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

• ClinicalTrials.gov Identifier: NCT03070782
• Recruitment Status: Completed
• First Posted: March 6, 2017
• Results First Posted: October 30, 2020
• Last Update Posted: October 30, 2020
• Sponsor: Akcea Therapeutics
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Akcea Therapeutics

Tracking Information

• First Submitted Date: January 31, 2017
• First Posted Date: March 6, 2017
• Results First Submitted Date: September 30, 2020
• Results First Posted Date: October 30, 2020
• Last Update Posted Date: October 30, 2020
• Actual Study Start Date: March 7, 2017
• Actual Primary Completion Date: July 26, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 30, 2020)

• Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) [ Time Frame: Up to 16 weeks post treatment period (up to approximately 1.3 years) ]
  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.
• Number of Participants With TEAEs by Maximum Severity [ Time Frame: Up to 16 weeks post treatment period (up to approximately 1.3 years) ]
  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.
• Number of Participants With TEAEs Leading to Study Discontinuation [ Time Frame: Up to 16 weeks post treatment period (up to approximately 1.3 years) ]
  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.

Original Primary Outcome Measures (submitted: February 28, 2017)

• Percent change in plasma Lp(a) from baseline at the primary analysis time point for ISIS 681257 treatment groups compared to placebo. [ Time Frame: 6 months ]
  Analysis will be the comparison of percent change from baseline to primary analysis time point in fasting Lp(a) between ISIS 681257 treatment groups and pooled placebo group.
• Safety and tolerability of different doses and dosing regimens of ISIS 681257 as measured by proportion of patients with treatment-related adverse events by severity, and number of patients meeting safety stopping rules [ Time Frame: 6 months and 12 months ]
  The safety and tolerability of ISIS 681257 will be assessed by determining the incidence, severity, and dose relationship of adverse effects and changes in the laboratory parameters by dose. Safety results in subjects dosed with ISIS 681257 will be compared with those from subjects dosed with placebo.

Current Secondary Outcome Measures (submitted: September 30, 2020)

• Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.
• Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.
• Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.
• Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.
• Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.
• Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) [ Time Frame: Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E) ]
  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.

Original Secondary Outcome Measures (submitted: February 28, 2017)

• Evaluate the effect of ISIS 681257 on the percent change from baseline in LDL-C. [ Time Frame: 6 months ]
  Percent change from baseline at the primary analysis time point in fasting LDL-C will be compared between each ISIS 681257 treatment groups and pooled placebo group.
• Evaluate the effect of ISIS 681257 on the proportion of patients who achieve plasma Lp(a) ≤ 50 mg/dL. [ Time Frame: 6 months ]
  Proportion of patients who achieve ≤ 50 mg/dL in fasting Lp(a) at the primary analysis time point will be compared between each ISIS 681257 treatment group and pooled placebo group.
• Evaluate the effect of ISIS 681257 on the percent change from baseline in plasma levels of apolipoprotein B (apoB). [ Time Frame: 6 months ]
  Percent change from baseline at the primary analysis time point in fasting apoB will be compared between ISIS 681257 treatment groups and pooled placebo group.
• Evaluate the effect of ISIS 681257 on the percent change from baseline in plasma levels of oxidized phospholipids (OxPL) on apolipoprotein (a) [apo(a)] [OXPL-apo(a)]. [ Time Frame: 6 months ]
  Percent change from baseline at the primary analysis time point in fasting OxPL apo(a) will be compared between ISIS 681257 treatment groups and pooled placebo group.
• Evaluate the effect of ISIS 681257 on the percent change from baseline in plasma levels of oxidized phospholipids (OxPL) on apoB (OXPL-apoB). [ Time Frame: 6 months ]
  Percent change from baseline at the primary analysis time point in fasting OxPL-apoB will be compared between ISIS 681257 treatment groups and pooled placebo group.

Current Other Pre-specified Outcome Measures (submitted: September 30, 2020)

• To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens. [ Time Frame: 6 months ]
  Cmax will be calculated for the treatment groups.
• To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens. [ Time Frame: 6 months ]
  Tmax will be calculated for the treatment groups.
• To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens. [ Time Frame: 6 months ]
  AUC values will be calculated for the treatment groups.

Original Other Pre-specified Outcome Measures (submitted: February 28, 2017)

• To evaluate plasma Cmax of ISIS 681257 across different doses and dose regimens. [ Time Frame: 6 months ]
  Cmax will be calculated for the treatment groups.
• To evaluate plasma Tmax of ISIS 681257 across different doses and dose regimens. [ Time Frame: 6 months ]
  Tmax will be calculated for the treatment groups.
• To evaluate plasma AUC values of ISIS 681257 across different doses and dose regimens. [ Time Frame: 6 months ]
  AUC values will be calculated for the treatment groups.

Descriptive Information

• Brief Title: Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in Participants With Hyperlipoproteinemia(a) and Cardiovascular Disease
• Official Title: 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)
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Elevated Lipoprotein(a)
• Cardiovascular Disease

Intervention

• Drug: ISIS 681257
  ISIS 681257 solution for SC injection.
  Other Name: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen
• Drug: Placebo
  Sterile normal saline (0.9% NaCl)

Study Arms

• Experimental: Cohort A: ISIS 681257: 20 mg Q4W
  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.
  Intervention: Drug: ISIS 681257
• Experimental: Cohort B: ISIS 681257: 40 mg Q4W
  Cohort B participants received 40 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
  Intervention: Drug: ISIS 681257
• Experimental: Cohort C: ISIS 681257: 60 mg Q4W
  Cohort C participants received 60 mg of ISIS 681257, SC injection, once Q4W, for up to 49 weeks and a maximum of 13 doses.
  Intervention: Drug: ISIS 681257
• Experimental: Cohort D: ISIS 681257: 20 mg Q2W
  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.
  Intervention: Drug: ISIS 681257
• Experimental: Cohort E: ISIS 681257: 20 mg QW
  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.
  Intervention: Drug: ISIS 681257
• Placebo Comparator: Placebo
  Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).
  Intervention: Drug: Placebo

Publications *

• Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, Kroon J, Schnitzler JG, Dzobo KE, Cupido AJ, Tsimikas S, Stroes ESG, de Winther MPJ, Bahjat M. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur Heart J. 2020 Jun 21;41(24):2262-2271. doi: 10.1093/eurheartj/ehaa171.
• Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, Baum SJ, Steinhagen-Thiessen E, Shapiro MD, Stroes ES, Moriarty PM, Nordestgaard BG, Xia S, Guerriero J, Viney NJ, O'Dea L, Witztum JL; AKCEA-APO(a)-LRx Study Investigators. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease. N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 12, 2018): 286
• Original Estimated Enrollment (submitted: February 28, 2017): 270
• Actual Study Completion Date: November 13, 2018
• Actual Primary Completion Date: July 26, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Denmark, Germany, Netherlands, United States

Administrative Information

• NCT Number: NCT03070782
• Other Study ID Numbers: ISIS 681257-CS6; 2016-003373-18 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Akcea Therapeutics
• Original Responsible Party: Ionis Pharmaceuticals, Inc.
• Current Study Sponsor: Akcea Therapeutics
• Original Study Sponsor: Ionis Pharmaceuticals, Inc.
• Collaborators: Ionis Pharmaceuticals, Inc.
• Investigators: Not Provided
• PRS Account: Akcea Therapeutics
• Verification Date: October 2020