Look up the origins of the word "enzyme" in the dictionary and you'll find it has a possible Greek root, related to the word "juice." Look up "juice," and you'll find that it can be defined as "strength, vigor, vitality" - words seldom associated with the biotechnology sector these days.

If any companies proved they have the juice in that sense last week, it was Genzyme General (a division of Genzyme Corp.) and BioMarin Pharmaceutical Inc., which nailed down unanimous votes in favor of their enzyme replacement therapy for the rare condition mucopolysaccharidosis-1 (MPS-1).

Specifically, the Endocrinologic and Metabolic Drugs Advisory Committee balloting declared the data indicated a meaningful effect on lung function and on benefit in walking distance, or endurance, with Aldurazyme (laronidase).

The FDA has granted the Aldurazyme biologics license application six-month priority review status and orphan drug designation, with an FDA action deadline of Jan. 28.

Genzyme and BioMarin entered a deal in 1998 under which they will split equally the Aldurazyme sales revenues, and BioMarin gets $12 million when the FDA approves the biologic.

BioMarin presented the Aldurazyme case to the panel and did the job smoothly and expertly, said Thomas Shrader, an analyst with Gerard Klauer Mattison.

"They soaked up what happened Monday [when Genzyme appeared before the panel on another matter]," he told BioWorld Financial Watch. "They said, It's our first time down the road. Let's do it with the Big Daddy of obscure drugs.'"

Genzyme had gotten other, more dramatic good news from the panel after last Monday's hearing on another biologic for a separate enzyme replacement therapy: Fabrazyme (agalsidase beta) for Fabry disease.

Committee members said in a 14-1 vote that Genzyme's surrogate endpoint in trials - which had been a subject of doubt among some analysts - was enough to predict a clinically meaningful result.

"It was an unbelievably positive experience for Genzyme," said Shrader, whose firm has no banking relationship with either firm and no ownership. "No one thought it would go that well. The panel was exuberant."

More juice.

Genzyme, Shrader said, wowed the panel with "a very professional presentation. It was crystal clear what they've done, what they plan to do next, why they think [Fabrazyme] will work" - even if it hasn't worked so far.

Genzyme's Trial Design, Strategy Brilliant'

The company that might be feeling somewhat wrung out, on the other hand, after panel consideration is Transkaryotic Therapies Inc., which has been in a long, bitter race with Genzyme. TKT's Fabry drug came away with a unanimous vote last week, too - against Replagal (agalsidase alfa), the panel members saying data fail to provide adequate proof of efficacy. (See BioWorld Financial Watch, Sept. 30, 2002.)

Analyst Buddy Lyons, of Morgan Keegan & Co., wrote in a research report that it was clear from FDA briefing documents released earlier that "reviewers were somewhat baffled by the entire Replagal development program." It was Greek to them.

The committee also said in an 8-7 vote that TKT's trial design wasn't reasonably likely to make possible a prediction of clinical benefit based on surrogate markers. Still kicking, TKT said it will meet with the FDA and seek approval based on kidney and heart data, plus renal pathology findings.

"Genzyme always went for a molecular surrogate endpoint, and TKT basically felt they could show their drug worked, so they went for the clinical [efficacy] endpoint," Shrader said. "But, just like Genzyme, they couldn't show any effect." So TKT is back to surrogate markers, too.

"It's a funny situation," he said. "You have an enzyme shortage, so you put the enzyme back in and you know it goes into many cell types. How can it not help them?" Yet some Genzyme patients have been on the drug for two and a half years, "and you can't show a single way they improved," he added.

TKT and Genzyme are competing to win orphan designation for their respective products in Fabry disease, which would ensure seven-year market exclusivity in the U.S., where the market is estimated at $350 million to $400 million.

Genzyme, unlike TKT, sought accelerated approval, which would let the FDA approve its drug based on a surrogate endpoint while a Phase IV study proceeds.

William Tanner, an analyst with Leerink Swann & Co., called this "a brilliant strategy on Genzyme's part": Use surrogate markers (instead of the harder-to-prove clinical efficacy), and ask for accelerated approval.

"The Phase IV outcome is irrelevant," Tanner told BioWorld Financial Watch. "The drug will never be removed from the market." You're not going to have that many people taking the drug, he said, because the disease is uncommon, "and if adverse events are rare, how long would you go before you decide it doesn't work?"

Shrader agreed, noting that, after the committee meeting, "some of the panel members were saying [Fabrazyme] should be approved even if the Phase IV trial is a total failure, because it might not be long enough."

He called that position "wildly enthusiastic" and predicted the FDA would not align with it.

"I thought the [panel] message was pretty clear to make sure the current trial gets done, and then take a chance," Shrader said. "I think that, in the minds of the FDA and the panel, there's a pretty good chance there will be a whiff of clinical activity."

The agency's action deadline for Fabrazyme is April 24, and he predicted an accelerated review starting in 2004, after the Phase IV trial is completed in its placebo-controlled form. TKT, Shrader said, also was hurt by the fact that it had no Phase IV trial under way.

Tanner said TKT didn't gain any points in October, either, when the company "finally agreed to disagree" with the FDA on its data, which the agency questioned.

About one person in 200 carries the Fabry gene and one in 40,000 has the disease, which is a shortage of the enzyme alpha galactosidase A (also known as ceramidetrihexosidase), causing a buildup in the body's blood vessels of the fatty substance globotriasylceramide. The condition is one in a group of lysosomal storage disorders.

Fabry starves tissues of blood supply and affects the skin, kidneys, heart, brain and nervous system, leaving patients at greater risk of strokes, heart attacks and kidney damage. As the FDA panel heard, the Fabry population may be small, but the need for a biologic treatment is serious and strong.

Replagal Stronghold In Europe Threatened?

TKT may not be the company to fill that need in the U.S. since, any way you squeeze it, the news for the company wasn't favorable. Tanner speculated in a report that TKT's Replagal bid might be "headed for the glue factory." Still, he found some value in the stock - and a slight chance for Replagal.

"The panel didn't totally shut them out," said Tanner, whose firm has an investment banking relationship with TKT. "At the end of the day, you have to regard the drugs as the same. If you tested them in the same manner, you'd probably come up with similar data. But Genzyme was smarter, put a low bar up and made it. TKT put up the high bar and didn't."

Both Fabry drugs already are approved in Europe, where Replagal is taking about 60 percent of the market outside the U.S. Tanner estimated sales in 2003 of $56 million and said that, although European physicians believe the FDA decision will influence the use of Fabry drugs in the U.S., "we doubt it will have a significant impact in 2003."

Later might be a different story. Shrader pointed out that "several panel members felt the TKT dose was too low. If that's true, Genzyme's going to take most of Europe as well, because to give the [much higher] Genzyme dose with the TKT drug costs almost a million dollars a year. TKT doesn't have a lot dose flexibility" - unless it conducts another time-consuming, expensive trial, he said.

Tanner estimated that, by the end of 2004, TKT will have a cash balance of about $100 million, with pivotal testing of its drug for Hunter syndrome (MPS II) slated to begin in the first half of this year. The treatment has been given orphan drug status in Europe and the United States.

TKT Research Revved' Genzyme's Effort

But the Replagal blow is damaging. Investors will be "rightly skeptical as to [TKT's] ability to flawlessly conduct a meaningful, supportive clinical trial," Tanner wrote.

What's left? TKT's Dynepo program has little worth, Tanner said, and TKT is unlikely to win a patent fight against Amgen Inc., which claims Dynepo (epoetin delta), TKT's gene-activated erythropoietin, infringes on Amgen's erythropoietin patents. Tanner predicted partner Aventis SA will return rights to TKT.

Shrader wasn't giving up on Replagal entirely, either.

"If [TKT] can show a clinical endpoint, they're back in," he said. "They have some patients in Europe who are starting to be on drug for a while. There ought to be some data there that can be harvested."

Both analysts pointed out the irony in Genzyme's benefiting from an "underachiever" stance in going for the surrogate endpoints. Tanner remarked on another twist: Genzyme had been working for years on Fabrazyme but "didn't get revved back up until TKT was breathing down their neck [with Replagal]. It came out at the panel that, despite the fact Genzyme has been saying these were pre-approved endpoints, they initiated the trial before engaging the FDA."

But Genzyme designed the trial shrewdly, he said.

"Did they choose what was appropriate [as an endpoint] or what they knew they could prove?" Tanner asked. "It was at least as much the latter as the former."

Shrader agreed.

"I hate to be that cynical, but it's almost like that," he said, noting yet another irony. Genzyme, by spending much effort in pursuing surrogate markers, behaved as if it didn't believe clinical efficacy could be shown, Shrader said - but it was Genzyme's data gathered over time that spurred TKT to shoot for the efficacy endpoint, which turned out to be TKT's downfall with the panel.

"It's bizarre," he said.