NCT03070782

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

Completed Phase 2 Results posted Last updated 30 October 2020

What this trial tests

Phase 2 trial testing ISIS 681257 in Elevated Lipoprotein(a) in 286 participants. Completed in 13 November 2018.

Timeline

7 March 2017

Primary endpoint
26 July 2018

13 November 2018

Quick facts

Lead sponsor	Akcea Therapeutics
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	triple
Primary purpose	treatment
Enrollment	286
Start date	7 March 2017
Primary completion	26 July 2018
Estimated completion	13 November 2018
Sites	32 locations across Denmark, Netherlands, Germany, Canada, United States

Drugs / interventions tested

• ISIS 681257 — full drug profile →
• Placebo

Conditions studied

• Elevated Lipoprotein(a) — all drugs for Elevated Lipoprotein(a) →
• Cardiovascular Disease — all drugs for Cardiovascular Disease →

Sponsor

Akcea Therapeutics — full company profile →

Who can join

Adults 18 to 80, any sex, with Elevated Lipoprotein(a) or Cardiovascular Disease. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percent Change From Baseline in Fasting Lipoprotein A [Lp(a)] at the Primary Analysis Time Point Primary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	-35	-45 – -22
Cohort B: ISIS 681257: 40 mg Q4W	-56	-63 – -48
Cohort C: ISIS 681257: 60 mg Q4W	-72	-76 – -67
Cohort D: ISIS 681257: 20 mg Q2W	-58	-65 – -50
Cohort E: ISIS 681257: 20 mg QW	-80	-83 – -76
Placebo	-6	-21 – 12

Number of Participants With Treatment Emergent Adverse Events (TEAEs) Primary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	46
Cohort B: ISIS 681257: 40 mg Q4W	43
Cohort C: ISIS 681257: 60 mg Q4W	43
Cohort D: ISIS 681257: 20 mg Q2W	41
Cohort E: ISIS 681257: 20 mg QW	44
Placebo	41

Number of Participants With TEAEs by Maximum Severity Primary · 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

Mild

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	20
Cohort B: ISIS 681257: 40 mg Q4W	21
Cohort C: ISIS 681257: 60 mg Q4W	16
Cohort D: ISIS 681257: 20 mg Q2W	24
Cohort E: ISIS 681257: 20 mg QW	21
Placebo	22

Moderate

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	20
Cohort B: ISIS 681257: 40 mg Q4W	19
Cohort C: ISIS 681257: 60 mg Q4W	21
Cohort D: ISIS 681257: 20 mg Q2W	15
Cohort E: ISIS 681257: 20 mg QW	20
Placebo	16

Severe

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	6
Cohort B: ISIS 681257: 40 mg Q4W	3
Cohort C: ISIS 681257: 60 mg Q4W	6
Cohort D: ISIS 681257: 20 mg Q2W	2
Cohort E: ISIS 681257: 20 mg QW	3
Placebo	3

Number of Participants With TEAEs Leading to Study Discontinuation Primary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	3
Cohort B: ISIS 681257: 40 mg Q4W	0
Cohort C: ISIS 681257: 60 mg Q4W	3
Cohort D: ISIS 681257: 20 mg Q2W	1
Cohort E: ISIS 681257: 20 mg QW	6
Placebo	2

Percent Change From Baseline in Fasting Low-Density Lipoprotein Cholesterol (LDL-C) Secondary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	-7	-16 – 3
Cohort B: ISIS 681257: 40 mg Q4W	-26	-33 – -18
Cohort C: ISIS 681257: 60 mg Q4W	-16	-24 – -7
Cohort D: ISIS 681257: 20 mg Q2W	-17	-25 – -8
Cohort E: ISIS 681257: 20 mg QW	-23	-31 – -14
Placebo	-1	-11 – 9

Percentage of Participants Who Achieved Plasma Lp(a) ≤ 125 Nanomoles Per Liter (Nmol/L) or ≤ 50 Milligrams Per Deciliter (mg/dL) Secondary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	22.9
Cohort B: ISIS 681257: 40 mg Q4W	62.5
Cohort C: ISIS 681257: 60 mg Q4W	80.9
Cohort D: ISIS 681257: 20 mg Q2W	64.6
Cohort E: ISIS 681257: 20 mg QW	97.9
Placebo	6.4

Percentage of Participants Who Achieved Plasma Lp(a) ≤ 75 Nmol/L or ≤ 30 mg/dL Secondary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	6.3
Cohort B: ISIS 681257: 40 mg Q4W	25.0
Cohort C: ISIS 681257: 60 mg Q4W	53.2
Cohort D: ISIS 681257: 20 mg Q2W	33.3
Cohort E: ISIS 681257: 20 mg QW	70.8
Placebo	0

Percent Change From Baseline in the Plasma Levels of Apolipoprotein B (apoB) Secondary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	-3	-9 – 4
Cohort B: ISIS 681257: 40 mg Q4W	-15	-20 – -10
Cohort C: ISIS 681257: 60 mg Q4W	-8	-14 – -2
Cohort D: ISIS 681257: 20 mg Q2W	-9	-15 – -3
Cohort E: ISIS 681257: 20 mg QW	-16	-21 – -10
Placebo	1	-5 – 8

Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein(a) [OxPL-apo(a)] Secondary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	-28	-41 – -12
Cohort B: ISIS 681257: 40 mg Q4W	-49	-58 – -38
Cohort C: ISIS 681257: 60 mg Q4W	-63	-70 – -55
Cohort D: ISIS 681257: 20 mg Q2W	-45	-55 – -33
Cohort E: ISIS 681257: 20 mg QW	-70	-75 – -62
Placebo	-20	-35 – -2

Percent Change From Baseline in the Plasma Levels of Oxidized Phospholipids (OxPL) on Apolipoprotein B (OxPL-apoB) Secondary · 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.

Group	Value	95% CI
Cohort A: ISIS 681257: 20 mg Q4W	-37	-52 – -17
Cohort B: ISIS 681257: 40 mg Q4W	-57	-67 – -45
Cohort C: ISIS 681257: 60 mg Q4W	-79	-84 – -73
Cohort D: ISIS 681257: 20 mg Q2W	-64	-72 – -53
Cohort E: ISIS 681257: 20 mg QW	-88	-91 – -84
Placebo	14	-12 – 49

Adverse events — posted to ClinicalTrials.gov

Time frame: Up to 16 weeks post-treatment period (up to approximately 1.3 years). Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cohort A: ISIS 681257: 20 mg Q4W

Serious: 7/48 (15%)

Deaths: 0/48

Cohort B: ISIS 681257: 40 mg Q4W

Serious: 7/48 (15%)

Deaths: 0/48

Cohort C: ISIS 681257: 60 mg Q4W

Serious: 7/47 (15%)

Deaths: 1/47

Cohort D: ISIS 681257: 20 mg Q2W

Serious: 3/48 (6%)

Deaths: 0/48

Cohort E: ISIS 681257: 20 mg QW

Serious: 4/48 (8%)

Deaths: 1/48

Placebo

Serious: 3/47 (6%)

Deaths: 0/47

Serious adverse events (29 terms)

Reaction	System	Cohort A: ISIS 681257: 20 …	Cohort B: ISIS 681257: 40 …	Cohort C: ISIS 681257: 60 …	Cohort D: ISIS 681257: 20 …	Cohort E: ISIS 681257: 20 …	Placebo
Acute myocardial infarction	Cardiac disorders	—	—	—	—	—	—
Angina unstable	Cardiac disorders	—	—	—	—	—	—
Angina pectoris	Cardiac disorders	—	—	—	—	—	—
Coronary artery disease	Cardiac disorders	—	—	—	—	—	—
Ventricular tachycardia	Cardiac disorders	—	—	—	—	—	—
Ankle fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Joint dislocation	Injury, poisoning and procedural complications	—	—	—	—	—	—
Lower limb fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Radius fracture	Injury, poisoning and procedural complications	—	—	—	—	—	—
Road traffic accident	Injury, poisoning and procedural complications	—	—	—	—	—	—
Gastrointestinal anastomotic stenosis	Injury, poisoning and procedural complications	—	—	—	—	—	—
Oesophagitis haemorrhagic	Gastrointestinal disorders	—	—	—	—	—	—
Pancreatitis acute	Gastrointestinal disorders	—	—	—	—	—	—
Malaise	General disorders	—	—	—	—	—	—
Non-cardiac chest pain	General disorders	—	—	—	—	—	—
Cyst	General disorders	—	—	—	—	—	—
Pneumonia	Infections and infestations	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Lung neoplasm	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Lung neoplasm malignant	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—	—	—	—	—
Syncope	Nervous system disorders	—	—	—	—	—	—
Ischaemic stroke	Nervous system disorders	—	—	—	—	—	—
Acute psychosis	Psychiatric disorders	—	—	—	—	—	—
Depression	Psychiatric disorders	—	—	—	—	—	—
Gout	Metabolism and nutrition disorders	—	—	—	—	—	—

Other adverse events (46 terms — click to expand)

Reaction	System	Cohort A: ISIS 681257: 20 …	Cohort B: ISIS 681257: 40 …	Cohort C: ISIS 681257: 60 …	Cohort D: ISIS 681257: 20 …	Cohort E: ISIS 681257: 20 …	Placebo
Injection site erythema	General disorders	—	—	—	—	—	—
Viral upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Urinary tract infection	Infections and infestations	—	—	—	—	—	—
Myalgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Fatigue	General disorders	—	—	—	—	—	—
Angina pectoris	Cardiac disorders	—	—	—	—	—	—
Back pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Headache	Nervous system disorders	—	—	—	—	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Upper respiratory tract infection	Infections and infestations	—	—	—	—	—	—
Influenza	Infections and infestations	—	—	—	—	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Blood creatine phosphokinase increased	Investigations	—	—	—	—	—	—
Blood bilirubin increased	Investigations	—	—	—	—	—	—
Diarrhoea	Gastrointestinal disorders	—	—	—	—	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Dyspnoea	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Sinusitis	Infections and infestations	—	—	—	—	—	—
Gastroenteritis	Infections and infestations	—	—	—	—	—	—
Influenza like illness	General disorders	—	—	—	—	—	—
Injection site pruritus	General disorders	—	—	—	—	—	—
Oedema peripheral	General disorders	—	—	—	—	—	—
Injection site bruising	General disorders	—	—	—	—	—	—
Pain in extremity	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Neck pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Epistaxis	Respiratory, thoracic and mediastinal disorders	—	—	—	—	—	—
Dizziness	Nervous system disorders	—	—	—	—	—	—
Hypertension	Vascular disorders	—	—	—	—	—	—
Bronchitis	Infections and infestations	—	—	—	—	—	—
Conjunctivitis	Infections and infestations	—	—	—	—	—	—
Injection site pain	General disorders	—	—	—	—	—	—
Pyrexia	General disorders	—	—	—	—	—	—
Muscle spasms	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Flank pain	Musculoskeletal and connective tissue disorders	—	—	—	—	—	—
Laboratory test abnormal	Investigations	—	—	—	—	—	—
Alanine aminotransferase increased	Investigations	—	—	—	—	—	—
Nausea	Gastrointestinal disorders	—	—	—	—	—	—
Vomiting	Gastrointestinal disorders	—	—	—	—	—	—

Most-reported serious reactions: Acute myocardial infarction, Angina unstable, Angina pectoris, Coronary artery disease, Ventricular tachycardia, Ankle fracture, Joint dislocation, Lower limb fracture.

Data from ClinicalTrials.gov NCT03070782 adverse events section.

Sponsor's own description

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).

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Noncoding RNA therapeutics - challenges and potential solutions.
   Winkle M, El-Daly SM, Fabbri M, Calin GA. · · 2021 · cited 1123× · PMID 34145432 · DOI 10.1038/s41573-021-00219-z
2. Lipoprotein(a) Reduction in Persons with Cardiovascular Disease.
   Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif JC, et al · · 2020 · cited 761× · PMID 31893580 · DOI 10.1056/nejmoa1905239
3. Advances in the delivery of RNA therapeutics: from concept to clinical reality.
   Kaczmarek JC, Kowalski PS, Anderson DG. · · 2017 · cited 467× · PMID 28655327 · DOI 10.1186/s13073-017-0450-0
4. Antisense technology: A review.
   Crooke ST, Liang XH, Baker BF, Crooke RM. · · 2021 · cited 237× · PMID 33600796 · DOI 10.1016/j.jbc.2021.100416
5. The powerful world of antisense oligonucleotides: From bench to bedside.
   Quemener AM, Bachelot L, Forestier A, Donnou-Fournet E, et al · · 2020 · cited 189× · PMID 32233021 · DOI 10.1002/wrna.1594
6. Bioconjugated Oligonucleotides: Recent Developments and Therapeutic Applications.
   Benizri S, Gissot A, Martin A, Vialet B, et al · · 2019 · cited 161× · PMID 30608140 · DOI 10.1021/acs.bioconjchem.8b00761
7. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a).
   Stiekema LCA, Prange KHM, Hoogeveen RM, Verweij SL, et al · · 2020 · cited 92× · PMID 32268367 · DOI 10.1093/eurheartj/ehaa171
8. RNA therapeutics: updates and future potential.
   Zhang C, Zhang B. · · 2023 · cited 81× · PMID 36100838 · DOI 10.1007/s11427-022-2171-2