FDA Reviewers Positive on Botulism Antidote

WASHINGTON -- A treatment for botulism under review by the FDA received positive feedback from agency staff after two successful animal trials as well as human safety studies, documents released before a Tuesday advisory committee meeting showed.

In a study of botulism antitoxin heptavalent (BAT), its manufacturer, Cangene, found more than 85% of 238 guinea pigs treated with placebo died when injected with one of 7 botulism neurotoxin (BoNT) strains. Meanwhile, all but one of the 238 treated with BAT survived after they were injected (P<0.0001).

Efficacy was less pronounced in a study of 60 monkeys. Again, after being given a lethal dose of botulism, the monkeys were monitored and administered a single BAT dose (0.26 mL/kg) or placebo after the first onset of botulism signs.

None of the placebo monkeys survived the 21-day trial, but 47% (14/30) who received the BAT survived (P<0.0001). Also, the average time to death was longer in the BAT arm, 189.5 hours compared to 74.5 hours (P<0.0001).

The FDA's Blood Products Advisory Committee will vote Tuesday on recommending approval for the agent.

"Overall, based upon its assessment, FDA considers that the benefits exceed the risks associated with the use of BAT to treat symptomatic botulism," agency reviewers concluded.

Botulism is caused by a potent neurotoxin that blocks the release of a neurotransmitter at the junction of peripheral motor nerves and autonomic cholinergic nerves. It's most commonly caused by improperly canned foods and can eventually lead to paralysis.

A treatment for botulism is considered an unmet medical need because there are no licensed treatments available for adults. Sanofi Pasteur produced a product that was withdrawn from the market after expiration of its last remaining lot, and its license was revoked.

The FDA did grant Cangene's agent priority review and expects to render its decision by March 20. The agency isn't bound to follow the advice of its advisory committees but usually does.

The CDC and the federal government consider botulism a potential agent of biological warfare. The FDA briefing documents said its use is being considered by terrorist groups such as Al-Qaeda.

BAT is a polyclonal hyper-immune product made from the plasma of horses immunized with botulism toxins.

One of the questions that the FDA advisory committee will consider is whether or not the animal efficacy studies are likely to predict clinical benefit. BAT was tested under the FDA's "animal rule," which allows efficacy trials in animals and safety studies in normal, human volunteers.

Because of its potentially life-threatening nature, Cangene studied the efficacy in treating symptomatic botulism in animals.

The company did conduct pharmacokinetic and pharmacodynamic studies in development to predict clinical human benefit.

BAT was tested in 229 healthy human volunteers, almost all of whom received one dose of the agent, the FDA said. The most common side effects were headache, somnolence, fever, rash, lymphadenopathy, nausea, extremity pain, and upper respiratory tract infections.

There were two serious adverse reactions, agency reviewers noted in briefing documents. While there were also 6 deaths, all were deemed by Cangene to be unrelated to BAT.

The agent was studied in seven children through the CDC, and two of them suffered adverse reactions, one of which was serious. The CDC also studied the drug in 20 seniors, who accounted for five of the six deaths in the safety studies.

"It is anticipated that treatment of symptomatic BoNT-exposed humans with BAT should prevent the need for mechanical ventilation or reduce the time of ventilator dependence and hospitalization," the FDA reviewers concluded.

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