From Medimmune's web site. Looks like we should be getting several study results reported this year:
MEDI-507: Anti-CD2 Humanized Monoclonal Antibody
MEDI-507 is a humanized monoclonal antibody being developed by MedImmune in collaboration with BioTransplant Incorporated. MEDI-507 was derived from a rat monoclonal antibody called BTI-322. Both MEDI-507 and BTI-322 bind specifically to the CD2 antigen receptor found on T cells and natural killer (NK) cells. Laboratory studies have suggested that BTI-322 and MEDI-507 primarily inhibit the response of T cells directed at transplant antigens while subsequently allowing immune cells to respond normally to other antigens. The selectivity and long lasting effects of this inhibition suggest that these molecules may have potential utility in applications in the transplantation field including treatment or prevention of graft-versus-host disease (GvHD), or in patients with certain autoimmune diseases.
GvHD is a potentially fatal complication of bone marrow or stem cell transplantation caused when certain white blood cells from the donor bone marrow attack the tissue of the recipient. Clinical manifestations include skin rash, severe diarrhea, and liver abnormalities and jaundice. GvHD is usually treated with a first-line therapy of corticosteroids. Patients who develop moderate or severe GvHD have over a 70 percent chance of death despite diverse treatments. Lack of understanding of the physiologic mechanism of disease has been a major impediment to the development of more effective treatments. Both T cells and NK cells may play a role in development of GvHD. MEDI-507, which specifically inhibits both types of cells, may provide certain advantages over current therapies. There are approximately 30,000 bone marrow and stem cell transplants done worldwide each year.
Autoimmune diseases are of major medical importance worldwide and include common afflictions such as rheumatoid arthritis, multiple sclerosis, Crohn's disease and psoriasis. The Company believes the unique immune modulatory properties of MEDI-507 observed in vitro may have utility in certain autoimmune indications. A Phase 1 trial in psoriasis is currently ongoing to address that possibility.
BTI-322 was initially discovered by Drs. Hervé Bazin and Dominique Latinne at the Experimental Immunology Unit of the Catholic University of Louvain in Belgium. BioTransplant exclusively licensed BTI-322 and MEDI-507 to MedImmune for evaluation and potential commercialization. MedImmune is responsible for all activities related to commercialization, and BioTransplant would receive milestone payments at various stages related to regulatory approval and royalties if the products are commercialized. BioTransplant has retained the right to use BTI-322 and/or MEDI-507 in its proprietary ImmunoCognance™ systems, which are designed to reeducate the immune system to accept foreign tissue: AlloMune™ for human-to-human transplants and XenoMune™ for porcine-to-human transplants.
BTI-322 has been studied in over 100 patients in the United States and Europe including in a Phase 2 for treatment of steroid-refractory GvHD, and in a Phase 1/2 for prevention of renal transplant rejection. In the Phase 2 clinical trial evaluating BTI-322 for treatment of steroid-refractory GvHD, the compound was believed to be generally well-tolerated and 55 percent of the patients responded positively to treatment, with either a complete response or a reduction in grade of GvHD. The study was conducted at six transplantation centers in 20 patients who received allogeneic (non-self donated) bone marrow or stem cell transplantation, and who experienced acute GvHD that was unresponsive to corticosteroid treatment. The primary endpoints in the study were safety and reduction in grade of GvHD. All 20 patients received a single daily dose of BTI-322 (0.1 mg/kg) for ten consecutive days, in conjunction with a standard immunosuppression treatment regimen. The grade of GvHD was measured on a scale of 1 (mild) to 4 (severe) with patients experiencing an overall reduction in the grade of GvHD from 2.95 to 1.80 (p=0.0005). For the trial, 11 patients responded positively to treatment, with six patients experiencing a complete response to treatment and five patients showing a reduction in the grade of GvHD. In three patients, the grade of GvHD did not progress to a more severe stage. The grade of GvHD decreased from 2.82 to 0.73 (p<0.00001) for the 14 patients who responded to the BTI-322 therapy. Aside from mild/moderate first dose reactions, BTI-322 in the trial was generally well-tolerated. Some of the patients responding to BTI-322 later experienced a relapse of GvHD after treatment was completed, indicating that further studies of extended treatment regimens would be necessary.
A Phase 1/2 trial was completed for the prevention of acute renal transplant rejection in which BTI-322 was given at the time of organ transplantation. Results of the trial suggested a 58 percent reduction at two years post-transplant in the incidence of kidney graft rejection episodes compared to conventional triple drug therapy alone.
Because of the encouraging results of studies evaluating BTI-322, MedImmune moved forward during 1998 to evaluate in the clinic MEDI-507, the humanized version of BTI-322. In the MEDI-507 antibody, the rat components of BTI-322 are replaced with human components thereby reducing the likelihood that a recipient will recognize the drug as foreign and develop an immune reaction. This potential reaction is especially possible if the antibody is administered chronically in a patient whose immune system is not severely suppressed, such as in many patients with autoimmune diseases. Because MedImmune believes that limiting an immune reaction to the molecule could be advantageous in many medical settings, the Company intends to suspend development of BTI-322 while it moves forward with studies evaluating MEDI-507.
During 1998, the Company announced data from the first clinical trial evaluating MEDI-507. The study was a Phase 1, open-label, dose-escalating safety trial in renal allograft recipients examining three dose levels (0.012, 0.06, and 0.12 mg/kg/dose) of MEDI-507. Thirteen patients were given an initial dose within six hours after kidney transplant surgery and a second dose 60-72 hours later. Results indicated that MEDI-507 was generally well-tolerated and no anti-MEDI-507 antibodies were detected following administration. During the first 30 days of follow up, two patients experienced acute rejection.
During 1998, the Company concluded a second clinical trial of MEDI-507, a Phase 1/2 study evaluating MEDI-507 for the treatment of GvHD in adult steroid-resistant stem cell transplant (SCT) or bone marrow transplant (BMT) patients. In one of the arms of this clinical trial, the MEDI-507 dosing regimen was extended past the initial 10 days of treatment. The data from this trial are currently being analyzed and the results are expected to be presented at a medical conference in 1999.
In December 1998, the Company announced plans to initiate two additional Phase 1/2 clinical trials to evaluate MEDI-507. Both studies are expected to be completed in 1999. In the first study, adult steroid-naïve SCT or BMT recipients will receive MEDI-507 or placebo combined with corticosteroids (methylprednisolone) for initial treatment of acute GvHD. Because this study would be the first to evaluate MEDI-507 as part of initial treatment of GvHD, all patients are expected to receive the standard initial GvHD treatment with corticosteroids. It is anticipated that this Phase 1/2 trial will include up to 32 patients recruited from up to 15 centers. At year-end 1998, the trial protocol had been approved by the FDA, and patient recruitment had begun.
In the second study, MEDI-507 will be assessed in an open-label trial for its ability to treat GvHD in pediatric SCT or BMT patients. Currently there are no agents approved for the treatment of GvHD in children. Up to 20 pediatric patients (age 2-17) are expected to be recruited from at least ten centers for this Phase 1/2 study. At year-end 1998, the clinical trial protocol had been submitted for approval to the FDA and if approved, the study would commence enrollment following the entry of initial patients in the adult trial.
A Phase 1 clinical study evaluating MEDI-507 for the treatment of psoriasis is currently ongoing. The Company expects to have results from this trial in 1999.
In 1998, the Company announced that MEDI-507 received orphan drug designation from the Office of Orphan Products Development of the FDA for MEDI-507 for the treatment of GvHD. The Orphan Drug Act was established to encourage development of drugs for rare diseases and conditions affecting a small patient population (generally less than 200,000 people). Orphan designation of a product can potentially provide a company with seven years of market exclusivity if the company is the first to receive FDA product marketing approval for the orphan drug in the designated indication. Additionally, this designation provides a company with tax credits of 50 percent for clinical research expenses and the opportunity for clinical research grants.
During 1998, MedImmune announced issuance of two patents from the United States Patent and Trademark Office: a patent covering composition of matter and the use of BTI-322 and MEDI-507 to inhibit T cell-mediated immune responses, and a patent covering the use of any antibody that binds to the target epitope recognized by the BTI-322 and MEDI-507 antibodies.
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