BioWorld International Correspondent
Swiss drug development firm Actelion Ltd. is planning to move the acute heart failure drug candidate Veletri (tezosentan) into Phase III trials before the year's end, following the release of promising data from a Phase II dose-optimization study.
That reverses an earlier setback with the same compound, an intravenous dual endothelin receptor antagonist that combats the vasoconstrictive effects that accompany excess endothelin production in acute heart failure.
Last year, tezosentan failed to reach its primary objective in a Phase III trial designed to demonstrate a reduction in dyspnea, or shortness of breath associated with acute heart failure. This time around, the Allschwil-based company tightened up the selection criteria for entry into the trial. Patients needed to have dyspnea at rest, had to be hospitalized for no longer than 24 hours prior to taking the drug and had to require hemodynamic monitoring.
"We are trying to select the real patients," Actelion's head of investor relations, Roland Haefeli, told BioWorld International.
It also adopted a significantly lower dosing regimen, with doses ranging from 0.2 mg/h to 25 mg/h. In the previous Ritz I trial, it observed adverse effects, including hypotension, headache and renal failure associated with excess vasodilation, at 50 mg/h and 100 mg/h. "The dose is the most difficult aspect of cardiovascular drug development," Haefeli said.
The primary efficacy endpoint was a change in cardiac index from baseline to six hours after drug initiation. "There was a significant increase in cardiac index after six hours with the 5 and 25 mg/h [doses], and there was no difference between the two, indicating that the 5 and the 25 are at the top of the dose response," Actelion's head of clinical development, Isaac Kobrin, told a conference call audience. "There were no clinically relevant differences between placebo and tezosentan regarding manifestation of excess vasodilatory side effects such as headache, hypotension and renal failure," he said.
"The study was not powered for identifying clinical endpoints but, of course, we were looking at them and we have seen encouraging trends in terms of worsening heart failure events and even dyspnea," Kobrin said.
Actelion now plans to commence a Phase III registration study that will focus on morbidity/mortality. That is a more ambitious endpoint than that with which Sunnyvale, Calif.-based Scios Inc. gained FDA approval for its acute heart failure drug, Natrecor. The latter is indicated for patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.
"We want to go on the market with a higher impact by having a much broader indication, a more clinically relevant indication," Actelion CEO Jean-Paul Clozel said in the conference call.
Genentech Inc., of South San Francisco, has an option to co-promote tezosentan in the U.S., which it could exercise following a successful Phase III trial. Actelion retains rights to the product, which it licensed from Basel, Switzerland-based F. Hoffmann-La Roche in 1998, for the rest of the world.