Multicenter, Controlled, Open-Label Extension (OLE) Study To Assess the Long-Term Safety and Efficacy of AMG 145 (study 20110110)

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.
This study is being conducted to gather information on the long-term safety and
efficacy of AMG 145. Many of the subjects in the parent Phase 2 studies are in
a high unmet medical need group such as heterozygous familial
hypercholesterolemia, or statin intolerance, or have failed to reach goal with
available therapies. For these populations, participation in this open label
extension will provide close medical supervision via healthcare professionals
while on current standard of care therapies and an opportunity to receive an
additional therapeutic option for LDL-C lowering.

Primary: Longterm safety and tolerability of AMG 145.
Secondary: Longterm efficacy of AMG 145.

Multicenter open-label controlled phase II parallel-group extension study.
Randomisation (2:1) to:
* Standard therapy plus AMG 145 420 mg (s.c. injections every 4 weeks)
* Standard therapy.
1st 12 weeks standard therapy as during previous study and blinded LDL-C
values. After 12 weeks unblinding and option to adjust standard therapy.
Study duration 1 year.
Approx. 1600 patients.

Treatment with AMG 145.

Risk: Adverse effects of study medication.
Burden: Max. study duration approx. 5 year (or until AMG 145 is commercially
available). monthly visits, duration approx. 1-2 h (control group 5 visits and
9 phone calls in 1st year). 6 fasting visits in 1 st year; thereafter every 3
months.
12 SC injections (6 mL) for experimental group in 1st year. Thereafter monthly
for all participants.
Physical examination 2x.
Blood tests 1st year for experimental group 7x, control group 6x 30-50
mL/occasion. After 1st year every 3 months. Plus samples for biomarker
development, 60 mL in total.
Steroid substudy: optional, 4x blood sample.
Pregnancy test (if relevant) 3-4x in 1st year, thereafter very 6 months.
ECG 1x.