Washington Editor

Orphan Therapeutics LLC plans to file for FDA approval of Lucassin (terlipressin) next year, a drug for Type I hepatorenal syndrome (HRS), despite missing statistical significance in a recently reported Phase III trial's primary endpoint and concurrently dissolving its partnership with PDL BioPharma Inc.

The investigational drug "has always [produced] a consistently positive result" in nearly a dozen clinical studies over the last decade, Orphan President Peter Teuber told BioWorld Today. The latest trial employed a new, unproven primary analysis for testing Lucassin's benefit in Type I HRS, a condition that kills patients within two to four weeks on average, and that's where the issue of missing statistical significance arose.

In analyzing this endpoint, Lucassin-treated patients had better Type I HRS outcomes than placebo patients, but to a lesser extent than expected: 27 percent of those who received the drug were alive after two weeks, with creatinine less than 1.5 mg/dl on two measurements 48 hours apart without relapse of creatinine after the improvement, compared to 16 percent of those on placebo (p=0.059). That result, first reported this summer and more recently at last month's American Association for the Study of Liver Diseases meeting, revealed myriad shortcomings with this assessment, Teuber said. (See BioWorld Today, Aug. 7, 2006.)

"These patients are very sick and have all sorts of other issues, confounding diseases, and so forth," he added. "We didn't think of all the possibilities when we designed that endpoint."

Nevertheless, the privately held specialty pharmaceutical company, of Lebanon, N.J., expects to begin a rolling submission in the second quarter after reaching a "positive" agreement with FDA officials last month on constructing a new drug application. Lucassin generated better responses on more traditional endpoints measured secondarily in the Phase III trial.

Specifically, the drug was significantly more effective than placebo in improving serum creatinine, reducing levels by 0.7 mg/dl from baseline to day 14 compared to 0 for placebo (p<0.009). In addition, Lucassin lowered creatinine to less than 1.5 mg/dl about two and a half times more than placebo, 34 percent compared to 13 percent (p=0.008), a commonly used measure of reversing HRS.

Lucassin's overall safety profile was similar to placebo.

"We missed our primary endpoint, but the primary endpoint might not have been perfectly designed," Teuber said. "There is a desire to look at the bigger picture, a holistic viewpoint on what else is out there. The FDA realizes that there is more to the story than just a 'p' value."

The agency's Division of Cardiovascular and Renal Products will first receive the clinical section, based largely on all those randomized, double-blinded Phase III results. A regulatory decision could come at some point in 2008.

The vasopressin analogue has fast-track status for Type I HRS, for which there is no drug treatment available despite affecting between 9,000 and 20,000 Americans every year. The life-threatening condition is characterized by rapid kidney failure in patients with end-stage liver cirrhosis because of a blood backup in the splanchnic system, causing those arteries to dilate. So a vasoconstrictor such as Lucassin, which also has orphan drug designation, is of benefit because it works in the splanchnic bay to constrict those arteries.

Concurrent with unveiling its filing plans, Orphan has reacquired full North American commercialization rights to Lucassin after mutually dissolving a partnership with PDL, of Fremont, Calif. That relationship dates back to June 2004, when it was formed with ESP Pharma Inc., now a subsidiary of PDL after a $475 million buyout nearly two years ago. (See BioWorld Today, Jan. 26, 2005.)

At this point, the drug isn't a focus for PDL. Teuber said no money changed hands between the companies as part of terminating their agreement, and added that Orphan has yet to decide whether to seek a new marketing partner.

Gilead Seeking Approval For Ambrisentan

Gilead Sciences Inc. filed for FDA approval of ambrisentan for the once-daily treatment of pulmonary arterial hypertension (PAH).

The new drug application, for 5-mg and 10-mg doses of the endothelin receptor antagonist, is supported by data from two Phase III studies and three Phase II trials. Results from the initial Phase III study, ARIES-1, showed once-daily dosing of 5 mg of ambrisentan produced a 59.4-meter improvement in the placebo-corrected mean change in six-minute walk distance at 12 weeks compared to baseline (p=0.0002), and data were similar in the second Phase III trial, ARIES-2. (See BioWorld Today, Dec. 13, 2005.)

Assuming approval, Foster City, Calif.-based Gilead is expected to launch the drug in early 2008.

The company acquired U.S. rights to ambrisentan through its $2.5 billion acquisition of Myogen Inc. earlier this year. GlaxoSmithKline plc, of London, holds ambrisentan's overseas rights and is expected to file for European approval next quarter. (See BioWorld Today, March 8, 2006, and Oct. 3, 2006.)

On Tuesday, Gilead's stock (NASDAQ:GILD) gained 85 cents to close at $64.64.