Orphan Therapeutics, LLC: Lucassin

We have completed our review of your application, and have determined that we cannot approve this application in its present form.

To support a claim for the treatment of patients with hepatorenal syndrome (HRS) type I, you submitted two studies, OT-0401 (a double-blind, placebo-controlled study in HRS type I patients) and TAHRS (a smaller, open-label, cross-over study in HRS type I and II patients).

In OT-0401, terlipressin, compared to placebo, appeared to show a modest reduction in serum creatinine, but the study failed to show durability of effect.

Your most favorable analysis, using an endpoint developed post-hoc with a generally unacceptable redefinition of treatment success, reaches statistical significance, but comes nowhere close to the p-value necessary to support approval based upon a single study.

The smaller, open-label TAHRS also failed on its pre-specified primary endpoint and failed to show a sustained effect on serum creatinine.

In terms of support for the safety of the 14-day terlipressin regimen proposed in labeling, your application includes experience in only 11 subjects in study OT-0401 and 9 subjects in TAHRS with exposure for 14 days.

The extent of exposure is clearly insufficient to support the safety of terlipressin for its intended use.

Moreover, although the numbers of adverse events were small, many important serious adverse events tended to occur more frequently, or earlier (i.e., death), in terlipressin-treated subjects, compared to subjects in the respective control groups.

We have provided draft recommendations to several sections of the labeling, but reserve comment on the remaining sections until the application is otherwise adequate.

Please submit draft labeling that incorporates revisions to the attached labeling.

Please submit draft carton and container labeling revised as follows:

Satisfactory resolution of these deficiencies is required before this application may be approved.