UT-15C Treprostinil Diolamine Sustained Release Tablets (Oral Treprostinil)

There are currently no approved oral prostacyclin therapies available to patients in the United States or Europe. We are developing a novel salt form of treprostinil for oral administration, treprostinil diolamine tablets. If we are successful in developing oral treprostinil, then patients and physicians may use prostacyclin earlier in the PAH disease continuum, which could increase demand for our PAH therapies.

In December 2011, we submitted to the FDA an NDA for the approval of oral treprostinil for treatment of PAH. Our NDA included the results of three phase III studies:

• Combination Therapy Studies (FREEDOM-C and FREEDOM-C2): Two separate 16-week studies of patients on approved background therapy using a PDE-5 inhibitor, such as Revatio, or an ETRA, such as Tracleer, or a combination of both. The FREEDOM-C and FREEDOM-C2 trials were completed in 2008 and 2011 respectively, and neither achieved statistical significance for its primary endpoint of improvement in six-minute walk distance at week 16 (p=0.072 and p=0.089, respectively).
• Monotherapy Study (FREEDOM M): A 12-week study of PAH patients who were not on any approved background therapy. In June 2011, we announced that the FREEDOM-M trial met its primary endpoint of improvement in six-minute walk distance at week 12. Analysis of the FREEDOM-M results demonstrated that patients receiving oral treprostinil improved their six-minute walk distance by a median of approximately 23 meters (p=0.0125, Hodges Lehmann estimate and non-parametric analysis of covariance in accordance with the trial’s pre-specified statistical analysis plan) as compared to patients receiving placebo. The median change from baseline at week 12 was 25 meters for patients receiving oral treprostinil and −5 meters for patients receiving placebo. 

We believe that patients in the FREEDOM-C and FREEDOM-C2 trials needed longer-term treatment with oral treprostinil to provide a statistically significant clinical trial outcome. As such, we began enrolling patients in a new phase III clinical trial (FREEDOM-EV) in the third quarter of 2012. FREEDOM-EV is a placebo controlled study of newly diagnosed patients who have initiated an approved background therapy (either an ETRA or a PDE-5 inhibitor, but not both), with one co-primary endpoint being the time to clinical worsening, generally defined as (1) death; (2) an unplanned hospitalization due to PAH; (3) initiation of prostacyclin for the treatment of PAH; (4) a decrease in six-minute walk distance of at least 15 percent from baseline (or too ill to walk) as a result of the progression of PAH; or (5) unsatisfactory long-term clinical response. The other co-primary endpoint is change in six minute-walk distance at week 24. We plan to enroll up to 858 patients in order to observe 349 clinical worsening events.

On October 23, 2012, the FDA issued a complete response letter in which it declined to approve our NDA. In January 2013, we filed a resubmission of our NDA in response to the concerns raised in the FDA’s complete response letter. The FDA has acknowledged our resubmission as complete and set a targeted response date of March 31, 2013. Despite the FDA’s complete response letter and uncertainty as to whether our resubmission will be approved, we remain committed to further studying oral treprostinil and seeking FDA approval before the end of 2016. We currently expect to seek approval of oral treprostinil in Europe upon completion of the FREEDOM-EV study. In 2005, the EMA announced that oral treprostinil had been designated an orphan medicinal product for the treatment of PAH.