Pharmacopoeia, an innovator in the discovery and development of novel small molecule therapeutics, has announced positive results from the initial phase 1 clinical trial of PS433540. The company's lead internal product candidate for the treatment of hypertension and diabetic nephropathy. Data from the single ascending dose (SAD) study indicated that PS433540 was well-tolerated at all six doses administered. In addition, study findings suggested that the compound possesses linear pharmacokinetics and a half-life that is consistent with once daily administration.

PS433540 is the first and only dual-acting angiotensin and endothelin receptor antagonist (DARA) in development. The compound, which possesses two clinically validated mechanisms of action in a single molecule, works by selectively blocking the action of two potent vasoconstrictor and mitogenic agents, angiotensin II (AII) and endothelin 1 (ET1), at their respective receptors.

PS433540 is highly selective (10,000-fold) for the AII receptor sub-type 1 and the ET receptor sub-type A. As such, PS433540 combines the properties of an angiotensin receptor blocker (ARB) and an endothelin receptor antagonist (ERA) in the same molecule. Preclinical data suggests that, compared to either mechanism alone, simultaneously blocking the actions of both AII and ET1 may provide improved treatment options for several cardiovascular diseases.

"By showing that PS433540 is well tolerated over a broad range of doses while also possessing characteristics consistent with once-a-day dosing, we have taken an important initial step in the development of this first-in-class compound," said Rene Belder, Pharmacopoeia's vice president of clinical and regulatory affairs. "Based on these findings, we are moving forward with our clinical development of DARA in an effort to complete the overall phase 1 program in a timely fashion."

The objective of this randomised, placebo-controlled, dose-escalation study was to evaluate the compound's preliminary safety and tolerability by treating six separate groups of healthy volunteers. Each group consisted of eight subjects, with six individuals receiving the active DARA compound and two receiving placebo. PS433540 doses administered to the study groups ranged from 20 mg to 1000 mg and were increased for each successive group. In addition to safety and tolerability, dose-related pharmacokinetics were also evaluated.

Pharmacopoeia's phase 1 programme for PS433540 is comprised of multiple studies. In addition to the recently completed SAD trial, other planned studies include a multiple ascending dose (MAD) study to further evaluate safety after repeated administration of PS433540 over 14 days, as well as an angiotensin challenge study and an endothelin challenge study to demonstrate PS433540's dual pharmacology. Pharmacopoeia expects the entire phase 1 programme to be complete in late 2007 with a phase 2 trial beginning in the first half of 2008.