A Double-blind, Randomized, Placebo and Ezetimibe Controlled, Multicenter Study to Evaluate Safety, Tolerability and Efficacy of AMG 145 on LDL-C in Combination With Statin Therapy in Subjects With Primary Hypercholesterolemia and Mixed Dyslipidemia (AMG 145 20110115)

AMG 145 is a fully human monoclonal immunoglobulin (Ig) G2 that binds
specifically to human proprotein convertase subtilisin/kexin type 9 (PCSK9) and
prevents the interaction of PCSK9 with the LDL receptor. AMG 145 caused a
dose-related inhibition of PCSK9 binding to the LDL receptor and of the
PCSK9-mediated reduction in low-density lipoprotein (LDL) uptake in hepatic
cells. Treatment of cells with a combination of AMG 145 and statin increased
LDL receptor protein levels more than treatment with either alone. Single
administrations in humans produced decreases in mean LDL-C with subsequent
returns to baseline. Across the dose groups, the decreases were dose-related.
Overall, AMG 145 appeared to be well tolerated at the IV and SC doses
administered in this FIH study. Incidences of overall adverse events and
treatment-related adverse events did not differ notably between treatment
groups.
The present study is designed to evaluate the effects of a subcutaneous AMG 145
every 2 and every 4 weeks, compared with placebo and ezetimibe, in subjects
with primary hypercholesterolemia and mixed dyslipidemia, who are on statin
therapy.

Primary: To evaluate the effect of 12 weeks of subcutaneous (SC) AMG 145
every-2-weeks (Q2W) and every-4-weeks (Q4W), compared with placebo, on percent
change from baseline in low-density lipoprotein cholesterol (LDL-C).
Secondary objectives: Safety and tolerability (compared to placebo and
ezetimibe). Other lipid parameters. Efficacy in comparison with ezetimibe.

Multicenter randomized double-blind phase III parallel-group placebo- and
ezetimibe-controlled study.
Randomisation to (open-label) treatment with:
* Atorvastatin (n=800) (1:1 to 10 and 80 mg per day)
* Rosuvastatin (n=600) (1:1 to 5 and 40 mg per day)
* Simvastatin (n=300) 40 mg per dag. Dependent on co-medication the dose of
simvastatin may be lower (see protocol page 38).
Randomisation within the statin groups to (double-blind) treatment with:
* Atorvastatin (1:1:1:1:2:2):
o Placebo AMG 145 sc every 2 weeks + placebo ezetimibe
o Placebo AMG 145 sc every 2 weeks + ezetimibe 10mg per dag
o Placebo AMG 145 sc every 4 weeks + placebo ezetimibe
o Placebo AMG 145 sc every 4 weeks + ezetimibe 10mg per dag
o AMG 145 140 mg sc every 2 weeks + placebo ezetimibe
o AMG 145 420 mg sc every 4 weeks + placebo ezetimibe
* Rosuvastatin (1:1:2:2):
o Placebo AMG 145 sc every 4 weeks
o Placebo AMG 145 sc every 4 weeks
o AMG 145 140mg sc every 2 weeks
o AMG 145 420 mg sc every 4 weeks
* Simvastatine (1:1:2:2):
o Placebo AMG 145 sc every 4 weeks
o Placebo AMG 145 sc every 4 weeks
o AMG 145 140mg sc every 2 weeks
* AMG 145 420 mg sc every 4 weeks

Screening period of max. 6 weeks. Treatment period 12-14 weeks.
Independent DSMB.
Approx. 1700 patients.

Treatment with rosuvastatin, atorvastatin or simvastatin plus AMG 145 or
placebo (the last two: every 2 or 4 weeks). In atorvastatin group: placebo to
AMG 145 +/- ezetimibe.

Risk: Adverse effects of study medication.
Burden: Max. study duration approx. 20 weeks. 6-8 visits; 6 visits fasting.
Duration 2 h.
3 SC injections (2 ml each) with placebo during screening period.
Physical examination 2x.
Blood tests 6x, 20-30 ml/occasion.
Samples for biomarker development (60 ml).
Optional pharmacogenetic/-genomics blood tests.
Optional extra PK blood sampling (3 extra visits, 1 sample to 5 ml/occasion).
Pregnancy test (if relevant) 5x.
Urine tests 2x.
ECG 4x.
Dietary counseling.