BIOTHERAPEUTICS

orBec®
DOR's lead product, orBec® (oral beclomethasone dipropionate), is a potent,locally-acting corticosteroid being developed for the treatment of gastrointestinal Graft-versus-Host disease (GI GVHD) as well as other gastrointestinal disorders characterized by severe inflammation. The company has recently filed a New Drug Application (NDA) with the Food and Drug Administration (FDA) for orBec® for the treatment of GI GVHD.

GI GVHD is a life-threatening condition and one of the most common causes for bone marrow and stem cell transplant failure. These procedures are being increasingly used to treat patients with leukemia and other cancers to eliminate residual disease and reduce the likelihood of relapse. orBec® represents a novel oral, locally active therapy and is intended to reduce the need for systemic immunosuppressive drugs such as prednisone, which is currently used to prevent and control GI GVHD. Drugs such as prednisone have the unwanted and potentially dangerous side effects of weakening the patient's immune system leaving them susceptible to opportunistic infections as well as substantially inhibiting the intended anti-cancer effect of bone marrow and stem cell transplants. orBec® is designed to reduce the need for systemic immunosuppressive drugs and thereby improve the outcome of bone marrow and stem cell transplantation.

The NDA filing is supported by data from two randomized, double-blinded, placebo controlled clinical trials. The first was a 129 patient pivotal Phase III clinical trial for orBec® conducted at 16 bone marrow/stem cell transplant centers in the U.S. and France. The second trial was a 60 patient Phase II clinical trial conducted at the Fred Hutchinson Cancer Institute. While orBec® did not achieve statistical significance in the primary endpoint of its pivotal trial, namely time to treatment failure through Day 50 (p-value 0.1177), orBec® did achieve statistical significance in other key outcomes such as median time to treatment failure through Day 80 (p-value 0.0226). The risk of treatment failure at study day 50 was reduced by 37% for patients in the orBec® group relative to the placebo group and the cumulative treatment failure rate at study day 80 was statistically significant (p-value 0.0048) in favor of orBec® with 22 treatment failures versus 39 for placebo.

Most importantly in the pivotal Phase III trial, analysis of patient survival at the pre-specified endpoint of 200 days post-transplant showed a clinically meaningful and statistically significant 66% reduction (p-value 0.0139) in mortality among patients randomized to orBec®. The mortality benefit in favor of orBec® was corroborated in a retrospective analysis of the Phase II study in which there was a 55% reduction in mortality at 200 days post transplant. At one year after randomization, there were relatively consistent 51% and 45% reductions in the risk of mortality among patients randomized to orBec® in both the Phase III and Phase II studies, respectively.

Oral Leuprolide
Leuprolide is a potent analogue agonist of the Luteinizing Hormone Releasing Hormone (LHRH), currently used to treat hormone responsive prostate cancer in men, endometriosis in women, and precocious puberty in children. The current injected LHRH analog formulations are depot formulations that are designed to be injected under the skin and release Leuprolide in a controlled fashion over 1 to 4 months (Lupron® marketed by TAP Pharmaceuticals and Zoladex® marketed by Astra Zeneca) and for periods up to 6 months (Eligard®, marketed in the U.S. by Sanofi). Leuprolide is used in treating prostate cancer to slow the growth of the cancer. In children with central precocious puberty, Leuprolide reduces the levels of estrogen and testosterone. Estrogens promote the growth of abnormal uterine tissue that exists outside the uterus and thus Leuprolide is used to reduce the production of estrogen and treat both fibroids and endometriosis.

DOR is developing the Lipid Polymer Micelle (LPM) system for enhancing the intestinal absorption of water-soluble drugs/peptides that are not ordinarily absorbed or are degraded in the gastrointestinal tract. As the first example of a peptide drug that can be delivered orally, DOR is developing an oral formulation of the peptide drug Leuprolide, The LPM™ system is composed of safe and well characterized ingredients to enhance intestinal absorption.

Based on promising preclinical data and high bioavailability achieved in animals with oral administration of Leuprolide in the LPM™ system, DOR believes that LPM™-Leuprolide may have a competitive role in a segment of the current Leuprolide market and effectively compete with the depot formulations of Leuprolide. Specifically, DOR believes that LPM™ -Leuprolide can be developed as a once-a-day oral formulation that can maintain blood levels of Leuprolide resulting in suppression of estrogen production in women suffering from endometriosis. We believe there is a need for a better formulation of a LHRH-like product, such as LPM™-Leuprolide that will increase compliance and efficacy, with fewer side effects.

In preclinical studies, DOR has demonstrated significant intestinal absorption enhancement of both LPM™-Leuprolide and Leuprolide in comparison to solution formulations of the peptides in rats and dogs. Based on these promising preclinical data, DOR plans further development of LPM-Leuprolide when resources permit, which will lead to clinical studies for the treatment of endometriosis. Because of the wide applicability of Leuprolide in other medical conditions, such as in prostate cancer, it is possible that an oral formulation will prove to be useful for other indications. Obtaining marketing approval for further indications will require additional clinical testing in patients. In addition to LHRH and agonists, DOR plans to evaluate other classes of water-soluble drugs/peptides with the LPM system when resources permit.

Oraprine™
DOR plans to develop its product called Oraprine™ for a variety of indications and are initiating a strategy to introduce new formulations of the active drug compound initially by an Abbreviated New Drug Application (“ANDA”) regulatory route, and then for other novel medical indications. The active compound in Oraprine™ is azathioprine (AZA), which is a widely used immunosuppressant to inhibit rejection of the transplanted organ, primarily used in kidney transplant patients. AZA is also prescribed as a ‘‘second-line’’ treatment for severe, active rheumatoid arthritis in patients who are refractory to commonly prescribed arthritis medications. There is no formulation of this drug that can be preferentially taken by patients unable to ingest tablets or pills or a formulation that is preferred for juvenile rheumatoid arthritis patients. Therefore DOR plans to develop an oral liquid formulation to occupy this potential market niche.

Based on the outcomes of two Phase I clinical trials of Oraprine™, DOR is planning to reformulate AZA (OraprineTM) as a stable oral liquid suspension with the intent of demonstrating bioequivalence to the branded oral azathioprine tablets currently marketed in the United States (Imuran® and Azasan®). One Phase I bioequivalence trial was conducted with an early formulation and demonstrated bioequivalence to the marketed product. There has also been a small physician’s sponsored clinical study which demonstrated the potential utility of an oral liquid formulation to ameliorate oral lesions arising from graft versus host disease. DOR proposes to position Oraprine™ initially in the market as a specialty generic product to be used by transplant or rheumatoid arthritis patients who cannot swallow medicines in tablet form. The Compnay anticipates that the market will include the pediatric transplant populations, the elderly, and cancer patients who have received stem cell transplants.