A Study to Assess the Safety and Efficacy of Treprostinil to Facilitate Liver Transplantation in Patients With Portopulmonary Hypertension

Portopulmonary hypertension (PoPH) is characterized by the presence of pulmonary arterial
hypertension (PAH) in the setting of portal hypertension, and is considered the third most
common cause of PAH[[1], [2]]. Approximately 2 to 6% of patients with portal hypertension
demonstrate significant pulmonary hypertension based on hemodynamic observation[[3], [4],
[5]]. In those patients undergoing liver transplant evaluation, the prevalence of PAH is
approximately 5-6%[[4], [6], [7]]. PoPH is associated with a median survival ranging from 8
months to 2.3 years.

Among patients undergoing liver transplantation, the presence of PoPH contributes
significantly to morbidity and mortality[[8], [9], [10]]. In particular, patients with PoPH
who undergo OLT with mean pulmonary artery pressure (PAPm) > 35 mmHg and/or pulmonary
vascular resistance (PVR) > 250 dyn/s/cm5 have > 90% risk of death posttransplant[[8]]. As
such, in many transplant centers, the presence of severe PoPH ((PAPm) > 35 mmHg and/or
pulmonary vascular resistance (PVR) > 250 dyn/s/cm5) is considered an absolute
contraindication to OLT[[6], [11], [12]]. These patients thus have limited treatment
options.

To date, pulmonary vasodilator medication use in the setting of PoPH has largely been
limited to single case reports or small case series. These include intravenous (IV)/inhaled
prostacyclin, sildenafil and bosentan [[15], [16], [17], [18], [19], [20], [21]]. More
recently, encouraging results have been published in open label studies with the use of IV
epoprostenol which was shown to improve pulmonary hemodynamics and possibly survival [[19],
[21], [22]]. Specifically, in patients with severe PoPH who were referred for OLT,
initiation of IV epoprostenol allowed for mPA < 35 mmHg in certain cases, allowing a
successful bridge to OLT [[21], [22]].

Treprostinil is approved as a continuous subcutaneous (SC) or intravenous (IV) infusion by
the FDA for the treatment of WHO group I PAH with New York Heart Association (NYHA) Class
II, III or IV symptomatology[[13], [14]]. To date, treprostinil has not been studied in the
setting of PoPH; however, it is commonly prescribed in this setting. This is an
observational, open-label, multi-center study will attempt to document the safety and
efficacy profile of this agent in PoPH to facilitate OLT efficacy profile of this agent in
PoPH to facilitate OLT.

Inclusion Criteria:

- Patients must:

1. Confirmed severe PoPH documented on standard of care right-heart catheterization
(RHC) with a plan to initiate treprostinil therapy, as recommended by the
treating physician state within 30 days.

2. Have portal hypertension.

3. Be otherwise suitable candidates for OLT.

4. Treprostinil therapy must be recommended by the treating physician per standard
of care.

5. Be NYHA Class II, III, or IV

6. Have Pulmonary Capillary Wedge Pressure (PCW) < 18 mmHg AND transpulmonary
gradient (TPG) ≥ 15 mmHg Severe PAH is defined as a resting mean pulmonary
artery pressure (mPA) > 25 mmHg AND pulmonary vascular resistance (PVR) ≥ 3
wood-units by right-heart catheterization (RHC) performed as part of standard of
care evaluation within 30 days of enrollment

Exclusion Criteria:

- Patients must not:

1. Be taking any investigational therapy as part of a clinical trial for any
indication within 30 days of enrollment.

2. Be receiving any vasodilator treatment for pulmonary hypertension (i.e.
bosentan, sitaxsentan, ambrisentan, sildenafil, tadalafil, epoprostenol,
beraprost, iloprost, inhaled treprostinil) at the time of enrollment.

3. Exhibit renal failure requiring hemodialysis.