Washington Editor

SILVER SPRING, Md. - While FDA advisers Tuesday said evidence from animal models evaluating Human Genome Sciences Inc.'s raxibacumab 40 mg/kg could reasonably predict the drug's response in treating people infected with inhalational anthrax, the panel was split about whether the antitoxin would impede the benefits of concurrent antibiotic therapy.

The FDA's Anti-Infective Drugs Advisory Committee said regulators should require HGS to provide more evidence that raxibacumab makes a contribution to the efficacy over antimicrobials alone.

But the FDA Tuesday tabled the major anticipated vote about whether raxibacumab should be approved.

Regulators determined that it was not possible for the panel to provide a complete judgment on licensure of raxibacumab after agency inspectors raised last-minute concerns about the quality and reliability of the human pharmacokinetic data in HGS' biologics license application (BLA).

Renata Albrecht, director of the FDA's Division of Special Pathogen and Transplant Products, said those data are essential to link raxibacumab human pharmacokinetic exposure to animal pharmacokinetic exposure for dose selection, a critical component of HGS' BLA.

Albrecht said the FDA in recent days had considered postponing Tuesday's advisory committee meeting, but determined that obtaining the panel's advice about the adequacy of the animal efficacy studies still would be useful at this point.

David Stump, executive vice president of R&D at HGS, told reporters after the meeting that the FDA had raised one specific issue with the way the firm did the pharmacokinetic assays in the human pharmacology study.

"We believe that we made a scientific judgment to do it in a certain way, and the FDA is asking if that was the correct way," he explained.

Stump said HGS still has its samples, "and in the worse case, if they want it done a different way, we'll do it a different way. Our goal was to get an agreement on this."

While the FDA restricted the voting questions posed to the committee to HGS' animal efficacy data of raxibacumab, the agency permitted the Rockville, Md.-based biotech to present its human pharmacokinetic data at Tuesday's meeting. However, Albrecht told panelists to ignore the information in its deliberations.

HGS is seeking approval of raxibacumab as a treatment for patients with inhalational anthrax, a disease caused by the Gram-positive bacterium Bacillus anthracis. The FDA is set to make a decision by mid-November.

While antimicrobials, such as ciprofloxacin and doxycycline, have been used to eradicate the bacterium, they have no activity against the three toxins produced by B. anthracis: protective antigen (PA), which is a binding moiety, and lethal factor and edema factor, which are enzymatic moieties.

Raxibacumab, a recombinant fully human monoclonal antibody, binds specifically and with high affinity to PA and inhibits the binding of PA to its receptors, which is a key step in protecting cells from the action of anthrax toxin.

Because naturally occurring inhalational anthrax infection in humans is rare to nonexistent and it would be unethical to deliberately expose healthy study participants to a lethal or permanently disabling toxic substance, such as aerosolized B. anthracis spores, HGS' efficacy studies were conducted in animals, with the safety of raxibacumab tested in 400 healthy human volunteers.

Raxibacumab is the first new drug developed since the 2001 U.S. anthrax attacks, in which 11 people were sickened, with five of those dying, to seek licensure under the FDA's animal rule, a regulatory structure created in 2002 that permits a drug's effectiveness to be demonstrated in animals when it is unethical or not feasible to conduct controlled clinical trials in humans.

Under the animal rule, a medication could be approved on the basis of adequate and well-controlled animal studies when the results establish that the product is reasonably likely to produce clinical benefit in humans.

In assessing the sufficiency of animal data, the FDA may take into account other data, including human data, available to the agency.

Under the rule, regulators rely on studies in animals to provide substantial evidence of a product's effectiveness only when there is a reasonably well-understood mechanism of action against a target with known pathophysiology; the effect is demonstrated in more than one animal species; the animal study endpoint is clearly related to the desired benefit in humans; and the data on the kinetics and pharmacodynamics of the product or other relevant data in animals and humans allows selection of an effective dose in humans.

It was the last of those four criteria where the FDA has raised questions about whether HGS had met the rule's requirements.

The U.S. government already has ordered at least 65,000 doses of raxibacumab, 20,000 of which have been delivered to the Strategic National Stockpile.

Dan Hanfling, a special adviser for emergency preparedness and response at Falls Church, Va.-based Inova Health System, who in 2001 treated two of the postal workers infected by the anthrax spores sent through the mail, urged the FDA to approve raxibacumab.

He insisted the antitoxin would fill the unmet need of providing protection against widespread deaths if the nation is again attacked with anthrax, such as if a crop-duster were to spray a community with aerosolized anthrax.

The FDA's committee Tuesday voted 16 to 7, with one abstention, that the evidence from HGS' animal models evaluating 40-mg/kg raxibacumab was sufficient to predict a response as a treatment of humans with inhalational anthrax disease.

The committee voted 11 to 10, with three abstentions, that the animal models of raxibacumab 40 mg/kg plus antimicrobial therapy supported the conclusion that the antitoxin did not diminish the efficacy of levofloxacin in rabbits or ciprofloxacin in monkeys.

Panel chairman Thomas Moore had initially voted "no" on that second vote, but admitted that he "meant to push the 'yes' button."

But the advisers voted 17 to 6, with one abstention, advising the FDA to require HGS to provide more evidence that raxibacumab makes a contribution to the efficacy over the antimicrobial alone in rabbit and monkey animal models.