Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties

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 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.

Immunogenicity

Anti-drug antibodies (ADA) were commonly detected.
The employed immunogenicity assay has limitations in detecting ADAs at early onset (prior to Day 361) in the presence of high concentrations of drug, therefore, the incidence of ADA might not have been conclusively determined. The impact on clearance of nirsevimab is uncertain. Subjects who were ADA positive at Day 361 had reduced nirsevimab concentrations at Day 361 compared to subjects who received nirsevimab and were ADA-negative.

The impact of ADA on the efficacy of nirsevimab has not been determined. No evidence of ADA impact on safety was observed.

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 MA 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 and children with chronic lung disease of prematurity or haemodynamically significant congenital heart disease entering their second RSV season.
Safety and pharmacokinetics of nirsevimab were also evaluated in an open-label, uncontrolled, single dose multicentre trial (MUSIC [Phase II]) in immunocompromised infants and children ≤24 months of age.

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 (17% <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 (Primary cohort) 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 (2.5% <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 of prematurity/bronchopulmonary dysplasia or haemodynamically significant 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 (Primary cohort) 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 (Primary cohort)

Incidence
Group                    Treatment         N                    Efficacya (95% CI) % (n)
Efficacy in infants against MA RSV LRTI through 150 days post dose
Very and moderately preterm GA ≥29       Nirsevimab       969       2.6 (25) to <35 weeks (D5290C00003)b                                                      70.1% (52.3, 81.2)c Placebo          484       9.5 (46)
Term and late preterm GA ≥35 weeks       Nirsevimab       994       1.2 (12) 74.5% (49.6, 87.1)c
(MELODY Primary cohort)                  Placebo          496       5.0 (25) Efficacy in infants against MA RSV LRTI with hospitalisation through 150 days post dose Very and moderately preterm GA ≥29       Nirsevimab       969       0.8 (8) 78.4% (51.9, 90.3)c to <35 weeks (D5290C00003)b              Placebo          484       4.1 (20) Term and late preterm GA ≥35 weeks       Nirsevimab       994       0.6 (6) 62.1% (-8.6, 86.8)
(MELODY Primary cohort)                  Placebo          496       1.6 (8) Efficacy in infants against very severe MA RSV LRTI through 150 days post dose Very and moderately preterm GA ≥29       Nirsevimab       969       0.4 (4) to <35 weeks (D5290C00003)b                           Placebo                 484   3.3 (16) 87.5% (62.9, 95.8)d
Term and late preterm GA ≥35 weeks                    Nirsevimab              994   0.5 (5) 64.2% (-12.1, 88.6)d
(MELODY Primary cohort)                               Placebo                 496   1.4 (7) 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.

MELODY continued to enrol infants following the primary analysis, and overall, 3 012 infants were randomised to receive Beyfortus (n=2 009) or placebo (n=1 003). Efficacy of nirsevimab against MA RSV LRTI, MA RSV LRTI with hospitalisation, and very severe MA RSV LRTI through 150 days post dose was a relative risk reduction of 76.4% (95% CI 62.3, 85.2), 76.8% (95% CI 49.4, 89.4) and 78.6% (95% CI 48.8, 91.0), respectively.

The rates of MA RSV LRTI events in the second season (day 361 to day 510 post-dose) were similar in both treatment groups [19 (1.0%) nirsevimab recipients and 10 (1.0%) placebo recipients].


Efficacy against MA RSV LRTI in infants at higher risk and children who remain vulnerable to severe RSV disease in their second season (MEDLEY and MUSIC)

MEDLEY randomised a total of 925 infants at higher risk for severe RSV disease including infants with chronic lung disease of prematurity or haemodynamically significant 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), followed by 4 once-monthly intramuscular doses of placebo,or 5 once-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 23.5% had chronic lung disease of prematurity; 11.2% had haemodynamically significant 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 (9.7% 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.
Children at higher risk of severe RSV disease with chronic lung disease of prematurity or haemodynamically significant congenital heart disease ≤24 months of age who remain vulnerable continued in the trial for a second RSV season. Subjects who received nirsevimab during their first RSV season received a second single dose of 200 mg nirsevimab entering their second RSV season (n=180) followed by 4 once-monthly intramuscular doses of placebo. Subjects who received palivizumab during their first RSV season were re-randomised 1:1 to either the nirsevimab or the palivizumab group entering their second RSV season. Subjects in the nirsevimab group (n=40) received a single fixed dose of 200 mg followed by 4 once-monthly intramuscular doses of placebo. Subjects in the palivizumab group (n=42) received 5 once-monthly intramuscular doses of 15 mg/kg palivizumab. Of these children 72.1% had chronic lung disease of prematurity, 30.9% had haemodynamically significant congenital heart disease; 57.6% were male; 85.9% were White; 4.6% were of African origin; 5.7% were Asian; and 2.3% weighed <7 kg. Demographic and baseline characteristics were comparable between the nirsevimab/nirsevimab, palivizumab/nirsevimab and palivizumab/palivizumab groups.

The efficacy of nirsevimab in infants at higher risk for severe RSV disease, including extremely preterm infants (GA <29 weeks) entering their first RSV season and children with chronic lung disease of prematurity or haemodynamically significant congenital heart disease ≤24 months of age entering their first or second RSV season,is established by extrapolation from the efficacy of nirsevimab in D5290C00003 and MELODY (Primary cohort) 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 in the first RSV season. There were no cases of MA RSV LRTI through 150 days post dose in the second RSV season.

In MUSIC, the efficacy in 100 immunocompromised infants and children ≤24 months who received the recommended dose of nirsevimab is established by extrapolation from the efficacy of nirsevimab in D5290C00003 and MELODY (Primary cohort) based on pharmacokinetic exposure (see section 5.2).
There were no cases of MA RSV LRTI through 150 days post dose.

Duration of protection

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

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

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 3).

Table 3: Nirsevimab intramuscular dose exposures, mean (standard deviation) [range], derived based on individual population pharmacokinetic parameters

N              Day 151
Study/Season             N           AUC0-365          AUCbaseline CL (Day 151        serum conc
(AUC)        mg*day/mL          mg*day/mL serum conc)          µg/mL
MELODY                    954         12.2 (3.5)          21.3 (6.5)            636            26.6 (11.1) (Primary cohort)                         [3.3-24.9]          [5.2-48.7]                           [2.1-76.6] MEDLEY/Season 1               591         12.3 (3.3)          22.6 (6.2)             457           27.8 (11.1) [4.1-23.4]           [7-43.8]                            [2.1-66.2]
MEDLEY/Season 2               189         21.5 (5.5)          23.6 (7.8)             163           55.6 (22.8) [7.5-41.9]          [8.2-56.4]                          [11.2-189.3]
MUSIC/Season 1            46          11.2 (4.3)          16.7 (7.3)             37            25.6 (13.4) [1.2-24.6]          [3.1-43.4]                           [5.1-67.4]
MUSIC/Season 2            50         16 (6.3) [2.2-        21 (8.4)              42            33.2 (19.3) 25.5]            [5.6-35.5]                           [0.9-68.5]
AUC0-365= area under the concentration time curve from 0-365 days post dose, AUCbaseline CL = 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.