A Study of Ubenimex in Patients With Pulmonary Arterial Hypertension (WHO Group 1) (LIBERTY)

A Phase 2, Randomized, Double-BLInd, Placebo- Controlled Study of UBEnimex in Patients With Pulmonary ARTerial HYpertension (WHO Group 1) (LIBERTY)

This proof-of-concept study is designed as a Phase 2, multicenter, randomized, double-blind, placebo controlled study comparing ubenimex with placebo in patients with pulmonary arterial hypertension (PAH) (World Health Organization [WHO] Group 1) and have a WHO/New York Heart Association (NYHA) Functional Classification (WHO/NYHA-FC) of II or III.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Other: placebo; Drug: ubenimex

Detailed Description

Ubenimex is being developed for the treatment of PAH (WHO Group 1) to improve exercise capacity and delay clinical worsening. This proof-of-concept study is designed as a Phase 2, multicenter, randomized, double-blind, placebo controlled study comparing ubenimex with placebo in patients with PAH (WHO Group 1) and have a WHO/NYHA Functional Classification (WHO/NYHA-FC) of II or III. The Primary Objectives for the study are:

• To evaluate the efficacy of ubenimex in patients with PAH (WHO Group 1).
• To evaluate the safety and tolerability of ubenimex in patients with WHO Group 1 PAH.

• Study Type: Interventional
• Enrollment (Actual): 61
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada, K1Y 4W7
      • University of Ottawa Heart Institute
    • Toronto, Ontario, Canada, M5G 2N2
      • Toronto General Hospital
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama at Birmingham
  • California
    • Beverly Hills, California, United States, 90211
      • California Heart Center Foundation, An Affiliate of Cedars-Sinai Heart Institute, Cedars-Sinai Medical Care Foundation
    • La Jolla, California, United States, 92103
      • Ucsd Medical Center
    • Stanford, California, United States, 94305
      • Stanford University Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Denver
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic, Florida
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • Kentuckiana Pulmonary Associates
  • Maine
    • South Portland, Maine, United States, 04106
      • Chest Medicine Associates
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Johns Hopkins University, Pulmonary and Critical Care Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University School of Medicine
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic College of Medicine
  • Missouri
    • Saint Louis, Missouri, United States, 63130
      • Washington University
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • The University of North Carolina at Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Respiratory Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15212
      • Allegheny General Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pennsylvania Medical Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Alpert Medical School of Brown University Rhode Island Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • San Antonio, Texas, United States, 78229
      • University Texas Health Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female, 18-75 years old.
2. Has a diagnosis of WHO Group 1 PAH.

3. Right heart catheterization performed at Screening with results that are:

   1. Mean pulmonary arterial pressure ≥25 mmHg (at rest) and
   2. Pulmonary venous hypertension (measured as pulmonary capillary wedge pressure (PCWP) ≤15 mmHg. If PCWP is not available, then mean left atrial pressure or left ventricular end-diastolic pressure ≤15 mmHg in the absence of left atrial obstruction. and
   3. Pulmonary vascular resistance (PVR) ≥300 dyn•s/cm5 (3.75 Wood units)
4. Has WHO/NYHA-FC of II or III.
5. Be on stable dose of at least one of the following PAH-specific therapies: endothelin receptor antagonist, an agent acting on the nitric oxide pathway (phosphodiesterase type 5 inhibitor or soluble guanylate cyclase stimulator), and/or a prostacyclin or prostacyclin analog.
6. Has a 6-minute walk distance that is ≥150 and ≤500 meters.
7. Have a ventilation-perfusion scan that rules out thromboembolic disease.

Exclusion Criteria:

Exclusions Related to Cardiovascular Disease

1. History of uncontrolled hypertension
2. Persistent hypotension at Screening.
3. Evidence or history of left-sided heart disease and/or clinically significant cardiac disease in which pulmonary hypertension is more likely WHO Group 2.
4. Acute decompensated heart failure within 1 month of Screening.

5. Recent initiation (<8 weeks from Screening) or planned initiation of cardiopulmonary rehabilitation exercise program.

   Exclusions Related to Pulmonary Disease

6. Newly diagnosed with PAH and not on PAH-specific therapy.

7. Pulmonary hypertension due to:

   1. Uncorrected congenital systemic-to-pulmonary shunt.
   2. Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
   3. Persistent pulmonary hypertension of the newborn
   4. WHO clinical classification Groups 2-5
8. Evidence of significant airway and/or parenchymal lung disease.

9. Chronic infection related to tuberculosis or fungal or mycobacterial disease.

   Exclusions Based on Other Medical Conditions

10. Chronic infections including, but not limited to tuberculosis (TB), hepatitis B virus (HBV) or hepatitis C virus (HCV).
11. History of portal hypertension or chronic liver disease, including positive serology for infection with HCV and/or HBV.
12. Evidence of active infection requiring intravenous or oral antibiotics within 4 weeks of Screening.
13. Body mass index ≥35.0 at Screening.
14. History of obstructive sleep apnea.
15. History of malignancy within the last 5 years, except nonmelanoma skin cancer and cervical carcinoma in situ treated with curative intent.
16. Neuropsychiatric disorders/symptoms or psychological conditions.
17. Pregnancy or breast-feeding

18. Prior treatment with B cell or lymphocyte-depleting agents (eg, rituximab, Campath)

    Exclusions Based on Concomitant Medication Use

19. Concurrent regular use of another leukotriene pathway inhibitor, including over-the-counter medications or herbal remedies.

    Exclusions Based on Laboratory Values

20. Significant/chronic renal insufficiency.
21. Transaminases (alanine transaminase, aspartate transaminase) levels >3 × upper limit of normal (ULN) and/or bilirubin level >2 × ULN.
22. Absolute neutrophil count <1500 mm3.
23. Hemoglobin concentration <9 g/dL at Screening.
24. Hepatic dysfunction as defined by Child-Pugh Class B or C

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ubenimex; ubenimex capsules 150 mg three times a day (TID), administered orally for a total of 24 weeks.	Drug: ubenimex; Other Names: UBX
Placebo Comparator: placebo; placebo capsules TID, administered orally for a total of 24 weeks	Other: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Pulmonary Vascular Resistance (PVR)	Change from Baseline at End of Treatment in PVR Using Worst Case Imputation in the Modified Intent to Treat Population. PVR was assessed by hemodynamic measurements obtained via right heart catheterization.	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in 6-minute Walk Distance (6MWD)	Change in exercise capacity from baseline to Week 24 as determined by the 6MWD	Baseline to Week 24

Collaborators and Investigators

• Sponsor: Eiger BioPharmaceuticals

Publications and helpful links

General Publications

• Tian W, Jiang X, Tamosiuniene R, Sung YK, Qian J, Dhillon G, Gera L, Farkas L, Rabinovitch M, Zamanian RT, Inayathullah M, Fridlib M, Rajadas J, Peters-Golden M, Voelkel NF, Nicolls MR. Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension. Sci Transl Med. 2013 Aug 28;5(200):200ra117. doi: 10.1126/scitranslmed.3006674.
• Qian J, Tian W, Jiang X, Tamosiuniene R, Sung YK, Shuffle EM, Tu AB, Valenzuela A, Jiang S, Zamanian RT, Fiorentino DF, Voelkel NF, Peters-Golden M, Stenmark KR, Chung L, Rabinovitch M, Nicolls MR. Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension. Hypertension. 2015 Dec;66(6):1227-1239. doi: 10.1161/HYPERTENSIONAHA.115.06370. Epub 2015 Oct 5.

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): January 1, 2018

Study Registration Dates

• First Submitted: January 21, 2016
• First Submitted That Met QC Criteria: January 26, 2016
• First Posted (Estimate): January 27, 2016

Study Record Updates

• Last Update Posted (Estimate): March 6, 2023
• Last Update Submitted That Met QC Criteria: March 3, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antineoplastic Agents; Immunologic Factors; Protease Inhibitors; Anti-Bacterial Agents; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Ubenimex
• Other Study ID Numbers: EIG-UBX-001