A Study of Ubenimex in Patients with Pulmonary Arterial Hypertension


About this study

The purpose of this study is to evaluate the safety, tolerability, and effectiveness of ubenimex in patients who have pulmonary arterial hypertension, to improve exercise capacity and delay clinical worsening.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria

  • Male or female
  • 18-75 years old
  • Has a diagnosis of WHO Group 1 Pulmonary Arterial Hypertension
  • Right heart catheterization performed at screening
    • Mean pulmonary arterial pressure ≥ 25 mmHg (at rest)
    • 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
    • Pulmonary vascular resistance (PVR) ≥300 dyn•s/cm5 (3.75 Wood units)
  • Has WHO/NYHA-FC of II or III
  • 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)
    • A prostacyclin or prostacyclin analog
  • Has a 6-minute walk distance that is ≥150 and ≤500 meters
  • Has a ventilation-perfusion scan that rules out thromboembolic disease

Exclusion Criteria

  • Related to Cardiovascular Disease
    • History of uncontrolled hypertension
    • Persistent hypotension at screening
    • Evidence or history of left-sided heart disease 
    • Clinically significant cardiac disease in which pulmonary hypertension is more likely WHO Group 2
    • Acute decompensated heart failure within 1 month of screening
    • Recent initiation (< 8 weeks from screening) or planned initiation of cardiopulmonary rehabilitation exercise program
  • Related to Pulmonary Disease
    • Newly diagnosed with PAH and not on PAH-specific therapy
    • Pulmonary hypertension due to
      • Uncorrected congenital systemic-to-pulmonary shunt
      • Pulmonary veno-occlusive disease and/or pulmonary capillary hemangiomatosis
      • Persistent pulmonary hypertension of the newborn
      • WHO clinical classification Groups 2-5
    • Evidence of significant airway and/or parenchymal lung disease
    • Chronic infection related to tuberculosis or fungal or mycobacterial diseas
  • Related to other Medical Conditions
    • Chronic infections including, but not limited to tuberculosis (TB), hepatitis B virus (HBV) or hepatitis C virus (HCV).
    • History of portal hypertension or chronic liver disease, including positive serology for infection with HCV and/or HBV
    • Evidence of active infection requiring intravenous or oral antibiotics within 4 weeks of screening
    • Body mass index ≥ 35.0 at screening
    • History of obstructive sleep apnea
    • History of malignancy within the last 5 years, except nonmelanoma skin cancer and cervical carcinoma in situ treated with curative intent
    • Neuropsychiatric disorders/symptoms or psychological conditions
    • Pregnancy or breast-feeding
    • Prior treatment with B cell or lymphocyte-depleting agents (eg, rituximab, Campath
  • Related to Concomitant Medication Use
    • Concurrent regular use of another leukotriene pathway inhibitor, including over-the-counter medications or herbal remedies
  • Related to Laboratory Values
    • Significant/chronic renal insufficiency
    • Transaminases (alanine transaminase, aspartate transaminase) levels >3 × upper limit of normal (ULN) and/or bilirubin level >2 × ULN
    • Absolute neutrophil count <1500 mm3
    • Hemoglobin concentration <9 g/dL at screening
    • Hepatic dysfunction as defined by Child-Pugh Class B or C

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status

Rochester, Minn.

Mayo Clinic principal investigator

Robert Frantz, M.D.

Closed for enrollment

More information


  • A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts. Read More on PubMed
  • Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of leukotriene A4 hydrolase (LTA4H), the biosynthetic enzyme for leukotriene B4 (LTB4). Moreover, macrophage-derived LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further, LTB4 induced proliferation and hypertrophy of human pulmonary artery smooth muscle cells. We found that LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial sphingosine kinase 1 (Sphk1)-endothelial nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with connective tissue disease-associated pulmonary arterial hypertension exhibited significantly higher LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting. Read More on PubMed

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