1 Name of Medicine
Nirsevimab.
2 Qualitative and Quantitative Composition
Beyfortus 50 mg solution for injection in prefilled syringe.
Each pre-filled syringe contains 50 mg of nirsevimab in 0.5 mL (100 mg/mL).
Beyfortus 100 mg solution for injection in prefilled syringe.
Each pre-filled syringe contains 100 mg of nirsevimab in 1 mL (100 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.3 Pharmaceutical Form
Solution for injection.
Clear to opalescent, colourless to yellow, pH 6.0 solution in a prefilled syringe.
4.1 Therapeutic Indications
Beyfortus is indicated for the prevention of Respiratory Syncytial Virus (RSV) lower respiratory tract disease in:
neonates and infants born during or entering their first RSV season;
children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.
Beyfortus should be used in accordance with official recommendations.
4.2 Dose and Method of Administration
Dosing recommendations.
Neonates and infants. First RSV season.
For neonates and infants born during or entering the RSV season, administer Beyfortus starting from birth. For infants born outside the RSV season, administer Beyfortus once prior to the start of the RSV season considering duration of protection provided by Beyfortus (see Section 5.1).
The recommended dosage of Beyfortus for neonates and infants born during or entering their first RSV season is based on body weight (see Table 1) and is administered as a single intramuscular (IM) injection.
Dosing in infants with a body weight from 1.0 kg to < 1.6 kg is based on extrapolation, no clinical data are available. Exposure in infants < 1 kg is anticipated to yield higher exposures than in those weighing more. The benefits and risks of nirsevimab use in infants < 1 kg should be carefully considered.
There are limited data available in extremely preterm infants (Gestational Age [GA] < 29 weeks) less than 8 weeks of age (see Section 4.8; Section 5.1; Section 5.2). No clinical data are available in infants with a postmenstrual age (gestational age at birth plus chronological age) of less than 32 weeks.
Children who remain at increased risk for severe RSV disease. Second RSV season.
For children up to 24 months of chronological age who remain at increased risk for severe RSV disease in their second RSV season, the recommended dosage of Beyfortus is a single 200 mg dose administered as two IM injections (2 x 100 mg) at the same visit.
Children undergoing cardiac surgery with cardiopulmonary bypass. For children undergoing cardiac surgery with cardiopulmonary bypass, an additional dose of Beyfortus is recommended as soon as the child is stable after surgery to ensure adequate nirsevimab serum levels. The recommended dosage of Beyfortus is administered as an IM injection.
First RSV season.
If surgery is within 90 days after receiving Beyfortus, the additional dose should be based on body weight at the time of the additional dose. See Table 1 for weight-based dosing.
If more than 90 days have elapsed since receiving Beyfortus, the additional dose should be 50 mg regardless of body weight.
Second RSV season.
If surgery is within 90 days after receiving Beyfortus, the additional dose should be 200 mg, regardless of body weight.
If more than 90 days have elapsed since receiving Beyfortus, the additional dose should be 100 mg, regardless of body weight.
The safety and efficacy of nirsevimab in children aged 2 to 18 years have not been established. No data are available.
Limited data or no data are available in infants with a range of underlying conditions, e.g. Down syndrome (n=13), cystic fibrosis (n=5), congenital airway anomalies (n=9), and neuromuscular disease (n=0; not evaluated in clinical trials).
Method of administration.
Beyfortus is for IM injection intended for administration by a healthcare professional.
Beyfortus is administered intramuscularly, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve. If two injections are required, different injection sites should be used.
Instructions for administration.
Beyfortus prefilled syringe is for single use in one patient only. Contains no antimicrobial preservative.
Visually inspect Beyfortus for particulate matter and discolouration prior to administration. Beyfortus is a clear to opalescent, colourless to yellow solution. Do not inject Beyfortus if the liquid is cloudy, discoloured or it contains large particles or foreign particulate matter.
Do not use if the Beyfortus prefilled syringe has been dropped or damaged, the security seal on the carton has been broken, or the expiry date (EXP) has passed.
Beyfortus is available in a 50 mg in 0.5 mL and a 100 mg in 1 mL prefilled syringe. Check the labels on the Beyfortus carton and prefilled syringe to make sure you have selected the correct 50 mg in 0.5 mL and a 100 mg in 1 mL presentation as required.
Beyfortus 50 mg in 0.5 mL.
Prefilled syringe with a purple plunger rod.
Beyfortus 100 mg in 1 mL.
Prefilled syringe with a light blue plunger rod.
Step 1: Holding the Luer lock in one hand (avoid holding the plunger rod or syringe body), unscrew the syringe cap by twisting it counter clockwise with the other hand.
Step 2: Attach a Luer lock needle to the prefilled syringe by gently twisting the needle clockwise onto the prefilled syringe until slight resistance is felt.
Step 3: Hold the syringe body with one hand and carefully pull the needle cover straight off with the other hand. Do not hold the plunger rod while removing the needle cover or the rubber stopper may move. Do not touch the needle or let it touch any surface. Do not recap the needle or detach it from the syringe.
Step 4: Administer the entire contents of the Beyfortus prefilled syringe as an intramuscular injection, preferably in the anterolateral aspect of the thigh. The gluteal muscle should not be used routinely as an injection site because of the risk of damage to the sciatic nerve.
Step 5: Dispose of the used syringe immediately (see Section 6.6 Special Precautions for Disposal).
If two injections are required, repeat steps 1-5 in a different injection site.4.3 Contraindications
Individuals with a history of severe hypersensitivity reactions, including anaphylaxis, to the active substances or to any of the excipients listed in Section 6.1 List of Excipients; Section 4.4 Special Warnings and Precautions for Use.
4.4 Special Warnings and Precautions for Use
Hypersensitivity including anaphylaxis.
Serious hypersensitivity reactions have been reported following Beyfortus administration. These reactions included urticaria, dyspnoea, cyanosis, and/or hypotonia. Anaphylaxis has been observed with human immunoglobulin G1 (IgG1) monoclonal antibodies. If signs and symptoms of anaphylaxis or other clinically significant hypersensitivity reaction occur, immediately discontinue administration and initiate appropriate medicinal products and/or supportive therapy.
Inform the patient's caregiver of the signs and symptoms of potential hypersensitivity reactions, and advise the caregiver to seek medical attention immediately if the child experience a hypersensitivity reaction to Beyfortus.
Use in individuals with clinically significant bleeding disorders.
As with any other IM injections, Beyfortus should be given with caution to individuals with thrombocytopenia, any coagulation disorder or to individuals on anticoagulation therapy.
Use in individuals with protein-losing conditions.
In some individuals with protein-losing conditions, an increased clearance of nirsevimab was observed in clinical trials (see Section 5.2 Pharmacokinetic Properties). Nirsevimab may not provide the same level of protection in individuals with significant protein loss.
Use in hepatic impairment.
See Section 5.2 Pharmacokinetic Properties.
Use in renal impairment.
See Section 5.2 Pharmacokinetic Properties.
Use in the elderly.
No data available.
Paediatric use.
The safety and effectiveness of Beyfortus have not been established in children older than 24 months of age. No data are available.
Effects on laboratory tests.
Nirsevimab does not interfere with reverse transcriptase polymerase chain reaction (RT-PCR) or rapid antigen detection RSV diagnostic assays that employ commercially available antibodies targeting antigenic site I, II, or IV on the RSV fusion (F) protein.4.5 Interactions with Other Medicines and Other Forms of Interactions
No interaction studies have been conducted. Monoclonal antibodies do not typically have significant drug-drug interaction potential, as they do not directly affect cytochrome P450 enzymes and are not substrates of hepatic or renal transporters.
Nirsevimab-mediated drug-drug interactions are unlikely as the target of nirsevimab is an exogenous virus.
Concomitant administration with vaccines.
Since nirsevimab is a monoclonal antibody, a passive immunisation specific for RSV, it is not expected to interfere with the active immune response to co-administered vaccines.
There is limited experience of co-administration with vaccines. In clinical trials, when nirsevimab was given with routine childhood vaccines, the safety and reactogenicity profile of the co-administered regimen was similar to the childhood vaccines given alone. Nirsevimab can be given concomitantly with childhood vaccines.
Nirsevimab should not be mixed with any vaccine in the same syringe or vial (see Section 6.2 Incompatibilities). When administered concomitantly with injectable vaccines, they should be given with separate syringes and at different injection sites.
Co-administration with immunoglobulin products.
There is no information regarding co-administration of Beyfortus with other immunoglobulin products. Palivizumab should not be administered to infants who have already received Beyfortus in the same season. There are no data regarding substitution of Beyfortus for palivizumab once prophylaxis treatment is initiated with palivizumab for the RSV season. Beyfortus may be administered prior to or during the second RSV season to children up to 24 months of age who remain vulnerable to severe RSV disease, and who received palivizumab in their first RSV season.4.6 Fertility, Pregnancy and Lactation
Effects on fertility.
Beyfortus is only indicated for children under 2 years of age. No human or animal data are available for possible effects on fertility.
(Category B2)
Beyfortus is only indicated for children under 2 years of age. No human or animal data are available to assess the associated risks in pregnancy.
Beyfortus is only indicated for children under 2 years of age. No human or animal data are available to assess the impact of nirsevimab on milk production, its presence in breast milk, or its effects on the breastfed infant.4.7 Effects on Ability to Drive and Use Machines
Not applicable.
4.8 Adverse Effects (Undesirable Effects)
Adverse reactions reported from controlled clinical trials are classified by MedDRA system organ class (SOC). Within each SOC, preferred terms are arranged by decreasing frequency and then by decreasing seriousness. The following CIOMS frequencies of occurrence of adverse reactions are defined as are used, when applicable: very common (≥ 10%); common (≥ 1 and < 10%); uncommon (≥ 0.1 and 1%); rare (≥ 0.01 and 0.1%); very rare (< 0.01%) and not known (cannot be estimated from available data).
Clinical trials experience.
Overall, 2,966 term and preterm infants (Gestational Age [GA] ≥ 29 weeks) received nirsevimab in two placebo-controlled clinical trials (D5290C00003 and MELODY).
Table 2 presents the adverse reactions of the pooled analysis from D5290C00003 and MELODY (All subjects).
Infants at higher risk and children vulnerable to severe RSV disease.
Safety was evaluated in MEDLEY in 918 infants at higher risk for severe RSV disease, including 196 extremely preterm infants (GA < 29 weeks) and 306 infants with CLD, or CHD entering their first RSV season, who received nirsevimab (614) or palivizumab (304). The safety profile of nirsevimab in infants who received nirsevimab in their first RSV season was comparable to the palivizumab comparator and consistent with the safety profile of nirsevimab in term and preterm infants GA ≥ 29 weeks (D5290C00003 and MELODY).
Safety was evaluated in MEDLEY in 220 children with CLD or CHD who received nirsevimab or palivizumab in their first RSV season and went on to receive nirsevimab entering their second RSV season. The safety profile of nirsevimab in children who received nirsevimab in their first and second RSV season (180) was comparable to that in children who received palivizumab in their first RSV season and then nirsevimab in their second RSV season (40). The safety profile of nirsevimab in these children from both arms was consistent with the safety profile of nirsevimab in term and preterm infants GA ≥ 29 weeks (D5290C00003 and MELODY) and comparable to children who received palivizumab for both RSV seasons.
Safety was also evaluated in MUSIC, an open label, uncontrolled, single dose trial in 100 immunocompromised infants and children ≤ 24 months, who received nirsevimab in their first or second RSV season. This included subjects with at least one of the following conditions: immunodeficiency (combined, antibody, or other aetiology) (33); systemic high-dose corticosteroid therapy (29); organ or bone marrow transplantation (16); receiving immunosuppressive chemotherapy (20); other immunosuppressive therapy (15), and HIV infection (8). The safety profile of nirsevimab administered in the first or second RSV season was consistent with that expected for a population of immunocompromised children and with the safety profile of nirsevimab in term and preterm infants GA ≥ 29 weeks (D5290C00003 and MELODY).
Post-marketing experience.
The following adverse reactions have been identified during post approval use of Beyfortus. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Not known.
Hypersensitivity reactions (see Section 4.4 Special Warnings and Precautions for Use.)
Reporting suspected adverse effects.
Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.4.9 Overdose
There is very limited experience of overdose with nirsevimab.
There is no specific treatment for an overdose with nirsevimab. In the event of an overdose, the individual should be monitored for the occurrence of adverse reactions and provided with symptomatic treatment as appropriate.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
5 Pharmacological Properties
5.1 Pharmacodynamic Properties
Mechanism of action.
Nirsevimab is a recombinant neutralising human IgG1κ 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 O/ on the prefusion protein with dissociation constants KD = 0.12 nanoM and KD = 1.22 nanoM 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 potential for rapid protection was evaluated in a cotton rat model of RSV infection using a non-YTE version of nirsevimab (IG7). Intramuscular administration 1 day prior to inoculation with RSV A or B provided complete protection from viral replication in the upper and lower respiratory tracts.
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 nanogram/mL (range 0.48 to 15 nanogram/mL) and 2.9 nanogram/mL (range 0.3 to 59.7 nanogram/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 surveillance trials.
In prospective, observational, global molecular epidemiology studies (OUTSMART-RSV and INFORM-RSV) genetic diversity of RSV F protein sequences has remained low (most amino acids in both RSV A and RSV B > 99% conserved) and prevalence of variants harbouring nirsevimab resistance-associated substitutions has been rare (< 1%). Since 2015, most amino acid residues in the nirsevimab binding site have remained highly conserved (> 99%) at all positions in RSV A and 22 of the 25 positions in RSV B. Co-occurring mutations I206M:Q209R in the binding site that have become prevalent in RSV B since 2017 retain full susceptibility to nirsevimab (I206M:Q209R, 0.23-fold change). The S211N substitution which has expanded in prevalence also retains susceptibility to nirsevimab, both individually (1.2-fold change) and as co-occurring substitutions (I206M:Q209R:S211N, 0.5-fold change).
In clinical trials.
In MELODY, MEDLEY, MUSIC and subjects who received the recommended dose of 50 mg nirsevimab if < 5 kg weight in D5290C00003, no subject with medically attended RSV lower respiratory tract infection (MA RSV LRTI) or any RSV case definition had an RSV isolate containing a nirsevimab resistance-associated substitution in any treatment group.
In D5290C00003 (subjects who received a single dose of 50 mg nirsevimab), 2 of 40 subjects with RSV infections corresponding to any case definition had a variant containing nirsevimab resistance-associated substitutions. RSV B variants occurred in two subjects receiving below the recommended nirsevimab dose and harboured I64T:K68E:I206M:Q209R co-occurring substitutions or the N208S substitution that showed reduced susceptibility to nirsevimab (IC50 > ULOQ). Resistance associated substitutions were not identified as major variants in any sampling timepoints in MELODY, MEDLEY or MUSIC studies, including post day 361 when nirsevimab titres have waned.
Minimal data are available that show that variants resistant to nirsevimab could have cross-resistance to other monoclonal antibodies targeting the F protein of RSV; palivizumab retained full neutralisation potency against resistant associated substitutions identified in D5290C00003. Nirsevimab retained activity against recombinant RSV harbouring palivizumab resistance-associated substitutions identified in molecular epidemiology studies and in neutralisation escape variants of palivizumab.
Pharmacokinetic/pharmacodynamic relationship(s). In D5290C00003 and MELODY (Primary cohort) 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 IM dose for infants in their first RSV season and a 200 mg IM dose for children entering their second RSV season was selected on the basis of these results.
Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralising antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and the paediatric population studied. For these reasons, comparison of the incidence of antibodies to nirsevimab to other products may be misleading.
In D5290C00003 and MELODY anti-nirsevimab antibodies were detected in 148/2493 (5.9%) infants who received a single dose of nirsevimab at the recommended dosing regimen during the 361 days post dosing period, and 110/2404 (4.6%) tested positive for anti-drug antibodies (ADA) against the YTE domain. In MELODY 26/1877 (1.4%) of subjects tested positive for nirsevimab neutralising antibodies. For subjects receiving a single dose of nirsevimab in their first RSV season in MEDLEY, anti-nirsevimab antibodies were detected in 32/587 (5.5%) of infants during the 361 days post dosing period. Nirsevimab neutralising antibodies were detected in 2/564 (0.4%) of infants and 29/564 (5.1%) of infants tested positive for ADA against the YTE domain. Of 180 subjects who received nirsevimab in two consecutive RSV seasons, 8 subjects (4.4%) and 13 (7.2%) became ADA positive for the first time in the first and second RSV season respectively. Only one subject was ADA positive in both RSV seasons. In the second RSV season, 8 subjects had anti-YTE ADA and one of the subjects also had neutralising antibodies. For subjects receiving nirsevimab in their first or second RSV season in MUSIC, anti-nirsevimab antibodies were detected in 11/97 (11.3%) of children during the 361 days post dosing period. Nirsevimab neutralising antibodies were detected in 1/97 (1.0%) of children and 11/97 (11.3%) of children tested positive for ADA against the YTE domain.
The development of ADA against nirsevimab appears to have no clinically relevant effect on its clearance (up to 5 months), efficacy or safety.
Clinical trials.
The efficacy and safety of Beyfortus were evaluated in two randomised, double-blind, placebo-controlled multicentre trials (D5290C00003 and MELODY) for the prevention of MA RSV LRTI in term and preterm infants (GA ≥ 29 weeks) entering their first RSV season. Safety and pharmacokinetics (PK) of Beyfortus were also evaluated in a randomised, double-blind, palivizumab-controlled multicentre trial (MEDLEY) in infants at higher risk for severe RSV disease, including extremely preterm infants (GA < 29 weeks) and infants with CLD of prematurity, or haemodynamically significant CHD, entering their first RSV season, and children with CLD or CHD entering their second RSV season. See Table 3.
Safety and PK of Beyfortus were also evaluated in an open-label, uncontrolled, single dose multicentre trial (MUSIC) in immunocompromised children ≤ 24 months of age.
Key demographics and baseline characteristics for MELODY, D5290C00003, and MEDLEY are summarised in Table 4 and Table 5. Across MELODY, D5290C00003 and MEDLEY, demographic and baseline characteristics were similar between the nirsevimab and comparator groups and the study populations were representative of the intended target population of all infants in their first RSV season and children who remain vulnerable to severe RSV disease in their second RSV season, including extremely preterm infants, and infants and children up to 24 months of age with CLD or CHD.
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 1453 very and moderately preterm infants (GA ≥ 29 to < 35 weeks) entering their first RSV season (2:1) to receive a single IM dose of 50 mg Beyfortus 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; and 59.5% weighed < 5 kg. The median age was 2.80 months (range: 0.1 to 11.9 months); 53.2% were ≤ 3.0 months; 32.6% were > 3.0 to ≤ 6.0 months, and 14.2% were > 6.0 months of age.
MELODY (Primary cohort) randomised a total of 1490 term and late preterm infants (GA ≥ 35 weeks) entering their first RSV season (2:1) to receive a single IM dose of Beyfortus (50 mg Beyfortus if < 5 kg weight or 100 mg Beyfortus 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; and 40.0% weighed < 5 kg. The median age was 2.60 months (range: 0.03 to 11.10 months); 57.9% were ≤ 3.0 months; 32.1% were > 3.0 to ≤ 6.0 months and 10.0% were > 6.0 months of age. MELODY continued to enrol infants following the primary analysis, and overall, 3012 infants (All subjects) were randomised to receive Beyfortus (2009) or placebo (1003). At randomisation, 12.0% were GA ≥ 35 to < 37 weeks; 88.0% were GA ≥ 37 weeks; 52.3% were male; 52.9% were White; 14.5% were of African origin; 5.3% were Asian; and 39.6% weighed < 5 kg. The median age was 2.53 months (range: 0.00 to 14.00 months); 59.0% were ≤ 3.0 months; 31.8% were > 3.0 to ≤ 6.0 months, and 9.1% were > 6.0 months of age.
Demographic and baseline characteristics were comparable between the Beyfortus 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). Beyfortus demonstrated efficacy in both individual trials in term and preterm infants (GA ≥ 29 weeks) entering their first RSV season (see Table 6).
Subgroup analyses of the primary efficacy endpoint by gestational age, gender, race and region showed results were consistent with the overall population.
The incidence of hospitalisation in infants with MA RSV LRTI and very severe MA RSV LRTI were evaluated. 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 defined as MA RSV LRTI with hospitalisation and requirement for supplemental oxygen or intravenous (IV) fluids. The efficacy of Beyfortus in D5290C00003 and MELODY (All subjects) in term and preterm infants (GA ≥ 29 weeks) entering their first RSV season against MA RSV LRTI with hospitalisation and very severe MA RSV LRTI are shown in Table 7.
In infants in D5290C00003 who received the recommended dose (50 mg if body weight < 5 kg at time of dosing), the efficacy of Beyfortus against MA RSV LRTI, MA RSV LRTI with hospitalisation, and very severe MA RSV LRTI in very and moderately preterm infants (GA ≥ 29 to < 35 weeks) was 86.2% (95% CI 68.0, 94.0), 86.5% (95% CI 53.5, 96.1) and 100.0% (95% CI 79.7, not evaluated), respectively.
A pooled analysis of D5290C00003 (recommended dose) and MELODY (Primary cohort) was specified after data on D5290C00003 had been revealed. Efficacy of Beyfortus against MA RSV LRTI, MA RSV LRTI with hospitalisation, and very severe MA RSV LRTI through 150 days post dose was 79.5% (95% CI 65.9, 87.7), 77.3% (95% CI 50.3, 89.7) and 86.0% (95% CI 62.5, 94.8), respectively.
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 Beyfortus vs placebo.
Efficacy against MA RSV LRTI in infants and children vulnerable to severe RSV disease (MEDLEY and MUSIC).
MEDLEY randomised a total of 925 infants at higher risk for severe RSV disease including infants with CLD or CHD and preterm infants GA < 35 weeks, entering their first RSV season. Infants received a single IM dose (2:1) of Beyfortus (50 mg Beyfortus if < 5 kg weight or 100 mg Beyfortus if ≥ 5 kg weight at the time of dosing), followed by 4 once-monthly IM doses of placebo, or 5 once-monthly IM 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 CLD; 11.2% had CHD; 53.5% were male; 79.2% were White; 9.5% were of African origin; 5.4% were Asian; and 56.5% weighed < 5 kg. The median age was 3.46 months (range: 0.07 to 12.25 months); 45.2% were ≤ 3.0 months; 33.6% were > 3.0 months to ≤ 6.0 months and 21.2% were > 6.0 months of age.
Children at higher risk with CLD or CHD ≤ 24 months of age continued in the trial for a second RSV season. Subjects who received Beyfortus during their first RSV season received a second single dose of 200 mg Beyfortus entering their second RSV season (180) followed by 4 once-monthly IM doses of placebo. Subjects who received palivizumab during their first RSV season were re-randomised 1:1 to either the Beyfortus or the palivizumab group entering their second RSV season. Subjects in the Beyfortus group (40) received a single fixed dose of 200 mg followed by 4 once-monthly IM doses of placebo. Subjects in the palivizumab group (42) received 5 once-monthly IM doses of 15 mg/kg palivizumab. Of these children 72.1% had CLD, 30.9% had CHD; 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 Beyfortus/Beyfortus, palivizumab/Beyfortus and palivizumab/palivizumab groups.
The efficacy of Beyfortus in infants at higher risk for severe RSV disease, including extremely preterm infants (GA < 29 weeks) and infants with CLD or CHD, and in children with CLD or CHD ≤ 24 months of age entering their second RSV season is established by extrapolation from the efficacy of Beyfortus in D5290C00003 and MELODY based on PK exposure. In MEDLEY, the incidence of MA RSV LRTI through 150 days post dose was 0.6% (4/616) in the Beyfortus group and 1.0% (3/309) in the palivizumab group. There were no cases of MA RSV LRTI through 150 days in the second RSV season.
In MUSIC, the efficacy of Beyfortus in immunocompromised infants and children ≤ 24 months entering their first or second RSV season, who received the recommended dose of Beyfortus is established by extrapolation from the efficacy of Beyfortus in D5290C00003 and MELODY based on PK exposure. There were no cases of MA RSV LRTI through 150 days post dose.
Duration of protection.
The minimum duration of protection offered by a single dose of nirsevimab is at least 5 months based on clinical and PK data.
5.2 Pharmacokinetic Properties
The PK properties of nirsevimab are based on data from individual studies and population PK analyses. The PK of nirsevimab were dose-proportional in children and adults following administration of clinically relevant IM doses over a dose range of 25 mg to 300 mg.
Absorption.
The estimated absorption half-life following IM administration was 1.7 days, and the estimated absolute bioavailability was 84% based on population PK analysis. The median time to maximum concentration was 6 days (range 1 to 28 days).
Distribution.
Based on population PK analysis, the estimated central and peripheral volume of distribution of nirsevimab were 216 mL and 261 mL, respectively, for an infant weighing 5 kg.
Metabolism.
Nirsevimab is a human IgG1κ monoclonal antibody that is degraded by proteolytic enzymes widely distributed in the body and not metabolised by hepatic enzymes.
Excretion.
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.
Based on population PK analysis, 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.
Special populations.
Race and ethnicity.
Based on population PK analysis there was no clinically relevant effect of race and ethnicity on the PK of nirsevimab.
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.
There was no significant influence of CLD or CHD on the PK of nirsevimab based on population PK analysis. Serum concentrations at day 151 in MEDLEY were comparable to those in MELODY.
In infants born extremely preterm (GA < 29 weeks) entering their first RSV season and children with CLD or CHD entering their first or second RSV season (MEDLEY), the pre-defined acceptance criteria for extrapolation were met; > 80% of infants/children achieved nirsevimab exposures associated with RSV protection following a single dose.
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 protein-losing conditions as evidenced by increased clearance of nirsevimab, 87% (71/82) achieved nirsevimab exposures associated with RSV protection.
5.3 Preclinical Safety Data
Genotoxicity.
Nirsevimab is a monoclonal antibody, as such genotoxicity studies have not been conducted. As a large protein molecule, nirsevimab is not expected to interact directly with DNA or other chromosomal material.
Carcinogenicity.
No carcinogenicity studies have been conducted because nirsevimab binds a viral-specific target that is not expressed in nonclinical models or in humans.6 Pharmaceutical Particulars
6.1 List of Excipients
Beyfortus solution for injection contains the excipients histidine, histidine hydrochloride monohydrate, arginine hydrochloride, sucrose, polysorbate 80 and water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicines.
6.3 Shelf Life
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.
6.4 Special Precautions for Storage
Store at 2°C to 8°C (Refrigerate. Do not freeze).
Beyfortus may be kept at room temperature (Store below 25°C) for a maximum of 8 hours. After removal from the refrigerator, Beyfortus must be used within 8 hours or discarded.
Keep the prefilled syringe in the outer carton in order to protect from light.
Do not shake or expose to heat.
6.5 Nature and Contents of Container
Siliconised Luer lock Type I glass prefilled syringe with a FluroTec-coated plunger stopper.
Each prefilled syringe contains 0.5 mL or 1 mL solution.
Pack size: 1 or 5 single use prefilled syringe(s)* without needles.
* Not all pack sizes may be available in Australia.
6.6 Special Precautions for Disposal
Dispose of the used syringe immediately, together with the needle, in a sharps disposal container.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.
6.7 Physicochemical Properties
General structure.
Nirsevimab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. The Fc region of nirsevimab has been engineered with a triple amino acid substitution (YTE) to extend serum half-life.
CAS number.
1989556-22-0.7 Medicine Schedule (Poisons Standard)
Prescription only medicine (Schedule 4).
Summary Table of Changes
