Familial Chylomicronemia
Conditions
Brief summary
The purpose of AROAPOC3-3001 is to evaluate the efficacy and safety of ARO-APOC3 (plozasiran) in adult participants with familial chylomicronemia syndrome (FCS). Participants who have met all eligibility criteria will be randomized to receive 4 doses of plozasiran or matching placebo administered subcutaneously. Participants who complete the randomized period will continue in a 2-year open-label extension period where all participants will receive plozasiran.
Interventions
DRUGPlozasiran
ARO-APOC3 subcutaneous (SC) injection
DRUGPlacebo
sterile normal saline (0.9% NaCl) SC injection
Sponsors
Arrowhead Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Fasting triglycerides (TG) ≥ 10 mmol/L (≥ 880 mg/dL) at screening refractory to standard lipid lowering therapy * Diagnosis of FCS * Willing to follow dietary counseling as per investigator judgement based on local standard of care * Participants of childbearing potential (males \& females) must use highly-effective contraception during the study and for at least 24 weeks following the last dose of study medication. Males must not donate sperm during the study and for at least 24 weeks following the last dose of study medication * Women of childbearing potential must have a negative pregnancy test at Screening and cannot be breastfeeding * Women of childbearing potential on hormonal contraceptives must be stable on the medication for ≥ 2 menstrual cycles prior to Day 1
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 newly diagnosed within 12 weeks of Screening or where 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 * Uncontrolled hypertension * On treatment with human immunodeficiency virus (HIV) antiretroviral therapy * Seropositive for hepatitis B virus (HBV) or hepatitis C virus (HCV) * New York Heart Association (NYHA) Clas II, III, or IV heart failure Note: Additional Inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percent Change From Baseline at Month 10 in Fasting Triglycerides (TG) | Baseline, Month 10 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Fasting TG at Month 10 and Month 12 (Averaged) | Baseline, Month 10, Month 12 | — |
| Percent Change From Baseline in Apolipoprotein C-III (APOC3) at Month 10 | Baseline, Month 10 | — |
| Percent Change From Baseline in Fasting APOC3 at Month 12 | Baseline, Month 12 | — |
| Percentage of Participants With Positively Adjudicated Events of Acute Pancreatitis (Randomized Period) | From first dose of study drug through Month 12 (Randomized Period) | All adverse events (AEs) and serious adverse events (SAEs) reported by the Investigator during the study that are consistent with an event of acute pancreatitis will be adjudicated by a blinded, independent committee according to the 2013 Atlanta definition meeting 2 of the following 3 criteria: 1. Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back) 2. Serum lipase activity (or amylase activity) ≥3 times the upper limit of normal (×ULN) 3. Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), or transabdominal ultrasonography. |
| Percentage of Participants With Positively Adjudicated Events of Acute Pancreatitis (Open-Label Period) | From first dose of study drug through Month 36 (Open-Label Period) | All adverse events (AEs) and serious adverse events (SAEs) reported by the Investigator during the study that are consistent with an event of acute pancreatitis will be adjudicated by a blinded, independent committee according to the 2013 Atlanta definition meeting 2 of the following 3 criteria: 1. Abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back) 2. Serum lipase activity (or amylase activity) ≥3 times the upper limit of normal (×ULN) 3. Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT), magnetic resonance imaging (MRI), or transabdominal ultrasonography. |
| Percent Change From Baseline in Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Month 10 | Baseline, Month 10 | — |
| Percent Change From Baseline in Non-HDL-C at Month 12 | Baseline, Month 12 | — |
| Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) at Month 10 | Baseline, Month 10 | — |
| Percent Change From Baseline in HDL-C at Month 12 | Baseline, Month 12 | — |
| Percent Change From Baseline in Fasting Triglycerides (TG) at Month 12 | Baseline, Month 12 | — |
| Percentage of Participants Achieving Fasting TG of <500, 880, and 1000 mg/dL at Month 10 | Month 10 | — |
| Percentage of Participants Achieving Fasting TG of <500, 880, and 1000 mg/dL at Month 12 | Month 12 | — |
| Percentage of Participants Achieving ≥40% and ≥70% Reduction From Baseline in Fasting TG at Month 10 | Baseline, Month 10 | — |
| Change From Baseline in Fasting TG Over Time | Baseline, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | — |
| Percent Change From Baseline in Fasting TG Over Time | Baseline, Months 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 | — |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and/or Serious Adverse Events (SAEs; Randomized Period) | From first dose of study drug through Month 12 (Randomized Period) | AE: any untoward medical occurrence which does not necessarily have to have a causal relationship with treatment. Treatment-emergent AEs (TEAEs): AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. SAE: AE that fulfills one or more of the following: results in death; is immediately life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event that may jeopardize the patient or may require medical intervention to prevent one of the outcomes listed above. Severity was reported as: mild, moderate, severe, life threatening, death. |
| Number of Participants With Treatment-Emergent AEs and/or SAEs (Open-Label Period) | From first dose of open-label study drug through Month 36 (Open-Label Period) | AE: any untoward medical occurrence which does not necessarily have to have a causal relationship with treatment. Treatment-emergent AEs (TEAEs): AEs with onset after administration of the study drug, or when a preexisting medical condition increases in severity or frequency after study drug administration. SAE: AE that fulfills one or more of the following: results in death; is immediately life-threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; results in a congenital abnormality or birth defect; is an important medical event that may jeopardize the patient or may require medical intervention to prevent one of the outcomes listed above. Severity was reported as: mild, moderate, severe, life threatening, death. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Croatia, France, Germany, Ireland, Israel, Japan, Mexico, New Zealand, Oman, Poland, Serbia, Singapore, South Korea, Spain, Turkey (Türkiye), United States
Participant flow
Pre-assignment details
In the 12-month Randomized Period, participants who successfully passed eligibility requirements at screening enrolled in parallel cohorts, with participants randomly assigned 2:1:2:1 to plozasiran 25 mg, volume-matched placebo, plozasiran 50 mg and volume-matched placebo, respectively. Results data is presented for the Randomized Period; per protocol, placebo arms were pooled for this analysis. An Open-label Extension Period is ongoing.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 42.6 years STANDARD_DEVIATION 10.85 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 26 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Asian | 5 Participants |
| Race/Ethnicity, Customized Other, not specified | 1 Participants |
| Race/Ethnicity, Customized White | 17 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 12 Participants |
| Triglycerides | 2369.07 mg/dL STANDARD_DEVIATION 1337.965 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 25 | 0 / 26 | 0 / 24 |
| other Total, other adverse events | 17 / 25 | 21 / 26 | 18 / 24 |
| serious Total, serious adverse events | 7 / 25 | 5 / 26 | 2 / 24 |
Outcome results
None listed