Results of a Phase I Trial of a Potential Anthrax Therapeutic Reported
By Michael Mair, M.P.H., July 11, 2005
A study published in the July 1, 2005 issue of Clinical Infectious Diseases (Subramanian et. al., Clin Infect Dis. 2005 Jul 1;41:12-20) reports on a Phase I trial of a fully human monoclonal antibody against the Bacillus anthracis protective antigen, PAmAb, that is being developed as a potential therapeutic for anthrax. This is the first published study of a clinical trial employing an anthrax therapeutic candidate.
Protective antigen (PA) is one of the three essential components of ‘anthrax toxin'—one of the two major determinates of the anthrax bacteria's virulence. Currently there is no anthrax anti-toxin available. PAmAB works by neutralizing PA, thereby blocking action of anthrax toxin.
The Phase I trial was a randomized, single-blind, placebo-controlled, dose-escalation study of PAmAb. The study was conducted with 105 healthy volunteers and was designed to evaluate the safety, pharmacokinetics, and bioactivity of PAmAb at 3 intramuscular dose levels (0.3, 1.0, and 3.0 mg/kg) and 5 intravenous dose levels (1.0, 3.0, 10, 20, and 40 mg/kg). Two different intramuscular injection sites were evaluated: gluteus maximus and vastus lateralis. Subjects were observed for 56 days after dosing.
In general, PAmAb was safe and well tolerated (<15% of subjects receiving PAmAb had an adverse event that was reported to be related to the PAmAb), and most of the adverse events reported were transient and mild to moderate in severity. There was no relationship between the number of subjects with adverse events and dose, administration route, or administration site. Key study findings are as follows:
Single injections of PAmAb resulted in detectable serum concentrations throughout the 56-day study period in most test subjects.
The mean terminal elimination half-life for PAmAB ranged from 15 to 19 days (consistent with other fully human monoclonal antibodies).
The pharmacokinetics of PAmAb were linear within each route and site of administration but were significantly different between the two sites of intramuscular injection. Injection into the vastus lateralis resulted in higher serum concentrations, greater exposure, and higher bioavailability than injection into the gluteus maximus.
The concentrations of PAmAB that were achieved are comparable to, or in excess of, anti-PA antibody levels that have been correlated with a significant survival benefit in animal models of inhalational anthrax.
Anthrax therapeutics are important in the armamentarium against B. anthracis. It is believed that the morbidity and mortality associated with anthrax infection are largely mediated by its toxins. This was observed in 2001, when the mortality of inhalational anthrax was 45% despite modern and meticulous medical care, which included combination antimicrobial therapy to a susceptible strain of B. anthracis.
The Department of Health and Human Services has stated that it intends to use BioShield funds to purchase large amounts of anthrax therapeutics to the Strategic National Stockpile; however, no award has been made to date.