Synagis Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: SYNAGIS 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 SYNAGIS. SYNAGIS 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 SYNAGIS was assessed in a randomized, placebo-controlled study of 35 pediatric patients tracheally intubated because of RSV disease. In these patients, SYNAGIS significantly reduced the quantity of RSV in the lower respiratory tract compared to control patients.
Efficacy: In a placebo-controlled trial of RSV disease prophylaxis in 1502 high-risk children (1002 palivizumab; 500 placebo), 5 monthly doses of 15mg/kg reduced the incidence of RSV related hospitalization by 55% (p<0.001).
Clinical Studies: The safety and efficacy of palivizumab were assessed in clinical trials of prophylaxis for serious RSV disease among children with premature birth and children with bronchopulmonary dysplasia or, hemodynamically significant congenital heart disease.
IMpact-RSV Trial: The trial, conducted at 139 centers in the United States, Canada and the United Kingdom, studied patients ≤ 24 months of age with bronchopulmonary dysplasia (BPD) and patients with premature birth (≤ 35 weeks gestation) who were ≤ 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 15mg/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.
The RSV hospitalisation rate was 10.6% in the placebo group. On this basis, the absolute risk reduction (ARR) is 5.8% which means the number needed to treat (NNT) is 17 to prevent one hospitalisation. The severity of RSV disease in children hospitalised despite prophylaxis with palivizumab in terms of days in ICU stay per 100 children and days of mechanical ventilation per 100 children was not affected. There was also a statistically significant reduction in RSV hospitalization for the subgroups of children with BPD (38.5% relative reduction, p=0.038) and those with prematurity (78.1% relative reduction for children with gestation ≤ 35 weeks, p<0.001 and 54% relative reduction for children with gestation ≤ 32 weeks, p<0.05). The smallest relative risk reductions and therefore the least benefit occurred in children with the most severe BPD - those requiring ongoing oxygen (94% relative risk) or oxygen in the last 6 months (70% relative risk). Children receiving ongoing steroids who were treated with palivizumab had a higher rate of hospitalization for RSV infection than did those receiving ongoing steroids who were not treated with palivizumab (relative risk 139%). No statistical significance levels are available for the BPD subgroups.
A total of 222 children from the IMpact-RSV Trial were enrolled in two separate studies to examine the safety of palivizumab when it is administered for a second RSV season. One hundred and three (103) children received monthly palivizumab injections for the first time, and 119 children received palivizumab for two consecutive seasons. No difference between groups regarding immunogenicity was observed in either study. However, as the efficacy of palivizumab when administered to patients as a second course of treatment during an ensuing RSV season has not been formally investigated in a study performed with this objective, the relevance of these data in terms of efficacy is unknown.
Pre-term Infants and Children with Chronic Lung Disease 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 15mg/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: In a placebo-controlled trial in 1287 patients ≤ 24 months of age with haemodynamically significant congenital heart disease (639 SYNAGIS; 648 placebo), 5 monthly doses of 15 mg/kg SYNAGIS reduced the incidence of RSV hospitalisations by 45% (p = 0.003) (congenital heart disease study). Groups were equally balanced between cyanotic and acyanotic patients. The RSV hospitalisation rate was 9.7% in the placebo group and 5.3% in the SYNAGIS group.
Secondary efficacy endpoints showed significant reductions in the SYNAGIS group compared to placebo in total days of RSV hospitalisation (56% reduction, p = 0.003) and total RSV days with increased supplemental oxygen (73% reduction, p = 0.014) per 100 children.
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 15mg/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: In an open label prospective trial designed to evaluate pharmacokinetics, safety, and immunogenicity after administration of 7 doses of palivizumab within a single RSV season, pharmacokinetic data indicated that adequate mean palivizumab levels were achieved in all 18 children enrolled. Transient, low levels of antipalivizumab antibody were observed in one child after the second dose of palivizumab that dropped to undetectable levels at the fifth and seventh dose.
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 cross-over 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 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 SYNAGIS.
In the cotton rat model, pretreatment with SYNAGIS 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 SYNAGIS concentration examined. No RSV mutants escaped therapy, and reinfection with RSV after SYNAGIS 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-naive 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%.