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

NCT03070782 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: ISIS 681257-CS62016-003373-18
• Study Type: interventional
• Target: 286
• Locations: 5 countries
• Sites: 32

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).

Conditions

Elevated Lipoprotein(a); Cardiovascular Disease

Keywords

IONIS-APO(a)-LRx; AKCEA-APO(a)-LRx; Dyslipidemia; Dyslipoproteinemia; Hyperlipidemia; Hyperlipoproteinemia; Hyperlipoproteinemia(a); Hyperlipoproteinemia a; Lipoprotein; Lipoprotein(a); Lipoprotein a; Lp(a); Lp a

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (6)

• Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C)

  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)

  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

  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)

  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)]

  Baseline and Month 6 (Week 25 for Cohorts A, B and C and Week 27 for Cohorts D and E)

Other Outcomes (3)

• To Evaluate Plasma Cmax of ISIS 681257 Across Different Doses and Dose Regimens.

  6 months

• To Evaluate Plasma Tmax of ISIS 681257 Across Different Doses and Dose Regimens.

  6 months

• To Evaluate Plasma AUC Values of ISIS 681257 Across Different Doses and Dose Regimens.

  6 months

Study Arms (6)

Cohort A: ISIS 681257: 20 mg Q4W

EXPERIMENTAL

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

Cohort B: ISIS 681257: 40 mg Q4W

EXPERIMENTAL

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

Cohort C: ISIS 681257: 60 mg Q4W

EXPERIMENTAL

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

Cohort D: ISIS 681257: 20 mg Q2W

EXPERIMENTAL

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

Cohort E: ISIS 681257: 20 mg QW

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

Participants in each cohort were randomized to receive placebo at a dose-matched volume of study drug (ISIS 681257).

Drug: Placebo

Interventions

ISIS 681257 DRUG

ISIS 681257 solution for SC injection.

Also known as: AKCEA-APO(a)-LRx, IONIS-APO(a)-LRx, TQJ230 and Pelacarsen

Cohort A: ISIS 681257: 20 mg Q4W; Cohort B: ISIS 681257: 40 mg Q4W; Cohort C: ISIS 681257: 60 mg Q4W; Cohort D: ISIS 681257: 20 mg Q2W; Cohort E: ISIS 681257: 20 mg QW

Placebo DRUG

Sterile normal saline (0.9% NaCl)

Placebo

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Akcea Therapeutics: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (32)

Clinical Site

Cottonwood, Arizona, 86326, United States

Location

Clinical Site

Huntington Beach, California, 92648, United States

Location

Clinical Site

La Jolla, California, 92103, United States

Location

Clinical Site

Los Angeles, California, 90048, United States

Location

Clinical Site

Stanford, California, 94305, United States

Location

Clinical Site

Colorado Springs, Colorado, 80909, United States

Location

Clinical Site

Boca Raton, Florida, 33434, United States

Location

Clinical Site

Jacksonville, Florida, 32216, United States

Location

Clinical Site

Kansas City, Kansas, 66160, United States

Location

Clinical Site

Baltimore, Maryland, 21201, United States

Location

Clinical Site

Boston, Massachusetts, 02114, United States

Location

Clinical Site

Cooperstown, New York, 13326, United States

Location

Clinical Site

New York, New York, 10016, United States

Location

Clinical Site

New York, New York, 10029, United States

Location

Clinical Site

Cleveland, Ohio, 44195, United States

Location

Clinical Site

Portland, Oregon, 97239, United States

Location

Clinical Site

Lancaster, Pennsylvania, 17602, United States

Location

Clinical Site

Philadelphia, Pennsylvania, 19104, United States

Location

Clinical Site

Providence, Rhode Island, 02906, United States

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Clinical Site

Houston, Texas, 77030, United States

Location

Clinical Site

Falls Church, Virginia, 22042, United States

Location

Clinical Site

Milwaukee, Wisconsin, 53215, United States

Location

Clinical Site

Chicoutimi, Quebec, G7H7K9, Canada

Location

Clinical Site

Montreal, Quebec, H1T 1C8, Canada

Location

Clinical Site

Montreal, Quebec, H3H 2L9, Canada

Location

Clinical Site

Québec, Quebec, G1V4W2, Canada

Location

Clinical Site

Ottawa, K1Y4W7, Canada

Location

Clinical Site

Herlev, 2730, Denmark

Location

Clinical Site

Viborg, 8800, Denmark

Location

Clinical Site

Berlin, 13353, Germany

Location

Clinical Site

Cologne, 50937, Germany

Location

Clinical Site

Amsterdam, 1105AZ, Netherlands

Location

Related Publications (3)

• Tekendo-Ngongang C, Gleeson JG, Mignon L. Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases. J Am Soc Nephrol. 2024 Dec 1;35(12):1774-1777. doi: 10.1681/ASN.0000000532. Epub 2024 Sep 27. No abstract available.

  PMID: 39331470 DERIVED

• 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.

  PMID: 32268367 DERIVED

• 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.

  PMID: 31893580 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias

Interventions

AKCEA-APO(a)-LRx; pelacarsen

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Study Director
• Organization: Akcea Therapeutics

clinicalstudies@akceatx.com

617-207-0289

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 31, 2017
• First Posted: March 6, 2017
• Study Start: March 7, 2017
• Primary Completion: July 26, 2018
• Study Completion: November 13, 2018
• Last Updated: October 30, 2020
• Results First Posted: October 30, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (22); NL (1); DE (2); DK (2); CA (5)