Nirsevimab

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 K_D = 0.12 nM and K_D = 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.

Antiviral activity

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.

Antiviral resistance

In cell culture

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 as compared to reference). 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.

In clinical trials

In MELODY, MEDLEY and MUSIC, no subject with medically attended RSV lower respiratory tract infection (MA RSV LRTI) had an RSV isolate containing nirsevimab resistance-associated substitutions in any treatment group.

In D5290C00003 (subjects who received a single dose of 50 mg nirsevimab irrespective of weight at time of dosing), 2 of 40 subjects in the nirsevimab group with MA RSV LRTI had an RSV isolate containing nirsevimab resistance-associated substitutions. No subjects in the placebo group had an RSV isolate containing nirsevimab resistance-associated substitution. Recombinant RSV B variants harbouring the identified I64T+K68E+I206M+Q209R (>447.1-fold) or N208S (>386.6-fold) F protein sequence variations in the nirsevimab binding site conferred reduced susceptibility to nirsevimab neutralisation.

Nirsevimab retained activity against recombinant RSV harbouring palivizumab resistance-associated substitutions identified in molecular epidemiology studies and in neutralisation escape variants of palivizumab. It is possible that variants resistant to nirsevimab could have cross-resistance to other monoclonal antibodies targeting the F protein of RSV.

The pharmacokinetic properties of nirsevimab are based on data from individual studies and population pharmacokinetic analyses. The pharmacokinetics of nirsevimab were dose-proportional in children and adults following administration of clinically relevant intramuscular doses over a dose range of 25 mg to 300 mg.

Absorption

Following intramuscular administration, the maximum concentration was reached within 6 days (range 1 to 28 days) and the estimated absolute bioavailability was 84%.

Distribution

The estimated central and peripheral volume of distribution of nirsevimab were 216 mL and 261 mL, respectively, for an infant weighing 5 kg. The volume of distribution increases with increasing body weight.

Biotransformation

Nirsevimab is a human IgG1κ monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not metabolised by hepatic enzymes.

Elimination

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 3.42 mL/day for an infant weighing 5 kg and the terminal half-life was approximately 71 days. Nirsevimab clearance increases with increasing body weight.

Special populations

Race

There was no clinically relevant effect of race.

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. However, in one individual with nephrotic syndrome, an increased clearance of nirsevimab was observed in clinical trials.

Hepatic impairment

IgG monoclonal antibodies are not primarily cleared via the hepatic pathway. However, in some individuals with chronic liver disease which may be associated with protein loss, an increased clearance of nirsevimab was observed in clinical trials.

Infants at higher risk and children who remain vulnerable to severe RSV disease in their second season

There was no significant influence of chronic lung disease of prematurity or haemodynamically significant congenital heart disease on the pharmacokinetics of nirsevimab. Serum concentrations at day 151 in MEDLEY were comparable to those in MELODY.

In children with chronic lung disease of prematurity or haemodynamically significant congenital heart disease (MEDLEY) and those that are immunocompromised (MUSIC), receiving a 200 mg intramuscular dose of nirsevimab in their second season, nirsevimab serum exposures were slightly higher with substantial overlap compared to those in MELODY (see table).

Nirsevimab intramuscular dose exposures, mean (standard deviation) [range], derived based on individual population pharmacokinetic parameters:

AUC_0-365 = area under the concentration time curve from 0-365 days post dose, AUC_baselineCL = area under the serum concentration-time curve derived from post hoc clearance values at dosing, Day 151 serum conc = concentration at day 151, visit day 151 ± 14 days.

Pharmacokinetic/pharmacodynamic relationship(s)

In D5290C00003 and MELODY (Primary cohort) a positive correlation was observed between a serum AUC (Area Under the Curve), 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 and a 200 mg intramuscular dose for children entering their second 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) entering their first RSV season and infants/children with chronic lung disease of prematurity or haemodynamically significant congenital heart disease entering their first or second RSV season, achieved nirsevimab exposures associated with RSV protection (serum AUC above 12.8 mg*day/mL) following a single dose (see section 5.1).

In MUSIC, 75% (72/96) of immunocompromised infants/children entering their first or second RSV season achieved nirsevimab exposures associated with RSV protection. When excluding 14 children with increased clearance of nirsevimab, 87% (71/82) achieved nirsevimab exposures associated with RSV protection.

Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity and tissue cross-reactivity studies.