Heterozygous Familial, Hypercholesterolemia
Conditions
Brief summary
Primary objective: Determine whether mipomersen (ISIS 301012) significantly reduces atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (severe HeFH), defined as low-density lipoprotein cholesterol (LDL-C) levels ≥200 mg/dL plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents (referred to as Cohort 1) compared to placebo. Two different mipomersen dosing regimens will be studied: subcutaneous (SC) mipomersen 200 mg once weekly versus placebo, and SC mipomersen 70 mg thrice weekly versus placebo. Secondary Objectives: * Determine whether there are qualitative differences between the safety profiles of the 2 dosing regimens and placebo in Cohort 1, patients with HeFH with LDL-C levels ≥160 mg/dL and \<200 mg/dL plus the presence of CHD/risk equivalents (referred to as Cohort 2), and the overall study population * Determine whether there are qualitative differences between the tolerability of the 2 dosing regimens and placebo in Cohort 1, Cohort 2, and the overall study population * Further characterize the pharmacokinetics (PK) of the 2 dosing regimens in Cohort 1, Cohort 2, and the overall study population * Determine whether the 2 mipomersen dosing regimens significantly reduce atherogenic lipid levels in Cohort 2 compared to placebo * Obtain additional data regarding ongoing safety and efficacy of mipomersen in patients with FH and inadequately controlled LDL-C who complete the primary efficacy assessment visit (PET) in the Blinded Treatment Period and continue treatment in Open-Label Continuation Period
Detailed description
The study consisted of a Screening period of up to 4 weeks, Blinded Treatment Phase of 60 weeks, Open-Label Continuation Period of 26 weeks, and Post-Treatment Phase of 24 weeks. Study Design, masking - Study treatment was blinded (double-blinded) through the Primary Efficacy Assessment Visit in the Blinded Treatment Period. Study treatment was open-label in the Open-Label Continuation Period.
Interventions
DRUGmipomersen sodium 200 mg
Subcutaneous mipomersen 200 mg once weekly
DRUGPlacebo
Placebo vehicle for subcutaneous injection.
DRUGmipomersen sodium 70 mg
Subcutaneous mipomersen 70 mg thrice weekly
Sponsors
Kastle Therapeutics, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of severe hypercholesterolemia (LDL-C ≥300 mg/dL (7.77 mmol/L) or LDL-C ≥200 mg/dL (5.18 mmol/L) with documented coronary heart disease (CHD) or CHD risk equivalents, or diagnosis of Heterozygous Familial Hypercholesterolemia and LDL-C ≥160 mg/dL (4.14 mmol/L) and \<200 mg/dL (5.18 mmol/L)) * On stable, maximally tolerated, statin therapy for at least 12 weeks or if statin intolerant, on at least 1 medication from another class of hypolipidemic agents (i.e., bile acid sequestrants, niacin/nicotinic acid, cholesterol absorption inhibitors, fibrates). * On stable, low fat diet for 12 weeks * Body mass index (BMI) ≤40 kg/m2 and stable weight for \> 6 weeks
Exclusion criteria
* Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes * Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 | Baseline and Week 61 | The percent change from baseline to PET in LDL-C was measured in Cohort 1, which included participants with severe heterozygous familial hypercholesterolemia (HeFH). Severe HeFH was defined as LDL-C levels ≥200 mg/deciliter (dL) plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline To PET In LDL-C In Cohort 2 | Baseline, PET (up to 60 weeks) | The percent change from baseline to PET in LDL-C was measured in Cohort 2, which included participants with HeFH with LDL-C levels ≥160 mg/dL and \<200 mg/dL, plus the presence of CHD/risk equivalents. |
| Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 | Baseline and Week 61 | The percent change from baseline to PET in Apo B was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period. |
| Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 | Baseline and Week 61 | The percent change from baseline to PET in Apo B was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period. |
| Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 | Baseline and Week 61 | The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period. |
| Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 | Baseline and Week 61 | The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period. |
Countries
Argentina, Australia, Belgium, Brazil, Canada, Croatia, Czechia, Denmark, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Netherlands, New Zealand, Norway, Poland, Russia, South Africa, South Korea, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly Participants received once weekly SC injections of mipomersen sodium 200 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week Post-Treatment Period. | 104 |
| Regimen A: Placebo, Once Weekly Participants received once weekly SC injections of Placebo during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week Post-Treatment Period. | 51 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly Participants received thrice weekly SC injections of mipomersen sodium 70 mg during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week Post-Treatment Period. | 102 |
| Regimen B: Placebo, Thrice Weekly Participants received thrice weekly SC injections of placebo during the 60-week Blinded Treatment Period, continued the dosing regimen during the 26-week Open-Label Continuation Period, and then entered the 24-week Post-Treatment Period. | 52 |
| Total | 309 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 41 | 15 | 27 | 11 |
| Overall Study | Death | 1 | 0 | 1 | 0 |
| Overall Study | Did not enter OLC | 15 | 11 | 15 | 11 |
| Overall Study | Lack of Efficacy | 0 | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 3 | 1 |
| Overall Study | Non-compliance with Study Drug | 1 | 2 | 4 | 0 |
| Overall Study | Other: Not available | 0 | 0 | 2 | 0 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 8 | 3 | 11 | 7 |
Baseline characteristics
| Characteristic | Total | Regimen A: Mipomersen, 200 mg, Once Weekly | Regimen A: Placebo, Once Weekly | Regimen B: Mipomersen, 70 mg, Thrice Weekly | Regimen B: Placebo, Thrice Weekly |
|---|---|---|---|---|---|
| Age, Continuous | 54.85 years STANDARD_DEVIATION 10.53 | 56.36 years STANDARD_DEVIATION 9.766 | 55.49 years STANDARD_DEVIATION 10.481 | 53.15 years STANDARD_DEVIATION 11.918 | 54.38 years STANDARD_DEVIATION 9.939 |
| Apolipoprotein B Baseline Values Cohort 1 | NA mg/dL | 172 mg/dL STANDARD_DEVIATION 52.1 | 170 mg/dL STANDARD_DEVIATION 35 | 182 mg/dL STANDARD_DEVIATION 37.9 | 174 mg/dL STANDARD_DEVIATION 45.2 |
| Apolipoprotein B Baseline Values Cohort 2 | NA mg/dL | 131 mg/dL STANDARD_DEVIATION 17.3 | 134 mg/dL STANDARD_DEVIATION 17 | 135 mg/dL STANDARD_DEVIATION 16.3 | 128 mg/dL STANDARD_DEVIATION 23.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 18 Participants | 4 Participants | 4 Participants | 4 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 285 Participants | 99 Participants | 45 Participants | 95 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 6 Participants | 1 Participants | 2 Participants | 3 Participants | 0 Participants |
| LDL-C Baseline Values Cohort 1 | NA mg/dL | 262 mg/dL STANDARD_DEVIATION 103.1 | 255 mg/dL STANDARD_DEVIATION 75 | 274 mg/dL STANDARD_DEVIATION 75.1 | 263 mg/dL STANDARD_DEVIATION 82.9 |
| LDL-C Baseline Values Cohort 2 | NA mg/dL | 177 mg/dL STANDARD_DEVIATION 20.8 | 179 mg/dL STANDARD_DEVIATION 25.6 | 178 mg/dL STANDARD_DEVIATION 17.6 | 169 mg/dL STANDARD_DEVIATION 26.6 |
| Lipoprotein (a) Baseline Values Cohort 1 | NA mg/dL | 43 mg/dL STANDARD_DEVIATION 39.5 | 50 mg/dL STANDARD_DEVIATION 45.6 | 38 mg/dL STANDARD_DEVIATION 40.3 | 51 mg/dL STANDARD_DEVIATION 50.8 |
| Lipoprotein (a) Baseline Values Cohort 2 | NA mg/dL | 52 mg/dL STANDARD_DEVIATION 58.4 | 48 mg/dL STANDARD_DEVIATION 65.6 | 59 mg/dL STANDARD_DEVIATION 49.3 | 27 mg/dL STANDARD_DEVIATION 28.2 |
| Sex: Female, Male Female | 168 Participants | 58 Participants | 29 Participants | 54 Participants | 27 Participants |
| Sex: Female, Male Male | 141 Participants | 46 Participants | 22 Participants | 48 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 104 | 0 / 51 | 1 / 102 | 0 / 52 |
| other Total, other adverse events | 82 / 104 | 27 / 51 | 78 / 102 | 33 / 52 |
| serious Total, serious adverse events | 17 / 104 | 13 / 51 | 23 / 102 | 11 / 52 |
Outcome results
Primary
Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1
The percent change from baseline to PET in LDL-C was measured in Cohort 1, which included participants with severe heterozygous familial hypercholesterolemia (HeFH). Severe HeFH was defined as LDL-C levels ≥200 mg/deciliter (dL) plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents.
Time frame: Baseline and Week 61
Population: The full analysis set for Cohort 1 included all randomized participants who took at least 1 dose of study drug in Cohort 1 (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly | Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 | -27.17 Percent | Standard Error 5.653 |
| Regimen A: Placebo, Once Weekly | Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 | -6.77 Percent | Standard Error 6.749 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly | Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 | -22.96 Percent | Standard Error 5.362 |
| Regimen B: Placebo, Thrice Weekly | Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 | -10.62 Percent | Standard Error 5.765 |
Secondary
Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1
The percent change from baseline to PET in Apo B was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period.
Time frame: Baseline and Week 61
Population: The full analysis set included all randomized participants who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 | -24.14 Percent | Standard Error 5.058 |
| Regimen A: Placebo, Once Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 | -2.83 Percent | Standard Error 6.115 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 | -21.43 Percent | Standard Error 4.861 |
| Regimen B: Placebo, Thrice Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 | -7.28 Percent | Standard Error 5.309 |
Secondary
Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2
The percent change from baseline to PET in Apo B was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period.
Time frame: Baseline and Week 61
Population: The full analysis set included all randomized participants who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 | -30.76 Percent | Standard Error 7.309 |
| Regimen A: Placebo, Once Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 | -6.67 Percent | Standard Error 8.758 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 | -36.34 Percent | Standard Error 7.039 |
| Regimen B: Placebo, Thrice Weekly | Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 | -3.77 Percent | Standard Error 8.109 |
Secondary
Percent Change From Baseline To PET In LDL-C In Cohort 2
The percent change from baseline to PET in LDL-C was measured in Cohort 2, which included participants with HeFH with LDL-C levels ≥160 mg/dL and \<200 mg/dL, plus the presence of CHD/risk equivalents.
Time frame: Baseline, PET (up to 60 weeks)
Population: The full analysis set included all randomized participants who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly | Percent Change From Baseline To PET In LDL-C In Cohort 2 | -31.20 Percent | Standard Error 8.927 |
| Regimen A: Placebo, Once Weekly | Percent Change From Baseline To PET In LDL-C In Cohort 2 | -9.25 Percent | Standard Error 10.621 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly | Percent Change From Baseline To PET In LDL-C In Cohort 2 | -43.60 Percent | Standard Error 8.342 |
| Regimen B: Placebo, Thrice Weekly | Percent Change From Baseline To PET In LDL-C In Cohort 2 | -13.57 Percent | Standard Error 9.066 |
Secondary
Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1
The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period.
Time frame: Baseline and Week 61
Population: The full analysis set included all randomized participants who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 | -18.84 Percent | Standard Error 7.87 |
| Regimen A: Placebo, Once Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 | -16.85 Percent | Standard Error 9.959 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 | -27.18 Percent | Standard Error 5.497 |
| Regimen B: Placebo, Thrice Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 | -10.08 Percent | Standard Error 5.992 |
Secondary
Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2
The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period.
Time frame: Baseline and Week 61
Population: The full analysis set included all randomized participants who took at least 1 dose of study drug (mipomersen or placebo), had a valid baseline LDL-C measurement, and had at least 1 post-baseline LDL-C measurement.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Regimen A: Mipomersen, 200 mg, Once Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 | -23.41 Percent | Standard Error 10.002 |
| Regimen A: Placebo, Once Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 | -11.86 Percent | Standard Error 11.871 |
| Regimen B: Mipomersen, 70 mg, Thrice Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 | -35.56 Percent | Standard Error 11.846 |
| Regimen B: Placebo, Thrice Weekly | Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 | 18.79 Percent | Standard Error 15.271 |