Effect of the PCSK9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia
Background—Homozygous familial hypercholesterolemia (HoFH), is a rare, serious disorder with substantial reduction in low-density lipoprotein (LDL) receptor function, severely elevated LDL cholesterol, cardiovascular disease, and often death, in childhood. Response to conventional drug therapies is modest. Monoclonal antibodies to proprotein convertase subtilisin/kexin 9 (PCSK9) reduce LDL cholesterol in heterozygous familial hypercholesterolemia. The effect in HoFH is unknown and uncertain. We evaluated the efficacy and safety of AMG 145 in an open-label, single arm, multicenter, dose-scheduling pilot study in patients with HoFH.
Methods and Results—Eight patients with LDL receptor negative or defective HoFH on stable drug therapy were treated with subcutaneous AMG 145 420 mg every 4 weeks for ≥12 weeks, followed by AMG 145 420 mg every 2 weeks for an additional 12 weeks. All patients completed both treatment periods. Mean (range) change from baseline in LDL cholesterol at week 12 was -16.5% (+5.2% to -43.6%; P=0.0781) and -13.9% (+39 .9 to -43.3%; P=0.1484) with 4- and 2-week dosing, respectively. No reduction was seen in the 2 receptor-negative patients. Over the treatment periods, mean (SD) LDL cholesterol reductions in the six LDL receptor-defective patients were 19.3% (16)% and 26.3% (20)% with 4- and 2-week dosing, respectively (P=0.0313 for both values) ranging from 4 to 48% with 2 week dosing. No serious side effects were reported.
Conclusions—This study demonstrates significant and dose related LDL cholesterol lowering with a PCSK9 monoclonal antibody in HoFH patients with defective LDL receptor activity but no reduction in those who were receptor negative.
- Homozygous Familial Hypercholesterolemia
- familial hypercholesterolemia
- low-density lipoprotein cholesterol
- Received June 24, 2013.
- Revision received August 16, 2013.
- Accepted August 23, 2013.