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FDA Says ‘No’ to Hypertension Drug Treprostinil for Second Time

Approval sought for treatment of PAH (Mar. 25)

For the second time, the FDA has declined to approve treprostinil diolamine extended-release tablets (oral treprostinil, United Therapeutics Corp.) for the treatment of pulmonary arterial hypertension (PAH).

The original new drug application (NDA) was submitted in February 2012, but the agency replied with a complete response letter in October of that year. A revised NDA was re-submitted in February 2013.

The FDA’s first rejection letter cited the questionable clinical importance of the effect on the 6-minute walk distance (6MWD) shown in the pivotal FREEDOM-M study; the inability to demonstrate an improvement in time to clinical worsening in all three phase III studies of oral treprostinil; and the inability to demonstrate a statistically significant effect on 6MWD in the two FREEDOM-C studies as reasons for being unable to approve the NDA at that time. The agency noted that it was unsure whether an additional clinical study could alter these impressions, but it suggested that the drug’s developer, United Therapeutics Corp., consider, among other things, a fixed-dose design and more frequent dosing.

Treprostinil diolamine (formerly UT-15C) is a salt form of treprostinil (a synthetic prostacyclin analog) for oral administration. A licensed tablet-coating technology allows the drug to be released into the body through a small hole that is laser-drilled into the coating of each tablet. This technology releases treprostinil at a relatively even rate in the gastrointestinal tract, according to the drug’s developer.

Two phase III placebo-controlled trials of oral treprostinil in patients with PAH were initiated in 2006. The FREEDOM-C trial was a 16-week study of patients on approved background therapy using a PDE-5 inhibitor or an endothelin receptor antagonist (ETRA), or a combination of both. The FREEDOM-M trial was a 12-week study of PAH patients who were receiving background therapy.

Both trials used a 1.0-mg tablet, but during an open-label extension trial (and an associated pharmacokinetic substudy), it was discovered that treprostinil concentrations were higher in PAH patients than in healthy individuals because of the difference in overall absorption, metabolism, and excretion of the drug between these two populations. These differences led to a number of discontinuations by patients randomized to receive the drug because of tolerability-related side effects. As a result, a 0.5-mg tablet was introduced in 2007, and a 0.25-mg tablet was introduced in 2008.

In November 2008, the drug’s developer announced that the FREEDOM-C trial did not meet statistical significance (P = 0.072) for its primary endpoint. Another study, FREEDOM-C(2), was begun in 2009. Again, this trial failed to achieve statistical significance (P = 0.089) for the primary endpoint of improvement in the 6MWD at week 16.

In 2011, it was announced that the FREEDOM-M trial had met its primary endpoint of improvement in the 6MWD at week 12. Patients receiving oral treprostinil improved their median 6MWD by approximately 23 meters compared with placebo-treated patients (P = 0.0125).

Source: United Therapeutics Corp.; March 25, 2013; October 23, 2012; and Pipeline.

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