By Randall Osborne

Editor

"Orphan drug." The phrase sounds forlorn, as if referring to a treatment that lacks parentage, and is condemned to wander the world unprescribed.

But the meaning is almost exactly the opposite. Not only do orphan drugs have "parents," in the form of biotech and pharmaceutical developers, but they also have rather wealthy parents and fortunate ones, at that.

An orphan drug (or biological product), as designated by the FDA, is one for which the maker has seven years of market exclusivity.

Almost always approved more quickly than other treatments, orphan drugs typically target serious and life-threatening, often rare diseases, but otherwise must submit to the usual FDA rigors before they gain the marketing go-ahead.

The FDA says about 890 orphan products have been designated. Of those, more than 170 have been approved.

Of course, it's much in a biotech/pharma combo's best interest to work on a drug for which orphan status has been given, or would be. The "orphan" tag guarantees an edge that can be gained almost no other way in a free-market economy: competitive untouchability, because no other treatment can threaten profits by jumping into the fight.

That's far from the case with non-orphan drugs for less serious conditions. Throughout their research, developers of those treatments constantly are calculating probable market share, based on others doing similar work, coming up behind them.

Orphan drug status doesn't always mean a free ride, though.

In fact, it can mean a very expensive journey albeit one at the end of which lie great rewards.

Facing off in the battle for approval of an orphan drug that will treat Fabry disease are Genzyme Corp. and Transkaryotic Therapies Inc.

The rare, inherited genetic disorder is a perfect candidate for a drug that would gain, and has gained, orphan drug status. Fabry disease is caused by deficient activity of the lysosomal enzyme alpha-galactosidase A, which leads to accumulations in the body of ceramidetrihexoside, resulting in extreme pain, serious renal and cardiovascular disease, and stroke.

It affects about one in 40,000 men worldwide, and death typically occurs around age 40 or 50. Between 1,000 and 2,000 patients in the U.S. are afflicted.

Genzyme's drug is Fabrazyme (agalsidase beta). The competing drug by Transkaryotic Therapies (TKT) is Replagal (alpha-galactosidase). Both are enzyme-replacement therapies. Both are the subjects of biologics license applications, filed with the FDA within a week of each other.

The race is on.

So are the lawsuits.

Genzyme filed a complaint in July against TKT in U.S. District Court, alleging the latter's manufacture and use of Replagal infringes on a patent licensed to Genzyme. Two months later, TKT filed papers against Genzyme, seeking declaratory judgment of patent non-infringement and invalidity.

The court battle continues. Meanwhile, at a meeting of the American Society of Human Genetics in Philadelphia, earlier this month, Genzyme disclosed encouraging results from its Phase III trial of Fabrazyme, and TKT presented positive pivotal clinical results for Replagal.

Analysts have proven reluctant to call winners. Dennis Harp, with Deutsche Bank Alex.Brown Inc., believes there won't be one, at least not at the FDA level.

"TKT, actually came from behind, and technically was first to submit its application to the FDA, ahead of Genzyme, even though they started [development of the Fabry drug] after," Harp noted. "But it's not sufficiently far ahead that the FDA will review them on a different time scale."

No advantage there. If the FDA evaluates both drugs at once, would it approve both? Harp believes the agency will.

"I think the FDA will dodge the orphan-drug issue," he told BioWorld Financial Watch.

And then . . .?

"The regulations are silent about what happens if the FDA gives simultaneous approval," Harp said. "It would be up to either of the parties, or both, to sue the FDA, to essentially assert a violation of the Orphan Drug Act. Or [the companies] might say, 'No, let's play this out in the marketplace.'"

Of course, any drug firm needs to think twice before challenging the gate-keeping federal agency that controls its drugs' access to market.

"You really don't want to create bad will," Harp said. "But, if one party felt disadvantaged [by the dual approval] in its ability to market the product, it might sue the FDA," Harp said. "That might be a reason to try to make the FDA make a choice."

He had no speculation on which company that might be.

Genzyme has helpful experience selling Ceredase and Cerezyme, which are enzymes for the treatment of Gaucher disease, another rare and serious condition.

"On the other hand, it would appear [Genzyme's Fabry disease drug] has a longer infusion time," Harp said, which could put the company at a disadvantage, experience or not, if both drugs make it to market.

Harp said either firm might decide suing the FDA is worth the sour taste court action might leave with the agency, "but I don't think so. Both have approvable products, and rather than try to litigate with the FDA, they should try to litigate with each other" as they are doing.

On the subject of airtight approvability, Harp noted, neither Genzyme nor TKT has a leg up. "Both met the standard for efficacy, in terms of having a clear, primary endpoint and achieving statistical significance," he allowed, but both also fell far short of the patient numbers usually required by the FDA in such trials.

The war, with both drugs on the market, might be decided by such weapons as price and consumer orientation matters such as helping patients get reimbursements for the cost of the drug.

"I'm sure that will be a factor," Harp said. "Genzyme already has an in-house group that works on that for the Gaucher disease product."

At the same time, TKT "has been quite savvy in building its own sales and marketing infrastructure," Harp said. "The company has hired some ex-Genzyme employees, and has used some of the same consultants Genzyme uses for its Gaucher drugs."

TKT has its hands full. The company is also scrapping with Amgen Inc. in court over patents on the red blood cell booster erythropoietin (EPO), patents upon which Amgen alleges TKT has infringed.

The venture by TKT into Amgen territory was smart, Harp said.

"From a business perspective, it's certainly worthwhile, even if [TKT] thought the chances are remote, to challenge Amgen on the [erythropoietin] patents, because the market opportunity is so huge," he said.

Although hefty legal fees are inevitable, they are not likely to slow TKT.

"I don't think that's going to matter in the end," he added. "Patent litigation is a distraction, but I don't think it will rise to the level of interfering with the launch [of the Fabry drug]."

TKT has found a potentially lucrative, niche-market area in protein products for small populations of patients products that do not require large clinical trials and can be sold with a relatively small sales force, Harp said. That's why the company went ahead with its Fabry drug in the first place, knowing Genzyme had one, too. It was part of the plan.

"I would expect TKT to challenge a number of patents, knowing full well they're not going to win all of them," Harp said. "They will not escape the Amgen patent, but every product will be a unique situation. They'll win some and, in my view, they should get out from under the Genzyme patent, provided TKT is using gene activation to make its product [as the company claims, and] as I believe they are."

Anyway, the patents Genzyme is asserting against TKT have "been around for some time," Harp said.

The upshot of the case will have ramifications not only for the marketing of the two firms' Fabry disease drugs, but for rules pertaining to orphan drugs, and the way the FDA handles future disputes.

"It's going to be very interesting to see how it plays out," Harp said. *

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