WASHINGTON -- An FDA advisory committee recommended Wednesday that the agency not approve the investigational drug motavizumab to treat respiratory infections, deciding that it didn't offer any advantages over the drug already on the market, and that it may be more dangerous.
The Antiviral Drugs Advisory Committee voted 14 to 3 that the FDA should not approve MedImmune's motavizumab for prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV).
The FDA is not required to follow the advice of its advisory committees, but it usually does.
MedImmune was seeking approval on the basis that their newest drug is more effective than their earlier drug, palivizumab (Synagis), which has been on the market since 1998 and is the only approved drug to treat RSV. The company argued that the drug works better than palivizumab because it binds more effectively to the RSV F protein. In rodent models, the drug -- which is a monoclonal antibody related to palivizumab -- also reduced viral load better than palivizumab.
But the panel was unconvinced that the drug actually did work better than palivizumab. And clinical trials showed motavizumab carried adverse skin reactions -- such as hives and allergic rashes -- that the earlier drug does not.
"What I see is that this drug is possibly better than what we have now, but I don't know that," said advisory committee member Susan Ellenberg, PhD. "We do know that it has a risk that the other drug doesn't seem to have."
RSV is the most common cause of bronchiolitis and pneumonia in infants and young children and is responsible for twice as many emergency room visits as influenza. Half of all infants are infected with the disease in the first year of life, and 90% of all children are infected by the age of 2, according to Octavio Ramilo, MD, an infectious disease pediatrician from Columbus Ohio who spoke on behalf of MedImmune.
The panel relied on data from three clinical trials. In one of the studies -- a phase III randomized, double-blind, multicenter trial -- researchers tested motavizumab against palivizumab in premature infants less than 6 months of age. Compared with children who received palivizumab, those treated with motavizumab had similar rates of hospitalization RSV (1.9% versus 1.4%), but had a 50% reduction in outpatient, RSV-specific, medically attended lower respiratory tract infection, or MALRI (2.0% versus 3.9%, P=0.005).
From that study, MedImmune researchers determined the newer drug is noninferior to the older palivizumab.
In briefing documents released in advance of Wednesday's hearing, FDA staff expressed concern that when data was stratified by Northern and Southern hemispheres, the noninferiority status didn't hold up.
When the 9% of patients enrolled in the Southern Hemisphere are removed from the analysis, the data fail to show motavizumab is at least as efficacious as palivizumab, the FDA said. The agency favors relying on U.S. data since it will be making regulatory decisions for a U.S. population.
A second study had similar outcomes, although it was not powered to test efficacy. In that study, 1,236 children under 2 with hemodynamically significant congenital heart disease were given one of the two drugs and appeared to fare better on motavizumab.
A third study pitted motavizumab against placebo in 1,410 Navajo and White Mountain Apache infants and found that children who received the drug had statistically fewer RSV hospitalizations than those who received placebo (12 versus 16, or 1.9% versus 2.6%).
Members on the panel appeared split over whether they believed MedImmune demonstrated a clear efficacy benefit of motavizumab over palivizumab.
"I think there is a strong suggestion that it is more efficacious that palivizumab, but some data cast doubt as to the degree of that," said panelist Yvonne Maldonado, MD, a professor of pediatrics at Stanford University School of Medicine.
But another panelist said she wasn't comfortable with extrapolating the Southern Hemisphere data to determine the drug isn't effective.
"I don't have any concerns that it's not efficacious," said Doris Strader, MD, a gastroenterologist from Burlington, Vermont, who was one of the three panel members who voted in favor of approving motavizumab.
Efficacy data aside, the panel was nearly universally concerned with the threefold increase in severe skin reactions seen in babies treated with motavizumab. In one trial, 38 patients receiving motavizumab had allergic reactions, compared with 13 patients receiving palivizumab.
Nine out of 13 patients who discontinued the trial stopped taking motavizumab because of skin/hypersensitivity reactions.
Looking at all of MedImmune's clinical trials, a total of 19 motavizumab patients had "high grade hypersensitivity" events, compared with no severe allergic reactions in the the palivizumab group.
Also, there were at least three cases suggestive of anaphylaxis in the motavizumab group, and no cases in the palivizumab group. There also were no cases of anaphylaxis in the clinical trials for palivizumab. Since palivizumab was approved, there have been 10 reports of anaphylaxis reported to the FDA's adverse event reports database. The drug has been used in approximately 1.2 million patients in the 12 years since it was approved.
Several panelist said patients in MedImmune's trials were too healthy, and that they'd like to see a future trial that enrolls sicker patients.
A spokeswoman for MedImmune said the company will work with the FDA to address the issues raised by the committee.
"We continue to believe motavizumab offers a meaningful clinical benefit to patients at high risk for a very common and serious illness," said Genevieve Losonsky, MD, vice president for clinical development of MedImmune's infectious disease division.
Wednesday's vote came just days after the Washington Business Journal reported that a former employee of MedImmune filed a lawsuit against the Gaithersburg, Md.-based company, alleging he was fired after raising concerns over discrepancies in test data for motavizumab.
The FDA referenced the pending lawsuit during the hearing, but a spokeswoman for MedImmune defended the company's trial design and data.
"MedImmune is confident that the data which will be presented to the Advisory Committee today are accurate," said Bahija Jallal, PhD, senior vice president of research and development for MedImmune.
"The pending lawsuit contains unsubstantiated allegations by a former employee," Jallal said. "MedImmune is confident that all data submitted for review for this application are true and accurate."