protein was abundant in vascular biopsies. Correlations to clinical parameters revealed a positive association between FURIN plaque levels and serum LDL, while PCSK6 was negatively associated with Hb. PCSK5/6/7 were all positively associated with adverse cardiovascular events. Our results show that PCSK6 is abundant in plaques and abdominal aneurysms, while FURIN upregulation is characteristic for thoracic aneurysms. PCSK9 protein, but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Integrating our results lead to the development of a novel 'molecular' 5D framework. Here, we conducted the first integrative study of the proprotein convertase family in this context. Our results using this translational pipeline, revealed primarily PCSK6, followed by PCSK5, PCSK7 and FURIN, as proprotein convertases with the highest novel therapeutic potential.

Dataset Information

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.

Publications

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.

Similar Datasets

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