Safety and Efficacy of Treprostinil in Ischemia and Reperfusion Injury in Adult Orthotopic Liver Transplantation

Prostaglandin-class drugs, including prostacyclin and its analogs, could represent an
important advance toward the goal of reducing transplant related morbidity, mortality and
associated costs by minimizing the effect of ischemia and re perfusion injury of the liver
graft. Additionally, the reduction in serum creatinine and reduced need for post operative
dialysis observed in some studies has implications in protecting the kidneys from the
nephrotoxic affects of the immunosuppressant agents, especially during the early
post-operative period. Routine use of prostaglandins (PGE1 and PGI2), however, was limited by
its instability and short half life.

Treprostinil, as a prostanoid (prostacyclin analog), is expected to facilitate restoration of
the blood supply to the revascularized graft and provide the well-characterized protective
effects of this class of compounds in liver transplant patients. Treprostinil has the
advantage of a longer elimination half-life than other prostanoids previously tested in these
patients. Treprostinil is expected to significantly protect the graft from ischemia and re
perfusion injury.

This is a pilot study to evaluate the safety, pharmacokinetics and preliminary efficacy of
Treprostinil in orthotopic liver transplant patients as a first step to evaluate its use in
prevention of ischemia and reperfusion injury of the grafted liver.

Inclusion Criteria:

1. Have signed appropriate informed consent.

2. Be between 18 years and 65 years of age.

3. Have been accepted as a liver transplant candidate at the University of Pittsburgh
Medical center (UPMC).

4. Be receiving a cadaver donor liver transplant.

5. Be treated in accordance with the standard of care protocol(s) currently in effect for
liver transplant recipients at the UPMC, including immunosuppression and other
elements of pre- and post-operative care.

Exclusion Criteria:

Subjects must not:

1. Be receiving a living donor liver transplant.

2. Be receiving a donor liver with a cold ischemia time less than 5 hours or greater than
12 hours.

3. Be receiving any investigational drug (a drug other than Treprostinil administered
under an IND) or participating in any other investigational study, with the exception
of alemtuzumab (Campath).

4. Be receiving any prostanoid to treat portopulmonary hypertension.

5. Have had a failed liver transplant within the previous 180 days.

6. Be undergoing multi-organ transplantation (transplantation of organs other than liver
at the same time as the liver transplantation procedure).

7. Have fulminant hepatic failure

8. Model for end stage liver diseases (MELD) score of > 40

9. Hepatitis C positive donor liver

10. On renal replacement therapy at the time of study

11. Be receiving any non-standard immunosuppression protocol or other non-standard
treatment that could affect interpretation of the study results.

12. Those currently receiving treatment for portopulmonary hypertension.

13. Those with significant cardiovascular disease including treatment with inotropes.

14. Have any known hypersensitivity to prostaglandins, prostacyclin or treprostinil.

15. If female, be pregnant or nursing (as confirmed by urine pregnancy test at Baseline).

16. HIV positive

17. Individuals who are allergic to iodine

18. Individuals who are receiving methylene blue

19. A donor liver with macrosteatosis greater than 40% if biopsy results are available