West Coast Editor

A lucrative therapeutic niche, such as the one made by lysosomal storage disorders, can keep attracting new companies - no matter how many big players already are far along in the field, no matter how onerous the patent battles of the past.

Case in point: ZyStor Therapeutics Inc., which completed the first tranche of an $8.5 million financing to develop drugs for LSDs, with an investigational new drug application expected in 2006.

"We're tackling the problem in a different scientific way," said Loren Peterson, president and CEO of ZyStor, which takes its name from the "zy" in enzyme and the "stor" in storage.

At the same time of the financing, ZyStor acquired for an undisclosed amount Glycosylation Independent Lysosomal Targeting (GILT) technology from Symbiontics Inc., of St. Louis, which enhances the binding ability of the replacement enzymes used to treat LSDs.

The technology is based on "attaching a peptide tag to the enzyme itself, and it's the tag that targets receptors on the surface of the cell," Peterson said. "Current therapies are simply targeting those receptors using the carbohydrates that occur naturally on the enzyme. The problem is that those carbohydrates also hit receptors on the liver, and as a result they're getting cleared out of the system faster than they can get to the target tissues."

ZyStor's method could improve potency, thus reducing the duration and frequency of infused doses.

The LSD group involves a deficiency of lysoenzymes, resulting in a dangerous buildup of proteins, sugars and fats in cells that can lead to respiratory and cardiac problems, organ enlargement, skeletal changes and even death.

Famously warring over LSD drugs were Cambridge, Mass.-based Genzyme Corp. and Transkaryotic Therapeutics Inc., also of Cambridge. At the start of this year, TKT surrendered its bid to win FDA approval of Replagal, an enzyme-replacement therapy for Fabry's disease that would have competed in the U.S. with Fabrazyme, from Genzyme. Genzyme had filed a lawsuit claiming TKT had infringed on its patent, but a federal judge dismissed the case in December 2001. Replagal was approved outside the U.S. (See BioWorld Today, Jan. 14, 2004.)

Genzyme, of course, has the blockbuster LSD drug Cerezyme (imiglucerase) for Type I Gaucher's disease, which sold in the third quarter $208.4 million, up from $189.2 million in the same period of 2003. In the pipeline the company also has Myozyme (alglucosidase alfa) for Pompe disease, for which the company plans to file for approval in Europe by the end of this year and in the U.S. during the first half of next year.

Pompe is the first indication ZyStor is pursuing, Peterson said.

"The enzyme associated with Pompe is very poorly phosphorylated, so 98 percent of the enzymes you're putting in can never be therapeutically useful," he said. "The doses that are being given are huge. We're looking at Pompe disease as a lead, simply because of the poor phosphorylation, but we're also looking at GILT tags for enzymes associated with Fabry's and Gaucher's disease."

Taking aim more recently at Fabry's, which is characterized by a lack of alpha-galactosidase A, was Amicus Therapeutics Inc., which in the spring raised $31 million to advance its compound to the clinic. New Brunswick, N.J.-based Amicus expects no patent problems since its small-molecule oral drug, AT1001, rather than replacing the enzyme like other products, is designed to enhance the patient's own enzyme activity. (See BioWorld Today, May 13, 2004.)

Another firm working in the space is Novato, Calif.-based BioMarin Pharmaceutical Inc., which over the summer disclosed favorable data from a Phase III trial of Aryplase, an enzyme-replacement therapy for mucopolysaccharidosis-VI patients, also known as MPS-VI or Maroteaux-Lamy syndrome, caused by a deficiency of the enzyme human N-acetylgalactosamine 4-sulfatase, also known as arylsulfatase B. (See BioWorld Today, June 4, 2004.)

BioMarin late last month filed for approval of Aryplase in the U.S., and said a European filing would come before the end of the year.

Preliminary results with the GILT approach were published in the Proceedings of the National Academy of Sciences in March, and showed in animal models an improvement in dosing.

"That's one of the big issues, that patients have to go in so frequently and get infusions that last up to eight hours," Peterson told BioWorld Today. "If we're able to reduce that by half, it would be a fairly significant improvement. We really think we have a better mousetrap here."

ZyStor's buyout of Symbiontics' GILT is somewhat more complicated than a straight purchase. Peterson was president and CEO of Symbiontics, which had tried to raise money itself to advance the technology. When the venture capitalists came along - with weighty participation by the State of Wisconsin Investment Board - the firm found the easier route was to form a new company and move it (along with Peterson and Symbiontics' scientists) to Wisconsin, as the investment board requires.

Symbiontics owns "a pretty good chunk" of ZyStor and will continue to exist for the purpose of carrying out contracts with St. Louis University and serving as a holding company for ZyStor stock, Peterson said.

Mason Wells, of Milwaukee, and Venture Investors, of Madison, Wis., led the syndicate of venture funds that participated in ZyStor's financing. The syndicate also included the state investment board; Prolog Ventures, of St. Louis; Hexagon Investments, of Denver; Apjohn Ventures, of Kalamazoo, Mich.; and Stonehenge Capital, of Milwaukee.