Pharmacology: Mechanism of Action: Palivizumab exhibits neutralizing and fusion-inhibitory activity against RSV. These activities inhibit RSV replication in laboratory experiments. Although resistant RSV strains may be isolated in laboratory studies, a panel of clinical RSV isolates were all neutralized by palivizumab. Palivizumab serum concentrations of approximately 30 mcg/mL have been shown to produce a mean 99% reduction in pulmonary RSV replication in the cotton rat model.
The in vivo neutralizing activity of the active ingredient in palivizumab was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, palivizumab significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients.
Clinical Studies: The safety and efficacy of palivizumab were assessed in a randomized, double-blind, placebo-controlled trial (IMpact-RSV Trial) of RSV disease prophylaxis among children with premature birth and children with bronchopulmonary dysplasia, and in a randomized, double-blind, placebo-controlled trial of RSV disease prophylaxis among children with hemodynamically significant congenital heart disease (CHD Study). Additional clinical studies conducted following the initial approval of palivizumab have provided further data on the safety and effectiveness of palivizumab prophylaxis for the prevention of RSV related diseases among the similar pediatric populations.
IMpact-RSV Trial: This trial, conducted at 139 centers in the United States, Canada and the United Kingdom, studied patients less than or equal to 24 months of age with bronchopulmonary dysplasia (BPD) and patients with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Patients with uncorrected congenital heart disease were excluded from enrollment. In this trial, 500 patients were randomized to receive five monthly placebo injections and 1,002 patients were randomized to receive five monthly injections of 15 mg/kg of lyophilized palivizumab. Subjects were randomized into the study, and were followed for safety and efficacy for 150 days. Ninety-nine percent of all subjects completed the study and 93% received all five injections. The primary endpoint was the incidence of RSV hospitalization.
RSV hospitalizations occurred among 53 of 500 (10.6%) patients in the placebo group and 48 of 1002 (4.8%) patients in the palivizumab group, a 55% reduction (p<0.001). The reduction of RSV hospitalization was observed both in patients enrolled with a diagnosis of BPD (34/266 [12.8%] placebo vs. 39/496 [7.9%] palivizumab) and patients enrolled with a diagnosis of prematurity without BPD (19/234 [8.1%] placebo vs. 9/506 [1.8%] palivizumab). The reduction of RSV hospitalization was observed throughout the course of the RSV season.
Among secondary endpoints, the incidence of ICU admission during hospitalization for RSV infection was lower among subjects receiving palivizumab (1.3%) than among those receiving placebo (3.0%), but there was no difference in the mean duration of ICU care between the two groups for patients requiring ICU care. Overall, the data do not suggest that RSV illness was less severe among patients who received palivizumab and who required hospitalization due to RSV infection than among placebo patients who required hospitalization due to RSV infection. Palivizumab did not alter the incidence and mean duration of hospitalization for non-RSV respiratory illness or the incidence of otitis media.
Pre-term Infants and Children with CLD of Prematurity (CLDP): This trial, conducted at 347 centers in the North America, European Union and 10 other countries, studied patients less than or equal to 24 months of age with CLDP and patients with premature birth (less than or equal to 35 weeks gestation) who were less than or equal to 6 months of age at study entry. Patients with hemodynamically significant congenital heart disease were excluded from enrollment in this study and were studied in a separate study. In this trial, patients were randomized to receive 5 monthly injections of 15 mg/kg of liquid palivizumab (N=3306) used as active control for an investigational monoclonal antibody (N=3329). Subjects were followed for safety and efficacy for 150 days. Ninety-eight percent of all subjects receiving palivizumab completed the study and 97% received all five injections. The primary endpoint was the incidence of RSV hospitalization. RSV hospitalizations occurred among 62 of 3306 (1.9%) patients in the palivizumab group. The RSV hospitalization rate observed in patients enrolled with a diagnosis of CLDP was 28/723 (3.9%) and in patients enrolled with a diagnosis of prematurity without CLDP was 34/2583 (1.3%).
CHD Study: This trial, conducted at 76 centers in the United States, Canada, France, Germany, Poland, Sweden and the United Kingdom, studied patients less than or equal to 24 months of age with hemodynamically significant CHD. In this trial, 648 patients were randomized to receive five monthly placebo injections and 639 patients were randomized to receive five monthly injections of 15 mg/kg of palivizumab. The trial was conducted during four consecutive RSV seasons. Subjects were stratified by cardiac lesion (cyanotic vs. other) and were followed for safety and efficacy for 150 days. Ninety-six percent (96%) of all subjects completed the study and 92% received all five injections. The primary endpoint was the incidence of RSV hospitalization.
RSV hospitalizations occurred among 63 of 648 (9.7%) patients in the placebo group and 34 of 639 (5.3%) patients in the palivizumab group, a 45% reduction (p=0.003). The reduction of RSV hospitalization was consistent over time, across geographic regions, across stratification by anatomic cardiac lesion (cyanotic vs. other), and within subgroups of children defined by gender, age, weight, race, and presence of RSV neutralizing antibody at entry. The secondary efficacy endpoints that showed significant reductions in the palivizumab group compared to placebo, included total days of RSV hospitalization (56% reduction, p=0.003) and total RSV days with increased supplemental oxygen (73% reduction, p=0.014).
CHD Study 2: This trial, conducted at 162 centers in North America, European Union and 4 other countries over two RSV seasons, studied patients less than or equal to 24 months of age with hemodynamically significant CHD. In this trial, patients were randomized to receive 5 monthly injections of 15 mg/kg of liquid palivizumab (N=612) used as active control for an investigational monoclonal antibody (N=624). Subjects were stratified by cardiac lesion (cyanotic vs. other) and were followed for safety and efficacy for 150 days. Ninety-seven percent of all subjects receiving palivizumab completed the study and 95% received all five injections. The primary endpoint was a summary of adverse events and serious adverse events, and the secondary endpoint was the incidence of RSV hospitalization. The incidence of RSV hospitalization was 16 of 612 (2.6%) in the palivizumab group.
CHD Post-marketing Study: A post-marketing retrospective, observational, noninterventional cohort study was conducted in children with hemodynamically significant congenital heart disease (HSCHD) in 32 sites in 10 European countries (Austria, Belgium, France, Germany, Italy, Norway, Poland, Slovenia, Spain, United Kingdom). Children with HSCHD who were less than 24 months of age when the first dose of lyophilized Synagis was administered (N=1009) were compared for the occurrence of primary serious adverse events (PSAEs) over an 8-month observational period with a historical cohort of matched children who were also diagnosed with HSCHD but did not receive lyophilized Synagis during the first 24 months of life (N=1009). Children were matched by age, type of cardiac lesion, and prior corrective cardiac surgery. PSAEs were defined as the SAEs of infection, arrhythmia, and death.
PSAEs of infection during the 8-month chart review period were reported at a statistically significantly lower rate in prophylaxed children (27.8% [281/1009]) compared to non-prophylaxed children (32.6% [329/1009]) (P=0.023). The incidence of arrhythmia PSAEs was 4.1% (41/1009) in prophylaxed children and 3.9% (39/1009) in non-prophylaxed children (P>0.100). The incidence of death PSAEs was numerically lower for prophylaxed children (0.9% [9/1009]) compared to non-prophylaxed children (1.0% [10/1009]).
The results of the study indicate no increased risk of serious infections, serious arrhythmias, or death in children with HSCHD associated with lyophilized Synagis prophylaxis compared with matched non-prophylaxed children.
Extended Dose Study: An open label, prospective safety and pharmacokinetics study examined the safety, tolerance and pharmacokinetics of palivizumab when administered for up to 7 months in Saudi Arabia, a subtropical region where the reported RSV season is frequently longer than in temperate countries. Eighteen preterm infants (less than 34 weeks gestation), ranging in age from newborn to 29 weeks, with or without chronic lung disease (CLD), judged to be at risk for RSV infection, and palivizumab naïve, were included in the study. Lyophilized palivizumab 15 mg/kg was injected once per month, for up to 7 months during the RSV season.
Palivizumab levels in the extended dose study were comparable to those achieved in the IMpact RSV trial. No significant elevations of anti-palivizumab antibody titer were observed.
Pharmacokinetics: The pharmacokinetics and safety of palivizumab liquid formulation and palivizumab lyophilized formulation, following 15 mg per kg intramuscular administration, were compared in a crossover trial of 153 infants less than or equal to 6 months of age with a history of prematurity (less than or equal to 35 weeks gestational age). The results of this trial indicated that the trough serum concentrations of palivizumab were similar between liquid formulation and the lyophilized formulation and bioequivalence of the liquid and the lyophilized formulation was demonstrated.
Toxicology: Preclinical Safety Data: In a human tissue cross-reactivity study, biotinylated palivizumab did not stain in a specific fashion to the more than 30 human adult and neonatal tissues studied.
Acute toxicity studies in three species, the Sprague Dawley rat, the cynomolgus monkey and the NZW rabbit demonstrated tolerance at the site of injection as well as lack of specific systemic toxicity.
Immunogenicity data in cynomolgus monkeys showed no generation of antibody against palivizumab.
In the cotton rat model, pretreatment with palivizumab was shown to reduce mean pulmonary viral titers (replication) by a mean of 99% at serum concentrations of approximately 30 mcg/mL. At no concentration was increased viral replication seen, nor was there an increase in pulmonary inflammation or histopathology at any palivizumab concentration examined. No RSV mutants escaped therapy, and reinfection with RSV after palivizumab exposure did not enhance RSV viral titers (replication) or the resultant pulmonary histopathology.
Binding and neutralization studies have been performed on RSV isolates collected from around the world, to determine whether palivizumab has specificity for a wide range of subtypes. Over 600 isolates, collected from 19 countries on 5 continents have been tested for binding and palivizumab bound to all samples. A subset of more than 100 of these isolates was evaluated for neutralization by palivizumab, and all samples were neutralized.
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenesis, mutagenesis and reproductive toxicity studies have not been performed.
Microbiology: Antiviral Activity: The antiviral activity of palivizumab was assessed in a microneutralization assay in which increasing concentrations of antibody were incubated with RSV prior to addition of the human epithelial cells HEp-2. After incubation for 4-5 days, RSV antigen was measured in an enzyme-linked immunosorbent assay (ELISA). The neutralization titer (50% effective concentration [EC50]) is expressed as the antibody concentration required to reduce detection of RSV antigen by 50% compared with untreated virus-infected cells. Palivizumab exhibited median EC50 values of 0.65 mcg per mL (mean [standard deviation] = 0.75 [0.53] mcg per mL; n=69, range 0.07-2.89 mcg per mL) and 0.28 mcg per mL (mean [standard deviation] = 0.35 [0.23] mcg per mL; n=35, range 0.03-0.88 mcg per mL) against clinical RSV A and RSV B isolates, respectively. The majority of clinical RSV isolates tested (n=96) were collected from subjects in the United States with the remainder from Japan (n=1), Australia (n=5) and Israel (n=2). These isolates encoded the most common RSV F sequence polymorphisms found among clinical isolates worldwide.
Resistance: Palivizumab binds a highly conserved region on the extracellular domain of mature RSV F protein, referred to as antigenic site II or A antigenic site, which encompasses amino acids 262 to 275. All RSV mutants that exhibit resistance to palivizumab have been shown to contain amino acid changes in this region on the F protein. No known polymorphic or non-polymorphic sequence variations outside of the A antigenic site on RSV F protein have been demonstrated to render RSV resistant to neutralization by palivizumab. At least one of the palivizumab resistance-associated substitutions, N262D, K272E/Q, or S275F/L was identified in 8 of 126 clinical RSV isolates from subjects who failed immunoprophylaxis, resulting in a combined resistance-associated mutation frequency of 6.3%. A review of clinical findings revealed no association between A antigenic site sequence changes and RSV disease severity among children receiving palivizumab immunoprophylaxis who develop RSV lower respiratory tract disease. Analysis of 254 clinical RSV isolates collected from immunoprophylaxis-naïve subjects revealed palivizumab resistance-associated substitutions in 2 (1 with N262D and 1 with S275F), resulting in a resistance-associated mutation frequency of 0.79%.