VALORTIM® - PROPHYLACTIC and THERAPEUTIC ANTI-ANTHRAX MONOCLONAL ANTIBODY (MAb)
Bacillus anthracis Infection
Bacillus anthracis is a spore forming, gram positive bacterium that has potential use as a weapon
of bioterror when delivered in an aerosolized form. Following germination of the spores, the bacteria
replicates and produces three toxins. Anthrax Protective Antigen (PA) initiates the onset of the
illness by attaching to cells in the infected person, and then facilitates the entry of the two
additional destructive toxins - Lethal Factor (LF) and Edema Factor (EF) into the cells.
Anthrax Monoclonal Antibody: Valortim®
Valortim® is a fully human monoclonal antibody designed to protect against inhalation anthrax, the
most lethal form of illness in humans caused by the Bacillus anthracis bacterium. The investigational
antibody targets a protein component of lethal toxins produced by the bacterium known as the anthrax
protective antigen. The anthrax protective antigen initiates the onset of the illness by attaching to
cells in the infected person, and then facilitates the entry of additional destructive toxins into
the cells. Valortim® is designed to target anthrax protective antigen and protect the cells from damage
by the anthrax toxins. In preclinical studies, Valortim® both protected against infection, and when
administered some time after exposure, it induced recovery and survival in animals exposed to lethal
doses of inhalation anthrax spores.
The key characteristics of Valortim®, the anthrax monoclonal antibody include:
-
Fully human monoclonal antibody with affinity
for PA.
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Prophylaxis setting: Nearly complete protection
of animals challenged with more than 100 times
the median lethal dose (LD50) of anthrax spores.
-
Equivalent efficacy at all doses tested; Lowest
dose tested = 1mg/kg.
-
Post exposure setting: Administration at 24-hours
post exposure to anthrax spore challenge provided
equivalent protection as prophylactic setting.
-
Therapeutic setting: Significant protection of
animals when administered after appearance of
disease symptoms.
-
Antibody binding to a novel site of PA
permitting protection after toxins have
already attached to the cell.
-
Superior activity in the toxin neutralization
assay (TNA), through a novel mechanism of
action.
Development Timeline
Preclinical efficacy trials have been completed with Valortim® and show evidence of therapeutic activity to
symptomatic animals in the rabbit inhalation anthrax model. Studies demonstrate that dose levels as low as
1 mg/kg and serum levels below 20 ug/ml are efficacious in preventing mortality in two animal models
(rabbit and monkey) before the clinical course of the disease has initiated. The lowest protective dose has
not yet been defined.
A study in non-human primates has demonstrated the potency of Valortim® using the potentially most clinically-useful
intramuscular route of administration. In this study, the animals were challenged with a target aerosol dose of 200
times the median lethal dose of B. anthracis spores; 6 animals received no treatment, 6 animals received 1 mg/kg of
Valortim intramuscularly, and 6 animals received 10 mg/kg of Valortim® intramuscularly, all at the time of aerosol
challenge. None of the animals were given antibiotics or other therapies. All control animals died within one week
of the challenge; all treated animals in both dose groups were reported alive 90 days post-challenge.
PharmAthene and Medarex have completed a Phase I open-label, dose-escalation clinical trial to evaluate the safety,
tolerability, immunogenicity, and pharmacokinetics of a single dose of ValortimTM administered intravenously or
intramuscularly in 46 healthy volunteers. The Phase I data showed that Valortim was safe and well-tolerated at the
doses administered. No drug-related or serious adverse events were reported. In addition, the data suggest that a
single dose of Valortim given by the convenient intramuscular route of administration could provide protection
against anthrax for up to two months, comparable to what is observed in previously immunized individuals.
Valortim® has received Fast Track and Orphan Drug designation from the Food and Drug Administration, indicating
that the FDA will facilitate the development and expedite the regulatory review of the product. Total government
funding committed to Valortim® now exceeds $24 million.
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Medarex and PharmAthene Collaboration
Medarex, Inc. (NASDAQ: MEDX) and PharmAthene entered into a collaborative agreement under which the companies plan
to jointly complete clinical development and commercialize Valortim®. Valortim® was developed by
Medarex using its UltiMAb Human Antibody Development System® in collaboration with Dartmouth Medical School and
United States Army Medical Research Institute for Infectious Diseases (USAMRIID).
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