Physicians' Academy for Cardiovascular Education

PCKS9 inhibition yields additional LDL reduction in HoFH with defective LDL-receptor function

Literature - Stein EA, Honarpour N, Wasserman SM et al. - Circulation. 2013 Sep 6

Effect of the PCSK9 Monoclonal Antibody, AMG 145, in Homozygous Familial Hypercholesterolemia.

Stein EA, Honarpour N, Wasserman SM et al.
Circulation. 2013 Sep 6. [Epub ahead of print]


In homozygous familial hypercholesterolaemia (HoFH), a substantial reduction in LDL-receptor function causes severely elevated cholesterol levels, and subsequently cardiovascular disease and often death, in childhood [1]. Most patients are compound heterozygotes, with a mutation in the LDL receptor, and/or apolipoprotein B and/or proprotein convertase subtilisin/kexin 9 (PCSK9) [2,3]. Negative (<2% function) or defective (2%-25% function) residual LDL receptor activity is associated with severity of LDL-c elevation and propensity for early cardiovascular disease [1].
Lowering LDL-c  with conventional therapies such as statines, ezetimibe and LDL apheresis, reduce cardiovascular disease morbidity and mortality [4]. Two new drugs (lomitapide and mipomersen) that reduce hepatic lipoprotein production and that are independent of LDL receptor function have been approved by the FDA solely for the treatment of HoFH [5,6].
The human monoclonal antibody to PCSK9, AMG145, reduces LDL-c in heterozygous familial hypercholesterolaemia [7]. It is currently unknown whether HoFH patients can benefit from PCSK9 inhibition, since they have no or minimal LDL-receptor function. The Trial Evaluating PCSK9 Antibody in Subjects with LDL Receptor Abnormalities (TESLA) study evaluated the efficacy and safety of AMG145 in an open-label, single arm, multicenter, dose-scheduling pilot study in patients with HoFH. All 8 patients in this study had LDL-receptor mutations confirmed in both alleles.

Main results

  • After 12 weeks of every-4-week-treatment, mean LDL-c had decreased with 17% (1.8 mmol/L [70.6 mg/dL]) from baseline, with a range from +5% to -44%, P=0.0781. Four patients showed a reduction of >15% and three patients of >30%.
    Two patients with negative LDL-receptor activity did not show LDL-c reductions.
  • After 12 weeks of every-2-week-treatment, mean LDL-c had decreased with 14% (1.6 mmol/L [60.8 mg/dL], P=0.1484) from baseline. Again, the LDL-receptor-negative patients showed no reduction.
  • When comparing the effect of the two dosing schemes in LDL-receptor-defective patients, mean LDL-c reductions were higher in the 2-week dosing scheme (26.3% + 20) than in the 4-week scheme (19.3% +16, P=0.0313).
  • Changes in apolipoprotein B were consistent with those seen in LDL-c. Mean change in lipoprotein (a) was -11.7+11% and -18.6+12% with the 4- and 2-week dosing schemes, respectively, which did not seem to be related to LDL-receptor activity.
    Triglycerides, HDL-c and apolipoprotein A1 were essentially unchanged with either dosing scheme.
    Mean reductions in free PCSK9 at week 12 were 22.7+37% and 87.6+8% for the 4- and 2-week AMG145 regimes.
  • 6 out of 8 patients reported adverse events, which were considered not serious and unrelated to treatment. No antibodies to AMG145 were detected. Creatine kinase was not elevated greater than five times the upper limit of normal, nor were liver enzymes greater than three times the upper limit of normal.


This proof-of-concept trial shows that PCSK9 inhibition with AMG145 can yield additional LDL cholesterol reduction in LDL-receptor defective HoFH patients, when given in addition to statin and ezetimibe. A larger, placebo-controlled study is ongoing to assess the value of PCSK9 targeted therapy in HoFH patients, including in LDL-receptor negative patients.


1. Goldstein JL, Hobbs HH, Brown MS. Familial Hypercholesterolemia. The Metabolic and Molecular Bases of Inherited Disease. 2001:2863-2913.
2. Abifadel M, Varret M, Rabes JP et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154-156.
3. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111:1795-1803.
4. Raal FJ, Pilcher GJ, Panz VR, et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011;124:2202-2207.
5. United States Food and Drug Administration. FDA approves juxtapid for homozygous familial hypercholesterolemia. 2012
6. United States Food and Drug Administration. FDA approves new orphan drug Kynamro to treat inherited cholesterol disorder 2013
7. Raal F, Scott R, Somaratne R, et al. 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. Circulation. 2012;126:2408-2417.

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