| Eligibility |
Inclusion Criteria:
- Males or nonpregnant (who do not plan to become pregnant), nonlactating females =18
years of age
- Able and willing to provide written informed consent prior to the performance of any
study-specific procedures
- Fasting TG =10 mmol/L (~880 mg/dL) at screening, that is refractory to standard lipid
lowering therapy (sample drawn after at least the minimum time on stable
lipid-lowering regimen described in protocol). Two repeat tests are allowed to
qualify.
- A diagnosis of FCS based on a documented history of fasting TG levels in excess of
1000 mg/dL on repeated testing (for at least one prior occasions), and at least one of
the following:
1. A supportive genetic test (from a source-verifiable medical record or based on
screening genotype). Supportive genetic testing includes but is not limited to
homozygous, compound heterozygous, or double heterozygote for loss-of-function or
otherwise inactivating mutations in genes affecting lipoprotein lipase activity
including LPL, APOC2, APOA5, GPIHBP1, GPD1, or LMF1; or evidence of low LPL
activity (<20% of normal) based on source-verifiable documentation; or
2. Documented history of recurrent episodes of acute pancreatitis, not caused by
alcohol or cholelithiasis; or
3. Documented history of recurrent hospitalizations for severe abdominal pain
without other explainable cause; or
4. Documented history of childhood pancreatitis; or
5. Family history of hypertriglyceridemia-induced pancreatitis
- Willing to follow dietary counseling as per PI judgment based on local standard of
care, consistent with an intake of =20 g of fat per day during the study
- If on medications for management of type 2 diabetes, or other medications specified in
protocol, the dosing regimen must be stable before collection of qualifying lipid
parameter at screening.
- Participants with a medical history of clinical atherosclerotic cardiovascular disease
(ASCVD) or those with elevated 10-year ASCVD risk (eg, =7.5% per American Heart
Association / American College of Cardiology risk calculator) must be on appropriate
lipid-lowering therapy as per local standard of care (ie, including moderate to high
intensity statin, as indicated) prior to collection of qualifying TG levels.
- Participants of childbearing potential must agree to use a highly effective form of
contraception in addition to a male condom, during the study and for at least 24 weeks
after the last dose of IP. Women of childbearing potential on a hormonal contraceptive
must be stable on the medication for =2 menstrual cycles prior to Day 1. Men must not
donate sperm during the study and for at least 24 weeks after the last dose of IP.
Exclusion Criteria:
- Current use or use within the last 365 days from Day 1 of any hepatocyte-targeted
siRNA or antisense oligonucleotide molecule
- Diabetes mellitus with any of the following:
- Newly diagnosed within 12 weeks of screening
- HbA1c =9.0% at screening
- Active pancreatitis within 12 weeks before Day 1
- History of acute coronary syndrome event within 24 weeks of Day 1
- History of major surgery within 12 weeks of Day 1
- Any of the following laboratory values at screening:
1. ALT or AST =3×ULN at screening
2. Total bilirubin =1.5×ULN (if the participant has a prior diagnosis and
documentation of Gilbert's syndrome, then total bilirubin must be =3 mg/dL at
screening)
3. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening, using the
Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) creatinine equation
4. Spot urine protein/spot urine creatinine ratio greater than 3 grams per day
5. Clinically significant abnormality in prothrombin time, partial thromboplastin
time, or INR
- Uncontrolled hypertension (blood pressure >160/100 mmHg at screening); if untreated,
participant may be rescreened once hypertension is treated and controlled
- Use of any of the following:
1. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day
1 or planned use during the study
2. GLP-1 receptor agonists
3. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study
4. Blood donation of 50 to 499 mL within 4 weeks of collection of qualifying lipid
parameter collection or of >499 mL within 8 weeks of qualifying lipid parameter
collection
- On treatment with HIV antiretroviral therapy (Note: determination of HIV status is not
a required study procedure)
- 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)
- New York Heart Association (NYHA) Class III or IV heart failure or last known ejection
fraction of <30%
- Clinical evidence of primary hypothyroidism (screening TSH > ULN and free T4<LLN),
primary subclinical hypothyroidism (screening TSH > ULN and free T4 WNL), or secondary
hypothyroidism (screening TSH < LLN and free T4< LLN)
- History of hemorrhagic stroke within 24 weeks of first dose
- History of bleeding diathesis or coagulopathy
- Current diagnosis of nephrotic syndrome
- Unwilling to limit alcohol consumption to within moderate limits for the duration of
the study, as follows: not more than 14 units per week for women and men (1 unit
approximately corresponds to 80 mL of wine, 200 mL of beer, or 25 mL of 40% alcohol)
- 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 PI's opinion, at risk of relapse for
recent cancer.
- Use of an investigational agent or device within 30 days or within 5 half-lives, based
on plasma 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.
- Any concomitant medical or psychiatric condition or social situation or any other
situation that, in the PI's judgment, would make it difficult to comply with protocol
requirements or put the participant at additional safety risk.
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