Shares in the USA’s United Therapeutics Corp have collapsed after the firm announced that a late-stage study of an oral formulation of Remodulin for the treatment of pulmonary artery hypertension has failed.

Remodulin (treprostinil) is already marketed as an injectable for PAH. However, the 354-patient Phase III study of the oral, sustained-release formulation of the treatment did not achieve statistical significance for the primary endpoint, a six-minute walk distance at week 16.

The Maryland-based firm said that exploratory analyses of the trial, called Freedom-C, suggest that “the inability to dose titrate was a limiting issue that muted the overall treatment effect”. Of the 174 patients who received active drug, 135 completed the study, 25 patients discontinued due to an adverse event and 33 patients were unable to titrate their dose above 1 mg twice-daily.

These 58 patients had a markedly lower exercise benefit at week 16 compared to the other patients who received active drug, with an observed median improvement of only 4 metres. Patients achieving a dose of 1.25 mg to 3.25 mg twice-daily improved by 18 metres and those on 3.25 mg to 16 mg twice-daily improved on average by 34 metres.

United chief operating officer Roger Jeffs said that despite the disappointment over the primary endpoint, “we believe the results fully support the continued development of oral treprostinil, especially when the treatment effect is evaluated based on the dose achieved in the Freedom-C study. He noted that the firm is excited about the prospects of a Phase III study of oral treprostinil, Freedom-M, which evaluates the drug without the presence of background therapy and will be reported at the end of March.

Additionally, Dr Jeffs said that enrollment of another late-stage study of oral treprostinil, Freedom-DR, will commence shortly, using the 0.25 mg dose, and also expressed high hopes for the inhaled version which is currently under review at the US Food and Drug Administration. A decision on the latter is expected in April and a submission in Europe is scheduled for January.

Dr Jeffs concluded by saying that the Freedom-C result “has not altered the fact that we believe that we have in place today all of the pieces that we need to continue growing our business." However his confidence does not appear to be shared by investors as the firm’s share price crashed 35.2% to close at $58.62.

Analysts seemed mixed as to whether the market had over-reacted. Andrew Fein at Piper Jaffray said in an investor note that he has low expectations for the success of the Freedom-M study, although Oppenheimer & Co analyst Bret Holley expects positive results from the latter trial.

United to sell Lilly’s Cialis for PAH
The disappointment of Freedom-C was offset by the news that United has entered into a licensing deal with Eli Lilly to sell the latter’s erectile dysfunction drug Cialis (tadalafil) in the USA as a treatment for PAH.

Under the terms of the agreement, United is making an upfront payment of $150 million upfront for the drug, which is currently being reviewed by regulators in the USA and Europe for the PAH indication. Lilly will manufacture and supply tadalafil, and will also buy $150 million of United’s common stock.

Martine Rothblatt, United’s chief executive, said the deal builds upon the success of Remodulin, and added that “we also welcome the support and confidence expressed by Lilly through their financial investment in our company”.