SILVER SPRING, MD. — More information on the risks and severity of hypersensitivity reactions associated with the monoclonal antibody motavizumab is needed before it is approved for preventing serious lower respiratory tract infections with respiratory syncytial virus in high-risk infants, according to the majority of a Food and Drug Administration advisory panel.
The FDA's Antiviral Drug Products Advisory Committee voted 14-3 against recommending approval of motavizumab for the indication proposed by its manufacturer, MedImmune LLC., which is the prevention of serious lower respiratory tract disease caused by respiratory syncytial virus (RSV) in children at high risk for RSV disease (premature infants, children with chronic lung disease of prematurity, and children with hemodynamically significant congenital heart disease).
Like palivizumab (Synagis), approved in 1998 for RSV prophylaxis, motavizumab is a monoclonal antibody that binds to the F protein of RSV, but has a higher binding affinity to the protein and exerts a greater degree of neutralizing activity against RSV isolates in vitro, according to MedImmune, which also manufactures palivizumab. The proposed dosing for motavizumab is the same as for palivizumab: 15 mg/kg, administered by intramuscular injection once a month during the RSV season. Several panelists voiced concerns that Medimmune would phase out palivizumab once motavizumab was approved; a MedImmune spokesperson said that the company has never made a statement about such plans.
Panelists agreed that motavizumab had been shown to be effective in preventing RSV, but although the data suggested that it might be more effective than palivizumab, they agreed that it had not been shown to be superior. Moreover, the potential for hypersensitivity reactions among those on motavizumab in clinical trials was a major safety concern that needed to be studied further before approval, including in children who were more severely ill than those in the clinical trials. Although these reactions were rare, they were significant when they occurred and appeared to have an immunologic basis, according to the panel.
“Hypersensitivity and skin issues aside, I'm not really seeing a difference,” said panelist Patrick Clay, Pharm.D., director of the Dybedal Center for Clinical Research, Kansas City (Mo.) University. While it would be helpful to have more than one option for RSV prophylaxis, he pointed out that with the data available, it was unclear how a clinician would choose one or the other.
Panelist Dr. Yvonne Maldonado, chief of infectious diseases, Packard Children's Hospital, Stanford (Calif.) University, said that there was a “strong suggestion” that motavizumab was more effective than palivizumab, but there were not enough differences between the two drugs at this point to help practicing clinicians decide when the newer drug should be used. A “better definition of the safety profile would be really helpful for the clinician,” she noted.
In a phase III randomized, double-blind noninferiority study, motavizumab was compared with palivizumab in 6,635 premature infants (under 35 weeks' gestation) who were younger than 6 months, and in children younger than 24 months who had been premature and had chronic lung disease, in a 1:1 ratio. (Both drugs were administered at a dosage of 15 mg/kg once a month for five doses.) The proportion of patients who were hospitalized for RSV, the primary end point, was 1.4% among those on motavizumab, compared with 1.9% of those on palivizumab, which met the noninferiority criteria for the study. (Most of the patients in each group completed the study and about 96% in each group received all five scheduled doses.)
The overall safety profiles were similar between the two groups, with the exception of hypersensitivity reactions: More patients who received motavizumab developed urticaria (0.4%) and allergic rash (0. 8%), compared with those on palivizumab (0.1% and 0.3%). In addition, eight of those on motavizumab had a grade 3-4 hypersensitivity reaction, compared with none of those on palivizumab.
In the five studies that comprised the entire safety database for motavizumab, there were 19 grade 3-4 hypersensitivity events among those on motavizumab, compared with none among those on palivizumab. Of the 5,360 patients who received motavizumab, there were three cases “suggestive of anaphylaxis,” according to the FDA reviewer.
In a study that was considered a supportive study, motavizumab was compared with placebo in 1,410 Native American term infants, who were at a greater risk of RSV infections. The incidence of RSV hospitalizations was 8.3% among those on motavizumab compared with 1.4% among those on placebo, a significant difference.
The allergist on the panel, Dr. Prescott Atkinson, professor and director of the division of pediatric allergy and immunology, Children's Hospital, Birmingham, Ala., said he voted against approval because he was convinced that the risks were higher with this drug, but “it's not clear to me that it's more efficacious than the drug we already have.”