Nirsevimab is a recombinant neutralising human IgG1ĸ long-acting monoclonal antibody to the prefusion conformation of the RSV F protein which has been modified with a triple amino acid substitution (YTE) in the Fc region to extend serum half-life. Nirsevimab binds to a highly conserved epitope in antigenic site Ø on the prefusion protein with dissociation constants KD = 0.12 nM and KD = 1.22 nM for RSV subtype A and B strains, respectively. Nirsevimab inhibits the essential membrane fusion step in the viral entry process, neutralising the virus and blocking cell-to-cell fusion.
The cell culture neutralisation activity of nirsevimab against RSV was measured in a dose-response model using cultured Hep-2 cells. Nirsevimab neutralised RSV A and RSV B isolates with median EC50 values of 3.2 ng/mL (range 0.48 to 15 ng/mL) and 2.9 ng/mL (range 0.3 to 59.7 ng/mL), respectively. The clinical RSV isolates (70 RSV A and 49 RSV B) were collected between 2003 and 2017 from subjects across the United States, Australia, Netherlands, Italy, China and Israel and encoded the most common RSV F sequence polymorphisms found among circulating strains.
Nirsevimab demonstrated in vitro binding to immobilised human FcγRs (FcγRI, FcγRIIA, FcγRIIB, and FcγRIII) and equivalent neutralising activity compared to parental monoclonal antibodies, IG7 and IG7-TM (Fc region modified to reduce FcR binding and effector function). In a cotton rat model of RSV infection, IG7 and IG7-TM exhibited comparable dose-dependent reduction in RSV replication in the lungs and nasal turbinates, strongly suggesting that protection from RSV infection is dependent on nirsevimab neutralisation activity rather than Fc-mediated effector function.
Escape variants were selected following three passages in cell culture of RSV A2 and B9320 strains in the presence of nirsevimab. Recombinant RSV A variants that showed reduced susceptibility to nirsevimab included those with identified substitutions N67I+N208Y (103-fold). Recombinant RSV B variants that showed reduced susceptibility to nirsevimab included those with identified substitutions N208D (>90,000-fold), N208S (>24,000-fold), K68N+N201S (>13,000-fold), or K68N+N208S (>90,000-fold). All resistance-associated substitutions identified among neutralisation escape variants were located in the nirsevimab binding site (amino acids 62-69 and 196-212) and were shown to reduce binding affinity to RSV F protein.
The pharmacokinetic properties of nirsevimab are based on data from individual studies and population pharmacokinetic analyses. The pharmacokinetics of nirsevimab were dose-proportional in infants and adults following administration of clinically relevant intramuscular doses over a dose range of 25 mg to 300 mg.
Following intramuscular administration, the maximum concentration was reached within 6 days (range 1 to 28 days) and the estimated absolute bioavailability was 85%.
The estimated central and peripheral volume of distribution of nirsevimab were 249 mL and 241 mL, respectively, for an infant weighing 5 kg. The volume of distribution increases with increasing body weight.
Nirsevimab is a human IgG1κ monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not metabolised by hepatic enzymes.
As a typical monoclonal antibody, nirsevimab is eliminated by intracellular catabolism and there is no evidence of target-mediated clearance at the doses tested clinically.
The estimated clearance of nirsevimab was 3.38 mL/day for an infant weighing 5 kg and the terminal half-life was approximately 69 days. Nirsevimab clearance increases with increasing body weight.
There was no clinically relevant effect of race.
No clinical studies have been conducted to investigate the effect of renal impairment. As a typical IgG monoclonal antibody, nirsevimab is not cleared renally due to its large molecular weight, change in renal function is not expected to influence nirsevimab clearance.
No clinical studies have been conducted to investigate the effect of hepatic impairment. As IgG monoclonal antibodies are not primarily cleared via the hepatic pathway, change in hepatic function is not expected to influence nirsevimab clearance.
There was no significant influence of chronic lung disease or congenital heart disease on the pharmacokinetics of nirsevimab.
In D5290C00003 and MELODY a positive correlation was observed between a serum AUC (based on clearance at baseline) above 12.8 mg*day/mL and a lower incidence of MA RSV LRTI. The recommended dosing regimen consisting of a 50 mg or 100 mg intramuscular dose for infants in their first RSV season was selected on the basis of these results.
In MEDLEY, >80% of infants at higher risk for severe RSV disease, including infants born extremely preterm (GA <29 weeks) and infants with chronic lung disease or congenital heart disease, achieved nirsevimab exposures associated with RSV protection (serum AUC above 12.8 mg*day/mL) following a single dose.
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity and tissue cross-reactivity studies.
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