A Phase 2 Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of ARO-APOC3 in Adults with Dyslipidemia

Dyslipidemia is defined as an imbalance in plasma lipids (eg, cholesterol,
low-density lipoprotein cholesterol [LDL-C], triglycerides [TG], and/or
high-density lipoprotein cholesterol [HDL-C]) that includes severely high
hypertriglyceridemia (SHTG) and mixed dyslipidemia (MD), two conditions that
are associated with clinical complications. SHTG is characterized by marked
elevations in TG levels, which can lead to acute pancreatitis, as well as an
increased risk of cardiovascular disease and atherosclerosis (Hegele 2014;
Scherer 2014). MD is defined as the presence of high LDL-C combined with at
least one other lipid abnormality (ie, high LDL-C with either low HDL-C and/or
high TG) and is a major risk factor for atherosclerotic cardiovascular disease
(ASCVD) (Kersten 2017). The prevalence of SHTG in adults in the US is
approximately 1.7%, based on the National Health and Nutrition Examination
Survey (NHANEs) database (2001-2006) of individuals with TG levels between 500
and 2000 mg/dL (5.65 to 22.6 mmol/L) (Christian 2011; Laufs 2020), while the
prevalence of MD in adults in the US is approximately 21% (42.0 M). Currently,
the therapeutic options that can adequately treat SHTG and MD are limited, and
additional treatments options are needed.
ApoC3 is an 8.8 kilodalton (kDa) protein component of triglyceride-rich
lipoproteins (TRLs), such as very-low-density lipoprotein cholesterol (VLDL-C),
intermediate-density lipoprotein cholesterol, chylomicrons, HDL-C, and remnant
particle lipoproteins. ApoC3 is synthesized predominantly in hepatocytes. It
inhibits the hydrolysis of TG on TRLs at the muscle and adipose tissue
capillary level through inhibition of lipoprotein lipase (LPL) and delays
clearance of lipoprotein remnants by the liver by inhibiting hepatocyte
receptor-mediated uptake. ApoC3 functions as a key regulator of fasting and
postprandial plasma TG levels.
ARO-APOC3 is a synthetic, double-stranded, hepatocyte-targeted RNA interference
(RNAi) trigger designed to specifically silence messenger RNA (mRNA)
transcripts from the APOC3 gene using an RNAi mechanism. Given the important
role of ApoC3 in serum TG level modulation and its primary source of synthesis
in hepatocytes, reduction of ApoC3 through a hepatocyte-targeted RNAi strategy
is likely to reduce circulating TG by preventing ApoC3-mediated inhibition of
LPL, thus allowing enhanced peripheral LPL activity. Additionally, ApoC3
silencing is expected to remove the steric blockade of ApoC3 at the hepatocyte,
leading to enhanced clearance of TRLs from circulation by the liver.

This study has been transitioned to CTIS with ID 2024-511331-96-00 check the CTIS register for the current data.

Primary Objective
• To evaluate the safety and efficacy of long-term treatment with ARO-APOC3 in
adults with dyslipidemia.

This is an open-label extension (OLE) Phase 2b clinical study. Subjects who
have signed an Ethics Committee (EC)/Institutional Review Board (IRB) approved
informed consent form (ICF) may be enrolled after completing either
AROAPOC3-2001 or AROAPOC3-2002 (parent studies). Subjects must continue to
maintain a stable diet and stable lipid-lowering therapy in accordance with
local standard of care, as well as other background medications taken during
the parent study (see Section 8.2), throughout the duration of the 24-month OLE
period (refer to Table 3).
All eligible subjects from AROAPOC3-2001 and AROAPOC3-2002 studies will receive
ARO-APOC3, administered open-label, consistent with the dose level and regimen
(once every 3 months [Q3M] or once every 6 months [Q6M]) as assigned in the
parent study. Subjects will remain blinded to their treatment assignment from
the parent study and will initially receive ARO-APOC3 in this OLE study at the
dose corresponding to their assigned study treatment dose in the parent study.
Thus, subjects who had previously received ARO-APOC3 10 mg, 25 mg, or 50 mg Q3M
(in Study AROAPOC3-2001); or ARO-APOC3 10 mg, 25 mg, or 50 mg Q3M, or ARO-APOC3
50 mg Q6M (in Study AROAPOC3-2002) will continue to receive the same dose in
this OLE study until a final dose is selected from the parent studies. Subjects
previously receiving placebo in the parent study will transition to active
treatment based on the initial dosing group to which they were assigned (ie, 10
mg Q3M, 25 mg Q3M, or 50 mg Q3M or Q6M). After the last subject in the parent
study reaches the Month 12/end of study (EOS) visit of the parent study and a
dose has been selected, all subjects in this OLE study will receive open-label
treatment with the selected ARO-APOC3 dosing regimen.

Investigational Product, Dosage, and Mode of Administration:
The test formulation is active ARO-APOC3 administered SC. The active
pharmaceutical ingredient contained in ARO-APOC3 is a synthetic,
double-stranded, small interfering RNA oligonucleotides (siRNA) duplex
conjugated to an N-acetyl galactosamine (NAG) targeting ligand to facilitate
hepatocyte delivery.

Dosage information: ARO-APOC3 on Day 1, then Q3M (or Q6M if assigned to the 50
mg dose group in study AROAPOC3-2002) through EOS: initial dosage, 10 mg, 25
mg, or 50 mg as assigned in the parent study (see Methodology).
Following the final data analysis in the parent studies, a single dose will be
determined and all active subjects will be transitioned to the selected dose
for the duration of the study.

Duration of Treatment:
The duration of the OLE study is approximately 2 years. All subjects in the
placebo group of the parent study who opt to continue will switch to active
drug during the OLE study.

Reference Therapy, Dosage and Mode of Administration:
Not applicable

ARO-APOC3 has been shown to have a favorable benefit-risk profile to date that
warrants further clinical investigation and longer exposure periods. As of the
October 08, 2020 (for non-safety) and October 15, 2020 (for safety) cutoff
dates, interim PD data from the Phase 1 study AROAPOC31001 showed that
administration of ARO-APOC3 at doses ranging from 10 to 100 mg resulted in
significant and durable reduction of serum APOC3 when compared with placebo in
healthy volunteers as well as in subjects with HTG and CM.
Silencing of APOC3 led to reductions in the levels of serum TG and other lipid
parameters. Results using single doses of ARO-APOC3 in normal healthy
volunteers (NHVs) demonstrated dose-dependent reductions in serum APOC3 of up
to -94%when compared to baseline. As would be predicted, knockdown of APOC3
resulted in decreased fasting serum TG (up to -66%) and non-HDL-C (up to -31%)
as well as increased serum HDL-C levels (up to +74%) with a dose response
generally correlating with APOC3 serum level reductions in subjects receiving
the active drug. Results for repeat doses of ARO-APOC3 in NHVs demonstrated
consistent reductions of APOC3 (up to -94%), TGs (up to -75%), and non-HDL-C
(up to -34%) and increases in HDL-C levels (up to +75%). These responses were
overall sustained through Week 16, which is 12 weeks after the last dose.
Results for repeat doses of ARO-APOC3 in subjects with HTG and/or CM
demonstrated similar or even larger effects of ARO-APOC3 at similar doses
studied in NHVs. Reductions of serum APOC3 (up to -98%), TGs (up to -88%),
non-HDL-C (up to -58%), and increases in HDL-C levels (up to +122%) were
observed. The effects of ARO-APOC3 treatment on these and other key lipid
parameters were sustained over the 16 weeks of study duration.
ARO-APOC3 has been generally well tolerated and has demonstrated favorable
safety and tolerability. There have been no deaths in the study or study
discontinuation due to AEs. Three (3) SAEs involving 3 subjects have been
reported, all of which were deemed not related to study drug, and the subjects
completed the study. There is no clear pattern of an increased frequency or
intensity of AEs with increasing dose level. The combined placebo TEAEs
reported were comparable to those seen in the ARO-APOC3 treatment group. The
majority of the reported TEAEs were not related to study treatment, and there
were no subjects that discontinued from the study due to TEAEs. The most
frequently reported AEs that were drug-related were the ISRs, which were all
mild in intensity. The AEs at the injection site are anticipated based on
similar findings reported in other clinical studies of SC-administered siRNA
therapeutics. Overall, there were no clinically significant adverse laboratory
trends observed. There were no clinically significant adverse ECG, vital sign,
or physical examination findings during the mentioned study period.
The totality of the data described above represents robust evidence to support
the continuation of the clinical development program for ARO-APOC3.