Dyslipidemias, Hyperlipidemias, Hyperlipoproteinemias
Conditions
Keywords
Primary hyperlipidemia, Mixed dyslipidemia, Lipid Metabolism Disorders, Metabolic Diseases
Brief summary
This is a multicenter, Phase 2b, double-blind, placebo-controlled, parallel group study to provide data on efficacy, safety, tolerability, and pharmacokinetics (PK) of PF-07285557 (hereafter, vupanorsen) administered subcutaneously (SC) at various doses and regimens in participants with dyslipidemia, defined in this study as participants with elevated non-HDL-C and TG who are receiving a stable dose of a statin. This study is also known as TaRgeting ANGPTL3 with an aNtiSense oLigonucleotide in AdulTs with dyslipidEmia (TRANSLATE-TIMI 70).
Detailed description
This study is intended to enable selection of a dose(s) for future development of vupanorsen for cardiovascular (CV) risk reduction and hypertriglyceridemia.
Interventions
DRUGVupanorsen
Vupanorsen and placebo will be provided as prefilled syringes packaged and dispensed in cartons with tamper-evident seals. Only single-use syringes will be used.
DRUGPlacebo
Vupanorsen and placebo will be provided as prefilled syringes packaged and dispensed in cartons with tamper-evident seals. Only single-use syringes will be used.
Sponsors
The TIMI Study Group
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female participants aged ≥40 years at Screening. 2. Fasting non-HDL-C at Screening ≥100 mg/dL. 3. Fasting TG at Screening of 150 to 500 mg/dL, inclusive, which may be repeated once if deemed necessary. 4. Participants must be on a stable dose of a statin for at least 1 month before Screening and plan to remain on the same medication and dose for the duration of the study. 5. Body weight ≥50 kg and ≤136 kg at Screening. 6. Capable of giving signed informed consent.
Exclusion criteria
1. Participant has active liver disease (other than NAFLD or NASH, which are permitted), including chronic active hepatitis B or C or primary biliary cirrhosis. 2. Uncontrolled hypertension (systolic blood pressure \>180 mmHg or diastolic blood pressure \>100 mmHg). Note: participants who are on an anti-hypertensive medication to treat hypertension should be on a stable dose at least 1 month prior to Screening. The investigator should ensure participant took anti-hypertensive medication as prescribed prior to evaluation of blood pressure. 3. Participant with a known bleeding diathesis or coagulation disorder. 4. Participants with ANY of the following abnormalities in clinical laboratory tests at Screening, as assessed by the central laboratory and confirmed by a single repeat test, if deemed necessary: HbA1c ≥9.5% eGFR \<30 mL/min/1.73 m2 (as determined by the CKD-Epi equation) ALT or AST \>2 × ULN Total bilirubin ≥1.5 × ULN; participants with a history of Gilbert's syndrome may have a direct bilirubin measured and would be eligible for this study provided the direct bilirubin is ≤ULN Platelet count \<LLN 5. History of clinically significant acute cardiac event within 3 months before Screening (includes ischemic stroke, transient ischemic attack, myocardial infarction, revascularization procedures, hospitalization for heart failure). 6. Presence of New York Heart Association Functional Classification IV heart failure symptoms at Screening. 7. 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. 8. Current history of alcoholism or drug addiction according to Diagnostic and Statistical Manual of Mental Disorders IV criteria within 12 months prior to Screening. Use of any recreational drugs within 12 months prior to Screening. 9. Other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study. Prior/Concomitant Therapy: 10. Prior treatment at any time with vupanorsen. 11. Prior treatment with any oligonucleotide (including small interfering ribonucleic acid) within 6 months of Screening or prior treatment with inclisiran within 12 months of Screening. 12. Use of TG lowering medication (eg, Vascepa \[icosapent ethyl\]), non-prescription dietary supplements (eg, fish oil) or other cholesterol lowering medication (eg, fibric acid derivatives, niacin, PCSK9 inhibitors, bile acid sequestrants, bempedoic acid) 30 days prior to Screening, other than statins and ezetimibe. 13. Use of warfarin or other coumarins, direct thrombin inhibitors, Factor Xa inhibitors, heparins or heparinoids 30 days prior to Screening. Prior/Concurrent Clinical Study Experience: 14. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half-lives preceding the first dose of study intervention used in this study (whichever is longer). Diagnostic Assessments: 15. Participant has a clinically significant ECG abnormality during the Screening Period that requires further diagnostic evaluation or intervention (eg, new, clinically significant arrhythmia or a conduction disturbance). Other Exclusions 16. Unstable weight (\>5% shift in past month) or plan to start a diet for the purpose of significant weight loss. 17. Hypersensitivity to the active substance or to any of the excipients or GalNAc. 18. Any major surgery, including bariatric surgery, within 3 months of Screening. 19. Participants with conditions contraindicated for MRI procedures including pacemakers or aneurysm clips; the presence of MRI incompatible implanted devices; metallic foreign bodies; metal tattoos (including permanent make-up); or severe claustrophobia impacting the ability to perform MRI. Participants who may require mild sedative or anxiolytic in order to complete the MRI may be enrolled. 20. Participants unwilling or unable to comply with study procedures, including follow-up, as specified by this protocol, or unwillingness to cooperate fully with the Investigator. 21. Investigator site staff or Pfizer employees directly involved in the conduct of the study, site staff otherwise supervised by the investigator, and their respective family members.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | Baseline, Week 24 | Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Baseline, Week 16 | Blood samples were collected from participants in a fasted state for the measurement of TG, ApoB, HDL-C and LDL-C. Fasting was required at least 10 hours before blood sample collection. Non-HDL-C was calculated as total cholesterol minus HDL cholesterol. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing. |
| Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | Baseline, Week 24 | Fasting was required for all lipid measures at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing. |
| Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | Baseline, Week 16 | ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the angiopoietin-like family of proteins. Blood samples were collected from participants in a fasted state for the measurement of ANGPTL3. Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing. |
| Percent Change From Baseline in ANGPTL3 at Week 24 | Baseline, Week 24 | ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the angiopoietin-like family of proteins. Blood samples were collected from participants in a fasted state for the measurement of ANGPTL3. Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing. |
Countries
Canada, Poland, United States
Participant flow
Recruitment details
Adult participants aged greater than equal to (\>=) 40 years with dyslipidemia on a stable dose of statin (with or without ezetimibe) were included in the study. The study was conducted across 3 countries.
Pre-assignment details
727 participants signed the inform consent form (ICF). 391 participants were screen failures who did not meet criteria and were not enrolled. 336 participants were enrolled into the study of which 50 participants were not randomized and 286 participants were assigned to a study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive vupanorsen (PF-07285557) matched placebo SC injection. Single or double administration was given at every 2 or 4 weeks (Q2W or Q4W) to match active treatment groups. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 44 |
| Vupanorsen: 80 mg Q4W Participants were randomized to receive vupanorsen 80 mg single SC injection at Q4W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 23 |
| Vupanorsen: 60 mg Q2W Participants were randomized to receive vupanorsen 60 mg single SC injection at Q2W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 24 |
| Vupanorsen: 120 mg Q4W Participants were randomized to receive vupanorsen 60 mg double SC injection (120 mg total) in different locations at Q4W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 23 |
| Vupanorsen: 80 mg Q2W Participants were randomized to receive vupanorsen 80 mg single SC injection at Q2W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 45 |
| Vupanorsen: 160 mg Q4W Participants were randomized to receive vupanorsen 80 mg double SC injection (160 mg total) in different locations at Q4W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 45 |
| Vupanorsen: 120 mg Q2W Participants were randomized to receive vupanorsen 60 mg double SC injection (120 mg in total) in different locations at Q2W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 46 |
| Vupanorsen: 160 mg Q2W Participants were randomized to receive vupanorsen 80 mg double SC injection (160 mg in total) in different locations at Q2W. Administration locations were upper arm, thigh, or abdomen quadrant, as preferred by the participant. Treatment duration was up to 24 weeks. Participants were followed up to 12 weeks after last dose of study intervention. | 36 |
| Total | 286 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Follow-up Period (12 Weeks) | Adverse Event | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Follow-up Period (12 Weeks) | Other | 0 | 1 | 0 | 2 | 0 | 0 | 0 | 0 |
| Follow-up Period (12 Weeks) | Withdrawal by Subject | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Adverse Event | 1 | 2 | 3 | 3 | 9 | 4 | 7 | 14 |
| Treatment Period (24 Weeks) | Lost to Follow-up | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Other | 1 | 0 | 0 | 2 | 2 | 4 | 2 | 0 |
| Treatment Period (24 Weeks) | Protocol Violation | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Treatment Period (24 Weeks) | Withdrawal by Subject | 0 | 2 | 1 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo | Vupanorsen: 80 mg Q4W | Vupanorsen: 60 mg Q2W | Vupanorsen: 120 mg Q4W | Vupanorsen: 80 mg Q2W | Vupanorsen: 160 mg Q4W | Vupanorsen: 120 mg Q2W | Vupanorsen: 160 mg Q2W | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 64.23 Years STANDARD_DEVIATION 8.09 | 65.78 Years STANDARD_DEVIATION 7.27 | 64.21 Years STANDARD_DEVIATION 9.92 | 61.04 Years STANDARD_DEVIATION 9.31 | 63.38 Years STANDARD_DEVIATION 8.41 | 63.09 Years STANDARD_DEVIATION 8.8 | 62.74 Years STANDARD_DEVIATION 8.64 | 64.47 Years STANDARD_DEVIATION 7.74 | 63.57 Years STANDARD_DEVIATION 8.48 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 1 Participants | 6 Participants | 4 Participants | 6 Participants | 2 Participants | 1 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 39 Participants | 21 Participants | 23 Participants | 17 Participants | 41 Participants | 39 Participants | 44 Participants | 35 Participants | 259 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 4 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 4 Participants | 4 Participants | 20 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants | 1 Participants | 4 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 38 Participants | 20 Participants | 21 Participants | 21 Participants | 38 Participants | 44 Participants | 37 Participants | 31 Participants | 250 Participants |
| Sex: Female, Male Female | 17 Participants | 13 Participants | 7 Participants | 9 Participants | 24 Participants | 17 Participants | 20 Participants | 19 Participants | 126 Participants |
| Sex: Female, Male Male | 27 Participants | 10 Participants | 17 Participants | 14 Participants | 21 Participants | 28 Participants | 26 Participants | 17 Participants | 160 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 | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 23 | 0 / 24 | 0 / 23 | 0 / 45 | 0 / 45 | 0 / 46 | 0 / 36 |
| other Total, other adverse events | 31 / 44 | 15 / 23 | 17 / 24 | 12 / 23 | 30 / 45 | 28 / 45 | 29 / 46 | 31 / 36 |
| serious Total, serious adverse events | 4 / 44 | 2 / 23 | 2 / 24 | 0 / 23 | 6 / 45 | 1 / 45 | 3 / 46 | 1 / 36 |
Outcome results
Primary
Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24
Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.
Time frame: Baseline, Week 24
Population: Full analysis set primary (FAS\_primary) included all participants randomized to study intervention and who took at least 1 dose of study intervention, had a baseline measurement and at least one post-baseline measurement with all observations that occurred after discontinuation of treatment or after initiation of severe hypertriglyceridemia excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -1.1 Percent change | Standard Error 2.76 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -23.5 Percent change | Standard Error 4.08 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -23.2 Percent change | Standard Error 4.02 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -25.3 Percent change | Standard Error 4.23 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -28.8 Percent change | Standard Error 3.02 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -27.8 Percent change | Standard Error 2.88 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -25.8 Percent change | Standard Error 2.84 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in Non-High-Density Lipoprotein-Cholesterol (Non-HDL-C) at Week 24 | -27.6 Percent change | Standard Error 3.57 |
p-value: <0.00195% CI: [-32.1, -12.7]Mixed Models Analysis
p-value: <0.00195% CI: [-31.7, -12.4]Mixed Models Analysis
p-value: <0.00195% CI: [-34.1, -14.2]Mixed Models Analysis
p-value: <0.00195% CI: [-35.7, -19.6]Mixed Models Analysis
p-value: <0.00195% CI: [-34.5, -18.8]Mixed Models Analysis
p-value: <0.00195% CI: [-32.5, -16.9]Mixed Models Analysis
p-value: <0.00195% CI: [-35.4, -17.6]Mixed Models Analysis
Secondary
Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16
ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the angiopoietin-like family of proteins. Blood samples were collected from participants in a fasted state for the measurement of ANGPTL3. Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.
Time frame: Baseline, Week 16
Population: FAS included all participants randomized to study intervention and who took at least 1 dose of study intervention and had a baseline measurement and at least one post-baseline measurement. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | 9.14 Percent change | Standard Deviation 36.729 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -51.12 Percent change | Standard Deviation 30.444 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -63.61 Percent change | Standard Deviation 16.934 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -58.19 Percent change | Standard Deviation 22.175 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -65.56 Percent change | Standard Deviation 21.908 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -60.35 Percent change | Standard Deviation 21.04 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -77.55 Percent change | Standard Deviation 15.469 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in Angiopoietin-like Protein 3 (ANGPTL3) at Week 16 | -75.14 Percent change | Standard Deviation 23.549 |
Secondary
Percent Change From Baseline in ANGPTL3 at Week 24
ANGPTL3 is a protein primarily synthesized and secreted by the liver and is a member of the angiopoietin-like family of proteins. Blood samples were collected from participants in a fasted state for the measurement of ANGPTL3. Fasting was required at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.
Time frame: Baseline, Week 24
Population: FAS\_primary included all participants randomized to study intervention and who took at least 1 dose of study intervention, had a baseline measurement and at least one post-baseline measurement with all observations that occurred after discontinuation of treatment or after initiation of severe hypertriglyceridemia excluded. Here, Overall Number of Participants Analyzed signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in ANGPTL3 at Week 24 | 13.3 Percent change | Standard Error 3.36 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in ANGPTL3 at Week 24 | -56.6 Percent change | Standard Error 4.92 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in ANGPTL3 at Week 24 | -66.3 Percent change | Standard Error 5.01 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in ANGPTL3 at Week 24 | -63.8 Percent change | Standard Error 5.22 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in ANGPTL3 at Week 24 | -73.0 Percent change | Standard Error 3.76 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in ANGPTL3 at Week 24 | -67.1 Percent change | Standard Error 3.46 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in ANGPTL3 at Week 24 | -78.9 Percent change | Standard Error 3.58 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in ANGPTL3 at Week 24 | -81.9 Percent change | Standard Error 4.48 |
p-value: <0.00195% CI: [-81.6, -58.1]Mixed Models Analysis
p-value: <0.00195% CI: [-91.5, -67.7]Mixed Models Analysis
p-value: <0.00195% CI: [-89.4, -64.9]Mixed Models Analysis
p-value: <0.00195% CI: [-96.2, -76.3]Mixed Models Analysis
p-value: <0.00195% CI: [-89.9, -70.9]Mixed Models Analysis
p-value: <0.00195% CI: [-101.9, -82.6]Mixed Models Analysis
p-value: <0.00195% CI: [-106.2, -84.2]Mixed Models Analysis
Secondary
Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24
Fasting was required for all lipid measures at least 10 hours before blood sample collection. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.
Time frame: Baseline, Week 24
Population: FAS\_primary included all participants randomized to study intervention and who took at least 1 dose of study intervention, had a baseline measurement and at least one post-baseline measurement with all observations that occurred after discontinuation of treatment or after initiation of severe hypertriglyceridemia excluded. Here, Number Analyzed signifies participants evaluable for specific rows.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -1.8 Percent change | Standard Error 3.71 |
| Placebo | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -1.2 Percent change | Standard Error 3.69 |
| Placebo | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | 0.3 Percent change | Standard Error 2.46 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -11.2 Percent change | Standard Error 5.41 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -14.8 Percent change | Standard Error 3.6 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -45.8 Percent change | Standard Error 5.53 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -9.1 Percent change | Standard Error 5.52 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -45.6 Percent change | Standard Error 5.5 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -10.3 Percent change | Standard Error 3.57 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -43.1 Percent change | Standard Error 5.76 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -11.2 Percent change | Standard Error 3.76 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -12.7 Percent change | Standard Error 5.63 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -12.2 Percent change | Standard Error 2.68 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -52.3 Percent change | Standard Error 4.1 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -17.3 Percent change | Standard Error 4 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -12.2 Percent change | Standard Error 2.55 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -47.7 Percent change | Standard Error 3.9 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -15.7 Percent change | Standard Error 3.92 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -5.6 Percent change | Standard Error 2.57 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -52.5 Percent change | Standard Error 3.85 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -9.1 Percent change | Standard Error 3.77 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | TG | -58.6 Percent change | Standard Error 4.9 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | ApoB | -8.1 Percent change | Standard Error 3.17 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in TG, ApoB, and LDL-C at Week 24 | LDL-C | -10.2 Percent change | Standard Error 4.74 |
Comparison: TGp-value: <0.00195% CI: [-57.1, -30.8]Mixed Models Analysis
Comparison: TGp-value: <0.00195% CI: [-56.9, -30.7]Mixed Models Analysis
Comparison: TGp-value: <0.00195% CI: [-54.8, -27.8]Mixed Models Analysis
Comparison: TGp-value: <0.00195% CI: [-61.4, -39.6]Mixed Models Analysis
Comparison: TGp-value: <0.00195% CI: [-56.5, -35.2]Mixed Models Analysis
Comparison: TGp-value: <0.00195% CI: [-61.2, -40.1]Mixed Models Analysis
Comparison: TGp-value: <0.00195% CI: [-68.9, -44.7]Mixed Models Analysis
Comparison: ApoBp-value: <0.00195% CI: [-23.7, -6.5]Mixed Models Analysis
Comparison: ApoBp-value: 0.01595% CI: [-19.2, -2.1]Mixed Models Analysis
Comparison: ApoBp-value: 0.01195% CI: [-20.3, -2.7]Mixed Models Analysis
Comparison: ApoBp-value: <0.00195% CI: [-19.7, -5.3]Mixed Models Analysis
Comparison: ApoBp-value: <0.00195% CI: [-19.5, -5.6]Mixed Models Analysis
Comparison: ApoBp-value: 0.09595% CI: [-13, 1]Mixed Models Analysis
Comparison: ApoBp-value: 0.03695% CI: [-16.4, -0.6]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.12995% CI: [-22.9, 2.9]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.23895% CI: [-21, 5.2]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.0995% CI: [-24.7, 1.8]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.00495% CI: [-26.7, -5.3]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.00895% CI: [-25.1, -3.9]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.13695% CI: [-18.3, 2.5]Mixed Models Analysis
Comparison: LDL-Cp-value: 0.13895% CI: [-20.8, 2.9]Mixed Models Analysis
Secondary
Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16
Blood samples were collected from participants in a fasted state for the measurement of TG, ApoB, HDL-C and LDL-C. Fasting was required at least 10 hours before blood sample collection. Non-HDL-C was calculated as total cholesterol minus HDL cholesterol. Baseline was calculated using the average of all values obtained at Screening and on Day 1 prior to dosing.
Time frame: Baseline, Week 16
Population: FAS included all participants randomized to study intervention and who took at least 1 dose of study intervention and had a baseline measurement and at least one post-baseline measurement. Here, Number Analyzed signifies participants evaluable for specific rows.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -2.53 Percent change | Standard Deviation 31.247 |
| Placebo | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | 0.66 Percent change | Standard Deviation 20.372 |
| Placebo | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -1.42 Percent change | Standard Deviation 24.092 |
| Placebo | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -3.25 Percent change | Standard Deviation 21.631 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -21.65 Percent change | Standard Deviation 24.347 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -12.12 Percent change | Standard Deviation 15.839 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -42.17 Percent change | Standard Deviation 28.081 |
| Vupanorsen: 80 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -10.40 Percent change | Standard Deviation 31.199 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -44.71 Percent change | Standard Deviation 22.725 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -24.71 Percent change | Standard Deviation 16.678 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -12.30 Percent change | Standard Deviation 12.604 |
| Vupanorsen: 60 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -12.61 Percent change | Standard Deviation 21.904 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -39.57 Percent change | Standard Deviation 32.546 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -10.41 Percent change | Standard Deviation 17.067 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -2.09 Percent change | Standard Deviation 26.921 |
| Vupanorsen: 120 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -20.06 Percent change | Standard Deviation 16.698 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -24.79 Percent change | Standard Deviation 18.266 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -11.38 Percent change | Standard Deviation 22.001 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -10.40 Percent change | Standard Deviation 14.69 |
| Vupanorsen: 80 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -49.21 Percent change | Standard Deviation 21.049 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -21.68 Percent change | Standard Deviation 23.898 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -10.88 Percent change | Standard Deviation 26.64 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -10.42 Percent change | Standard Deviation 19.332 |
| Vupanorsen: 160 mg Q4W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -40.33 Percent change | Standard Deviation 21.311 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -27.23 Percent change | Standard Deviation 12.799 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -50.55 Percent change | Standard Deviation 20.234 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -13.78 Percent change | Standard Deviation 19.861 |
| Vupanorsen: 120 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -11.74 Percent change | Standard Deviation 15.56 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | ApoB | -6.76 Percent change | Standard Deviation 18.89 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | LDL-C | -6.30 Percent change | Standard Deviation 29.825 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | Non-HDL-C | -22.44 Percent change | Standard Deviation 24.145 |
| Vupanorsen: 160 mg Q2W | Percent Change From Baseline in Triglyceride (TG), Apolipoprotein B (ApoB), Low-Density Lipoprotein-Cholesterol (LDL-C), and Non-HDL-C at Week 16 | TG | -55.76 Percent change | Standard Deviation 14.625 |