United Therapeutics Corporation (NASDAQ: UTHR) announced the completion of its FREEDOM-M Phase 3 trial of treprostinil diethanolamine (oral treprostinil), an investigational sustained release oral formulation of treprostinil, a stable synthetic form of prostacyclin, in patients with pulmonary arterial hypertension (PAH). Preliminary analysis demonstrates that the trial has met its primary endpoint.

FREEDOM-M was a randomized, double-blind, placebo-controlled trial of patients with PAH, a chronic, life-threatening illness. The study enrolled 349 patients who were not receiving any approved PAH medication, with the population for the primary analysis consisting of the 228 patients who had access to the 0.25 mg tablet at randomization. These patients were administered oral treprostinil or placebo twice daily, with the doses titrated to effect over the course of the 12-week trial. The majority of patients were in World Health Organization (WHO) Functional Class II (~33%) and Class III (~66%) of varied etiologies, including idiopathic or familial PAH (~75%), collagen vascular disease associated PAH (~19%), and PAH associated with HIV or other associated conditions (~6%). The patients' mean baseline six-minute walk distance (6MWD) was approximately 330 meters.

The primary efficacy endpoint of the trial was the change in 6MWD at 12 weeks for the 228 patients. Preliminary analysis of the FREEDOM-M results demonstrates that those patients receiving oral treprostinil improved their median 6MWD by 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 was 25 meters for oral treprostinil and -5 meters for placebo at week 12.

The combined 6MWD and Borg Dyspnea Score rating (shortness of breath test) was significantly improved (p=0.0497). Preliminary analysis of other secondary efficacy measures, including change in Borg Dyspnea Score rating, trough walk at Week 11, change in Dyspnea Fatigue Index, change in WHO functional class, time to clinical worsening (as defined by death, transplant, atrial septostomy, hospitalization due to PAH or at least a 20% decrease in six-minute walk and initiation of another approved PAH therapy), and PAH signs and symptoms did not differ significantly between oral treprostinil and placebo (p>0.05).

An analysis of all 349 FREEDOM-M patients demonstrates that those patients receiving oral treprostinil improved their median 6MWD by approximately 25.5 meters (p=0.0001, Hodges-Lehmann estimate and non-parametric analysis of covariance) as compared to patients receiving placebo.

Adverse events seen in the trial included headache, nausea, diarrhea, and flushing, which are common in patients receiving prostanoid therapy. Detailed analysis of adverse events is ongoing. All patients in the trial had the option to continue receiving oral treprostinil in an open-label continuation study after completion of the 12-week period. Of the 287 patients who were eligible to enroll, approximately 279 patients entered the open-label continuation study. Of these, approximately 183 patients are currently being treated with oral treprostinil, with the longest duration of treatment exceeding three years.

"This is my dream come true," said Martine Rothblatt, Ph.D., Chairman and Chief Executive Officer of United Therapeutics. "PAH patients have approved therapies available to them by only three routes of administration parenteral, inhaled and oral and no therapy other than treprostinil is available by two of these. The FREEDOM-M trial presents a potentially transformative opportunity to extend treprostinil across all available approved routes of administration."

"These results build upon the treprostinil franchise we have established with Remodulin and Tyvaso. We are excited that the primary efficacy analysis of this trial confirms the benefits of oral treprostinil on 6MWD, as the delivery of treprostinil via a twice daily oral tablet, if it secures regulatory approval, would provide a critically important additional treatment option for patients with this severe disease," said Roger Jeffs, Ph.D., President and Chief Operating Officer of United Therapeutics. "We will now focus our energies on finishing our FREEDOM-C(2) trial and completing the necessary regulatory filings next year so that patients can have access to oral treprostinil as a prescribed route of delivery."

The 313-patient FREEDOM-C(2) trial is studying oral treprostinil in PAH patients who are receiving an endothelin receptor antagonist and/or a PDE-5 inhibitor. Preliminary analysis of the results of the trial are expected to be announced in September 2011.

About Tyvaso (treprostinil) Inhalation Solution

Indication

Tyvaso is a prostacyclin vasodilator indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability. Studies establishing effectiveness included predominately patients with NYHA Functional Class III symptoms and etiologies of idiopathic or heritable PAH (56%) or PAH associated with connective tissue diseases (33%).

The effects diminish over the minimum recommended dosing interval of 4 hours; treatment timing can be adjusted for planned activities.

While there are long-term data on use of treprostinil by other routes of administration, nearly all controlled clinical experience with inhaled treprostinil has been on a background of bosentan (an endothelin receptor antagonist) or sildenafil (a phosphodiesterase type 5 inhibitor). The controlled clinical experience was limited to 12 weeks in duration.

Important Safety Information

-- TYVASO is intended for oral inhalation only. TYVASO is approved for use only with the TYVASO Inhalation System.

-- The safety and efficacy of TYVASO have not been established in patients with significant underlying lung disease (such as asthma or chronic obstructive pulmonary disease) and in patients under 18 years of age. Patients with acute pulmonary infections should be carefully monitored to detect any worsening of lung disease and loss of drug effect.

-- TYVASO may increase the risk of bleeding, particularly in patients receiving anticoagulants.

-- In patients with low systemic arterial pressure, TYVASO may cause symptomatic hypotension. The concomitant use of TYVASO with diuretics, antihypertensives, or other vasodilators may increase the risk of symptomatic hypotension.

-- Hepatic or renal insufficiency may increase exposure to TYVASO and decrease tolerability. TYVASO dosage adjustments may be necessary if inhibitors of CYP2C8 such as gemfibrozil or inducers such as rifampin are added or withdrawn.

-- The most common adverse events seen with TYVASO in greater than or equal to 4% of PAH patients and more than 3% greater than placebo in the placebo-controlled clinical study were cough (54% vs 29%), headache (41% vs 23%), throat irritation/pharyngolaryngeal pain (25% vs 14%), nausea (19% vs 11%), flushing (15% vs