Graft vs. Host Disease (GVHD) is an expensive life-threatening complication following allogeneic hematopoietic cell transplantation in some patients that receive this life-saving treatment for certain cancers. The proposed open-label, multi-center, two-part Phase 2 clinical study is designed to evaluate the potential of orBec(R), a novel formulation of oral beclomethasone 17,21- dipropionate (BDP), as a treatment for chronic gastrointestinal cGVHD. OrBec(R), as developed by Soligenix, is formulated as two separate drug products for oral administration as an immediate release and delayed release tablet, each containing 1 mg of BDP, a potent, locally-acting corticosteroid originally developed primarily for the prevention and treatment of acute gastrointestinal graft versus host disease (aGVHD). The reduced systemic bioavailability of oral BDP offers a major therapeutic advantage over systemic glucocorticoids such as prednisone and methylprednisolone, which have well-recognized adverse effects (e.g., development of glucose intolerance, Cushingoid habitus, muscle weakness and fatigue, bone demineralization, and increased risks of infections). Adverse effects of systemic glucocorticoid administration can be avoided by use of topically active glucocorticoids. The protocol for this Phase 2 CLINICAL STUDY was submitted to IND 20,212 June 24, 2011. To date, no additional FDA feedback on the study design has been noted by the FDA. We will conduct this Phase 2 clinical study with the following specific goals, which form the Specific Aims of this proposal: To conduct a FDA reviewed and accepted Phase 2 clinical study: the study will be a point estimate design aimed at elucidating the dose response needed to define future placebo-controlled studies. The placebo-controlled study will be the Phase 3 clinical study that will be described in the Phase II SBIR proposal. This study will estimate the proportion of subjects who achieve a complete response (CR), partial response (PR) and overall response (OR) of GI GVHD signs and symptoms when treated with orBec(R), 2 mg four times a day (8 mg/day) for up to 16 weeks, in patients with cGVHD. The secondary objectives of this study are to determine the: i. proportion of subjects who experience a flare/worsening of GI GVHD;ii. time to flare/worsening of GI GVHD at each dose-level;iii. time to CR during the initial 16 weeks of orBec(R) treatment;and iv. time to flare/worsening of GI GVHD signs and symptoms during each of the planned orBec(R) dose reductions in Part 2 of the study. The safety objectives are to evaluate safety and tolerability of orBec(R) in subjects with cGVHD. Upon completion of the Phase 2 clinical study, Soligenix will be in a position to begin the process for a Phase 3 FDA reviewed and accepted clinical study, on the road to the first drug to be approved for treatment for cGVHD.
Currently there are no FDA approved therapies specifically for prevention or treatment of chronic GVHD (cGVHD). Furthermore, there are no FDA approved therapies for the prevention of the gastrointestinal manifestation of cGVHD. Off-label treatments (e.g., prednisone) are typically used;however, they can be associated with serious side effects that seriously diminish the quality of life for cancer survivors that have undergone life saving hematopoietic cell transplantation. More simply stated the underlying hematologic malignancy can be cured;however, the treatment utilized comes with its own set of negative consequences. This grant application requests funding to initiate (via a Phase 2 clinical study) the clinical evaluation of orBec(R), oral beclomethasone 17,21- dipropionate (BDP) for use in treating the gastrointestinal signs and symptoms associated with cGVHD. OrBec(R) is a two tablet system consisting of 1 delayed release and 1 immediate release tablet each containing 1mg BDP. The development of cGVHD and its GI complications significantly impacts the patient's quality of life and can in some cases be fatal. Based on previous clinical studies and the pharmacology of BDP, Soligenix and its medical advisors believe that orBec(R) has the potential to treat the GI manifestation of cGVHD, thereby improving the quality of life of cancer survivors as well as potentially impacting overall mortality. Upon completion of the proposed clinical study, Soligenix intends to evaluate the data generated with the intent of designing a placebo-controlled clinical study (e.g., Phase 3) to demonstrate both the safety and efficacy of orBec(R) for use in this indication.