A Phase 3 Study of ARO-APOC3 / VSA001 / SAR449124 (Plozasiran) in Chinese Adults With Familial Chylomicronemia Syndrome

A Phase 3 Study to Evaluate the Efficacy and Safety of ARO-APOC3 / VSA001 / SAR449124 Injection in Chinese Adults With Familial Chylomicronemia Syndrome

This is a randomized, double-blinded, placebo controlled, two periods phase 3 clinical study. The primary objective of the study was to evaluate the efficacy and safety of Plozasiran injection in Chinese adults with familial chylomicronemia syndrome (FCS). A total of 37 participants were enrolled in the study. The duration of the study randomized period was approximately 112 weeks, including a screening period of up to 8 weeks and a treatment period of up to 104 weeks. Participants who completed the randomized period will continue in a 1-year open-label extension period where all participants will receive Plozasiran.

Study Overview

• Status: Completed
• Conditions: Familial Chylomicronemia Syndrome
• Intervention / Treatment: Drug: Plozasiran; Drug: Placebon

Detailed Description

Familial chylomicronemia syndrome (FCS) is a severe and ultrarare genetic disease, with a prevalence of approximately 1 in 1,000,000, often caused by various monogenic mutations. FCS leads to extremely high fasting triglyceride (TG) levels, typically over 900 mg/dL. Such severe elevations lead to various serious signs and symptoms including acute pancreatitis (which can be fatal), chronic daily abdominal pain, type 2 diabetes mellitus, hepatic steatosis, and cognitive issues.

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 (IDL-C), chylomicrons, high-density lipoprotein cholesterol (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.

VSA001 is a synthetic, double-stranded, hepatocyte-targeted RNA interference (RNAi) trigger (also referred to as a small interfering RNA [siRNA]) 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, benefiting several patient populations, including patients with FCS.

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Huashan Hospital Affiliated to Fudan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Males or nonpregnant (who do not plan to become pregnant), nonlactating females ≥18 years of age
• Fasting triglycerides (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
• 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 qualified 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 investigational product (IP). Women of childbearing potential on a hormonal contraceptive must be stable on the medication for ≥1 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:

  1. Newly diagnosed within 12 weeks of screening
  2. 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

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plozasiran 25 mg; Plozasiran 25 mg administered every 3 months for 12 months (randomized period), followed by an open-label period of 12 months	Drug: Plozasiran; Subcutaneous injection; Other Names: ARO-APOC3; SAR449124; VSA001
Experimental: Plozasiran 50 mg; Plozasiran 50 mg administered every 3 months for 12 months (randomized period), followed by an open-label period of 12 months	Drug: Plozasiran; Subcutaneous injection; Other Names: ARO-APOC3; SAR449124; VSA001
Placebo Comparator: Placebo; Matching placebo administered every 3 months for 12 months	Drug: Placebon; Subcutaneous injection; Other Names: Normal saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting Serum Triglyceride (TG) at Month 10	Blood samples for lipid parameters were collected at the specified time points. Fasting serum TG at Month 10 was defined as geometric mean of 2 measurements taken during Month 10, or the other non-missing measurement if any one of the two measurements was missing during Month 10. Analysis was performed on the basis of the handling strategy for intercurrent events, missing fasting serum was imputed mainly based on the Pattern Mixture Models (PMM). Descriptive statistics were calculated based on non-imputed data.	Baseline to Month 10

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting Serum TG at Months 10 and 12 (Averaged)	Blood samples for lipid parameters were collected at the specified time points. Fasting serum TG at Month 10 and Month 12 was defined as the geometric mean of the measurements in Month 10 and Month 12 or the non-missing measurement in the other month if measurement in any one of the two months was missing. Analysis was performed on the basis of the handling strategy for intercurrent events, missing fasting serum TG was imputed mainly based on the PMM. Descriptive statistics were calculated based on non-imputed data.	Baseline to Months 10 and 12 (averaged)
Percent Change From Baseline in Fasting Serum Apolipoprotein C3 (APOC3) at Month 10	Blood samples for lipid parameters were collected at the specified time points. Baseline of fasting serum APOC 3 was defined as the last non-missing value prior to or on the first dosing date. Analysis was performed on the basis of the handling strategy for intercurrent events, missing values were imputed using the PMM. Descriptive statistics were calculated based on non-imputed data.	Baseline to Month 10
Percent Change From Baseline in Fasting Serum APOC3 at Month 12	Blood samples for lipid parameters were collected at the specified time points. Baseline of fasting serum APOC 3 was defined as the last non-missing value prior to or on the first dosing date. Analysis was performed on the basis of the handling strategy for intercurrent events, missing values were imputed using the PMM. Descriptive statistics were calculated based on non-imputed data.	Baseline to Month 12
Percent Change From Baseline in Fasting Serum Non-high Density Lipoprotein Cholesterol (Non-HDL-C) and High Density Lipoprotein Cholesterol (HDL-C) at Month 10	Blood samples for lipid parameters were collected at the specified time points. Baseline was defined as the last non-missing value prior to or on the first dosing date.	Baseline to Month 10
Percent Change From Baseline in Fasting Serum TG, Non-HDL-C, and HDL-C at Month 12	Blood samples for lipid parameters were collected at the specified time points. Non-HDL-C and HDL-C baseline was defined as the last non-missing value prior to or on the first dosing date.	Baseline to Month 12
Percentage of Participants Achieving Fasting Serum TG of <500 mg/dL at Month 10	Blood samples for lipid parameters were collected at the specified time points.	10 Month
Percentage of Participants Achieving Fasting Serum TG of <500 mg/dL at Month 12	Blood samples for lipid parameters were collected at the specified time points.	12 Month
Change From Baseline at Each Scheduled Assessment in Fasting Serum TG up to Month 12	Blood samples for lipid parameters were collected at the specified time points.	From baseline up to Month 12, at Months 1,2,3,4,5,6,7,8,9,10,11 and 12
Percent Change From Baseline at Each Scheduled Assessment in Fasting Serum TG up to Month 12	Blood samples for lipid parameters were collected at the specified time points.	From baseline up to Month 12, at Months 1,2,3,4,5,6,7,8,9,10,11 and 12
Number of Participants With Positively Adjudicated Events of Acute Pancreatitis	Any AEs and SAEs reported by the investigator during the study that were consistent with acute pancreatitis events were adjudicated by the blinded Data Safety Committee based on the Atlanta Classification for Acute Pancreatitis 2013 for fulfillment of any 2 of the following 3 criteria: Abdominal pain consistent with symptoms of acute pancreatitis (acute episodes of persistent, severe upper abdominal pain often radiating to the back); Serum lipase activity (or amylase activity) ≥3 × upper limit of normal (ULN); Characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) or transabdominal ultrasonography	From first administration of study treatment (Day 1) through Month 12.

Collaborators and Investigators

• Sponsor: Visirna Therapeutics HK Limited
• Collaborators: Arrowhead Pharmaceuticals
• Investigators: Study Chair: Dong YOU, MD., PhD., Visirna Therapeutics HK Limited

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2023
• Primary Completion (Actual): November 26, 2024
• Study Completion (Actual): January 9, 2026

Study Registration Dates

• First Submitted: May 31, 2023
• First Submitted That Met QC Criteria: June 9, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): February 27, 2026
• Last Update Submitted That Met QC Criteria: February 6, 2026
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Disease; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Familial hyperchylomicronemia syndrome; Pharmaceutical Preparations; Crystalloid Solutions; Isotonic Solutions; Solutions; Saline Solution; plozasiran
• Other Study ID Numbers: VSA001-3001; U1111-1330-5258 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes