Clinical trial NCT02664558
Conditions: Pulmonary Arterial Hypertension
Sponsor: Eiger BioPharmaceuticals
Start date: 2016-04-01; Completion date: 2018-01-01
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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.

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.

Arms: arm 1: ubenimex capsules 150 mg three times a day (TID), administered orally for a total of 24 weeks. arm 2: placebo capsules TID, administered orally for a total of 24 weeks
Interventions: intervention 1: ubenimex intervention 2: placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
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Title: A Phase 2, Randomized, Double-BLInd, Placebo-
Controlled Study of UBEnimex in 
Patients with Pulmonary ARTerial HYpertension (WHO Group 
1) (LIBERTY) 
 
 
NCT02664558 
 
 
 
Document date: 10/11/2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol:  
Objectives  
The primary objective for the study is to obtain long-term safety and tolerability data for 
ubenimex in patients with pulmonary arterial hypertension (PAH). 
Methodology 
This proof-of-concept study was designed as a Phase 2, multicenter, randomized, 
double-blind, placebo-controlled study comparing ubenimex (150 mg 3 times daily [TID]) 
with placebo in patients with PAH who have a WHO/New York Heart Association 
Functional Classification (WHO/NYHA-FC) of II or III. 
Eligible patients must have been on a stable dosage of at least 1 approved PAH-
specific therapy before Screening and were willing to remain on the same dosage 
throughout the study. The treatment period is 24 weks, with 4 weeks follow-up period. 
Approximately 60 patients were planned to be enrolled in the study. Patients were 
randomized 2:1 to receive either ubenimex 150 mg TID (total daily dose of 450 mg) or 
matching placebo TID. Study drug was administered orally for 24 weeks. Eligible 
patients were stratified by PAH etiology and by number of PAH-specific therapies at 
baseline (1 versus 2 or more). 
The primary endpoint for clinical efficacy was change from baseline to Week 24 in 
pulmonary vascular resistance (PVR), as assessed by hemodynamic measurements 
obtained via right heart catheterization (RHC). Secondary efficacy endpoints included 6-
minute walk distance (6MWD) and Borg dyspnea score assessments; changes in NT-
proBNP, WHO/NYHA-FC status, and disease severity (clinical worsening); and QoL 
assessments using CAMPHOR. 
Steady-state PK characteristics of ubenimex were determined using plasma ubenimex 
concentrations measured from serial blood samples at Week 4. Safety was evaluated 
by monitoring adverse events (AEs), clinical laboratory test results, physical 
examinations, electrocardiograms (ECGs), and vital sign measurements. In addition, an 
independent data safety monitoring board (DSMB) consisting of 2 expert PAH clinicians 
and a biostatistician conducted regular safety reviews. 
Patients who completed Study EIG-UBX-001 treatment through to Week 24 were 
eligible to enroll in an open-label extension study, EIG-UBX-002. Eligibility for EIG-UBX-
002 was assessed at the Week 24 visit in EIG-UBX-001; if the patient was eligible and 
enrolled in EIG-UBX-002, treatment with open-label ubenimex was initiated. Patients 
who did not enter the open-label extension study attended a follow-up visit. 
Inclusion Criteria 
A patient was included in this study if he or she met all of the following criteria: 
1. Male or female, 18-75 years old. 


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2. Has a diagnosis of WHO Group 1 PAH. 
3. Right heart catheterization performed at Screening with results that are: 
a. Mean pulmonary arterial pressure ≥25 mmHg (at rest) and 
b. 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 
c. 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: 
a. Uncorrected congenital systemic-to-pulmonary shunt. 
b. Pulmonary veno-occlusive disease and/or pulmonary capillary 
hemangiomatosis 
c. Persistent pulmonary hypertension of the newborn 


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d. 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 
Dose and Mode of Administration  
150 mg administered orally three times a day (at 8 ± 2 h intervals), with or without food. 
Duration of Treatment 


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Duration of treatment was 24 weeks. Total study participation lasted up to 32 weeks (4 
weeks for screening, 24 weeks for treatment, and 4 weeks for follow-up). 
Criteria for Evaluation 
All endpoints were changes from baseline to Week 24, and comparisons were made 
with placebo. Primary efficacy endpoint is the change in PVR. Secondary efficacy 
endpoints included 6-minute walk distance (6MWD) and Borg dyspnea score 
assessments; changes in NT-proBNP, WHO/NYHA-FC status, and disease severity 
(clinical worsening); and QoL assessments using CAMPHOR. 
Safety Endpoints included treatment-emergent (TE) AEs: TEAEs, TE serious adverse 
events (SAEs), treatment related TEAEs, treatment-related TE SAEs and deaths, 
TEAEs leading to early discontinuation of study treatment, TEAEs leading to dose 
reduction, changes in vital signs, clinical laboratory findings, ECGs. 
 
Statistical Methods 
Efficacy Analyses 
The analyses of the primary and secondary endpoints were performed using the 
following two stratification factors as covariates: (1) the number of PAH therapies at 
baseline (1 vs 2 or more) and (2) etiology: PAH associated with connective tissue 
disease [CTD] vs PAH not associated with CTD. All tests were conducted at the 0.05 
level of significance.  
Primary endpoint—The change from Baseline to Week 24 in PVR was analyzed using 
the modified intended to treat population after missing Week 24 values were imputed 
using multiple imputation. To correct for departures from normality, the data were log-
transformed before analysis (and hence the endpoint was the ratio change from 
baseline). An analysis of covariance (ANCOVA) was used with treatment, the 
stratification factors, and baseline PVR in the model. The adjusted placebo-adjusted 
treatment effect with its 95% confidence interval and p-value will be presented. 
Secondary endpoints—Change in exercise capacity as determined by the 6MWD—
because of departure from normality, analyzed nonparametrically using rank-based 
ANCOVA. Change in Borg dyspnea score is analyzed using ANCOVA with treatment, 
the stratification factors, baseline Borg dyspnea score, and baseline PVR in the model. 
Change in WHO/NYHA Functional Classification—analyzed using logistic regression 
with treatment, the stratification factors, baseline WHO/NYHA-FC, and baseline PVR in 
the model. Time to clinical worsening—analyzed by Cox regression. Patients not 
experiencing clinical worsening were censored on their last day of treatment. The model 
included treatment, the stratification factors, and baseline PVR. Results for each of the 
3 subscales of the CAMPHOR questionnaire were analyzed using ANCOVA with 
treatment, the stratification factors, the respective scale baseline, and baseline PVR in 


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the model. Change in disease biomarkers BNP/NT-proBNP is analyzed using ANCOVA 
with treatment, the stratification factors, baseline BNP/NT-proBNP, and baseline PVR in 
the model. 
Safety Analyses 
AEs, deaths, concomitant medications, vital signs, electrocardiogram data, and 
laboratory data will be listed for each patient and summarized by treatment group. 
Adverse events were coded using MedDRA version 18.1.