A Study of Olezarsen (Formerly Known as AKCEA-APOCIII-LRx) Administered to Patients With Familial Chylomicronemia Syndrome (FCS) (BALANCE)

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of AKCEA-APOCIII-LRx Administered Subcutaneously to Patients With Familial Chylomicronemia Syndrome (FCS)

The purpose of the study was to evaluate the efficacy of olezarsen as compared to placebo on the percent change in fasting triglycerides (TG) from baseline.

Study Overview

• Status: Completed
• Conditions: Familial Chylomicronemia Syndrome
• Intervention / Treatment: Drug: Placebo; Drug: Olezarsen

Detailed Description

This was a multi-center, double-blind, Phase 3 study in up to 60 patients with FCS. Participants were randomized in a 2:1 ratio to receive Olezarsen or matching placebo in a 53-week treatment period. The length of participation in the study was approximately 74 weeks, which included an up to 8-week screening period, a 53-week treatment period, and a 13-week post-treatment evaluation period. Following the treatment period, eligible patients had the option to enroll in the Open-label Extension (OLE) Study ISIS 678354-CS13 (NCT05130450).

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 3

Expanded Access

Approved for sale to the public. See expanded access record.

Contacts and Locations

Study Locations

• Canada
  • Montréal, Canada, H2W 1R7
    • Institute de Recherches Cliniques de Montreal
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Montréal, Quebec, Canada, H2W 1R7
      • Nathalie Saint-Pierre
    • Québec, Quebec, Canada, G1V 4W2
      • Clinique des Maladies Lipidiques de Quebec Inc.
• France
  • Bron, France, 69677
    • Hôpital Louis Pradel - HCL
  • Dijon, France, 21000
    • CHU Dijon - Bocage
  • Marseille, France, 13385
    • Assistance Publique - Hopitaux de Marseille
• Italy
  • Milano, Italy, 20162
    • ASST Grande Ospedale Metropolitano Niguarda
  • Napoli, Italy, 80131
    • Azienda Ospedaliera Universitaria Federico Ii
  • Palermo, Italy, 90127
    • Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone
  • Roma, Italy, 00161
    • Azienda Ospedaliero Universitaria Policlinico Umberto I
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Academic Medical Center - Department of Vascular Medicine
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus MC
  • Utrecht, Netherlands, 3584 CX
    • Universitair Medisch Centrum Utrecht
• Norway
  • Oslo, Norway, 0372
    • The Lipid Clinic (Oslo University Hospital)
• Portugal
  • Carnaxide, Portugal, 2790-134
    • Centro Hospitalar de Lisboa Ocidental. E.P.E, - Hospital Santa Cruz
  • Creixomil, Portugal, 4835-044
    • Hospital da Senhora da Oliveira - Guimarães
  • Lisboa, Portugal, 1349-019
    • Centro Hospitalar de Lisboa Ocidental, EPE - Hospital Egas Moniz
• Slovakia
  • Bratislava, Slovakia, 83301
    • Metabolicke centrum MUDr Katariny Raslovej s. r. o.
• Spain
  • A Coruña, Spain, 15001
    • Hospital Abente y Lago
  • Barcelona, Spain, 08036
    • Hospital Clínic Barcelona
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen del Rocio
  • Tarragona, Spain, 43204
    • Fundacio Pere Virgili
• Sweden
  • Göteborg, Sweden, 413 45
    • Sahlgrenska University Hospital
  • Solna, Sweden, 171 76
    • Karolinska University Hospital
• United Kingdom
  • London, United Kingdom, SE1 7EH
    • St. Thomas' Hospital
  • London, United Kingdom, NW3 2QG
    • The Royal Free Hospital
  • Manchester, United Kingdom, MI39WL
    • Manchester University NHS Foundation Trust (MFT)
  • West Bromwich, United Kingdom, B71 4HJ
    • Sandwell General Hospital
• United States
  • California
    • Huntington Beach, California, United States, 92648
      • Diabetes/Lipid Management & Research Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco (UCSF) - Medical Center
  • Florida
    • Boca Raton, Florida, United States, 33434
      • Excel Medical Clinical Trials, LLC
  • Illinois
    • Evanston, Illinois, United States, 60201
      • Northshore University Health System
    • Park Ridge, Illinois, United States, 60068
      • Advocate Health and Hospitals Corporation - Lutheran General Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46290
      • Ascension St. Vincent Cardiovascular Research Institute
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center (KUMC)
  • Michigan
    • Ann Arbor, Michigan, United States, 48105
      • University of Michigan- Endocrinology & Metabolism
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10016
      • New York University (NYU) Langone Medical Center
  • North Carolina
    • Greensboro, North Carolina, United States, 27401
      • Moses H. Cone Memorial Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Virginia
    • Norfolk, Virginia, United States, 23510
      • York Clinical Research LLC
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University Heart and Vascular Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• A diagnosis of genetically confirmed Familial Chylomicronemia Syndrome (type 1 Hyperlipoproteinemia)
• Fasting TG ≥ 880 mg/dL (10 millimoles per liter (mmol/L) at Screening
• History of pancreatitis. Patients without a documented history of pancreatitis are also eligible but their enrollment will be capped at 35%
• Stable doses of statins, omega-3 fatty acids, fibrates, or other lipid-lowering medications are allowed

Key Exclusion Criteria:

• Acute coronary syndrome within 6 months of Screening
• Major surgery within 3 months of Screening
• Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion, or could interfere with participating in or completing the study

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants received olezarsen-matching placebo, once every 4 weeks by subcutaneous (SC) injection, during Weeks 1 to 49 of the 53-week treatment period.	Drug: Placebo; Olezarsen-matching placebo was administered by SC injection.
Experimental: Olezarsen 50 mg; Participants received olezarsen, 50 milligrams (mg), once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.	Drug: Olezarsen; Olezarsen was administered by SC injection.; Other Names: ISIS 678354; AKCEA-APOCIII-LRx
Experimental: Olezarsen 80 mg; Participants received olezarsen 80 mg, once every 4 weeks by SC injection, during Weeks 1 to 49 of the 53-week treatment period.	Drug: Olezarsen; Olezarsen was administered by SC injection.; Other Names: ISIS 678354; AKCEA-APOCIII-LRx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent Change From Baseline in Fasting TG at Month 6	Baseline, Month 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Fasting TG at Month 12		Baseline, Month 12
Percent Change From Baseline in Fasting Apolipoprotein C-III (apoC-III) at Months 6 and 12		Baseline, Months 6 and 12
Percentage of Participants With ≥ 40% Reduction in Fasting TG at Month 6	Percentages are rounded off to the nearest single decimal place.	Month 6
Percent Change From Baseline in Fasting Apolipoprotein B-48 (apoB-48) at Months 6 and 12		Baseline, Months 6 and 12
Percent Change From Baseline in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Months 6 and 12		Baseline, Months 6 and 12
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During the Treatment Period (Week 1 Through Week 53) in Participants With Prior History of Pancreatitis	All AEs and SAEs that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the Acute Pancreatitis Adjudication Committee (PAC) Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. The adjudicated event rate represents the average number of events per 100 participant-years during the treatment period.	During the treatment period Week 1 through Week 53
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During the Treatment Period (Week 1 Through Week 53)	All AEs and SAEs that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. The adjudicated event rate represents the average number of events per 100 participant-years during the treatment period.	During the treatment period Week 1 through Week 53
Adjudicated Acute Pancreatitis Mean Event Per 100 Participant-Years Rate During Week 13 Through Week 53 in Participants With Prior History of Pancreatitis	All AEs and SAEs that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. The adjudicated event rate represents the average number of events per 100 participant-years during the specified duration.	Week 13 through Week 53
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During Week 13 to Week 53	All AEs and SAEs that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. The adjudicated event rate represents the average number of events per 100 participant-years during the specified duration.	Week 13 through Week 53
Percentage of Participants With ≥ 70% Reduction in Fasting TG at Month 6	Percentages are rounded off to the nearest single decimal place.	Month 6
Percentage of Participants With Fasting TG ≤ 880 mg/dL at Month 6	Percentages are rounded off to the nearest single decimal place.	Month 6
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During Treatment Period in Participants With ≥ 2 Events in 5 Years Prior to Enrollment	All AEs and SAEs that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. The adjudicated event rate represents the average number of events per 100 participant-years during the treatment period.	During the treatment period Week 1 through Week 53
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years From Week 13 to Week 53 in Participants With ≥ 2 Events in 5 Years Prior to Enrollment	All AEs and SAEs that consistently occurred during the study with an event of acute pancreatitis were adjudicated by a blinded, independent committee according to the Atlanta classification of acute pancreatitis as outlined in the PAC Charter. These events were categorized as 1) documented pancreatitis, 2) probable pancreatitis, 3) possible pancreatitis, 4) unable to adjudicate and 5) no diagnosis of acute pancreatitis. The adjudicated event rate represents the average number of events per 100 participant-years during the specified duration.	Week 13 to Week 53
Percentage of Participants With Fasting TG ≤ 500 mg/dL at Month 6	Percentages are rounded off to the nearest single decimal place.	Month 6

Collaborators and Investigators

• Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborators: Akcea Therapeutics

Publications and helpful links

General Publications

• Stroes ESG, Alexander VJ, Karwatowska-Prokopczuk E, Hegele RA, Arca M, Ballantyne CM, Soran H, Prohaska TA, Xia S, Ginsberg HN, Witztum JL, Tsimikas S; Balance Investigators. Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome. N Engl J Med. 2024 May 16;390(19):1781-1792. doi: 10.1056/NEJMoa2400201. Epub 2024 Apr 7.

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2020
• Primary Completion (Actual): July 14, 2023
• Study Completion (Actual): October 17, 2023

Study Registration Dates

• First Submitted: September 23, 2020
• First Submitted That Met QC Criteria: September 23, 2020
• First Posted (Actual): September 29, 2020

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 13, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: FCS
• 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; Syndrome; Hyperlipoproteinemia Type I
• Other Study ID Numbers: ISIS 678354-CS3; 2020-002536-67 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/.

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