Elevated Lipoprotein(a)
Conditions
Keywords
High Lipoprotein(a)
Brief summary
The purpose is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS-APO(a)Rx given to participants with high lipoprotein(a) for 12 weeks.
Detailed description
Lipoprotein(a) \[Lp(a)\] is a genetic variant of low-density lipoprotein (LDL) in which the apolipoprotein B (apoB) -100 component of LDL is linked by a disulfide bond to apolipoprotein(a) \[apo(a)\], the distinct protein component of Lp(a) that is mainly responsible for its signature structural and functional properties. Lp(a) is now recognized as an important genetic risk factor for coronary artery disease, stroke and aortic stenosis. The purpose of this study is to determine if ISIS-APO(a)Rx can reduce the production of apolipoprotein(a), or apo(a). This study will enroll 50 participants with Lipoprotein(a) ≥50 and \<175 mg/dL and 10 participants with Lipoprotein(a) ≥175 mg/dL.
Interventions
DRUGISIS-APO(a)Rx
ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated.
DRUGPlacebo
Normal saline as Placebo, subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males or females aged 18-65 inclusive * Females must be non-pregnant and non-lactating, and either surgically sterile (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy, bilateral oophorectomy) or post-menopausal (defined as 12 months of spontaneous amenorrhea without an alternative medical cause and follicle-stimulating hormone (FSH) levels in the postmenopausal range for the laboratory involved) * Males must be surgically sterile, abstinent or if engaged in sexual relations with a female of child-bearing potential, the participant must be using an acceptable contraceptive method from the time of signing the informed consent form until at least 16 weeks after the last dose of Study Drug * Body mass index (BMI) ≤40 kg/m2 * Lipoprotein(a) ≥50 and \<175 mg/dL at time of screening (Cohort A) * Lipoprotein(a) ≥175 mg/dL at time of screening (Cohort B)
Exclusion criteria
* Clinically significant abnormalities in medical history (e.g., documented previous myocardial infarction, percutaneous coronary intervention (PCI), or major surgery within 3 months of screening, planned surgery that would occur during the study) or physical examination at screening * Clinically significant abnormalities in screening laboratory values that would render a participant unsuitable for inclusion * Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 * Known history or positive test for human immunodeficiency virus (HIV), hepatitis C, or chronic hepatitis B * Malignancy within 5 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated * History of bleeding diathesis or coagulopathy * Recent history of, or current drug or alcohol abuse * Participant with Lp(a) ≥50 and \<175 mg/dL may not receive concomitant niacin therapy during the period 8 weeks prior to screening through the end of the Post-Treatment Evaluation Period * Use of statins, ezetimibe or fibrates unless on a stable regimen for at least 8 weeks prior to dosing and will remain on a stable regimen for the duration of the study * Use of lipid or Lp(a)-specific apheresis within 4 weeks prior to Screening through the end of the Post-Treatment Evaluation Period * Use of concomitant drugs (including herbal or over-the-counter (OTC) medications other than ibuprofen, Benadryl or topical steroids) unless authorized by the Sponsor Medical Monitor * Blood donation of 50-499 mL within 30 days of screening or of \>499 mL within 8 weeks of screening * Have any other conditions, which, in the opinion of the Investigator would make the participant unsuitable for inclusion, or could interfere with the participant participating in or completing the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 | Day 85/Day 99 | Data are reported for evaluable participants. |
| Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | Up to approximately 32 weeks | An adverse event is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product. |
Countries
Canada, Denmark, Germany, Netherlands, United Kingdom
Participant flow
Recruitment details
A total of 51 participants were enrolled in Cohort A and 13 participants were enrolled in Cohort B.
Pre-assignment details
A total of 86 participants were screened for the study and 64 participants were randomized into Cohort A and Cohort B and received study treatment. Two participants in Cohort B did not complete the study treatment but completed the post-treatment follow-up.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A: Placebo Participants received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. | 26 |
| Cohort A: ISIS-APO(a)Rx < 2000 mg Participants received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated. | 4 |
| Cohort A: ISIS-APO(a)Rx >= 2000 mg Participants received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated. | 21 |
| Cohort B: Placebo Participants received placebo (normal saline) subcutaneously on Days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78. | 3 |
| Cohort B: ISIS-APO(a)Rx < 2000 mg Participants received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated. | 2 |
| Cohort B: ISIS-APO(a)Rx >= 2000 mg Participants received ISIS-APO(a)Rx subcutaneously: 100 mg on Days 1, 8, 15, and 22; 200 mg on Days 29, 36, 43, and 50 unless down-titrated; and 300 mg on Days 57, 64, 71, and 78 unless down-titrated. | 8 |
| Total | 64 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event or Serious Adverse Event | 0 | 1 | 0 | 1 | 2 | 0 |
Baseline characteristics
| Characteristic | Cohort A: Placebo | Cohort A: ISIS-APO(a)Rx < 2000 mg | Cohort A: ISIS-APO(a)Rx >= 2000 mg | Cohort B: Placebo | Cohort B: ISIS-APO(a)Rx < 2000 mg | Cohort B: ISIS-APO(a)Rx >= 2000 mg | Total |
|---|---|---|---|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 10 | 50 years STANDARD_DEVIATION 9 | 56 years STANDARD_DEVIATION 6 | 62 years STANDARD_DEVIATION 8 | 45 years STANDARD_DEVIATION 11 | 61 years STANDARD_DEVIATION 8 | 55 years STANDARD_DEVIATION 8.9 |
| Race/Ethnicity, Customized Black | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 26 Participants | 4 Participants | 21 Participants | 3 Participants | 2 Participants | 8 Participants | 64 Participants |
| Race/Ethnicity, Customized Other Race | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 25 Participants | 4 Participants | 20 Participants | 3 Participants | 2 Participants | 8 Participants | 62 Participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 12 Participants | 3 Participants | 2 Participants | 6 Participants | 31 Participants |
| Sex: Female, Male Male | 20 Participants | 2 Participants | 9 Participants | 0 Participants | 0 Participants | 2 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 4 | 0 / 21 | 0 / 3 | 0 / 2 | 0 / 8 |
| other Total, other adverse events | 23 / 26 | 3 / 4 | 21 / 21 | 2 / 3 | 2 / 2 | 8 / 8 |
| serious Total, serious adverse events | 0 / 26 | 2 / 4 | 0 / 21 | 1 / 3 | 0 / 2 | 0 / 8 |
Outcome results
Primary
Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE)
An adverse event is any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the study or use of investigational drug product, whether or not the AE is considered related to the investigational drug product.
Time frame: Up to approximately 32 weeks
Population: The Safety Set included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort A: Placebo | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 23 Participants |
| Cohort A: ISIS-APO(a)Rx < 2000 mg | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 4 Participants |
| Cohort A: ISIS-APO(a)Rx >= 2000 mg | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 21 Participants |
| Cohort B: Placebo | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 2 Participants |
| Cohort B: ISIS-APO(a)Rx < 2000 mg | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 2 Participants |
| Cohort B: ISIS-APO(a)Rx >= 2000 mg | Number of Participants With at Least One Treatment-emergent Adverse Event (TEAE) | 8 Participants |
Primary
Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99
Data are reported for evaluable participants.
Time frame: Day 85/Day 99
Population: The Per-Protocol Set included the subset of the Full Analysis Set who received at least 9 doses of Study Drug within the 12-week treatment period and who had no significant protocol deviations that would have been expected to affect efficacy assessments. Day 85/Day 99 result is defined as the result at Day 85 or Day 99.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort A: Placebo | Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 | -3.7 percent change | Standard Deviation 13.7 |
| Cohort A: ISIS-APO(a)Rx < 2000 mg | Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 | -44.5 percent change | Standard Deviation 13.1 |
| Cohort A: ISIS-APO(a)Rx >= 2000 mg | Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 | -70.0 percent change | Standard Deviation 19.6 |
| Cohort B: Placebo | Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 | -5.6 percent change | Standard Deviation 3.9 |
| Cohort B: ISIS-APO(a)Rx >= 2000 mg | Percent Change From Baseline in Lipoprotein Lp(a) Plasma Concentration at Day 85/Day 99 | -71.6 percent change | Standard Deviation 13 |
p-value: <0.001ANOVA
p-value: <0.001ANOVA
p-value: 0.044Exact Wilcoxon Rank Sum Test