BEYFORTUS Solution for injection Ref.[50357] Active ingredients: Nirsevimab

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies
ATC code: J06BD08

Mechanism of action

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.

Pharmacodynamic effects

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). 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 and MEDLEY, 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 25 subjects in the nirsevimab group with MA RSV LRTI had an RSV isolate containing nirsevimab resistance-associated substitutions (RSV A: 0 of 11 subjects and RSV B: 2 of 14 subjects). 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.

Clinical efficacy

The efficacy and safety of nirsevimab were evaluated in two randomised, double-blind, placebo controlled multicentre trials (D5290C00003 [Phase IIb] and MELODY [Phase III]) for the prevention of RSV LRTI in term and preterm infants (GA ≥29 weeks) entering their first RSV season. Safety and pharmacokinetics of nirsevimab were also evaluated in a randomised, double-blind, palivizumab-controlled multicentre trial (MEDLEY [Phase II/III]) in infants GA <35 weeks at higher risk for severe RSV disease, including extremely preterm infants (GA <29 weeks) and infants with chronic lung disease of prematurity, or haemodynamically significant congenital heart disease, entering their first RSV season.

Efficacy against MA RSV LRTI, MA RSV LRTI hospitalisation, and very severe MA RSV LRTI in term and preterm infants (D5290C00003 and MELODY)

D5290C00003 randomised a total of 1 453 very and moderately preterm infants (GA ≥29 to <35 weeks) entering their first RSV season (2:1) to receive a single intramuscular dose of 50 mg nirsevimab or placebo. At randomisation, 20.3% were GA ≥29 to <32 weeks; 79.7% were GA ≥32 to <35 weeks; 52.4% were male; 72.2% were White; 17.6% were of African origin; 1.0% were Asian; 59.5% weighed <5 kg (11.6% <2.5 kg); 17.3% of infants were ≤1.0 month of age, 35.9% were >1.0 to ≤3.0 months, 32.6% were >3.0 to ≤6.0 months, and 14.2% were >6.0 months.

MELODY randomised a total of 1 490 term and late preterm infants (GA ≥35 weeks) entering their first RSV season (2:1) to receive a single intramuscular dose of nirsevimab (50 mg nirsevimab if <5 kg weight or 100 mg nirsevimab if ≥5 kg weight at the time of dosing) or placebo. At randomisation, 14.0% were GA ≥35 to <37 weeks; 86.0% were GA ≥37 weeks; 51.6% were male; 53.5% were White; 28.4% were of African origin; 3.6% were Asian; 40.0% weighed <5 kg (1.7% <2.5 kg); 24.5% of infants were ≤1.0 month of age, 33.4% were >1.0 to ≤3.0 months, 32.1% were >3.0 to ≤6.0 months, and 10.0% were >6.0 months.

The trials excluded infants with a history of chronic lung disease/bronchopulmonary dysplasia or congenital heart disease (except for infants with uncomplicated congenital heart disease). Demographic and baseline characteristics were comparable between the nirsevimab and placebo group in both trials.

The primary endpoint for D5290C00003 and MELODY was the incidence of medically attended lower respiratory tract infection (inclusive of hospitalisation) caused by RT-PCR-confirmed RSV (MA RSV LRTI), characterised predominantly as bronchiolitis or pneumonia, through 150 days after dosing. Signs of LRTI were defined by having one of the following findings at physical examination indicating lower respiratory tract involvement (e.g., rhonchi, rales, crackles, or wheeze); and at least one sign of clinical severity (increased respiratory rate, hypoxemia, acute hypoxic or ventilatory failure, new onset apnoea, nasal flaring, retractions, grunting, or dehydration due to respiratory distress). The secondary endpoint was the incidence of hospitalisation in infants with MA RSV LRTI. RSV hospitalisation was defined as hospitalisation for LRTI with a positive RSV test, or worsening of respiratory status and positive RSV test in an already hospitalised patient. Very severe MA RSV LRTI was also evaluated, defined as MA RSV LRTI with hospitalisation and requirement for supplemental oxygen or intravenous fluids.

The efficacy of nirsevimab in term and preterm infants (GA ≥29 weeks) entering their first RSV season against MA RSV LRTI, MA RSV LRTI with hospitalisation and very severe MA RSV LRTI are shown in Table 2.

Table 2. Efficacy in term and preterm infants against MA RSV LRTI, MA RSV LRTI with hospitalisation and very severe MA RSV LRTI through 150 days post dose, D5290C00003 and MELODY:

^a Based on relative risk reduction versus placebo.
^b All subjects who received 50 mg irrespective of weight at the time of dosing.
^c Prespecified multiplicity controlled; p-value =<0.001.
^d Not multiplicity controlled.

Subgroup analyses of the primary efficacy endpoint by gestational age, gender, race and region showed results were consistent with the overall population.

The severity of breakthrough cases of subjects hospitalised for MA RSV LRTI was assessed. The percentage of subjects who required supplementary oxygen was 44.4% (4/9) vs. 81.0% (17/21), subjects who required continuous positive airway pressure [CPAP]/high flow nasal cannula [HFNC] was 11.1% (1/9) vs. 23.8% (5/21), and 0% (0/9) vs. 28.6% (6/21) subjects were admitted to intensive care unit, for nirsevimab vs. placebo, respectively.

Efficacy against MA RSV LRTI in infants at higher risk for severe RSV disease (MEDLEY)

MEDLEY randomised a total of 925 infants at higher risk for severe RSV disease including infants with chronic lung disease or congenital heart disease and preterm infants GA <35 weeks, entering their first RSV season. Infants received a single intramuscular dose (2:1) of nirsevimab (50 mg nirsevimab if <5 kg weight or 100 mg nirsevimab if ≥5 kg weight at the time of dosing) or 5 monthly intramuscular doses of 15 mg/kg palivizumab. At randomisation, 21.6% were GA <29 weeks; 21.5% were GA≥29 to <32 weeks; 41.9% were GA ≥32 to <35 weeks; 14.9% were GA ≥35 weeks. Of these infants 23.6% had chronic lung disease; 11.2% had congenital heart disease; 53.5% were male; 79.2% were White; 9.5% were of African origin; 5.4% were Asian; 56.5% weighed <5 kg (6.4% were <2.5 kg); 11.4% of infants were ≤1.0 month of age, 33.8% were >1.0 to ≤3.0 months 33.6% were >3.0 months to ≤6.0 months, and 21.2% were >6.0 months.

The efficacy of nirsevimab in infants at higher risk for severe RSV disease is extrapolated from the efficacy of nirsevimab in D5290C00003 and MELODY based on pharmacokinetic exposure (see section 5.2). In MEDLEY, the incidence of MA RSV LRTI through 150 days post dose was 0.6% (4/616) in the nirsevimab group and 1.0% (3/309) in the palivizumab group.

Duration of protection

Based on clinical and pharmacokinetic data, the duration of protection afforded by nirsevimab is at least 5 months.