A Dose-Ranging Study With Vupanorsen (TRANSLATE-TIMI 70)

A Phase 2b Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Dose-Ranging Study to Assess the Efficacy, Safety, and Tolerability of Vupanorsen (PF-07285557) in Statin-Treated Participants With Dyslipidemia

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).

Study Overview

• Status: Completed
• Conditions: Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias
• Intervention / Treatment: Drug: Placebo; Drug: Vupanorsen

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.

• Study Type: Interventional
• Enrollment (Actual): 286
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Quebec, Canada, G2J 0C4
    • ALPHA Recherche Clinique
  • Quebec, Canada, G1J 0H4
    • IRM Quebec - Complexe Synase
  • Quebec, Canada, G1J 0H4
    • IRM Quebec Synase
  • Quebec, Canada, G1N 4V3
    • Diex Recherche Quebec Inc.
  • Quebec, Canada, G1W4R4
    • Centre de Recherche Saint-Louis
  • Alberta
    • Edmonton, Alberta, Canada, T6H 2L4
      • C-Endo
    • Edmonton, Alberta, Canada, T6J 5E5
      • MIC Medical Imaging
    • Sherwood Park, Alberta, Canada, T8H 0N2
      • Synergy Medical Clinic
  • British Columbia
    • Surrey, British Columbia, Canada, V3S 9A5
      • Access MRI
    • Surrey, British Columbia, Canada, V3V 0C6
      • SMH Cardiology Clinical Trials Inc.
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • Nova Scotia Health Authority QE II Health Sciences Centre
    • Halifax, Nova Scotia, Canada, B3H 2Y9
      • Nova Scotia Health Authority QE II Health Sciences Centre
  • Ontario
    • Barrie, Ontario, Canada, L4N 7L3
      • LMC Clinical Research Inc. (Barrie)
    • Brampton, Ontario, Canada, L6T 0G1
      • Aggarwal and Associates Limited
    • Concord, Ontario, Canada, L4K 4M2
      • LMC Clinical Research Inc. (Thornhill)
    • Etobicoke, Ontario, Canada, M9R 4E1
      • LMC Clinical Research Inc. (Etobicoke)
    • Guelph, Ontario, Canada, N1H 1B1
      • Dawson Clinical Research
    • Kitchener, Ontario, Canada, N2M 5N4
      • KMH Cardiology Centres Inc.
    • London, Ontario, Canada, N5W 6A2
      • Milestone Research Inc.
    • London, Ontario, Canada, N6A 5B7
      • Robarts Research Institute, Western University
    • Mississauga, Ontario, Canada, L5R 3K6
      • GNMI Medical Imaging
    • Mississauga, Ontario, Canada, L5R 3K7
      • GNMI Medical Imaging
    • Mississauga, Ontario, Canada, L6R 3K7
      • GNMI MRI and CT Medical Imaging
    • North York, Ontario, Canada, M6B 3H7
      • North York Diagnostic and Cardiac Centre
    • Sarnia, Ontario, Canada, N7T 4X3
      • Bluewater Clinical Research Group Inc.
    • Toronto, Ontario, Canada, M4G 1R8
      • Holland Bloorview Kids Rehabilitation Hospital
    • Toronto, Ontario, Canada, M9V 4B4
      • Dr. Anil K. Gupta Medicine Professional Corporation
    • Woodstock, Ontario, Canada, N4S 5P5
      • Devonshire Clinical Research Inc.
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Ecogene-21
    • Chicoutimi, Quebec, Canada, G7H 4J1
      • Resonance Magnetique du Saguenay-Lac-Saint-Jean
    • Mirabel, Quebec, Canada, J7J 2K8
      • Manna Research (Mirabel)
    • Montreal, Quebec, Canada, H1T 1C8
      • Montreal Heart Institute
    • Montreal, Quebec, Canada, H1M 1B1
      • Recherche GCP Research
    • Montreal, Quebec, Canada, H4A 3J1
      • Research Institute of the McGill University Health Center
    • Montreal, Quebec, Canada, H4A 3J1
      • Research Institute of the McGill University Health Centre
    • Pointe-Claire, Quebec, Canada, H9R 4R9
      • Radimed West Island
    • St-Charles-Borromee, Quebec, Canada, J6E 2B4
      • Diex Recherche Joliette
• Poland
  • Bialystok, Poland, 15-402
    • NZOZ Kendron
  • Bialystok, Poland, 15-879
    • ClinicMed Daniluk, Nowak Spolka Jawna
  • Chrzanow, Poland, 32-500
    • Malopolskie Centrum Sercowo-Naczyniowe PAKS - Chrzanow
  • Gdansk, Poland, 80-546
    • Centrum Badań Klinicznych PI-House sp. z o.o.
  • Gdynia, Poland, 81-366
    • Centrum Medyczne Enel-Med., Oddzial Alfa Plaza - Gdynia
  • Katowice, Poland, 40-555
    • Kardio Brynow
  • Katowice, Poland, 40-752
    • Niepubliczny Zaklad Opieki Zdrowotnej "TERAPIA OPTIMA"
  • Katowice, Poland, 40-760
    • HELIMED Katowice - Rezonans Magnetyczny, Tomografia Komputerowa (MRI)
  • Katowice, Poland, 40-760
    • HELIMED Katowice - Rezonans Magnetyczny, Tomografia Komputerowa
  • Lublin, Poland, 20-857
    • "TWOJA PRZYCHODNIA" Sp. z o.o.
  • Lublin, Poland, 20-883
    • Top Medical Lublin
  • Poznan, Poland, 60-589
    • Centrum Zdrowia Metabolicznego Pawel Bogdanski
  • Puszczykowo, Poland, 62-041
    • Arterieart Sp. z o.o.
  • Tychy, Poland, 43-100
    • SZPITAL SW. ELZBIETY W KATOWICACH Polsko-Amerykanskie Kliniki Serca
  • Wroclaw, Poland, 50-088
    • Futuremeds
  • Wroclaw, Poland, 50-450
    • Skanmex (MRI)
  • Wroclaw, Poland, 51-685
    • Wro Medica
  • Wroclaw, Poland, 53-234
    • TOMMA Pracownia rezonansu magnetycznego we Wroclawiu
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85295
      • Horizon Clinical Research Associates, PLLC
    • Gilbert, Arizona, United States, 85297
      • Scottsdale Medical Imaging Research, LLC
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • CARTI
    • Little Rock, Arkansas, United States, 72209
      • Atria Clinical Research
  • California
    • Lincoln, California, United States, 95648
      • Clinical Trials Research
    • Sacramento, California, United States, 95825
      • Diagnostic Radiological Imaging
    • Santa Ana, California, United States, 92705
      • West Coast Radiology
    • Tustin, California, United States, 92780
      • University Clinical Investigators, Inc.
  • Florida
    • Brandon, Florida, United States, 33511
      • Tower Radiology Parsons
    • Brandon, Florida, United States, 33511
      • Tower Radiology
    • Clearwater, Florida, United States, 33756
      • Innovative Research Of West Florida, Inc.
    • Jacksonville, Florida, United States, 32205
      • Westside Center for Clinical Research
    • Jacksonville, Florida, United States, 32256
      • Borland-Groover Clinic
    • Jacksonville, Florida, United States, 32256
      • Precision Imaging Centers
    • Jacksonville, Florida, United States, 32277
      • Care Partners Clinical Research, Llc
    • New Port Richey, Florida, United States, 34653
      • Advanced Research Institute, Inc.
    • Orlando, Florida, United States, 32819
      • Sand Lakes Imaging
    • Saint Augustine, Florida, United States, 32086
      • St Johns Center For Clinical Research
    • Winter Haven, Florida, United States, 33880
      • Clinical Research of Central Florida
  • Kansas
    • El Dorado, Kansas, United States, 67042
      • Alliance For multispecialty Research, LLC
    • El Dorado, Kansas, United States, 67042
      • Susan B. Allen Memorial Hospital
  • Kentucky
    • Louisville, Kentucky, United States, 40213
      • L-MARC Research Center
    • Louisville, Kentucky, United States, 40222
      • Heartland Imaging
  • Maryland
    • Baltimore, Maryland, United States, 21229
      • Maryland Cardiovascular Specialists
    • Baltimore, Maryland, United States, 21229
      • Seton Imaging Center
  • Massachusetts
    • Burlington, Massachusetts, United States, 01805
      • Lahey Clinic Hospital and Medical Center
    • Haverhill, Massachusetts, United States, 01830
      • Pentucket Medical Associates
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital - HealthPartners
  • Nevada
    • Henderson, Nevada, United States, 89014
      • Viable Research Management LLC
    • Henderson, Nevada, United States, 89074
      • Pueblo Medical Imaging
  • New York
    • Albany, New York, United States, 12211
      • Capital Cardiology Associates
    • Latham, New York, United States, 12110
      • ImageCare Latham
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Randolph Health Internal Medicine
    • Asheboro, North Carolina, United States, 27205
      • Randolph Health MRI Center
    • Cary, North Carolina, United States, 27518
      • PMG Research of Raleigh, LLC d/b/a PMG Research of Cary
    • Cary, North Carolina, United States, 27518
      • Wake Radiology
    • Raleigh, North Carolina, United States, 27609
      • PMG Research of Raleigh, LLC
    • Raleigh, North Carolina, United States, 27609
      • Accellacare - Raleigh
    • Raleigh, North Carolina, United States, 27609
      • Wake Radiology Diagnostic Imaging Inc
    • Winston-Salem, North Carolina, United States, 27103
      • PMG Research of Winston-Salem, LLC
  • Ohio
    • Cincinnati, Ohio, United States, 45224
      • Hightop Medical Research Center
    • Cincinnati, Ohio, United States, 45229
      • Imaging Research Center-Cincinnati Children's
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Perelman Center for Advanced Medicine, Hospital of the University of Pennsylvania
  • South Carolina
    • Orangeburg, South Carolina, United States, 29118
      • Clermont Radiology Orangeburg
    • Orangeburg, South Carolina, United States, 29118
      • South Carolina Clinical Research LLC
  • Tennessee
    • Tullahoma, Tennessee, United States, 37388
      • Tennessee Center for Clinical Trials
    • Tullahoma, Tennessee, United States, 37388
      • Tullahoma HMA, LLC d\b\a Tennova HealthCare Harton
  • Texas
    • Dallas, Texas, United States, 75230
      • Dallas Diabetes Research Center
    • Dallas, Texas, United States, 75231
      • Southwest Diagnostic Imaging Center
    • Houston, Texas, United States, 77030
      • SimonMed Houston
    • Houston, Texas, United States, 77074
      • Southwest Clinical Trials
    • Odessa, Texas, United States, 79761
      • Medical Center Hospital
    • Odessa, Texas, United States, 79761
      • Permian Research Foundation
  • Utah
    • Salt Lake City, Utah, United States, 84121
      • J. Lewis Research, Inc. / Foothill Family Clinic South
  • Virginia
    • Richmond, Virginia, United States, 23294
      • National Clinical Research, Inc.
  • Washington
    • Renton, Washington, United States, 98057
      • Rainier Clinical Research Center
    • Seattle, Washington, United States, 98166
      • Bellevue Medical Imaging
    • Tacoma, Washington, United States, 98405
      • Universal Research Group, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; No drug	Drug: Placebo; 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.
Experimental: Vupanorsen 80 mg every 4 weeks; 80 milligrams (mg) given subcutaneously every 4 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557
Experimental: Vupanorsen 60 mg every 2 weeks; 60 mg given subcutaneously every 2 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557
Experimental: Vupanorsen 120 mg every 4 weeks; 120 mg given subcutaneously every 4 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557
Experimental: Vupanorsen 80 mg every 2 weeks; 80 mg given subcutaneously every 2 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557
Experimental: Vupanorsen 160 mg every 4 weeks; 160 mg given subcutaneously every 4 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557
Experimental: Vupanorsen 120 mg every 2 weeks; 120 mg given subcutaneously every 2 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557
Experimental: Vupanorsen 160 mg every 2 weeks; 160 mg given subcutaneously every 2 weeks.	Drug: Vupanorsen; 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.; Other Names: PF-07285557

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Baseline, Week 16
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.	Baseline, Week 24
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.	Baseline, Week 16
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.	Baseline, Week 24

Collaborators and Investigators

• Sponsor: Pfizer
• Collaborators: TIMI Study Group

Publications and helpful links

General Publications

• Bergmark BA, Marston NA, Bramson CR, Curto M, Ramos V, Jevne A, Kuder JF, Park JG, Murphy SA, Verma S, Wojakowski W, Terra SG, Sabatine MS, Wiviott SD; TRANSLATE-TIMI 70 Investigators. Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70. Circulation. 2022 May 3;145(18):1377-1386. doi: 10.1161/CIRCULATIONAHA.122.059266. Epub 2022 Apr 3.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): September 28, 2020
• Primary Completion (Actual): September 29, 2021
• Study Completion (Actual): December 6, 2021

Study Registration Dates

• First Submitted: August 13, 2020
• First Submitted That Met QC Criteria: August 13, 2020
• First Posted (Actual): August 18, 2020

Study Record Updates

• Last Update Posted (Actual): October 4, 2022
• Last Update Submitted That Met QC Criteria: September 6, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Lipid Metabolism Disorders; Metabolic Diseases; Primary hyperlipidemia; Mixed dyslipidemia
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias
• Other Study ID Numbers: C4491011; 2020-002796-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No