By Randall Osborne

Editor

Baby boomers may recall days of their youth when an oft-run TV commercial for an over-the-counter remedy bemoaned "the heartbreak of psoriasis," prompting any number of mock-maudlin teen-ager jokes about the disorder.

The generation became more sensitive with time. Many got psoriasis themselves, a sobering development. Like the once-uproarious hemorrhoids and rheumatoid arthritis (as in, "My rheumatiz is acting up"), psoriasis is no longer funny.

It never was.

Afflicting some 7 million Americans, the chronic, autoimmune disease's most common form, plaque psoriasis, is known by the thick, red patches of raised skin it bestows upon sufferers. No cure exists. For suppression, patients often are treated with combined or rotated therapies including topical and systemic approaches, as well as ultraviolet light.

The scientific name for the condition -; psoriasis vulgaris -; hints at one of the disorder's most objectionable features: the scaly dead cells that shed constantly from the plaques or lesions, which crack, itch and hurt.

Seventy-five percent to 80 percent of those afflicted have what is classified as mild psoriasis, with the remainder enduring moderate to severe cases.

In the mild form, less than 2 percent of the patient's body is affected, typically the knees, elbows, scalp, hands and feet. Moisturizers and ointments can deal with this form. "Moderate" means 2 percent to 10 percent of the body surface is involved -; arms, legs, torso, scalp. Topical treatments, ultraviolet light, and oral medications may be used.

In severe psoriasis, more than 10 percent of the body is covered with plaques or erythrodermic (peeling) lesions. Patients with this form may also end up with psoriatic arthritis, a condition that bespeaks the autoimmune link between psoriasis and rheumatoid arthritis.

That link being is being investigated by drug developers with approved treatments for RA, such as Immunex Corp. and Centocor Inc., which are testing Enbrel (etanercept) and Remicade (infliximab), respectively, for psoriasis. Both are in Phase II studies.

They are not alone. The market opportunity -; with about 2.5 million people seeking treatment each year in the U.S., about a third of them in the moderate to severe category -; has drawn a crop of players. Elise Wang, analyst with Salomon Smith Barney in New York, sees "a major multihundred-million dollar" market for a psoriasis drug that proves its mettle.

Who's trying? Aside from Immunex and Centocor, whose drugs target the tumor necrosis factor, a number of companies are experimenting with monoclonal antibodies at the Phase II level: Abgenix Inc. with ABX-IL8; IDEC Pharmaceuticals Corp. with IDEC-114; Protein Design Labs Inc. with Zenapax (dacluzimab); and MedImmune Inc. with MEDI-507.

Many paraded their data at the International Psoriasis Symposium in San Francisco last month, and emerging as the clear leaders with potential treatments for moderate to severe psoriasis were Biogen Inc., with Amevive (alefacept), a fusion protein that blocks activation of T cells by interfering in the LFA3/CD2 pathway; and Genentech Inc., with Xanelim (efalizumab), a humanized monoclonal antibody directed against the CD11a subunit of a ligand receptor on T cells.

Xanelim, being developed with Xoma Ltd. in a $35 million collaboration that dates back to 1996, blocks the receptor's binding to adhesion molecules on endothelial cells, and inhibits T-cell activation.

Amevive binds to the CD2 molecule on the surface of T cells, preventing interaction with LFA3 on the surface of antigen-presenting cells. It apparently works selectively, thus with fewer side effects than other, broader approaches.

Positive Phase III data on both drugs were offered at the symposium, but neither took a distinct lead, in the view of Wang, who wrote in a research note that "outstanding issues remain" for both products. The questions include "the optimal regimen, the optimal formulation (in particular, for Amevive), the durability of response, the long-term safety profile, and the use in combination with other therapies," she wrote.

More data are expected on both drugs in the next six to 12 months, Wang said.

"It's a little bit of a race," Wang told BioWorld Financial Watch. "They're neck and neck, although I think Biogen has more data."

Amevive has been tested in 1,500 patients, several hundred of those getting two courses of treatment and over 100 of them given multiple courses, as many as five courses over four years.

Biogen, she added, "disseminated some of their data in less than the best way," dividing it so that observers may not have seen the complete picture, by comparison with Genentech's presentation.

Still, data suggest patients "may take longer to achieve a response with Amevive but upon achieving [clearance] or near clearance of their disease, these patients may remain in remission for a prolonged period of time," Wang wrote.

This means Amevive "may represent a robust remittive, intermittent therapy, while Xanelim represents a potential strong induction therapy that must be given chronically," she wrote.

Given the many-pronged treatment attack made on psoriasis, could the drugs work in tandem?

"They'll both end up being used, but it remains to be seen whether they will be used together," Wang said.

Alex Hittle, biotechnology analyst with A.G. Edwards & Sons Inc. in St. Louis, said combining the drugs "makes intuitive sense," but neither company seems likely to embrace the concept. As Hittle put it: "I don't think anybody at the moment is thinking about doing combined trials."

Biogen "needs to round out its product offerings, and its most advanced candidate is Amevive," Hittle told BioWorld Financial Watch. The company's share of the multiple sclerosis market, by way of Avonex (interferon beta-1a) is "likely to flatten a little," he added.

Ares Serono SA, with its interferon beta-1a formulation, Rebif, wants to break into the U.S. market, and has been trying to prove the drug superior to Avonex in comparative studies. Serono's goal is to beat the orphan drug status granted Avonex by the FDA until 2003 for patients with relapsing-remitting MS.

Meanwhile, Wang predicted Biogen will submit regulatory filings for Amevive in the U.S. and Europe in the second half of this year, with a launch possible as early as the end of next year. Genentech and Xoma will sift their Phase III data, adding follow-up beyond the 12-week treatment phase, and then decide about filing the biologics license application for Xanelim, which could come late this year and lead to a launch in 2003, Wang said.

Biogen has a "slight lead" in terms of a regulatory filing, in Wang's view.

Hittle agreed. Opinions could change "if the FDA managed to guide both into a simultaneous panel review," he added, "but it seems Biogen is farther along, and the safety data have been quite clean."

Route of administration matters especially, he said.

"The key thing we were watching [with regard to Amevive] is whether or not intramuscular had comparable efficacy to intravenous," he said. "You don't put the psoriasis doctors in the position of having to do IV administration. We're hearing that gives them pause."

As it turned out, data showed the intramuscular shot had slightly more efficacy, Hittle noted. Xanelim also is a shot, self-given at home, like insulin.

"You're going to get stuck [with a needle] with either one," he said, but if the Biogen product required an IV route, Genentech could end up with an advantage.

Biogen's sales from Avonex will top $900 million this year, Hittle said, making it still the world's top-selling MS drug. But the market share has been eroding, thanks to competition from Teva Pharmaceutical Industries Ltd.'s Copaxone in the U.S., and Rebif in Europe.

Hittle predicted the FDA will let Rebif into the U.S. market in the middle of next year, and its sales will roughly equal Avonex's in five years.

With Biogen's problems -; a "hole in the middle" of its clinical pipeline and declining royalties -; Hittle said the company has cause to view the career of its psoriasis drug as plenty significant.

"It's important to Biogen, there's no two ways about it, whatever the outcomes of the Avonex-Rebif war," he said. *

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