A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70)
Condition: Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias
MeSH terms: Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias
Intervention: Vupanorsen; Placebo
Intervention description: 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.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 286.0
Sex: All
Minimum age: 40 Years
Healthy volunteers: No
Keywords: Primary hyperlipidemia; Mixed dyslipidemia; Lipid Metabolism Disorders; Metabolic Diseases

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).
    

Eligibility criteria:

        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.