Homozygous Familial Hypercholesterolemia
Conditions
Brief summary
The purpose of this study is to assess the safety, tolerability, and efficacy of ALN-PCSSC in participants with homozygous familial hypercholesterolemia.
Interventions
DRUGALN-PCSSC
ALN-PCSSC is a small interfering ribonucleic acid (siRNA) that inhibits PCSK9 synthesis and is given as SC injections.
DRUGStandard of Care
Included maximally-tolerated statin therapy and/or other low density lipoprotein-cholesterol (LDL-C)-lowering therapies.
Sponsors
The Medicines Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females, ≥12 years of age with a diagnosis of homozygous familial hypercholesterolemia by genetic confirmation or a clinical diagnosis based on a history of an untreated low-density lipoprotein cholesterol (LDL-C) concentration \>500 mg/deciliter (dL) \[13 millimoles/liter (mmol/L)\] together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents. * Stable on a low-fat diet. * Stable on pre-existing, lipid-lowering therapies (such as statins, cholesterolabsorption inhibitors, bile-acid sequestrants, or combinations thereof) for at least 4 weeks with no planned medication or dose change for the duration of study participation. * Fasting central lab LDL-C concentration \>130 mg/dL (3.4 mmol/L) and triglyceride concentration \<400 mg/dL (4.5 mmol/L). * Body weight of 40 kilograms (kg) or greater at screening.
Exclusion criteria
* LDL or plasma apheresis within 8 weeks prior to the screening visit, and no plan to receive it during the study because of the attendant difficulty in maintaining stable concentrations of LDL-C while receiving apheresis. * Use of mipomersen or lomitapide therapy within 5 months of screening. * Previous treatment with monoclonal antibodies directed towards PCSK9 within 8 weeks of screening. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Day 1 to Day 90 in LDL-C | Day 1, Day 90 | Due to the small number of subjects, and the fact that the data are not normally distributed, the data are presented as descriptive statistics with no inferential and limited summary statistics presented. |
| Percentage Change From Day 1 to Day 180 (or Final Visit) in LDL-C | Day 1, Day 180 (or Final Visit) | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Day 1 to Day 60 and to Day 90 in PCSK9 | Day 1, Day 60, Day 90 | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in LDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1 | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1 | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a | Day 1, Day 90, Day 180 (or Final Visit) | The reported percent change value is the per participant calculated Mean. |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C | Day 1, Day 90, Day 180 (or Final Visit) | — |
| Percentage Change From Day 1 to Day 60 and to Day 90 in PCSK9 | Day 1, Day 60, Day 90 | — |
Countries
Netherlands, South Africa, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inclisiran 300 milligrams (mg) administered subcutaneous (SC) on Day 1. Participants with a mean serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels not suppressed by \>70% at Day 60 or Day 90, as compared to baseline, will receive a second dose at Day 90 or Day 104, respectively, based on PCSK9 levels from the previous visit. Participants also received standard of care as background therapy.
Inclisiran: Inclisiran is a small interfering ribonucleic acid (siRNA) that inhibits PCSK9 synthesis and is given as SC injections.
Standard of Care: Included maximally-tolerated statin therapy and/or other low density lipoprotein-cholesterol (LDL-C)-lowering therapies. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Screen Failure | 4 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Inclisiran |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 37.0 years STANDARD_DEVIATION 13.04 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 4 Participants |
| Region of Enrollment Netherlands | 1 participants |
| Region of Enrollment South Africa | 3 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 4 |
| other Total, other adverse events | 3 / 4 |
| serious Total, serious adverse events | 1 / 4 |
Outcome results
Primary
Percentage Change From Day 1 to Day 180 (or Final Visit) in LDL-C
Time frame: Day 1, Day 180 (or Final Visit)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 180 (or Final Visit) in LDL-C | -20.96 percent change |
Primary
Percentage Change From Day 1 to Day 90 in LDL-C
Due to the small number of subjects, and the fact that the data are not normally distributed, the data are presented as descriptive statistics with no inferential and limited summary statistics presented.
Time frame: Day 1, Day 90
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 in LDL-C | -12.26 percent change |
Secondary
Absolute Change From Day 1 to Day 60 and to Day 90 in PCSK9
Time frame: Day 1, Day 60, Day 90
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 60 and to Day 90 in PCSK9 | Day 60 | -654.1 ng/mL | Standard Deviation 564.67 |
| Inclisiran | Absolute Change From Day 1 to Day 60 and to Day 90 in PCSK9 | Day 90 | -602.3 ng/mL | Standard Deviation 559.61 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1 | Day 90 | -11.5 mg/dL | Standard Deviation 17.52 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1 | Day 180 | -19.8 mg/dL | Standard Deviation 19 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B | Day 90 | -95.3 mg/dL | Standard Deviation 78.16 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B | Day 180 | -86.3 mg/dL | Standard Deviation 72.02 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C | Day 180 | -9.5 mg/dL | Standard Deviation 4.73 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C | Day 90 | -6.0 mg/dL | Standard Deviation 9.13 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in LDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in LDL-C | Day 90 | -56.3 mg/dL | Standard Deviation 115.18 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in LDL-C | Day 180 | -105.3 mg/dL | Standard Deviation 116.44 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a | Day 90 | 13.5 nmol/L | Standard Deviation 21.92 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a | Day 180 | -23.8 nmol/L | Standard Deviation 52.73 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C | Day 90 | -71.8 mg/dL | Standard Deviation 97.7 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C | Day 180 | -108.5 mg/dL | Standard Deviation 99.38 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol | Day 90 | -77.8 mg/dL | Standard Deviation 103.41 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol | Day 180 | -118.0 mg/dL | Standard Deviation 103.52 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides | Day 90 | -35.5 mg/dL | Standard Deviation 38.76 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides | Day 180 | -26.3 mg/dL | Standard Deviation 24.64 |
Secondary
Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C | Day 90 | -15.5 mg/dL | Standard Deviation 28.41 |
| Inclisiran | Absolute Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C | Day 180 | -3.3 mg/dL | Standard Deviation 37.32 |
Secondary
Percentage Change From Day 1 to Day 60 and to Day 90 in PCSK9
Time frame: Day 1, Day 60, Day 90
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 60 and to Day 90 in PCSK9 | Day 60 | -64.9 percent change | Standard Deviation 18.33 |
| Inclisiran | Percentage Change From Day 1 to Day 60 and to Day 90 in PCSK9 | Day 90 | -59.0 percent change | Standard Deviation 16.46 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1 | Day 90 | -8.3 percent change | Standard Deviation 12.95 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein A1 | Day 180 | -14.2 percent change | Standard Deviation 14.44 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B | Day 90 | -26.6 percent change | Standard Deviation 14.98 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Apolipoprotein B | Day 180 | -25.0 percent change | Standard Deviation 14.5 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C | Day 90 | -12.1 percent change | Standard Deviation 17.98 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in HDL-C | Day 180 | -19.8 percent change | Standard Deviation 11.78 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a
The reported percent change value is the per participant calculated Mean.
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a | Day 90 | -3.5 percent change | Standard Deviation 15.7 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Lipoprotein-a | Day 180 | -11.8 percent change | Standard Deviation 15.15 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C | Day 90 | -13.9 percent change | Standard Deviation 14.78 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Non-HDL-C | Day 180 | -19.7 percent change | Standard Deviation 13.93 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol | Day 90 | -13.9 percent change | Standard Deviation 14.84 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Total Cholesterol | Day 180 | -19.8 percent change | Standard Deviation 13.68 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides | Day 90 | -21.0 percent change | Standard Deviation 30.99 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in Triglycerides | Day 180 | -20.13 percent change | Standard Deviation 11.67 |
Secondary
Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C
Time frame: Day 1, Day 90, Day 180 (or Final Visit)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C | Day 90 | 8.5 percent change | Standard Deviation 65.28 |
| Inclisiran | Percentage Change From Day 1 to Day 90 and to Day 180 (or Final Visit) in VLDL-C | Day 180 | 55.5 percent change | Standard Deviation 131.92 |