Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial.

Abstract

BACKGROUND:

Despite statin treatment, many patients with heterozygous familial hypercholesterolemia do not reach desired low-density lipoprotein cholesterol (LDL-C) targets. AMG 145, a fully human monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease, demonstrated significant reductions in LDL-C in phase 1 studies. This phase 2, multicenter, double-blind, randomized, placebo-controlled, dose-ranging study evaluated the efficacy and safety of AMG 145 in heterozygous familial hypercholesterolemia patients.

METHODS AND RESULTS:

Patients with heterozygous familial hypercholesterolemia diagnosed by Simon Broome criteria with LDL-C ≥2.6 mmol/L (100 mg/dL) despite statin therapy with or without ezetimibe were randomized 1:1:1 to AMG 145 350 mg, AMG 145 420 mg, or placebo-administered subcutaneously every 4 weeks. The primary end point was percentage change from baseline in LDL-C at week 12. Of 168 patients randomized, 167 received investigational product and were included in the full analysis set (mean [SD] age, 50 [13] years; 47% female; 89% white; mean [SD] baseline LDL-C, 4.0 [1.1] mmol/L (156 [42] mg/dL)). At week 12, LDL-C reduction measured by preparative ultracentrifugation (least squares mean [standard error (SE)]) was 43 (3)% and 55 (3)% with AMG 145 350 mg and 420 mg, respectively, compared with 1 (3)% increase with placebo (P<0.001 for both dose groups). Serious adverse events (not considered treatment-related) occurred in 2 patients on AMG 145.

CONCLUSIONS:

AMG 145 administered every 4 weeks yielded rapid and substantial reductions in LDL-C in heterozygous familial hypercholesterolemia patients despite intensive statin use, with or without ezetimibe, with minimal adverse events and good tolerability.

CLINICAL TRIAL REGISTRATION:

URL: http://www.clinicaltrials.gov. Unique identifier: NCT01375751.

• Authors: Frederick Raal, Rob Scott, Ransi Somaratne, Ian Bridges, Gang Li, Scott M Wasserman, Evan A Stein
• Journal: Circulation (Circulation) Vol. 126 Issue 20 Pg. 2408-17 (Nov 13 2012) ISSN: 1524-4539 [Electronic] United States
• PMID: 23129602 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Anticholesteremic Agents
• Azetidines
• Cholesterol, LDL
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• PCSK9 protein, human
• Proprotein Convertase 9
• Proprotein Convertases
• Serine Endopeptidases
• Ezetimibe
• evolocumab

Topics

• Adult
• Antibodies, Monoclonal (adverse effects, immunology, therapeutic use)
• Antibodies, Monoclonal, Humanized
• Anticholesteremic Agents (therapeutic use)
• Azetidines (therapeutic use)
• Cholesterol, LDL (blood)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Therapy, Combination
• Ezetimibe
• Female
• Heterozygote
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (therapeutic use)
• Hyperlipoproteinemia Type II (blood, drug therapy, genetics)
• Male
• Middle Aged
• Proprotein Convertase 9
• Proprotein Convertases (antagonists & inhibitors, immunology)
• Serine Endopeptidases (immunology)
• Treatment Outcome