Washington Editor

GAITHERSBURG, Md. - The FDA's Vaccines and Related Biological Products Advisory Committee voted 11-0 that Acambis plcs's smallpox vaccine ACAM2000 is safe and effective for use in high-risk situations.

That's in line with the company's biologics license application to use the live vaccinia virus product in those types of settings, including use by the military, first-responders or health care workers. It's not designed for sale to the general public, although the Department of Health and Human Services (HHS) considers smallpox a potentially major bioterror threat.

"As long as variola virus exists anywhere, there will be the need to have a smallpox vaccine," said John Neff of the Seattle Children's Hospital and Regional Medical Center, speaking on behalf of Acambis. "It's in our best interest to have a modern smallpox vaccine available."

ACAM2000 is a clonal isolate of Dryvax, the only FDA-licensed smallpox vaccine. But unlike that older product, which is no longer manufactured and only exists in limited supplies at this point, ACAM2000 is manufactured using cell-culture technology, making it more readily reproducible going forward. In fact, the company already has delivered 192.5 million doses of ACAM2000 to the U.S. government for the strategic national stockpile through contracts with HHS.

Despite the panelists' positive recommendation, they also suggested post-approval evaluations of the newer product's safety, particularly related to an issue that gave pause to them and FDA reviewers: a relatively high rate of myopericarditis in vaccinia-naïve subjects who received ACAM2000 in one of the pivotal trials underlying the submission. The condition involves inflammation in the muscular wall of the heart and of the enveloping pericardium.

Acambis, of Cambridge, UK, already has proposed a risk-management plan that includes pharmacovigilance elements and a two-year surveillance program to be done in collaboration with the Department of Defense. The latter would screen for risk rates by looking for symptoms and administering a troponin blood test in 10,000 military troops. In addition, a risk-minimization action plan would preclude subjects with certain risk factors from receiving ACAM2000 in the first place.

Panelists suggested performing electrocardiograms on vaccinees soon after dosing and including a control group in the Phase IV study.

Thomas Monath, formerly the chief medical officer at Acambis, attributed the myopericarditis issue to a "vaccinia class effect," a claim corroborated by prior military use of Dryvax in select territories that resulted in similar myopericarditis problems in troops who had received the vaccine. But with both products, most symptoms completely resolve within six months.

Jay Mason, a medical professor at the University of Utah, said that "there is no real increase in" myopericarditis that surfaces following vaccination with ACAM2000 compared to that induced by Dryvax, which was made by Madison, N.J.-based Wyeth. He added that the outcome "is quite good" in patients who developed the condition after the vaccination, which he said is different and less severe than classical myopericarditis in the general population.

Monath also added that common adverse events such as inoculation-site reactions weren't a problem for ACAM2000.

Acambis' submission includes clinical data from more than 3,800 subjects, principally from two Phase III studies. One demonstrated its non-inferiority to Dryvax in producing a major cutaneous reaction among vaccine-naïve people, a generally accepted surrogate endpoint. As in other highly pathogenic diseases, typical efficacy testing isn't possible.

Specifically, there was a 96 percent response in the ACAM2000 group compared to 99 percent in the Dryvax group. Panelist Monica Farley said this finding proved most compelling, given that treatment-naïve military personnel are the most likely users of this product. The other study demonstrated its non-inferiority to Dryvax in immune responses among subjects already exposed to the older vaccine, with a geometric mean titer of 286 in the ACAM2000 group compared to 445 in the Dryvax group.

Since naturally occurring smallpox was eradicated more than 25 years ago, little work had been done until the late 1990s, said HHS official Gerald Parker. In addition, half the U.S. population has no smallpox immunity at this point, and the remaining half is only partly immune.

"We have a very vulnerable population," he said, adding that the government plans to acquire 300 million doses of smallpox vaccine for the stockpile, enough for emergency use by every American.

Licensure would not only seem to put ACAM2000 on better footing to further supplement such a market, but also serves as a prerequisite for the company to qualify for a contract from the Centers for Disease Control and Prevention that would allow Acambis to ramp up domestic production to meet on-order demand from the U.S. government.

The company already sells its product to about a dozen foreign governments.

On Thursday, its stock (NASDAQ:ACAMF) lost 10 cents to close at $2.45.