BioWorld International Correspondent
A Phase II trial miss is usually nothing to shout about, but Actelion Pharmaceuticals Ltd. put an optimistic gloss on macitentan's failure to demonstrate efficacy in idiopathic pulmonary fibrosis (IPF), emphasizing its favorable safety profile, which could augur well for an ongoing Phase III trial in pulmonary arterial hypertension (PAH).
Although the drug, an endothelin receptor antagonist (ERA), failed to attain the primary endpoint in the 178-patient study an improvement in forced vital capacity its effect on liver enzyme elevations was no different from that of placebo.
The company said elevations of liver alanine or aspartate aminotransferases greater than three times the upper limit of normal occurred in four patients (3.4 percent of the total) who received macitentan (3.4 percent of the total) vs. three patients (5.1 percent) who received placebo. (The study randomized subjects to drug or placebo arms in a 2:1 ratio).
The data represent the most convincing evidence to date that macitentan avoids the liver toxicity problems generally associated with the ERA drug class.
"There is a big sigh of relief on the safety profile," Roland Haefeli, head of investor relations and public affairs at Allschwil, Switzerland-based Actelion, told BioWorld International. The 10-mg dose used in the IPF study is the same as the higher of two doses under evaluation in the Phase III trial of macitentan in PAH. Patients took the drug for an average duration of more than 14 months.
Class-related adverse events were more frequent in the treatment arm than in the placebo arm and included fluid retention, which resulted in one patient discontinuing treatment, and decreases in hemoglobin. Neither of the effects were considered clinically relevant, Actelion said. Moreover, macitentan did not appear to cause headache, hypotension, nasopharyngitis, rhinitis or hot flush, all of which are generally associated with ERAs.
Macitentan, which Actelion discovered in house, has long been touted as a successor to Tracleer (bosentan), the first drug to gain approval in PAH. Its potential in that indication will become apparent by early to mid-2012, when the event-driven Phase III trial, called SERAPHIN, is expected to report data.
Its failure to demonstrate efficacy in IPF has no implications for the PAH trial, according to Haefeli. "While the read across on the safety is warranted, a read across on efficacy cannot be done," he said.
The company's expectations in IPF had been modest in any case, given the previous failure of Tracleer in a Phase III trial in the same indication. (See BioWorld International, March 3, 2010.)
"It was borderline for sure," Haefeli said.
Another ERA, Letairis (Volibris, ambrisentan), marketed by Gilead Sciences Inc., in PAH, also failed a Phase III trial in IPF.
"It's a graveyard for everything that's been tested, except for the one that's coming right now," said Haefeli, referring to InterMune Inc.'s Esbriet (pirfenidone), which is about to be launched in Germany, having gained European approval in March. Brisbane, Calif.-based InterMune launched a second Phase III trial in the U.S., after receiving a complete response letter from the FDA. Bristol-Myers Squibb Co., of New York, has also moved into the IPF space, with its recent $475 million cash-and-milestones acquisition of San Diego-based Amira Pharmaceuticals Inc.
But Actelion's investors appear to value the reassurance on the PAH side more highly than the lost potential in IPF. Its stock (ZURICH:ATLN) closed at CHF33.88 (US$41.45) Monday, a gain of more than 4 percent.