Washington Editor

Transkaryotic Therapies Inc. said it dosed its first patient in a 12-month Phase III pivotal trial for its lead clinical candidate, iduronate-2-sulfatase in Hunter syndrome.

The 90-patient study, referred to as AIM, or Assessment of Iduronate-2-Sulfatase in MPS II, will be enrolled at eight sites around the world, Justine Koenigsberg, director of corporate communications for Transkaryotic Therapies (TKT), told BioWorld Today.

The company intends to evaluate a composite endpoint of pulmonary function and functional capacity measured by a six-minute walk test, Koenigsberg said. "We're certainly thrilled to start the study because there's no effective therapy for patients to date," she added.

Hunter syndrome, an orphan disease affecting up to 2,000 patients worldwide, according to TKT's count, is a genetic disorder often called MPS II. It is characterized by the body's inability to produce the enzyme iduronate-2-sulfatase, which is essential in the continuous process of replacing and breaking down glycosaminoglycans (GAG). Without the enzyme, GAG is stored in cells, often causing progressive damage. In severe cases, life expectancy is 10 to 15 years of age.

Symptoms include enlarged liver and spleen, heart failure, obstructive airway disease, sleep apnea, joint stiffness and, in severe cases, central nervous system involvement, the company said.

The Phase III patients will be randomized equally to three treatment groups receiving either weekly or every-other-week infusions of induronate-2-sufatase (I2S) at a dose of 0.5 mg/kg or weekly infusions of placebo for 12 months. Aside from pulmonary function and the six-minute walk test, other efficacy endpoints will be joint range of motion and combined liver and spleen size.

Koenigsberg said if all goes well with the trial, TKT believes it would file for U.S. and European regulatory approval in 2005. TKT does not expect to partner I2S, except in Japan.

Patients who participated in initial studies of I2S saw significant improvements in overall activity levels and treatment was generally well tolerated, Joseph Muenzer, of the University of North Carolina at Chapel Hill and a lead investigator of the study, said in a prepared statement.

Results of the Phase I/II randomized, double-blind, placebo-controlled trial demonstrated evidence of clinical activity in several areas of the disease, including respiratory function and functional capacity, TKT said. Three doses were studied and within each dose group, three patients were randomized to receive I2S and one patient to receive placebo biweekly for six months. The data were presented in October 2002 at the American Society of Human Genetics annual meeting.

Meanwhile, long-term results from the open-label extension portion of the study were presented recently at the 9th International Congress of Inborn Errors of Metabolism meeting in Australia and additional data from the study will be presented in November at the annual meeting of the American Society of Human Genetics.

All of this follows a tough year for TKT, of Cambridge, Mass.

It began in January when the FDA's Endocrinologic and Metabolic Drugs Advisory Committee failed to support approval of Replagal (agalsidase alfa), TKT's product for Fabry's disease, also a genetic disease affecting very few patients worldwide. (See BioWorld Today, Jan. 15, 2003.)

While Replagal never made it to market in the U.S., the product is cleared in 26 countries, including in the European Union.

Soon after the defeat, TKT released a plan to narrow its focus to protein replacement therapies, and cut staff by about 100 people. The company now employs about 320 people. (See BioWorld Today, March 20, 2003.)

TKT's stock (NASDAQ:TKTX) fell 5 cents Friday to close at $12.63.

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