CompletedNCT04568434BALANCEUpdated Mar 6, 2025Results posted

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

A Phase 3 interventional study of Olezarsen and Placebo in Familial Chylomicronemia Syndrome, sponsored by Ionis Pharmaceuticals, Inc.. Completed at 47 sites in 11 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2025-03-06.

Sponsored by Ionis Pharmaceuticals, Inc. · Phase 3, Interventional, and Treatment

Phase: Phase 3
Study type: Interventional
Enrollment: 66
Allocation: Randomized
Ages: 18 Years and older
Sex: All

Study summary

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.

Read the 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).

Conditions studied

Familial Chylomicronemia Syndrome

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Keywords

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility criteria

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 design

Phase: Phase 3
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: Double (Participant, Investigator)
Enrollment: 66 participants (actual)

Study arms

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
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
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

Interventions

DrugOlezarsen
Olezarsen was administered by SC injection.
Also known as: ISIS 678354, AKCEA-APOCIII-LRx
DrugPlacebo
Olezarsen-matching placebo was administered by SC injection.

What researchers measure

Primary outcomes

Percent Change From Baseline in Fasting TG at Month 6
Time frame: Baseline, Month 6

Secondary outcomes

Percent Change From Baseline in Fasting TG at Month 12
Time frame: Baseline, Month 12
Percent Change From Baseline in Fasting Apolipoprotein C-III (apoC-III) at Months 6 and 12
Time frame: 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.
Time frame: Month 6
Percent Change From Baseline in Fasting Apolipoprotein B-48 (apoB-48) at Months 6 and 12
Time frame: Baseline, Months 6 and 12
Percent Change From Baseline in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Months 6 and 12
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Month 6
Percentage of Participants With Fasting TG ≤ 880 mg/dL at Month 6
Percentages are rounded off to the nearest single decimal place.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Month 6

Results

Posted Mar 6, 2025

Participant flow

Participants took part in the study at investigative sites in the United States, Canada, France, Italy, Netherlands, Norway, Portugal, Slovakia, Spain, Sweden and the United Kingdom from 18 November 2020 to 17 October 2023.

Participant flow — Overall Study
Milestone	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Started	23	21	22
Completed	22	19	19
Not completed	1	2	3
Withdrew: Voluntary withdrawal	0	1	1
Withdrew: Adverse events (ae) or serious adverse events (sae)	0	1	2
Withdrew: Investigator judgement	1	0	0

Outcome measures

PrimaryPercent Change From Baseline in Fasting TG at Month 6

Time frame:: Baseline, Month 6
Reported as:: Least squares mean · percent change

Percent Change From Baseline in Fasting TG at Month 6
percent change	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Percent Change From Baseline in Fasting TG at Month 6	11.52 (-5.321 to 28.356)	-10.85 (-27.797 to 6.095)	-31.99 (-49.031 to -14.940)

Statistical analysis

Placebo vs Olezarsen 80 mg · ANCOVA · p = =0.0009 (ANCOVA model included effects of treatment (olezarsen 80 mg, olezarsen 50 mg, or placebo): dependent variable, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.) · Ls mean difference: -43.5 · 95% CI -69.085 to -17.921
Placebo vs Olezarsen 50 mg · ANCOVA · p = =0.0775 (Analysis of covariance (ANCOVA) model included effects of treatment (olezarsen 80 mg, olezarsen 50 mg, or placebo): dependent variable, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.) · Least squares (ls) mean difference: -22.37 · 95% CI -47.200 to 2.463

SecondaryPercent Change From Baseline in Fasting TG at Month 12

Time frame:: Baseline, Month 12
Reported as:: Least squares mean · percent change

Percent Change From Baseline in Fasting TG at Month 12
percent change	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Percent Change From Baseline in Fasting TG at Month 12	20.89 (1.016 to 40.764)	-22.92 (-42.505 to -3.336)	-38.50 (-58.187 to -18.815)

Statistical analysis

Placebo vs Olezarsen 50 mg · ANCOVA · p = =0.0044 (ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.) · Ls mean difference: -43.81 · 95% CI -73.928 to -13.692
Placebo vs Olezarsen 80 mg · ANCOVA · p = =0.0002 (ANCOVA model included percent change from baseline in fasting TG at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline TG: covariate.) · Ls mean difference: -59.39 · 95% CI -90.663 to -28.119

SecondaryPercent Change From Baseline in Fasting Apolipoprotein C-III (apoC-III) at Months 6 and 12

Time frame:: Baseline, Months 6 and 12
Reported as:: Least squares mean · percent change

Percent Change From Baseline in Fasting Apolipoprotein C-III (apoC-III) at Months 6 and 12
percent change	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Month 6	7.57 (-5.229 to 20.359)	-57.91 (-71.193 to -44.631)	-66.13 (-79.437 to -52.823)
Month 12	17.08 (2.149 to 32.009)	-59.98 (-75.163 to -44.795)	-64.20 (-79.408 to -48.984)

Statistical analysis

Placebo vs Olezarsen 50 mg · ANCOVA · p = <0.0001 (ANCOVA model included percent change from baseline in fasting apoC-III at Month 6: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline apoC-III: covariate.) · Ls mean difference: -65.48 · 95% CI -82.634 to -48.320
Placebo vs Olezarsen 80 mg · ANCOVA · p = <0.0001 (ANCOVA model included percent change from baseline in fasting apoC-III at Month 6: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline apoC-III: covariate.) · Ls mean difference: -73.69 · 95% CI -94.553 to -52.837
Placebo vs Olezarsen 50 mg · ANCOVA · p = <0.0001 (ANCOVA model included percent change from baseline in fasting apoC-III at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline apoC-III: covariate.) · Ls mean difference: -77.06 · 95% CI -98.938 to -55.177
Placebo vs Olezarsen 80 mg · ANCOVA · p = <0.0001 (ANCOVA model included percent change from baseline in fasting apoC-III at Month 12: dependent variable, treatment group, protocol specified 2 randomization stratification factors: fixed effects, log-transformed baseline apoC-III: covariate.) · Ls mean difference: -81.28 · 95% CI -104.656 to -57.894

SecondaryPercentage of Participants With ≥ 40% Reduction in Fasting TG at Month 6

Percentages are rounded off to the nearest single decimal place.

Time frame:: Month 6
Reported as:: Number · percentage of participants

Percentage of Participants With ≥ 40% Reduction in Fasting TG at Month 6
percentage of participants	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Percentage of Participants With ≥ 40% Reduction in Fasting TG at Month 6	4.3	33.3	40.9

SecondaryPercent Change From Baseline in Fasting Apolipoprotein B-48 (apoB-48) at Months 6 and 12

Time frame:: Baseline, Months 6 and 12
Reported as:: Least squares mean · percent change

Percent Change From Baseline in Fasting Apolipoprotein B-48 (apoB-48) at Months 6 and 12
percent change	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Month 6	24.50 (-9.972 to 58.973)	-8.78 (-42.976 to 25.406)	-59.46 (-93.164 to -25.765)
Month 12	-3.52 (-53.159 to 46.124)	-36.41 (-77.689 to 4.860)	-79.15 (-118.442 to -39.861)

Statistical analysis

Placebo vs Olezarsen 50 mg · ANCOVA · p = =0.1860 (ANCOVA model included percent change from baseline in fasting apoB-48 to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline apoB-48: covariate.) · Ls mean difference: -33.29 · 95% CI -82.612 to 16.041
Placebo vs Olezarsen 80 mg · ANCOVA · p = =0.0019 (ANCOVA model included percent change from baseline in fasting apoB-48 to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline apoB-48: covariate.) · Ls mean difference: -83.97 · 95% CI -136.949 to -30.982
Placebo vs Olezarsen 50 mg · ANCOVA · p = =0.4219 (ANCOVA model included percent change from baseline in fasting apoB-48 to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline apoB-48: covariate.) · Ls mean difference: -32.9 · 95% CI -113.254 to 47.459
Placebo vs Olezarsen 80 mg · ANCOVA · p = =0.0560 (ANCOVA model included percent change from baseline in fasting apoB-48 to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline apoB-48: covariate.) · Ls mean difference: -75.63 · 95% CI -153.195 to 1.927

SecondaryPercent Change From Baseline in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Months 6 and 12

Time frame:: Baseline, Months 6 and 12
Reported as:: Least squares mean · percent change

Percent Change From Baseline in Fasting Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Months 6 and 12
percent change	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Month 6	5.33 (-5.345 to 16.014)	-12.35 (-23.541 to -1.163)	-18.86 (-29.952 to -7.774)
Month 12	12.01 (-2.480 to 26.494)	-17.84 (-32.128 to -3.545)	-27.69 (-41.722 to -13.664)

Statistical analysis

Placebo vs Olezarsen 50 mg · ANCOVA · p = =0.0401 (ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline non-HDL-C: covariate.) · Ls mean difference: -17.69 · 95% CI -34.571 to -0.801
Placebo vs Olezarsen 80 mg · ANCOVA · p = =0.0036 (ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 6: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline non-HDL-C: covariate) · Ls mean difference: -24.2 · 95% CI -40.484 to -7.911
Placebo vs Olezarsen 50 mg · ANCOVA · p = =0.0134 (ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline non-HDL-C: covariate.) · Ls mean difference: -29.84 · 95% CI -53.490 to -6.198
Placebo vs Olezarsen 80 mg · ANCOVA · p = =0.0009 (ANCOVA model included percent change from baseline in fasting non-HDL-C to Month 12: dependent variable, treatment group, protocol prespecified randomization stratification factors: fixed effects \& log-transformed baseline non-HDL-C: covariate.) · Ls mean difference: -39.7 · 95% CI -63.108 to -16.292

SecondaryAdjudicated 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.

Time frame:: During the treatment period Week 1 through Week 53
Reported as:: Mean · events per 100 participant-years

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
events per 100 participant-years	Placebo	Pooled Olezarsen
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	66.22 (30.490 to 143.817)	6.73 (1.612 to 28.087)

Statistical analysis

Placebo vs Pooled Olezarsen · Negative Binomial Regression Model · p = =0.0052 (Regression model: treatment group \& previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1 to 53:offset variable.) · Mean rate ratio: 0.1 · 95% CI 0.020 to 0.506

SecondaryAdjudicated 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.

Time frame:: During the treatment period Week 1 through Week 53
Reported as:: Mean · events per 100 participant-years

Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During the Treatment Period (Week 1 Through Week 53)
events per 100 participant-years	Placebo	Pooled Olezarsen
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During the Treatment Period (Week 1 Through Week 53)	36.31 (14.700 to 89.685)	4.37 (0.942 to 20.298)

Statistical analysis

Placebo vs Pooled Olezarsen · Negative Binomial Regression Model · p = =0.0144 (Regression model: treatment group \& previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1 to 53:offset variable.) · Mean rate ratio: 0.12 · 95% CI 0.022 to 0.656

SecondaryAdjudicated 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.

Time frame:: Week 13 through Week 53
Reported as:: Mean · events per 100 participant-years

Adjudicated Acute Pancreatitis Mean Event Per 100 Participant-Years Rate During Week 13 Through Week 53 in Participants With Prior History of Pancreatitis
events per 100 participant-years	Placebo	Pooled Olezarsen
Adjudicated Acute Pancreatitis Mean Event Per 100 Participant-Years Rate During Week 13 Through Week 53 in Participants With Prior History of Pancreatitis	57.89 (24.469 to 136.972)	8.17 (1.952 to 34.177)

Statistical analysis

Placebo vs Pooled Olezarsen · Negative Binomial Regression Model · p = =0.0174 (Regression model: treatment group \& previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 13 to 53:offset variable) · Mean rate ratio: 0.14 · 95% CI 0.028 to 0.709

SecondaryAdjudicated 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.

Time frame:: Week 13 through Week 53
Reported as:: Mean · events per 100 participant-years

Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During Week 13 to Week 53
events per 100 participant-years	Placebo	Pooled Olezarsen
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During Week 13 to Week 53	33.43 (13.250 to 84.321)	5.42 (1.229 to 23.897)

Statistical analysis

Placebo vs Pooled Olezarsen · Negative Binomial Regression Model · p = =0.0314 (Regression model: treatment group \& previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 13 to 53:offset variable) · Mean rate ratio: 0.16 · 95% CI 0.031 to 0.850

SecondaryPercentage of Participants With ≥ 70% Reduction in Fasting TG at Month 6

Percentages are rounded off to the nearest single decimal place.

Time frame:: Month 6
Reported as:: Number · percentage of participants

Percentage of Participants With ≥ 70% Reduction in Fasting TG at Month 6
percentage of participants	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Percentage of Participants With ≥ 70% Reduction in Fasting TG at Month 6	0	4.8	9.1

SecondaryPercentage of Participants With Fasting TG ≤ 880 mg/dL at Month 6

Percentages are rounded off to the nearest single decimal place.

Time frame:: Month 6
Reported as:: Number · percentage of participants

Percentage of Participants With Fasting TG ≤ 880 mg/dL at Month 6
percentage of participants	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Percentage of Participants With Fasting TG ≤ 880 mg/dL at Month 6	0	10.0	14.3

SecondaryAdjudicated 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.

Time frame:: During the treatment period Week 1 through Week 53
Reported as:: Mean · events per 100 participant-years

Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During Treatment Period in Participants With ≥ 2 Events in 5 Years Prior to Enrollment
events per 100 participant-years	Placebo	Pooled Olezarsen
Adjudicated Acute Pancreatitis Mean Event Rate Per 100 Participant-Years During Treatment Period in Participants With ≥ 2 Events in 5 Years Prior to Enrollment	118.59 (61.226 to 229.698)	16.59 (4.051 to 67.948)

Statistical analysis

Placebo vs Pooled Olezarsen · Negative Binomial Regression Model · p = =0.0137 (Regression model: treatment group \& previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 1 to 53:offset variable) · Mean rate ratio: 0.14 · 95% CI 0.029 to 0.669

SecondaryAdjudicated 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.

Time frame:: Week 13 to Week 53
Reported as:: Mean · events per 100 participant-years

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
events per 100 participant-years	Placebo	Pooled Olezarsen
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	106.91 (50.204 to 227.682)	21.36 (5.233 to 87.219)

Statistical analysis

Placebo vs Pooled Olezarsen · Negative Binomial Regression Model · p = =0.0480 (Regression model:treatment group \& previous treatment (volanesorsen):factors adjudicated acute pancreatitis events in 5 years prior enrollment:covariate. Logarithm of time in year that each participant was observed from Week 13 to 53:offset variable) · Mean rate ratio: 0.2 · 95% CI 0.040 to 0.986

SecondaryPercentage of Participants With Fasting TG ≤ 500 mg/dL at Month 6

Percentages are rounded off to the nearest single decimal place.

Time frame:: Month 6
Reported as:: Number · percentage of participants

Percentage of Participants With Fasting TG ≤ 500 mg/dL at Month 6
percentage of participants	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Percentage of Participants With Fasting TG ≤ 500 mg/dL at Month 6	0	0	13.6

Adverse events

Collected over From the first dose of study drug up to end of the follow-up (up to Week 66). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Placebo	0/23 (0%)	9/23 (39.1%)	19/23 (82.6%)
Olezarsen 50 mg	1/21 (4.8%)	4/21 (19%)	17/21 (81%)
Olezarsen 80 mg	0/22 (0%)	3/22 (13.6%)	18/22 (81.8%)

Most frequent serious events

Showing 10 of 17

Most frequent serious events
Event	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
PancreatitisGastrointestinal disorders	4/23	1/21	1/22
Pancreatitis acuteGastrointestinal disorders	3/23	0/21	0/22
Pancreatitis necrotisingGastrointestinal disorders	2/23	0/21	0/22
Sudden deathGeneral disorders	0/23	1/21	0/22
Gastroenteritis bacterialInfections and infestations	0/23	1/21	0/22
Intentional overdoseInjury, poisoning and procedural complications	0/23	1/21	0/22
Intestinal perforationGastrointestinal disorders	0/23	0/21	1/22
Hepatic cirrhosisHepatobiliary disorders	0/23	0/21	1/22
Gastric varicesGastrointestinal disorders	1/23	0/21	0/22
Gastric varices haemorrhageGastrointestinal disorders	1/23	0/21	0/22

Most frequent other events

Showing 10 of 30

Most frequent other events
Event	Placebo	Olezarsen 50 mg	Olezarsen 80 mg
Abdominal painGastrointestinal disorders	8/23	3/21	4/22
COVID-19Infections and infestations	8/23	6/21	3/22
DiarrhoeaGastrointestinal disorders	6/23	1/21	2/22
HeadacheNervous system disorders	3/23	4/21	1/22
FatigueGeneral disorders	4/23	1/21	1/22
InfluenzaInfections and infestations	2/23	3/21	1/22
Urinary tract infectionInfections and infestations	0/23	3/21	1/22
ArthralgiaMusculoskeletal and connective tissue disorders	0/23	3/21	1/22
AnxietyPsychiatric disorders	0/23	3/21	0/22
Platelet count decreasedInvestigations	1/23	1/21	3/22

Baseline characteristics

Full Analysis Set (FAS) included all participants that were randomly assigned to treatment and received at least 1 dose of olezarsen or placebo.

Age, Continuous
Age, Continuous(years)	Placebo	Olezarsen 50 mg	Olezarsen 80 mg	Total
Mean	44.0 ± 14.67	43.2 ± 12.11	47.7 ± 13.30	45 ± 13.38

Sex: Female, Male
Sex: Female, Male(Participants)	Placebo	Olezarsen 50 mg	Olezarsen 80 mg	Total
Female	12	15	11	38
Male	11	6	11	28

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Placebo	Olezarsen 50 mg	Olezarsen 80 mg	Total
Hispanic or Latino	3	3	1	7
Not Hispanic or Latino	20	18	21	59
Unknown or Not Reported	0	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Placebo	Olezarsen 50 mg	Olezarsen 80 mg	Total
American Indian or Alaska Native	0	0	0	0
Asian	0	3	3	6
Native Hawaiian or Other Pacific Islander	0	1	0	1
Black or African American	0	0	0	0
White	22	17	17	56
More than one race	1	0	2	3
Unknown or Not Reported	0	0	0	0

Fasting Triglycerides (TG)
Fasting Triglycerides (TG)(milligrams per deciliter (mg/dL))	Placebo	Olezarsen 50 mg	Olezarsen 80 mg	Total
Mean	2595.7 ± 1255.72	2683.8 ± 1235.06	2613.1 ± 1498.96	2629.5 ± 1315.45

Study locations

47 sites

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

References and documents

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. PubMed 38587247 ↗

Study documents

Protocol and statistical analysis plan · Aug 2, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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/.

Registry details

Key details

Study ID: NCT04568434
Lead sponsor: Ionis Pharmaceuticals, Inc.
Responsible party: Sponsor
First posted: Sep 29, 2020
Start date: Nov 18, 2020
Primary completion: Jul 14, 2023
Completion: Oct 17, 2023
Results posted: Mar 6, 2025
Last update: Mar 6, 2025

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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