Prostacyclin Analogues
Overview
Prostacyclin analogues’ short half-lives have historically presented problems in respect to drug delivery. An important step forward in improving patient convenience while maintaining efficacy in this drug class was the development of treprostinil (United Therapeutics’ Remodulin). This compound is more stable than epoprostenol (GlaxoSmithKline’s Flolan) and has a longer half-life, thus permitting its delivery by subcutaneous infusion. However, clinical studies revealed that subcutaneous treprostinil caused infusion-site pain in 85% of patients, leading to the discontinuation of therapy in 8%. An open-label study revealed that the pain persisted for up to 18 months. The issue of infusion-site pain prompted United Therapeutics to investigate other formulations of this highly effective agent with a view to maximizing patient care. This section discusses two formulations (inhaled and oral) of treprostinil under development.
Mechanism Of Action
Prostacyclin analogues mediate their effects (vasodilation and antiplatelet activity) through activation of G-protein-coupled receptors, known as IP receptors, on target cells. These IP receptors are coupled to the adenyl cyclase intracellular signaling cascade, and activation triggers the production of intracellular cyclic adenosine monophosphate (cAMP), culminating in cellular responses.
Treprostinil (Inhaled Preparation)
United Therapeutics is developing an inhaled preparation of treprostinil as a potential first-line therapy for pulmonary arterial hypertension. Phase II studies are under way in the United States and Europe. Inhaled treprostinil’s mechanism of action follows that outlined for the prostacyclin analogues in general.
The development program is known as the TRIUMPH project. The goal of TRIUMPH is to develop a portable prostacyclin therapy that can be inhaled for not more than one to two minutes and administered no more than three to four times per day. United Therapeutics reports that approximately 180 patients have already been dosed with the agent acutely and 10 patients are receiving the agent chronically; the key centers involved are Giessen, Germany, and the University of California in San Diego.
In one open-label study, presented at the AHA meeting in 2004, treprostinil administered via a nebulizer (three inhalations) was given to 17 patients in the acute setting, during catheterization. Two patients continued to receive this therapy (four inhalations per day) on a compassionate-use basis for more than three months following acute testing. Both patients improved their NYHA functional class, and one patient’s 6MWD increased from 0m (bedridden) to 143m and the other patient’s increased by 176m from baseline. The treatment was well tolerated, and no side effects were observed.
United Therapeutics is employing several measures to reduce this product’s time to market. For example, it is using an off-the-shelf nebulizer, which has reduced the device R&D time. The company expects to submit an NDA to the FDA and the European Medicines Agency in 2007.
Treprostinil (Oral Preparation). United Therapeutics is developing an oral, sustained-release formulation of treprostinil for the treatment pulmonary arterial hypertension and peripheral arterial disease. Phase I studies for peripheral arterial disease have begun, but the compound remains in the preclinical phase of development for pulmonary arterial hypertension. Oral treprostinil’s mechanism of action is as described for the prostacyclin class in general.
Studies investigating the actions of oral treprostinil in animal models of pulmonary arterial hypertension and in pulmonary arterial hypertension patients are not available in the public domain.
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