Beclometasone Oral - DOR BioPharma: Beclomethasone Oral - DOR BioPharma. Drugs in R&D [Drugs R D] Journal article

DOR BioPharma is developing an oral tablet formulation of beclometasone diproprionate for the treatment and prevention of gastrointestinal graft-versus-host disease (GvHD) and for the treatment of gastrointestinal radiation injury. Beclometasone is a potent corticosteroid that has been marketed worldwide since the early 1970s as the active ingredient in a nasal spray and in a metered-dose inhaled formulation for the treatment of allergic rhinitis and asthma.The oral formulation under development with DOR, known as orBec((R)), is a single product consisting of two enteric-coated tablets. One tablet is intended to release beclometasone in the proximal portions of the gastrointestinal tract, while the other tablet is intended to release the agent in the more distal portions of the tract. orBec((R)) is designed to reduce the need for systemic immunosuppressive drugs, thereby improving the outcome of bone marrow and stem cell transplantation. DOR is awaiting regulatory approval of orBec((R)) in the EU and the US for the treatment of acute gastrointestinal GvHD. The product is also the subject of a phase II trial for the prevention of GvHD, and a preclinical animal study in radiation injury. orBec((R)) may also have application in treating other gastrointestinal disorders characterized by severe inflammation including irritable bowel syndrome, ulcerative colitis and Crohn's disease. DOR BioPharma has stated that orBec((R)) has the potential to be of significant benefit to paediatric patients with Crohn's disease.The oral beclometasone formulation was initially in development with Enteron Pharmaceuticals, a subsidiary of Corporate Technology Development. Enteron obtained the rights to oral beclometasone through an exclusive, worldwide, royalty-bearing license agreement with George B. McDonald, M.D., in October 1998. The agreement provided Enteron with the option to grant sublicenses for the rights to the intellectual property and know-how relating to the agent. However, Corporate Technology Development was acquired by Endorex Corporation in December 2001 and the resulting company underwent a name change to become DOR BioPharma.In February 2008, DOR BioPharma entered into a Letter of Intent with BL&H in regard to the administration of a Named Patient Program (NPP) for orBec((R)) to patients with gastrointestinal GvHD in South Korea. This agreement gives the right for medical practitioners to prescribe investigational drugs to patients who qualify. DOR will be responsible for the manufacture and supply of orBec((R)) while BL&H will be covering distribution costs in Korea.According to a letter of intent signed in November 2007, Orphan Australia has agreed to act as a sponsor for DOR BioPharma with regard to the administration of a Named Patient Access Program (NPAP) for orBec((R)) to patients with gastrointestinal GvHD in Australia, New Zealand and South Africa. Under the NPAP compassionate use drug supply programme, the Therapeutic Goods Administration (TGA) allows medical practitioners to supply investigational drugs to patients who qualify. Both Orphan Australia and DOR will receive revenue for supplying orBec((R)) under the NPAP. New Zealand and South Africa also have similar access mechanisms for supply under a named patient basis.DOR BioPharma received $US3 million under a non-binding letter of intent from Sigma-Tau Pharmaceuticals in January 2007. The agreement granted Sigma-Tau an exclusive right to negotiate terms and conditions for a possible business transaction or strategic alliance regarding orBec((R)) and potentially other DOR BioPharma pipeline compounds until 1 March 2007. Under the terms of the agreement, Sigma-Tau purchased $US1 million of DOR BioPharma's common stock, with an additional $US2 million paid in cash. However, as no agreement was reached by the specified date, DOR returned the $US2 million to Sigma-Tau in June 2007. DOR BioPharma received an unsolicited proposal from Cell Therapeutics, Inc. to acquire DOR BioPharma in January 2007. Because of the non-binding agreement already signed with Sigma-Tau, DOR BioPharma was not able to consider the merger proposal.In November 2001, Corporate Technology Development (now DOR BioPharma) initiated a phase II trial in the US to evaluate the efficacy of orBec((R)) in the treatment of Crohn's disease. This trial is no longer active but DOR BioPharma is exploring the possibility of continuing the testing of orBec((R)) for Crohn's Disease.The US FDA issued a non-approvable letter in October 2007 in response to the NDA submitted by DOR BioPharma for the use of orBec((R)) in the treatment of gastrointestinal GvHD. The non-approvable letter followed on from a ruling by the Oncologic Drugs Advisory Committee (ODAC) of the FDA in May 2007 that the data package supporting the product did not show substantial evidence of efficacy for the treatment of gastrointestinal GvHD. The FDA requested data from additional clinical trials to demonstrate safety and efficacy of the product, as well as information regarding other sections of the NDA.Research for this compound has been aided by a $8.5 million common stock purchase agreement between DOR BioPharma and Fusion Capital Fund II, LLC, which was confirmed in February 2008.In February 2008, DOR BioPharma completed clinical trials for the use of the drug in the treatment of gastrointestinal GvHD. It showed that signficantly fewer patients randomized to orBec((R)) had deterioration of pulmonary diffusing capacity by transplant day 80 compared with placebo. It may have a protective effect accompanied by prevention of clinical pulmonary events. These beneficial effects on the lungs may be due to the delivery of the immunosuppressant 17-BMP, an active metabolite of BDP, to the pulmonary artery. Therefore oral BDP may prevent pulmonary interstitial inflammation and subsequent lung injury.The data provided in the MAA and NDA submissions demonstrated that orBec((R)) provided a lower risk of mortality compared with the standard of care. Both filings were supported by data from two randomized, double-blind, placebo-controlled clinical trials. The first trial was a 60-patient phase II trial conducted at the Fred Hutchinson Cancer Research Centre. The additional trial was a 129-patient pivotal phase III trial of orBec((R)) conducted at 16 centres in the US and France. The phase III trial failed to meet its primary endpoint of treatment failure through 50 days after allogeneic haemopoietic stem cell transplantation. However, orBec((R)) did achieve statistical significance in the secondary endpoints of time to treatment failure through day 80, and a reduction in mortality compared with placebo. In this trial, patient survival at the pre-specified endpoint of 200 days post-transplant showed a statistically significant 66% reduction in mortality among patients randomized to orBec((R)). DOR BioPharma believes the primary endpoint was not achieved as a result of a higher than expected rate of treatment failures during the initial 10 days in both treatment groups.The EMEA commenced a review of the MAA for orBec((R)) in the treatment of gastrointestinal GvHD, in November 2006. A response is expected by DOR BioPharma in the first half of 2008.DOR BioPharma has commenced a phase II trial of orBec((R)) to prevent gastrointestinal GvHD in patients undergoing a donor stem cell transplant for haematological cancer. The trial is supported by a National Institutes of Health (NIH) grant awarded to the Fred Hutchinson Cancer Research Center. The randomized, double-blind trial will enroll 138 patients, with 92 patients in the orBec((R)) arm and 46 patients in the placebo arm. Treatment will be administered in conjunction with a conditioning regimen and will continue for 75 days after transplant. The trial aims to determine if prophylactic administration of orBec((R)) can favourably influence the incidence and severity of acute GvHD, thereby decreasing the need for high-dose systemic corticosteroid treatment. DOR received FDA clearance to conduct the phase II trial in March 2007. Patient enrolment is expected to be completed in the second quarter of 2008.

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