MEDAREX AND ANTHRAX
Promising Results of Medarex’ Drug Valortim in Preventing and Treating Anthrax infection

Valortim™ is an investigational fully human monoclonal antibody developed by Medarex and the private firm PharmAthene. The drug is designed to protect against anthrax infection, including inhalation anthrax, the most lethal form of illness caused by the Bacillus anthracis bacterium. The investigational antibody, also known as MDX-1303, is designed to target a protein component, anthrax protective antigen (PA), of the deadly toxin complex produced by the bacterium. PA is believed to initiate the onset of the illness and facilitate the entry of additional destructive toxins into the cells. Results of recent studies of Valortim™ on an improved new primate model of inhaled anthrax infection developed at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) suggests that the drug is effective.

RESULTS: Valortim or saline (control) were introduced by intravenous injection. The results demonstrate that 50% of the Valortim-treated animals survived compared to none of the saline-treated animals. These survival results are considered very promising in view of the fact that the animals were poised to manifest severe symptoms and death at the time they when they were given Valortim.

In preclinical studies, Valortim has, indeed, induced recovery and survival in animals exposed to lethal doses of inhaled anthrax spores. In non-human primates, the drug demonstrated potency by intramuscular (IM) route, which is the most clinically useful. The animals in this study were challenged with 200 times the median lethal dose of B. anthracis spores; 6 animals received no treatment, 6 animals received Valortim 1 mg/kg IM, and 6 animals received Valortim 10 mg/kg IM, all at the time of aerosol challenge. None of the animals were given antibiotics or other therapies. All treated animals in both dose groups were reported alive 60 days post-challenge. All control animals died within one week of the challenge. The effectiveness of doses even lower than 1.0 mg/kg may be studied in future preclinical research.

In a completed Phase I study Valortim was administered intravenously (IV) and intramuscularly to healthy human volunteers. The drug was well tolerated at doses as high as 20 mg/kg IV, and was not immunogenic. A single intramuscular dose of Valortim produced levels of antibodies in humans that correspond to protective levels in animal models and is well tolerated. Based on the impressive human safety and animal efficacy data collected to date, Medarex and ParmAthene believe that the results meet the needs of the U.S. Government and Valortim could ultimately be selected for inclusion in the Strategic National Stockpile to provide protection to the American public.

Medarex and PharmAthene plan to continue to collaborate with USAMRIID to further refine the model and determine the optimal therapeutic dose for Valortim. The current studies in a non-human primate model that may be more relevant to human disease provide additional confirmation for the results. The methodological advances of the group at USAMRIID may help to better define the therapeutic potency of Valortim and other agents in this challenge setting.

“We believe that there are distinct characteristics of Valortim that make it an ideal choice for military and civilian protection against an anthrax bioterrorist attack,” commented David P. Wright, President and Chief Executive Officer of PharmAthene. “As our Phase I results have demonstrated, a single intramuscular dose of Valortim produces levels of antibodies in humans that correspond to protective levels in animal models and is well tolerated. Based on the impressive human safety and animal efficacy data collected to date, we believe that Valortim could meet the needs of the U.S. Government and could ultimately be selected for inclusion in the Strategic National Stockpile to provide protection to the American public.”

In the pilot study conducted at USAMRIID, adult African Green monkeys were exposed to aerosolized anthrax spores and blood samples were collected at regular intervals beginning 24 hours post-exposure. The samples were closely monitored for evidence of bacteremia. Protective antigen is one of the toxins produced by B. anthracis and its presence in the blood is being evaluated as a surrogate marker for symptomatic anthrax disease. Once bacteremia was detected, animals were administered either Valortim or saline (control) by intravenous injection. In the study, 50% of the Valortim-treated animals survived compared to none of the saline-treated animals.

Preclinical studies describing the activity of Valortim against anthrax infection were published in the October 2006 issue of the journal Infection and Immunity. An article abstract is available on the journal web site at:
http://iai.asm.org/cgi/content/abstract/74/10/5840.

Conclusion: Valortim is not the first or the last investigational drug in Medarex’ pipeline that demonstrates safety and efficacy.

MEDAREX (MEDX) announced the receipt of a Special Protocol Assessment (SPA) letter from the FDA for the initiation of a registrational clinical trial of ipilimumab (also known as MDX-010) used in combination with chemotherapy in previously untreated (first-line) metastatic melanoma patients. The SPA agreement with the FDA concerns the suitability of the trial design to support regulatory approval.

The clinical trial is expected to commence shortly and to enroll approximately 500 patients with previously untreated Stage 3 or Stage 4 metastatic melanoma. Patients will receive 10 mg/kg of ipilimumab in combination with dacarbazine, or dacarbazine alone once every three weeks for up to four doses. Subsequently, patients who have not experienced disease progression at week 24 will continue with a single dose of ipilimumab once every 12 weeks until disease progression. The study is designed to assess progression-free survival as the primary endpoint. Secondary endpoints include overall survival, progression-free survival rate at week 12, best overall objective response rate and duration of responses, and disease control rate (complete and partial responses plus stable disease).

Medarex believes that the combination of ipilimumab and chemotherapy may provide a potentially important treatment for metastatic melanoma, an area where new therapies are urgently needed.