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An Open-Label Extension Trial of UT-15C SR in Subjects with Pulmonary Arterial Hypertension


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Conference: 2014 International PHA Conference and Scientific Sessions

Release Date: 06.22.2014

Presentation Type: Abstracts

Background: Treprostinil diolamine (TRE) is an oral prostacyclin recently approved for thetreatment of pulmonary arterial hypertension (PAH).

Methods: Three double-blind, placebo-controlled studies have been completed. Following completion of these studies, patients were eligible for an open-label extension study to evaluate long-term safety/tolerability of higher doses; exercise capacity was also assessed. A recent amendment allows patients the option of a three times-daily (TID) dosing regimen; in a subset ofpatients that transitioned from BID to TID dosing, we carefully evaluated pharmacokinetics,adverse events, and exercise capacity.

Results: A total of 824 subjects initially enrolled into this ongoing study. The average age was 47 years (range 12-76); most were female (78%) with a diagnosis of IPAH/HPAH (70%). Thirty three percent were not receiving PAH background therapy at entry while 16% were receiving an ERA alone, 22% a PDE5-I alone, and 28% receiving both. During the study approximately 21% of subjects received additional oral PAH therapy (i.e., ERA or PDE 5-I). Over 6 years, 452(55%) subjects discontinued the study with 565, 267, 170, and 113 subjects exposed for 1, 2, 3,and 4 years, respectively, at the time of this data cut. Reasons for discontinuation included progression of disease (15%), adverse event (16%), death (13%), and other (11%). The average exposure to TRE thus far is 98 weeks with a maximum exposure of 5.7 years. Investigators haveincreased doses to (mean ± SD) 3.6 ± 2.7, 4.1 ± 3.1, and 5.0 ± 3.7 mg BID at 6 (n=649), 12(n=433), and 24 months (n=238), respectively. Currently, 63 subjects have successfully transitioned to TID dosing (average 3.5 mg TID); there appears to be a more favorable adverseevents profile following transition. In the 522 subjects that completed the 12-month visit, the 6MWD improved from baseline (prior to any TRE exposure) by an average of 24 meters. Ofthese 522 subjects, 333 were on approved PAH-specific background therapy and 189 were takingoral TRE monotherapy; there was a 20 and 30 meter improvement in 6MWD, respectively. Overall survival was 93, 87, and 82% at years 1, 2, and 3, respectively, which is influenced bymultiple PAH therapies. The most common adverse events included headache (75%), diarrhea (61%), nausea (52%), flushing (42%), jaw pain (34%), and vomiting (34%).

Conclusions: Interim data from this open-label study indicate that oral TRE may providesustained exercise benefits for the selected group of subjects who continued therapy at one year (60% of those initially enrolled). Over time, these subjects appear to tolerate doses higher than those achieved in the shorter placebo-controlled studies. Adverse events were primarily relatedto prostacyclin pharmacology; no new safety issues have arisen with long-term exposure. There is increasing experience with TID dosing which may be more easily tolerated.

Type: Clinical Science