As expected following positive Phase III results earlier this year, Lev Pharmaceuticals Inc. submitted a biologics license application for its C1 inhibitor, Cinryze, in hereditary angioedema, making it the first company to file for approval in the competitive U.S. HAE market.

The BLA seeks approval for Cinryze for the acute treatment of HAE, a genetic disorder characterized by painful swelling affecting the face, urogenital tract, abdomen and larynx, based on results from the 71-patient CHANGE (C1-inhibitor in Hereditary Angioedema Nanofiltration Generation evaluating Efficacy) pivotal trial reported in March.

Cinryze met its primary endpoint in that study, defined as a statistically significant reduction in the time to relief of acute HAE symptoms. Pending FDA acceptance of the BLA, expected within 60 days, Lev anticipates receiving priority six-month review based on the drug's orphan status, said Joshua Schein, CEO of the New York-based firm. (See BioWorld Today, March 15, 2007.)

"So we hope for approval early next year," he said. That would be a coup for patients in the U.S., "who have been terribly frustrated" with the lack of FDA-approved treatments for HAE, "especially since C1 inhibitors have been available in Europe for years."

The BLA filing also represents a milestone for the company, which just improved its chance to be first to market with a C1 inhibitor. If approved, its orphan designation would ensure seven years of marketing exclusivity, likely delaying the U.S. introduction of competing products, such as King of Prussia, Pa.-based ZLB Behring's C1 inhibitor Berinert and Leiden, the Netherlands-based Pharming Group NV's Rhucin, a C1 inhibitor derived from the milk of transgenic rabbits. Both are in Phase III development.

HAE is caused by a defective gene for C1 inhibitors, and drugs such as Cinryze work as replacement therapies to restore function in that gene.

Cinryze's orphan status, however, likely won't preclude products working via other mechanisms of action, and Dyax Corp.'s DX-88 (ecallantide), a recombinant plasma kallikrien inhibitor, is not far behind Cinryze in development. Cambridge, Mass.-based Dyax, which reported positive results from the first Phase III in April and is conducting a confirmatory study, has said it anticipates gaining approval as soon as late 2008.

Another late-stage product is Berlin-based Jerini AG's Icatibant, a synthetic peptidomimetic agent, which demonstrated statistical significance in one Phase III study and missed in another. Jerini, which is partnered with Abbott, of Abbot Park, Ill., has said it plans to combine data from those trials for a new drug application, possibly to be submitted later this year.

But Lev is hoping to gain an edge in the HAE market, which is estimated to be about 10,000 patients in the U.S.

"We're approaching the market differently because we're developing both acute and prophylactic treatments," Schein told BioWorld Today. The company completed a prophylactic portion of its CHANGE trial in late May, and "if the data are available within the next three months, we'll submit an amended BLA" to include twice-weekly preventative treatments.

Lev, which gained North American rights to the C1 inhibitor technology from the Sanquin Blood Supply Foundation, a not-for-profit group based in Amsterdam, the Netherlands, plans to commercialize Cinryze on its own. "We've been building our own commercial operations for the past year," Schein said, and last month the firm completed the formation of its marketing and sales team.

While much of its efforts to date have focused on HAE, Lev also anticipates developing its C1 inhibitor program in other diseases involving inflammatory pathways. C1 inhibitors have demonstrated preclinical efficacy in areas such as myocardial infarction, lung transplantation, burn injuries, coronary bypass surgery, Gram-negative septicemia and bone marrow transplantation.

Shares of Lev (OTC BB:LEVP) closed at $1.57 Tuesday, down 12 cents.