By Kim Coghill
Two Cambridge, Mass., companies in a race to develop a product to treat Fabry disease continued their head-to-head competition Thursday as each presented positive clinical results at a meeting of the American Society of Human Genetics in Philadelphia.
Genzyme Corp. for the first time disclosed results of its Phase III clinical trial of Fabrazyme, an investigational enzyme replacement therapy. Transkaryotic Therapies Inc. then presented positive pivotal clinical results of Replagal, its enzyme replacement therapy.
Both companies have filed biologics license applications (BLAs) with the FDA, and submissions have been accepted for review. The first product to gain approval gets orphan status, which gives it seven years of market exclusivity. (See BioWorld Today, June 19, 2000, p. 1; and June 26, 2000, p. 1.)
"Completion of the Phase III clinical trial is significant because Fabrazyme likely will be Genzyme's next major product and it is likely to be approved at the end of the year," said Bo Piela, a Genzyme company spokesman. The company anticipates launching the drug in January.
Piela would not speculate on the amount of revenue the drug is expected to generate.
But there is some competition, and developing a drug to treat the same rare inherited disease is not all Genzyme and TKT have in common.
Back in July, Genzyme filed a lawsuit against TKT in U.S. District Court in Wilmington, Del., alleging patent infringement. According to the suit, TKT's manufacture and use of Replagal (alpha-galactosidase) infringes on a patent licensed to Genzyme. (See BioWorld Today, July 26, 2000, p. 1.)
Then in September, TKT turned around and filed a complaint against Genzyme in U.S. District Court of Massachusetts seeking declaratory judgment of patent non-infringement and invalidity. In the complaint, TKT says Replagal does not infringe U.S. Patent No. 5,356,804 and that the patent is invalid.
In Thursday's announcement of Fabrazyme's success, Piela said, "We feel very good about the data we have presented to the FDA."
The pivotal trial's primary endpoint - a nearly complete clearance of GL-3 from the blood vessels of the kidney - was met with high statistical significance (p<0.0001). Fabry disease is caused by a deficiency of the enzyme alpha-galactosidase, which results in the body's inability to break down certain naturally occurring glycolipids, primarily GL-3, which accumulate in the lining of the blood vessels within the kidney, heart, skin and other organs.
According to Christine Eng, of Mount Sinai School of Medicine in New York, who presented the data in Philadelphia, the primary endpoint required achieving a score of zero on a scale of 0-3 measuring the level of GL-3 in the kidney vasculature. Twenty of the 29 patients treated with Fabrazyme achieved a score of zero, indicating that their blood vessels were restored to a near normal state and providing strong evidence that the kidney should function normally as a result of treatment. Eight of the remaining nine treated patients also improved from baseline scores but did not yet achieve a score of zero during the first 20 weeks of treatment. None of the 29 placebo patients achieved a score of zero.
The Phase III clinical trial was a double-blinded, randomized, placebo-controlled study. It enrolled 58 patients at eight medical centers in the United States and Europe.
TKT's data presented Thursday was the result of a randomized, double-blind, placebo-controlled pivotal Phase II study conducted to assess the safety and efficacy of Replagal enzyme replacement therapy over six months. Twenty-six patients with Fabry disease were randomized to receive either Replagal or placebo every two weeks.
Representatives of TKT were not available late Thursday afternoon, but Raphael Schiffmann, principal investigator of Replagal clinical testing at the National Institutes of Health in Bethesda, Md., said, "Patients participating in this study demonstrated clinically and statistically significant improvements in multiple manifestations of Fabry disease, including a reduction in a number of pain measures as well as stabilization in kidney function and concomitant improvement in kidney pathology. There also were extensive decreases in accumulation of globotriaosylceramide (Gb) in various organs that were significant. These data are very encouraging to the medical and patient communities."
At six months, patients receiving 0.2 mg/kg every other week in 20- to 40-minute infusions had a reduction in severe debilitating pain compared to no change for the placebo group. Patients on Replagal treatment also experienced a reduction in the number of days off pain medication, with several patients permanently discontinuing pain medications for the duration of the trial.
Patient kidney function stabilized or improved in the group receiving Replagal, whereas patients in the placebo arm experienced a decline in kidney function.
"We are pleased with the outcome of the Replagal clinical development program and the effect our investigational product has had on treating this underserved patient population," Thomas Schuetz, vice president of clinical affairs at TKT, said in a written statement. "We believe Replagal offers a clinically meaningful treatment with a favorable safety profile."
Genzyme's stock (NASDAQ:GENZ) closed Thursday at $62.875, down $1.187. TKT's stock (NASDAQ:TKTX) closed Thursday at $46.625, up $4.562 or 10.85 percent.