FDA Panel Endorses Novel Treatment for Inhalational Anthrax

Miriam E. Tucker

November 05, 2012

SILVER SPRING, Maryland — A US Food and Drug Administration (FDA) advisory panel has endorsed the use of a novel treatment for inhalational anthrax.

At a hearing on November 2, the FDA's Anti-Infective Drugs Advisory Committee (AIDAC) voted 16 to 1 (with 1 abstention) to endorse the clinical benefit of the recombinant human monoclonal antibody raxibacumab. The panel also voted unanimously, 18 to 0, in support of the product's safety.

In contrast to antibiotics, which eradicate the Bacillus anthracis bacterium itself, raxibacumab targets the toxins produced by B anthracis. These toxins are the cause of death in most human inhalational anthrax disease cases, including the 5 of 11 infected people who died, despite receiving antibiotic treatment, after being exposed to anthrax via letters that were sent through the US mail in the fall of 2001.

"Intensive antibiotic treatment is effective, but sometimes insufficient in treating the toxemia associated with late-stage infection," explained Gerald R. Kovacs, PhD, director of the Division of Chemical, Biological, Radiological, and Nuclear Medical Countermeasures Division of the Biomedical Advanced Research and Development Authority (BARDA) office, a division of the US Department of Health and Human Services.

Moreover, antibiotics would be of limited value in the case of multidrug-resistant anthrax, he noted.

The US government views anthrax as a category A threat agent, meaning that it "poses greatest possible threat" to the public. "Anthrax spores can be readily produced in vitro, and with the right technology, even weaponized," Dr. Kovacs said.

Raxibacumab was developed by Human Genome Sciences (HGS) under a US government contract solicited by BARDA after the 2001 anthrax attack. The drug is now a product of GlaxoSmithKline, which acquired HGS in July 2012. Raxibacumab is already included in the US Strategic National Stockpile, which includes vaccines, antibiotics, and antitoxins targeting anthrax. Several of these products are not yet licensed but are currently under study, Dr. Kovacs noted.

Raxibacumab is administered in a single 2-hour intravenous infusion.

Relying on Animal Data

Because naturally occurring inhalational anthrax infection in humans is rare and studies deliberately exposing humans to the pathogen would be unethical, efficacy studies of raxibacumab were conducted in animals under the FDA's Animal Rule. Established in 2002, the rule allows companies to seek approval for the marketing of drugs or biologics based on efficacy data from animal studies, provided certain criteria are met. Safety data can be collected from humans, however, as was done with raxibacumab.

If the FDA approves raxibacumab, it would be the first monoclonal antibody to be licensed under the Animal Rule.

At a previous hearing in 2009, the AIDAC had rejected raxibacumab based on 2 main concerns: one pertaining to efficacy and the other to safety. At the current hearing, officials from HGS and FDA presented data addressing those concerns.

In an "added benefit" study in 180 rabbits randomly assigned to receive raxibacumab plus levofloxacin or levofloxacin alone at 84 hours after anthrax challenge, 104 rabbits died before randomization. Of the remaining 76 rabbits, survival at day 35 was 82% with the combination vs 65% for levofloxacin alone. This 17% difference did not quite reach statistical significance (P = .0874).

According to HGS Senior Vice President Sally Bolmer, PhD, the lack of statistical significance was expected because the study would have had to include thousands of rabbits to be adequately powered, and was therefore not feasible. However, further statistical analysis determined a strong probability of a treatment effect beyond that of the antibiotic alone, she said.

The timing of drug administration in the new efficacy study differed from one presented to the panel in 2009, in which survival with antimicrobials alone was 100% compared with 85% to 94% with antimicrobials plus raxibacumab. In that study, the treatments were given at the first sign of clinical disease. The question arose whether that was too early to show benefit for raxibacumab and also whether it reflected a real-world scenario, FDA medical officer Yuliya Yasinskaya, MD, noted.

She said the new data suggest that raxibacumab does not interfere with efficacy of levofloxacin. In subsequent discussion, panel members noted that the data also suggest that both antimicrobials and raxibacumab should be given as soon as possible after anthrax exposure.

The safety issue that had raised concern in 2009 pertained to an apparent increased incidence and severity of central nervous system (CNS) lesions among raxibacumab-treated nonsurviving animals compared with placebo-treated nonsurviving animals. In a new CNS toxicity study, pathological CNS findings were absent in levofloxacin/raxibacumab-treated nonsurvivors compared with findings of meningitis in 2 (15%) of 13 rabbits treated with levofloxacin alone, and no lesions were seen in any of the surviving animals.

Another safety issue was the development of grade 1 to 2 infusion reactions that arose in studies involving 326 healthy human volunteers. Initially, the rash developed in 22% of the participants. After the initiation of diphenhydramine before treatment, rash incidence dropped to just 3%.

Addressing an Unmet Need

In voting unanimously for raxibacumab's safety, most panel members stated that they were satisfied that safety concerns about the product had been addressed. There was more discussion regarding efficacy, given the lack of study power, and also questions regarding human dosing as well as the many potential logistical issues that would be involved with delivering 2-hour infusions to many people in a large-scale anthrax attack.

Dean Follman, PhD, chief of the Division of Clinical Research, Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, Maryland, voted in favor of raxibacumab's efficacy. He said that when trying to extrapolate animal data to humans, "we have to do things a little differently." And in particular, "If we think about multidrug-resistant anthrax...the answer to that question in my mind, [supporting raxibacumab] is much easier."

Michael N. Neely, MD, assistant professor of clinical pediatrics at the University of Southern California, Los Angeles, also voted yes. "I think that I'm willing to be a little bit more generous on that [statistical] threshold for a first-in-kind product for a very unmet need," he commented.

Lyman Barth Reller, MD, DTM&H, professor of medicine and pathology and director of clinical microbiology at Duke University Medical Center in Durham, North Carolina, said, "I'm reassured that there is some benefit." However, he added that he would like "more specificity into how this would be deployed in a priority sense.... If there were a huge event, it would be exceedingly taxing to give everyone a 2-hour [intravenous] infusion who might have inhalational anthrax."

The sole "no" vote came from Steve Leppla, PhD, chief of the Microbial Pathogenesis Section of the Laboratory of Parasitic Diseases in the Division of Intramural Research at NIAID. He said he was not convinced of raxibacumab's efficacy beyond that of antibiotic alone and would like to see a study with a larger number of animals. However, he pointed out, in the event of an anthrax exposure the drug is still available for use from the stockpile.

Being Prepared

Dr. Thomas A. Moore

In an interview with Medscape Medical News, committee chair Thomas A. Moore, MD, echoed the need to establish how raxibacumab would be used in a real-life event. "People seeking treatment and those who receive the treatment will overwhelm the hospital system. There has to be some other method by which people would be screened to see if they qualify for this treatment."

According to Dr. Moore, clinical professor of medicine at the University of Kansas School of Medicine–Wichita Campus, "You can never be fully prepared for an event like this, and you can bankrupt your national economy trying to prepare for all the things that could happen, but you should at least try to be as prepared as possible within reason."

The FDA is expected to announce a decision on raxibacumab by December 15, according to a GlaxoSmithKline statement.

Other than industry representatives, participants in FDA advisory committee hearings with potential conflicts of interest must be granted waivers to participate. No waivers were granted for this meeting.

FDA Anti-Infective Drugs Advisory Committee Meeting. November 2, 2012. Silver Spring, Maryland.