Washington Editor

GAITHERSBURG, Md. - An FDA panel of experts voted in favor of Raptiva, a humanized monoclonal antibody made by Genentech Inc. and XOMA Ltd. for the treatment of moderate to severe plaque psoriasis in adults.

In a unanimous vote, the Dermatologic and Ophthalmic Drugs Advisory Committee said the overall risk-benefit comparison of Raptiva is favorable. Panel members also said by a 9-2 margin that the drug was efficacious. The committee will forward its decision to the FDA, which is not bound by the recommendation.

Raptiva (efalizumab, formerly Xanelim) is a targeted T-cell modulator designed to selectively and reversibly block the activation, migration to the skin and trafficking of the T cells that play an underlying role in psoriasis.

"Clearly, we're excited for the company and the psoriasis patients, because Raptiva has so much potential for psoriasis patients," said Charles Johnson, Genentech's senior director and therapeutic unit head, specialty biotherapeutics.

The product is attractive to many sufferers because it's a once-weekly subcutaneous injection that can be self-administered. Genentech estimates that of the 4.5 million Americans who have psoriasis, 1.5 million are considered to have moderate to severe disease. Mike King, managing director, Banc of America Securities in New York, believes U.S. sales of Raptiva will reach $178 million by 2008.

Genentech, of South San Francisco, and XOMA, of Berkeley, Calif., submitted a biologics license application complete with four Phase III trials and a database of 2,700 patients. Previously, the companies had said they expected FDA action in October. If that is the case, Genentech would be prepared to launch in December, Johnson said.

Genentech will get 75 percent of U.S. revenues, with XOMA getting 25 percent.

While the panel agreed that Raptiva is efficacious, several members raised concerns about long-term or interrupted use of the product. As for long-term use, the companies provided two-year data on only 218 patients, an amount considered insufficient by Robert Katz, a panel member and dermatologist at the Dermatology Clinic in Rockville, Md.

Katz and others recommended that Genentech and XOMA conduct Phase IV trials to look at use beyond 12 weeks and 24 weeks, as analyzed in the Phase III trials.

Beyond that, panel members questioned the companies about intermittent use of Raptiva, after learning that most serious adverse events occurred following discontinuation of the product. Among the trial population, including placebo groups, 19 participants, or 0.7 percent, experienced a "serious" adverse event. Fourteen out of the 19 occurred on stopping the drug.

Indeed, Johnson said flare-ups or rebounds could occur in certain patients who abruptly end Raptiva treatments. The numbers are so small that it cannot be said definitively that the rebounds are related to taking the drug, he said.

To that, Kathleen Sawada, a panelist and dermatologist at the Alpine Dermatology Associates P-LLC in Lakewood, Colo., recommended that the companies warn physicians about the downfalls of intermittent use on the label.

Most patients' Psoriasis Area and Severity Index scores improve in clinical trials.

Raptiva was studied in four randomized, placebo-controlled Phase III trials in patients with stable, chronic, moderate to severe plaque psoriasis.

The primary efficacy endpoint was the proportion of patients with 75 percent or greater improvement from baseline in PASI scores.

In the pivotal Phase III, the PASI-75 and PASI-50 (or PASI-50 percent) responses were statistically significantly higher for the Raptiva group, compared to the placebo group (p<0.001), the companies reported. In all three supportive studies, the benefit of Raptiva treatment was consistent with the pivotal trial.

After 12 weeks of treatment, the companies said 27 percent of patients had PASI-75 improvement while 59 percent of patients had a PASI-50, compared with placebo rates of 4 percent and 14 percent, respectively. Raptiva's efficacy improves with continuous treatment after 12 weeks. After 24 weeks of Raptiva treatment, 44 percent of patients had PASI-75 improvement and 66 percent of patients had PASI-50 improvement.

Although PASI scores accounted for both the primary and secondary endpoints, Robert Stern, acting chairman and professor of dermatology at Beth Israel Deaconess Medical Center in Boston, cautioned that a decreased PASI does not necessarily correspond to whether the patient is improving. "PASI is not a gold standard; it is a brass standard, and some believe it may be less than that," he said.

But, before casting his vote in favor of Raptiva, Katz said the drug shouldn't necessarily be used as first-line therapy because only one in five clinical trial participants achieved a PASI of 75 percent of greater. "We're talking about 1,000 bucks for one shot for 12 weeks," he said, also mentioning a desire to see long-term data on the drug.

As for safety, the FDA reported seven deaths in the entire 2,700-person database, including two who died during the trials and five who died afterward. Deaths were attributed to a number of causes including cancer, infection and in one case a car accident.

Serious or non-serious psoriasis-related events (headaches, nausea, chills, pain, fever) occurred in 52 out of 1,620 people, or 3.2 percent of treated patients, and 10 of 715, or 1.4 percent, of placebo patients.

When Raptiva enters the market, it will be joining several other medications including Amevive (alefacept), an immunosuppressive and the first biologic agent approved for psoriasis, made by Cambridge, Mass.-based Biogen Inc. Enbrel, a TNF blocker made by Amgen Inc., is approved for psoriatic arthritis, rheumatoid arthritis and spinal arthritis. It is often used off label as a treatment for psoriasis. (See BioWorld Today, Feb. 3, 2003, and Sept. 16, 2002.)

Amgen, of Thousand Oaks, Calif., has filed to market Enbrel as a treatment for psoriasis, and expects FDA action in the first half of 2004. Other TNF blockers under development in psoriasis are Remicade (infliximab), made by Centocor Inc., of Malvern, Pa., and Humira, Abbott Laboratories' product for rheumatoid arthritis.