FDA approves raxibacumab to treat inhalational anthrax
First monoclonal antibody approved using the Animal Efficacy Rule
The U.S. Food and Drug Administration today approved raxibacumab injection to treat inhalational anthrax, a form of the infectious disease caused by breathing in the spores of the bacterium Bacillus anthracis. Raxibacumab also is approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate.
Raxibacumab is a monoclonal antibody that neutralizes toxins produced by B. anthracis that can cause massive and irreversible tissue injury and death. A monoclonal antibody is a protein that closely resembles a human antibody that identifies and neutralizes foreign material like bacteria and viruses. Anthrax is a potential biological terrorism threat because the spores are resistant to destruction and can be easily spread by release in the air.
The FDA granted raxibacumab fast track designation, priority review, and orphan product designation. The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.
Raxibacumab is the first monoclonal antibody approved under the FDA’s Animal Efficacy Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct trials in humans. In this case, because inhalational anthrax is a rare and lethal disease, it is not possible to conduct adequate efficacy trials in humans.
“In addition to antibiotics, raxibacumab will be a useful treatment to have available should an anthrax bioterrorism event occur,” said Edward Cox, M.D., M.P.H, director of the Office of Antimicrobial Products in FDA’s Center for Drug Evaluation and Research. “Although antibiotics are approved to prevent and treat anthrax infection, raxibacumab is the first approved agent that acts by neutralizing the toxins produced by B. anthracis.”
Raxibacumab’s effectiveness for inhalational anthrax was demonstrated in one study in monkeys and three studies in rabbits. All animals were administered aerosolized B. anthracis spores, and efficacy was determined by survival at the end of the studies. Animals received varying doses of raxibacumab, placebo or antibiotics normally used to treat anthrax.
More animals treated with raxibacumab lived compared to animals treated with placebo. Sixty-four percent of animals in the monkey study and 44 percent of animals in one rabbit study receiving the 40 milligrams per kilogram dose of raxibacumab survived exposure to anthrax, compared with none in the placebo groups. All surviving animals developed toxin-neutralizing antibodies. Another study in rabbits showed that 82 percent of animals treated with antibiotics and raxibacumab survived exposure to anthrax compared with 65 percent of animals receiving antibiotic treatment alone.
The safety of raxibacumab was evaluated in 326 healthy human volunteers. Common side effects included rash, extremity pain, itching and drowsiness.
Raxibacumab was developed by Rockville, Md.-based Human Genome Sciences, in conjunction with the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority. Human Genome Sciences has since been acquired by GlaxoSmithKline.
Sentiment: Strong Buy
To clarify the somewhat misleading title, the latest drug approval using FDA’s Animal Rule is to expand the approved indications for Levaquin to the treatment and prevention of plague due to pulmonic or systemic infection with Yersinia pestis. Although other antibiotics are indicated as treatment for Y. pestis infection, the novel component of the Levaquin indication is its potential widespread use as a preventive agent in emergency situations. Y. pestis only infrequently causes plague at this time in history, several thousand cases worldwide and very rarely in the U.S. However, with the Center for Biologics Evaluation and Research’s efforts over the past decade to develop and license vaccines and treatments for agents of potential bioterrorism, Y. Pestis has now joined pathogens such as anthrax, smallpox and others as selected biowarfare targets of interest. Given the limited natural occurrence of plague and the ethical impossibility to test drugs in human volunteers with experimental exposures, the development program for such therapeutics falls to the Animal Rule.
The Animal Rule, issued in 2002, established guidelines for development of drugs as “medical counter-measures” against chemical, biologic, and radiologic threats based principally on animal data. The pathway sounds rather simplistic, i.e., provide evidence of the drug’s efficacy and safety in a relevant animal model with only limited requirements for human clinical safety information, including pharmacokinetic and pharmacodynamic data which would aid in establishing human dosing directions. As one might expect, the logical first candidates for such an agent would be a marketed drug, with an established safety profile and evidence of therapeutic activity, now to be approved for the supplemental indication via the Animal Rule. However, drug development according to this paradigm has been limited, with previous approvals only to cyanokit for cyanide poisoning and pyridostigmine for nerve gas poisoning. Each of these drugs brought along considerable human prior experience.
As discussed in a recent review (P. Aebersold. 2012. FDA experience with medical countermeasures under the Animal Rule, Adv Prevent Med vol. 2012, article ID 507571), development of a third potential drug via this pathway (a specific monoclonal antibody therapy for the infectious agent of anthrax) has been languishing for several years. The reasons for this situation appear to include several scientific issues, some of which should have been successfully resolved via better communication between the pharmaceutical sponsor and FDA. Although the anthrax drug is actually available via the Strategic National Stockpile, the nation’s repository of selected antibiotics, vaccines and various antidotes if the need arises in the setting of a natural pandemic or act of bioterrorism, it suggests a somewhat unfortunate conclusion: development of truly novel medical countermeasures may prove to be too costly to be practical. Given that the probability of a drug’s human efficacy and safety based on extrapolation from animal data is at best a scientific judgment, perhaps never to be confirmed with human data, it would seem reasonable for FDA to facilitate development of the broadest possible variety of therapeutic agents in the arsenal. The successful development and subsequent approval of Levaquin for the treatment and prevention of plague is the first approval via the Animal Rule of an anti-infective agent, and perhaps will set the stage for the approval of the anthrax agent as well. Bioterrorism continues to be a realistic risk, and it is reassuring to know that treatment options based on strong science are in progress.
Sentiment: Strong Buy
“Sixty-four percent of animals in the monkey study and 44 percent of animals in one rabbit study receiving the 40 milligrams per kilogram dose of raxibacumab survived exposure to anthrax”
You mean 36 percent of the monkeys DIED!!! And, it was approved? Inconceivable.
But, seriously, thanks King! VERY interesting.