DOR BioPharma Inc. closed out 2004 with topline results of its pivotal Phase III trial of orBec for intestinal graft-vs.-host disease, showing the oral therapy missed its primary endpoint but demonstrating a highly statistically significant reduction in mortality.

The company's stock (AMEX:DOR) rose 17 percent, or 10 cents on Thursday, to close at 70 cents. By Monday, the stock had returned almost to its starting point, closing at 61 cents. It dropped another 4 cents on Tuesday to close at 58 cents.

DOR had been targeting the early part of 2005 for a new drug application submission, but that most likely will be delayed while the company meets with the FDA to determine whether another trial is required.

"We do intend to assemble this data and have a meeting with the FDA," said Michael Sember, CEO of Miami-based DOR. "We'll be requesting that meeting virtually immediately, within the next 30 to 60 days. And the next step would be to present the data."

Sember declined to give new guidance on a potential NDA filing until after the FDA meeting.

The pivotal trial of orBec began in 2001 and took about three years to complete. It enrolled 129 post-bone marrow transplant patients with Grade II intestinal graft-vs.-host disease (iGVHD).

The randomized, double-blind, placebo-controlled trial was conducted at 16 bone marrow transplant centers in the U.S. and France. All patients were treated for the first 10 days with high-dose prednisone in combination with an oral dose of either orBec at 8 mg per day or placebo. If patients responded to treatment, the high-dose prednisone was tapered and patients received orBec or placebo for an additional 40 days.

The primary endpoint was the time to treatment failure, at which point the patients needed additional therapy. Secondary endpoints included the proportion of treatment failures and clinical scores at days 10, 30, 50, 60 and 80, as well as the cumulative exposure to systemic steroids and mortality at day 200 post-transplant.

OrBec did not achieve statistical significance in its primary endpoint (p=0.1177), but it did achieve it in the secondary endpoint of time to treatment failure through day 80 (p=0.0226).

"The process with the FDA requires that you predetermine an endpoint and you are more or less stuck with that," Sember told BioWorld Today. "But in retrospect, it is important to recognize that that endpoint is a nonclinical endpoint.

"We had statistical significance at 80 days, showing trends in favor of orBec," he added. "Coupled with the mortality data, that makes the whole thing more positive."

OrBec demonstrated a 70 percent reduction in mortality. Only five deaths in orBec-treated patients occurred by day 200, compared with 17 deaths in the placebo group (p=0.006).

The missed primary endpoint might be due to a higher-than-expected rate of treatment failures during the first 10 days of the study, when patients were receiving high-dose prednisone with orBec or placebo. DOR is in discussions with the FDA as it further analyzes that group and considers its statistical impact on the primary endpoint. The company said the treatment failure rate at day 50 approached statistical significance (p=0.0515).

In a previous Phase II study, orBec achieved statistical significance in the primary endpoint showing that at day 30, iGVHD patients were able to consume at least 70 percent of their daily caloric intake by mouth, as compared to intravenous parenteral nutrition administration in the hospital. That trial enrolled 60 patients, with 71 percent in the orBec arm and 41 percent in the placebo arm showing a treatment response (p=0.02).

Intestinal graft-vs.-host disease is a life-threatening side effect of bone marrow transplants, which are used to treat leukemia and other cancers. When iGVHD develops, the current standard of care is systemic corticosteroids, such as prednisone, and other immunosuppressants, such as cyclosporine. However, those therapies substantially inhibit the graft-vs.-leukemia effect of bone marrow transplants.

"It's sort of a paradoxical situation," Sember said, "that the side effect you're dealing with here, iGVHD, requires use of systemic immunosuppressives," which then reduce the benefits of the transplant.

OrBec acts locally by treating the gastrointestinal manifestation of GVHD, and it is intended to reduce the need for systemic immunosuppressives. By being locally administered, orBec should have less of a negative effect on the "underlying bone marrow transplant's success," Sember said.

OrBec is an oral formulation of beclomethasone dipropionate, which has been marketed in the U.S. and worldwide since the early 1970s as a nasal spray and in a metered-dose inhaler to treat patients with allergic rhinitis and asthma. The product has orphan drug and fast-track designations from the FDA.

"This is not, in all likelihood, a billion-dollar market in terms of iGVHD," Sember said. "But we think it's going to be a fairly attractive market."

In the U.S., there are about 8,000 transplant patients per year, half of whom are at risk for iGVHD. About 2,000 to 3,000 of them have Grade II disease.

However, the potential for orBec goes beyond iGVHD.

"We think that there's a possibility that orBec will be useful in much more commercially attractive indications, such as irritable bowel syndrome, ulcerative colitis and Crohn's disease," Sember said.

The company expects to make decisions and possibly start development in those indications in the "near term."

George McDonald of the Fred Hutchinson Cancer Research Center invented orBec, which came into DOR's hands through its 2001 acquisition of Corporate Technology Development Inc., of Miami. At that time, DOR was known as Endorex Corp.

Aside from its focus on biotherapeutics, DOR is concentrating on developing vaccines against bioterrorism agents, such as the ricin and botulinum toxins. Human clinical trials are about to begin at the University of Texas Southwestern Medical Center for DOR's ricin vaccine, RiVax. As for its botulinum toxin vaccine, BT-VACC, DOR is engaged in manufacturing and scale-up development efforts, Sember said.

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