Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease

Study Overview
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Brief Summary
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This is a multicenter, randomized, double-blind, placebo-controlled, dose-ranging study to evaluate the safety, including tolerability, of ISIS 681257 and to assess the efficacy of different doses and dosing regimens of ISIS 681257 for reduction of plasma Lipoprotein(a) [Lp(a)] levels in participants with hyperlipoproteinemia(a) and established cardiovascular disease (CVD).

Official Title
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A Randomized, Double-blind, Placebo-Controlled, Dose-Ranging Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) Administered Subcutaneously to Patients With Hyperlipoproteinemia(a) and Established Cardiovascular Disease (CVD)

Conditions
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Elevated Lipoprotein(a), Cardiovascular Disease

Intervention / Treatment
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* Drug: ISIS 681257
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Clinical diagnosis of CVD defined as documented coronary artery disease, stroke, or peripheral artery disease Lp(a) plasma level ≥ 60 mg/dL Must be on standard-of-care preventative therapy for other than elevated Lp(a) CVD risk factors Key Exclusion Criteria: Within 6 months of Screening: acute coronary syndrome, major cardiac surgery, or stroke/TIA Within 3 months of Screening: coronary, carotid, or peripheral arterial revascularization, major non-cardiac surgery, or lipoprotein apheresis Heart failure New York Heart Association (NYHA) class IV

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A: ISIS 681257: 20 mg Q4W<br>Cohort A participants received 20 milligrams (mg) ISIS 681257, subcutaneous (SC) injection, once every 4 weeks (Q4W), for up to 49 weeks and a maximum of 13 doses. | Drug: ISIS 681257<br>* ISIS 681257 solution for SC injection.<br>* Other names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen;|
| Experimental: Cohort B: ISIS 681257: 40 mg Q4W<br>Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses. | Drug: ISIS 681257<br>* ISIS 681257 solution for SC injection.<br>* Other names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen;|
| Experimental: Cohort C: ISIS 681257: 60 mg Q4W<br>Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses. | Drug: ISIS 681257<br>* ISIS 681257 solution for SC injection.<br>* Other names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen;|
| Experimental: Cohort D: ISIS 681257: 20 mg Q2W<br>Cohort D participants received 20 mg of ISIS 681257, SC injection, once every 2 weeks (Q2W), for up to 51 weeks and a maximum of 26 doses. | Drug: ISIS 681257<br>* ISIS 681257 solution for SC injection.<br>* Other names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen;|
| Experimental: Cohort E: ISIS 681257: 20 mg QW<br>Cohort E participants received 20 mg of ISIS 681257, SC injection, once weekly (QW), for up to 52 weeks and a maximum of 52 doses. | Drug: ISIS 681257<br>* ISIS 681257 solution for SC injection.<br>* Other names: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen;|
| Placebo Comparator: Placebo<br>Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257). | Drug: Placebo<br>* Sterile normal saline (0.9% NaCl)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point | An ANCOVA model was performed on the log ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of Lp(a) value at the Primary Analysis Time Point to Lp(a) value at Baseline - 1) × 100. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. | Up to 16 weeks post treatment period (up to approximately 1.3 years) | 
| Number of Participants With TEAEs by Maximum Severity | An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAEs was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. The severity of TEAEs was assessed based on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. TEAEs were graded on a 5-point scale where 1 = Mild, 2 = Moderate, 3 = Severe, 4 = Potentially life-threatening and 5 = Death. | Up to 16 weeks post treatment period (up to approximately 1.3 years) | 
| Number of Participants With TEAEs Leading to Study Discontinuation | An AE was defined as any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE was considered related to the investigational drug product. TEAE was defined as any AE with onset after the first administration of study medication through the end of the study, or any event that was present at baseline but worsened in intensity or was subsequently considered drug-related by the Investigator through the end of the study. | Up to 16 weeks post treatment period (up to approximately 1.3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) | An ANCOVA model was performed on the log ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of LDL-C value at the Primary Analysis Time Point to LDL-C value at Baseline - 1) × 100. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 
| Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) | The percentage of participants who achieved ≤ 125 nmol/L or ≤ 50 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 
| Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL | The percentage of participants who achieved ≤ 75 nmol/L or ≤ 30 mg/dL in fasting Lp(a) at the primary analysis time point were compared between each ISIS 681257 treatment group and pooled placebo group using a logistic regression model with log-transformed baseline Lp(a) as a covariate. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 
| Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) | An ANCOVA model was performed on the log ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of apoB value at the Primary Analysis Time Point to apoB value at Baseline - 1) × 100. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 
| Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] | An ANCOVA model was performed on the log ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apo(a) value at the Primary Analysis Time Point to OxPL-apo(a) value at Baseline - 1) × 100. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 
| Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) | An ANCOVA model was performed on the log ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline. The estimate of the log ratio was converted back to the original scale and percent change was calculated using formula: = (ratio of OxPL-apoB value at the Primary Analysis Time Point to OxPL-apoB value at Baseline - 1) × 100. | Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lipoprotein, Lipoprotein(a), Lipoprotein a, Dyslipoproteinemia, IONIS-APO(a)-LRx, AKCEA-APO(a)-LRx, Dyslipidemia, Hyperlipidemia, Hyperlipoproteinemia, Hyperlipoproteinemia(a), Hyperlipoproteinemia a, Lp(a), Lp a