A First-in-Human (FIH), Randomized, Dose-Escalation, Double-Blind, Placebo-Controlled Study to Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of SPC5001 Administered to Healthy Subjects and Subjects with Familial Hypercholesterolemia (FH)

The number of LDL receptors (LDL-R) expressed on the surface of hepatocytes is
the primary determinant of plasma LDL levels. LDL in the plasma binds to LDL-R
on the hepatocyte surface, mediating LDL uptake and delivery to the endosomal
system where the LDL particle is released, and the LDL-R is recycled back to
the hepatocyte surface. Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9)
protein binds to the extracellular EGF-A domain of the LDL-R and is
internalized along with the LDL-R. The LDL-R/PCSK9 complex is directed toward
the lysosomal compartment for degradation. Thus, PCSK9 inhibits the recycling
of LDL-R back to the cell surface and decreases the expression of the LDL-R on
the hepatocyte cell membrane.
Overexpression of PCSK9 in mice and gain-of-function mutations in humans
enhance hepatocyte degradation of the LDL-R, resulting in elevations of plasma
LDL-C. The human gain-of-function phenotype is difficult to distinguish from
the phenotype of familial hypercholesterolemia (FH) because of mutations in the
LDL-R gene itself. Conversely, loss-of-function mutations of PCSK9 result in
increases in LDL-R density on the hepatocyte cell membrane and result in lower
LDL-C levels. Further, loss-of-function mutations in humans are associated with
a more-than-predicted level of protection against cardiovascular disease (CVD).
PCSK9 has been targeted with siRNAs, antisense oligonucleotides, and polyclonal
antibodies. A monoclonal antibody against PCSK9 has been shown to lower
circulating LDL in mice and non-human primates.
SPC5001 is a phosphorothioate antisense oligonucleotide complementary to a
portion of the mRNA encoding PCSK9 protein. Binding of the complementary
oligonucleotide sequence of SPC5001 to PCSK9 mRNA will reduce PCSK9 protein
synthesis and increase LDL-R recycling to the cell surface. SPC5001 has the
potential to reduce LDL-C either as monotherapy or in combination with existing
cholesterol lowering drugs. Stimuli that lead to activation of LDL-R synthesis,
such as statins, also activate expression and secretion of PCSK9, which
attenuates the LDL lowering activity of the LDL-R induction. Thus, a regimen
including a statin and a PCSK9 inhibitor has potential to be synergistic.

- To evaluate the safety and toleration of SPC5001 in healthy subjects and in
subjects with FH.
- To assess the lipid lowering effect of SPC5001 in healthy subjects and in
subjects with FH.
- To assess the pharmacokinetics of SPC5001 in healthy subjects and in subjects
with FH.

This will be a FIH, randomized, dose-escalation, double-blind,
placebo-controlled study. The study will enroll 4 cohorts of 8 healthy
subjects each for a total of 32 healthy subjects. Cohort 5 and 6 will consist
of 8 FH subjects without a past history of cardiovascular disease (CVD) and
will be enrolled after completion of the healthy subject cohorts. FH subjects
in cohort 5 will have washed-out their statin therapy for 4 weeks prior to
receiving their first doses of study drug. FH subjects will receive the highest
SPC5001 dose (or placebo) that was well-tolerated by the healthy subject
cohorts. Study drug will be administered as a subcutaneous (SC) injection on
Days 1, 8, and 15. Subjects in each cohort will be randomized to receive
either SPC5001 or placebo in a 6:2 ratio. FH patients in cohort 6 will continue
their standard statin treatment.

Multiple doses of SPC5001 (0.5 mg/kg, 1.5mg/kg, 5mg/kg or 10mg/kg (dose to be
determined for FH subjects, highest dose that was well-tolerated in healthy
subjects)) will be evaluated in healthy subjects and in subjects with FH. The
doses will be administered as a subcutaneous injection. Each subject will
participate in one cohort and will receive either multiple doses of SPC5001 or
placebo (0.9% saline), administered in a randomized fashion.

Unexpected adverse events / Hypersensitivity reactions
Clinical significant findings during screening
Hematoma following venapunctures