Topical Steroid, Now a Pill, Lowers Risk of GvHD

SEATTLE, Jan. 24 -- Gastrointestinal graft-versus-host disease has been significantly reduced following allogeneic stem-cell transplants by the use of a common topical corticosteroid that was reformulated into pill form, according to researchers here.

The drug -- orBec (beclomethasone dipropionate, or BDP) -- reduced overall mortality as well in a multicenter phase III randomized, placebo-controlled trial of 129 patients, David Hockenbery, M.D., of the Fred Hutchinson Cancer Research Center here, and colleagues, reported online in Blood.

They also reported data from an earlier phase II randomized controlled trial of 60 patients conducted at the Hutchinson center.

The standard treatment for gastrointestinal graft-versus-host disease GvHD, which affects up to 60% of patients getting an allogeneic stem-cell transplant, is immune suppression with prednisone at between 1 mg/kg and 2 mg/kg, Dr. Hockenbery and colleagues noted.

The prednisone is tapered off to avoid its side effects, but the GVHD often recurs, they said.

BDP is usually formulated either as a topical medication for skin conditions or as a nasal spray for allergies. In orBec, the medication is in two 1 mg pills, one in an immediate-release formulation and one enteric-coated for a delayed release. The medication is taken four times daily for a total dose of eight mg.

The idea is that the drug will target the stomach and mid-small intestine, Dr. Hockenbery said, and allow the prednisone to be tapered off more rapidly. "Oral BDP provides much more tailored and targeted control of gastrointestinal GvHD and it allows patients to move away from the side effects of standard prednisone therapy," he said.

In the phase III study, patients were given 10 days of prednisone treatment and randomized to either orBec or placebo. If symptoms resolved by day 10, the prednisone was tapered off. On an intent-to-treat basis, the risk of GvHD-treatment failure was reduced, but not significantly for the BDP group at day 50 (hazard ratio 0.63, 95% CI 0.35-1.13).

However, the outcome of all clinically important secondary endpoints, including were statistically significantly better in the BDP group.

• Among the 117 patients who were eligible for prednisone tapering, the risk of GvHD recurrence was significantly reduced by day 50, compared with the placebo group. The hazard ratio (HR) was 0.39 with a 95% confidence interval from 0.19 to 0.81, which was significant at P=0.009.

• By day 200 post-transplant, five orBec patients had died, compared with 16 on placebo, a 67% reduction in the hazard of mortality, which was statistically significant at P=0.03.

At one year after randomization, the mortality benefit was still apparent -- 28 patients (42%) in the placebo group and 18 patients (29%) in the orBec group had died. The hazard ratio was 0.54 with a 95% confidence interval from 0.30 to 0.99, which was significant at P=0.04.

"I think this is a very convincing clinical trial because by targeting topical therapy to the areas most affected, we were able to keep symptoms at bay while minimizing systemic immune suppression," Dr. Hockenbery said.

The results confirm findings from the earlier study, Dr. Hockenbery said. That trial showed a 45% reduction in mortality a year after randomization, as well as a significant response at the end of the treatment phase.

The data were part of regulatory filings to the FDA and the European Medicines Evaluation Agency (EMEA) by DOR BioPharma, Inc., of Miami, which makes orBec.

The study was supported by a grant from the FDA and by Enteron Pharmaceuticals, Inc., a subsidiary of DOR BioPharma.

Three of the authors -- Scott Cruickshank, Ph.D. and Timothy Rodell, M.D., both of Enteron, and George McDonald, M.D., of the Hutchinson center - reported financial links with the study sponsor. Each is a consultant to DOR BioPharma and Dr McDonald has an equity position in DOR BioPharma, Inc.