The primary objective of the study is to evaluate the safety and efficacy of ARO-APOC3 in adults with SHTG and to select a dosing regimen for later stage clinical studies in this patient population.
ID
Source
Brief title
Condition
- Lipid metabolism disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is:
• Percent change from baseline at Week 24 in fasting TG.
Secondary outcome
The following are the secondary endpoints to be evaluated in this study:
• Percent change over time through Week 48 in fasting TG;
• Percent change from baseline at Week 24 and over time through Week 48 in
apolipoprotein (Apo)C-III;
• Percent change from baseline at Week 24 and over time through Week 48 in
fasting non high-density lipoprotein-cholesterol (non HDL-C);
• Percent change from baseline at Week 24 and over time through Week 48 in
fasting HDL C;
• Percent change from baseline at Week 24 and over time through Week 48 in
fasting total ApoB;
• Percent change from baseline at Week 24 and over time through Week 48 in
fasting low density lipoprotein-cholesterol (LDL C) using ultracentrifugation;
• Change from baseline in plasma concentrations of ARO-APOC3 over time through
Week 12; and
• The frequency and severity of AEs and SAEs over time through Week 48.
Background summary
Severely high hypertriglyceridemia (SHTG) is a disorder characterized by marked
elevations in triglyceride (TG) levels which can lead to acute pancreatitis, as
well as an increased risk of cardiovascular disease and atherosclerosis (Hegele
2014, Scherer 2014). Acute pancreatitis
typically causes severe upper abdominal pain and may result in emergency room
visits, hospitalizations, and even deaths (Chatila 2019, Scherer, 2014). The
National Cholesterol Education Program (NCEP) Adult Treatment Panel III
recommends TG-lowering therapy when TG are >=500 mg/dL (>=5.65 mmol/L) to prevent
acute pancreatitis (NCEP 2002, Pedersen 2016).
The prevalence of SHTG in adults in the US is approximately 1.7%, based on the
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). The prevalence of adults with TG
levels
>885 mg/dL (>10 mmol/L) or >1000 mg/dL (>11.3 mmol/L) are even lower (range
1:600 to
1:1000, or between 0.1% to 0.2%) (Laufs 2020, Brown 2018). SHTG can be caused
by many
factors, including a combination of genetics, diet, lifestyle choices (eg,
excessive alcohol intake),
and comorbid conditions, such as obesity, metabolic syndrome, hypothyroidism,
and Type 2
diabetes mellitus (Laufs 2020, Yuan 2007). Genetic causes of SHTG, are
typically associated
with high TG levels in excess of 885 mg/dL (10 mmol/L) and can have both
monogenic
(Familial Chylomicronemia Syndrome [FCS or hypertriglyceridemia Type 1]) and
polygenic
(Multifactorial Chylomicronemia [MCM or Type 5 hyperlipoproteinemia])
determinants
(Paquette 2019).
ARO-APOC3 is a synthetic, double-stranded, hepatocyte-targeted RNAi trigger
designed to
specifically silence mRNA transcripts from the APOC3 gene using an RNAi
mechanism.
Preclinical distribution studies show that ARO-APOC3 is primarily distributed
to the liver,
where the trigger molecule is taken up by hepatocytes via receptor-mediated
endocytosis.
Introduction of the double-stranded RNAi trigger into the cytoplasm of
hepatocytes results in its
association with the protein components of the RNA-induced silencing complex
(RISC),
resulting in *on target* highly sequence-specific degradation of messenger RNA
complementary
to the antisense strand of the RNAi trigger. Active RISC is a multiple turnover
enzyme complex,
therefore, incorporation of a single RNAi trigger into RISC can result in the
degradation of many
mRNA molecules, and subsequently, prolonged reduction of the expression of the
corresponding
protein. The persistence of pharmacologic activity significantly beyond the
period of plasma
exposure is due in part to this unique RNAi mechanism in which a small amount
of guide strand
can persist and be active within RISC in the cytoplasm of target cells for
extended periods of
time.
Silencing of hepatic APOC3 using ARO-APOC3 is expected to lower serum TG by
preventing
APOC3-mediated inhibition of LPL, thus allowing enhanced peripheral LPL
activity.
Additionally, APOC3 silencing will remove the steric blockade of APOC3 at the
hepatocyte,
leading to enhance clearance of TRLs from circulation by the liver.
Study objective
The primary objective of the study is to evaluate the safety and efficacy of
ARO-APOC3 in adults with SHTG and to select a dosing regimen for later stage
clinical studies in this patient population.
Study design
This is a randomized, double-blind, placebo-controlled, Phase 2b clinical
study. After informed consent participants will be assessed for eligibility.
Participants who have met all the protocol eligibility criteria during
Screening may be enrolled and randomly assigned to treatment in a double-blind
fashion. Participants will be randomly assigned 3:1 to receive 1 of 3 ARO-APOC3
dosing regimens or matched placebo (see Study Schema). All dose cohorts will
enroll in parallel. Enrolled participants will be counseled to remain on stable
background medications and on the specified diet throughout the study, as
recommended by the Investigator in accordance with local standard of care. The
specifics of the diet will be at the discretion of the Investigator based on
each individual*s diagnosis and medical needs.
Intervention
There will be 2 study treatments; 1 active (Test Formulation) and 1 placebo
(Reference Formulation).
Test Formulation:
The test formulation is active ARO-APOC3 Injection (also referred to as
ARO-APOC3) administered subcutaneously (SC). The active pharmaceutical
ingredient (API) contained in ARO APOC3 is a synthetic, double-stranded, small
interfering RNA (siRNA) duplex conjugated to an N-acetyl-galactosamine
targeting ligand to facilitate hepatocyte delivery.
Reference Formulation:
The reference formulation is placebo: normal saline (0.9%) administered SC,
volume matched to the corresponding ARO-APOC3 dose volume.
Doses and Number of Doses per Treatment:
Three dose levels of ARO-APOC3 will be compared to placebo in participants with
severely high triglycerides (TG), or SHTG, who had mean fasting TG of >=500
mg/dL (5.65 mmol/L) at Screening. A total of approximately 216 participants
will be enrolled in the study. All dose cohorts will enroll in parallel with 72
participants per dose cohort randomly assigned in a 3:1 ratio to receive ARO
APOC3 or placebo. Each participant will receive SC injections on Day 1 and Week
12 for a total of 2 injections as follows:
• ARO-APOC3 10 mg (n=54) or volume-matched placebo (n=18) at Day 1 and Week 12;
• ARO-APOC3 25 mg (n=54) or volume-matched placebo (n=18) at Day 1 and Week 12;
or
• ARO-APOC3 50 mg (n=54) or volume-matched placebo (n=18) at Day 1 and Week 12.
The duration of the study is approximately 54 weeks from Screening to the Week
48 End-of-Study examination.
Study burden and risks
Risk Assessment for Participants
• Embryo-Fetal: Limited GLP toxicology and clinical studies have been
conducted. Accordingly, eligible participants enrolled in this study, both male
and female (including partners), must agree to use 2 highly-effective forms of
contraception during the study, or agree to abstinence (acceptable only if this
method is in alignment with the normal lifestyle of the participant).
• Liver Function: ARO-APOC3 targets the liver. siRNA literature has described
ALT changes associated with off-target effects of the siRNA seed region on
microRNAs in the hepatocyte (Janas 2018). The siRNA sequence of the ARO-APOC3
sense and antisense molecules have been screened for potential mRNA and
microRNA homology and sequences with homology were excluded from consideration.
Thus, no such off-target effects are anticipated. In the AROAPOC31001 study,
transient mild to moderate elevations in ALT were occasionally seen (See IB for
details) without accompanying elevation in international normalized ratio (INR)
or total bilirubin. To mitigate this risk, the proposed study protocol has
built in stopping rules for ALT and AST elevation. Blood samples will be drawn
as specified in the Schedule of Assessments (SOA) (Table 1) to evaluate liver
injury and liver function. The Data Safety Committee (DSC) will review all
available safety data including laboratory data periodically.
• Injection Site Adverse Events (AEs): Other SC administered modified siRNA
drug candidates evaluated in clinical studies have been associated with mild to
moderate injection site reactions (eg pain, erythema). Generally mild injection
site AEs have been reported in the AROAPOC1001 study. In this study, steps will
be taken to minimize injection site reactions such as rotating injection sites
and allowing the ARO-APOC3 solution to come to room temperature prior to
injection.
• Glycemic Control: An administrative analysis of the 2 ongoing Phase 2 studies
has indicated increases in serum glycated hemoglobin (HbA1c) in the ARO-APOC3
treatment group versus the placebo group. The increased HbA1c values were
observed in a small group of subjects who had preexisting diabetes at baseline
and particularly in a subset of subjects in the highest (50 mg) ARO-APOC3 dose
group.
To mitigate the risk of worsening glycemic control investigators are encouraged
to evaluate the diabetes status and adjust diabetes treatment according to
clinical practice and diabetes care guidance.
In addition, any subject with worsening diabetic control may return for an
unscheduled visit for evaluation of HbA1c prior to the next planned dose to
confirm continued treatment eligibility.
For those subjects who, despite diabetes treatment adjustments, remain with
elevated HbA1c above protocol pre-established level a number of study drug
discontinuation criteria have been established.
Routine monitoring of HbA1c and fasting glucose concentrations will be assessed
as part of the clinical laboratory panels to monitor glycemic control.
East Colorado Boulevard, Suite 700 177
Pasadena CA 91105
US
East Colorado Boulevard, Suite 700 177
Pasadena CA 91105
US
Listed location countries
Age
Inclusion criteria
To be eligible for enrollment, participants must meet all the following
inclusion criteria:
1. Males or nonpregnant (who do not plan to become pregnant), nonlactating
females >=18 years of age;
2. Based on medical history, evidence of triglycerides fasting (TG) >=500 mg/dL
(5.65 mmol/L) ;
3. A mean fasting TG >=500 mg/dL (5.65 mmol/L) and <=4000 mg/dL (45.2 mmol/L)
collected at two separate and consecutive visits at least 7 days apart and no
more than 14 days apart during the Screening period.
4. If the participant has a medical history of clinical atherosclerotic
cardiovascular disease (ASCVD) or those with elevated 10-year ASVCD risk (e.g.,
>=7.5% per American Heart Association / American College of Cardiology [ACC/AHA]
risk calculator) for subjects >=40 years of age or Framingham risk score
calculator for subjects under the age of 40) must be on appropriate
lipid-lowering therapy as per local standard of care (i.e., including moderate
to high intensity statin, as indicated) prior to collection of qualifying TG
levels;
5. Able and willing to provide written informed consent prior to the
performance of any study specific procedures;
6. Willing to follow diet counseling and maintain a stable diet as per
Investigator judgment based on local standard of care;
7. Participants of childbearing potential must agree to use highly effective
contraception, during the study and for at least 24 weeks following the last
dose of IP. Males must not donate sperm during the study and for at least 24
weeks following the or last dose of IP;
8. Women of childbearing potential on hormonal contraceptives must be stable on
the medication for >=2 menstrual cycles prior to Day 1; and
9. Participants on any of the following medications must be on a stable regimen
for the specified duration prior to collection of Screening visit (S2)
laboratory tests and for the duration of study participation:
Medication: Time on stable regimen prior to collection of Screening visit (S2)
laboratory tests
• Lipid lowering therapies (including statins): >= 4 weeks
• Beta-blockers, thiazide diuretics: >= 4 weeks
• Fibrates: >= 6 weeks
• PCSK9 inhibitors: >= 8 weeks
• Retinoids: >= 8 weeks
• Atypical antipsychotics: >= 12 weeks
• Diabetes mellitus medications: >= 12 weeks
• Anticoagulation therapy >=12 weeks
• Thyroid hormone replacement therapy >=12 weeks
• Testosterone replacement therapy >=16 weeks
• Oral estrogens, tamoxifen, raloxifene: >= 16 weeks
• Immunosuppressants: >= 24 weeks
NOTE: All laboratory tests used as inclusion criteria will be assessed by a
central laboratory and may be repeated once and the repeat value may be used
for inclusion purposes. Local laboratory testing may be permitted in limited
circumstances and only with prior Sponsor approval.
Exclusion criteria
Exclusion Criteria:
1. Current use or use within the last 365 days from Day 1 of any hepatocyte
targeted siRNA or antisense oligonucleotide molecule;
2. Active pancreatitis within 12 weeks prior to Day 1;
3. Known genetically confirmed diagnosis of Familial Chylomicronemia Syndrome
4. Any planned bariatric surgery or similar procedures to induce weight loss
during the period starting at consent through the end of the study;
5. History of major surgery within 12 weeks of Day 1 or planned major surgery
during the study;
6. Planned coronary intervention (such as stent placement or heart bypass)
during the study;
7. History of acute coronary syndrome event within 24 weeks of Day 1;
8. New York Heart Association (NYHA) Class II, III, or IV heart failure or last
known ejection fraction of <30%;
9. Uncontrolled hypertension (sitting blood pressure >160/100 mmHg at
Screening); participant may be re-screened once hypertension is controlled;
10. History of hemorrhagic stroke within 24 weeks of Day 1;
11. History of bleeding diathesis or coagulopathy;
12. Current diagnosis of nephrotic syndrome;
13. Any of the following laboratory values at Screening:
a. Hepatic: ALT or AST >2× ULN at Screening,
b. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (using the
Modification of Diet in Renal Disease [MDRD] equation) at Screening,
c. HbA1c >9.0% (or >75 mmol/mol [IFCC] units) at screening;
d. Spot urine protein/spot urine creatinine ratio >3 grams per day;
e. Clinically significant abnormality in PT, aPTT, or INR;
14. Use of any of the following:
a. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to
Day 1 or planned use during the study, (stable doses of testosterone
replacement therapy >16 weeks prior to Screening (visit S2) is permitted for a
documented history of hypogonadism [low testosterone] as verified in subject
health records)
b. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study;
15. Blood donation of 50 to 499 mL within 4 weeks of Screening (visit S2)
laboratory collection or of >499 mL within 8 weeks of Screening (visit S2)
laboratory collection;
16. Known history of human immunodeficiency virus infection;
17. Seropositive (hepatitis B surface antigen [HBsAg] +) for hepatitis B virus
(HBV) or hepatitis C virus (HCV) (HCV seropositivity requires positive test for
antibodies confirmed with positive test for HCV RNA);
18. Clinical evidence of uncontrolled hypothyroidism or hyperthyroidism as per
Investigator*s judgment;
19. History of malignancy within the last 2 years prior to the date of consent
requiring systemic treatment except for adequately treated basal cell
carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ
cervical cancer. Currently receiving systemic cancer treatment(s) or, in the
Investigator's opinion, at risk of relapse for recent cancer;
20. Use of an investigational agent or device within 30 days or within 5
half-lives, based on plasma pharmacokinetics (PK) (whichever is longer) prior
to Day 1 or current participation in an interventional investigational study.
Participants previously exposed to ARO APOC3, or ARO-ANG3 will require a
washout period of at least 1 year from last dose;
21. Unwilling to limit alcohol consumption to within moderate limits for the
duration of the study, as follows: not more than 14 units per week (1 unit =
80 mL of wine, 200 mL of beer, or 25 mL of 40% alcohol); or
22. Any concomitant medical or psychiatric condition or social situation or any
other situation that, in the Investigator*s judgment, would make it difficult
to comply with protocol requirements or put the participant at additional
safety risk.
All laboratory tests used as exclusion criteria may be repeated once and the
repeat value may be used for exclusion purposes.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-000687-30-NL |
| ClinicalTrials.gov | NCT04720534 |
| CCMO | NL77807.000.21 |