Clesrovimab-cfor (Monograph)

Brand name: Enflonsia
Drug class: Monoclonal Antibodies

Introduction

Clesrovimab-cfor, a fully human immunoglobulin G1 kappa (IgG1) monoclonal antibody, is a respiratory syncytial virus (RSV) F protein-directed fusion inhibitor.¹

Uses for Clesrovimab-cfor

Clesrovimab-cfor has the following uses:

Clesrovimab-cfor is indicated for the prevention of RSV lower respiratory tract disease in neonates and infants who are born during or entering their first RSV season.¹

Clesrovimab-cfor Dosage and Administration

General

Clesrovimab-cfor is available in the following dosage form(s) and strength(s):

Injection: 105 mg/0.7 mL in a single-dose prefilled syringe for IM injection.¹

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

Clesrovimab-cfor must be administered by a healthcare provider.¹

Recommended dosage of clesrovimab-cfor for neonates and infants born during or entering their first RSV season is 105 mg administered as a single IM injection.¹

For neonates and infants born during the RSV season, administer clesrovimab-cfor once starting from birth.¹ For infants born outside the RSV season, administer clesrovimab-cfor once prior to the start of their first RSV season considering the duration of protection provided by clesrovimab.¹

See Full Prescribing Information for additional details on preparation and administration of clesrovimab-cfor prefilled syringes and for recommendations on co-administration with childhood vaccines and immunoglobulin products.¹

Cautions for Clesrovimab-cfor

Contraindications

Clesrovimab-cfor is contraindicated in infants with a history of serious hypersensitivity reactions, including anaphylaxis, to any component of clesrovimab.¹

Warnings/Precautions

Hypersensitivity Including Anaphylaxis

Serious hypersensitivity reactions, including anaphylaxis, have been observed with other human immunoglobulin G1 (IgG1) monoclonal antibodies.¹ If signs or symptoms of a clinically significant hypersensitivity reaction or anaphylaxis occur, initiate appropriate medications and/or supportive therapy.¹

RSV Diagnostic Test Interference

Clesrovimab-cfor may interfere with some immunologically-based RSV diagnostic assays (i.e., rapid antigen tests) as observed in laboratory studies.¹ Confirmation using a reverse transcriptase polymerase chain reaction (RT-PCR) assay is recommended when rapid antigen assay results are negative and clinical observations are consistent with RSV infection ¹

Specific Populations

Pregnancy

Clesrovimab-cfor is not indicated for use in females of reproductive potential.¹

Lactation

Clesrovimab-cfor is not indicated for use in females of reproductive potential.¹

Pediatric Use

The safety and effectiveness of clesrovimab-cfor have been established for the prevention of RSV lower respiratory tract disease in neonates and infants born during or entering their first RSV season and the information on this use is discussed throughout the labeling.¹

The safety and effectiveness of clesrovimab-cfor have not been established in children older than 12 months of age.¹

Common Adverse Effects

Most common adverse reactions were injection-site erythema (3.7%), injection-site swelling (2.7%) and rash (2.3%).¹

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions and Spectrum

Mechanism of Action

Clesrovimab-cfor is a recombinant human immunoglobulin G1 kappa (IgG1κ) neutralizing monoclonal antibody with a YTE triple amino acid substitution (M252Y/S254T/T256E) in the Fc region which increases binding to the neonatal Fc receptor leading to an extended serum half-life.¹ Passive immunity is provided by clesrovimab, which targets the extracellular domain of the RSV fusion (F) protein to prevent fusion of the viral and cellular membranes and viral entry.¹ Clesrovimab binds to a conserved epitope on antigenic site IV on the F protein and binds to RSV A pre-fusion F glycoprotein and post-fusion F glycoprotein with equilibrium dissociation constant values (K_D) of 71 pM and 480 pM, respectively. ¹

Spectrum

A neutralization assay in Hep-2 cells was used to determine clesrovimab-cfor potency against RSV A and RSV B isolates.¹ Clesrovimab-cfor neutralized 47 RSV clinical isolates collected from North America locations between 1987 and 2016, with median EC₅₀ values for RSV A isolates of 25 pM (3.71 ng/mL) (n=24; range of 1.2 to 74 pM [0.18 to 11.11 ng/mL]), and for RSV B isolates of 30 pM (4.48 ng/mL) (n=23; range of 4 to 198 pM [0.59 to 29.65 ng/mL]).¹ Clesrovimab-cfor also neutralized 12 contemporary isolates isolated from Texas, US, between 2016 and 2021, with a median EC₅₀ value for RSV A isolates of 121 pM (18.02 ng/mL) (n=6; range of 59 to 186 pM [8.79 to 27.74 ng/mL]), and for RSV B isolates of 130 pM (19.41 ng/mL) (n=6; range of 95 to 153 pM [14.22 to 22.92 ng/mL]).¹ The relatively high EC₅₀ values for contemporary isolates compared with historical isolates is thought to be related to assay differences because the values for the control viruses also increased.¹

Resistance

Resistance in cell culture: Clesrovimab-resistant RSV variants were identified after serial passage in cell culture of RSV A or RSV B in the presence of clesrovimab-cfor.¹ Four variants were generated after 6 passages with RSV A, and one variant after 9 passages of RSV B.¹ These variants each had reduced susceptibility to clesrovimab-cfor of >3,800-fold (RSV A) or >360-fold (RSV B) when assessed in cell culture, and harbored the following clesrovimab-cfor binding site substitutions: G446E, S443P+K445N, S443P+G446E, or S443P for the four RSV A variants, respectively, and S443P substitution for the RSV B variant.¹

Resistance in surveillance trials: In sequences reported in the GenBank database (accessed April 15, 2024), the RSV binding epitope for clesrovimab-cfor was highly conserved (99.8%), with 13 polymorphisms identified at contact residues.¹ Of these polymorphisms, the most common (I432T, 0.04% of sequences) conferred 4-fold (RSV A) or 1.6-fold (RSV B) reductions in susceptibility to clesrovimab-cfor in a cell culture neutralization assay.¹ One polymorphism seen in 3 RSV A sequences, G446E, is a resistance-associated substitution selected in cell culture.¹ In a global surveillance study conducted between 2019 and 2023 in 8 countries across Northern and Southern Hemispheres, the clesrovimab-cfor binding site was highly conserved (>99%) in 300 RSV A and 255 RSV B sequences in clinical samples collected from individuals of various ages (<1 year to >60 years of age).¹

Resistance in clinical trials: In Trial 004, more substitutions in the clesrovimab-cfor binding site (amino acid positions 426 to 447) were observed at ≥3% variant allele frequency (VAF) in RSV infections of clesrovimab-cfor-treated participants (15/156 [9.6%]) compared with placebo participants (2/150 [1.3%]) from Day 1 through 180 post-dose.¹ The majority of the binding site substitutions affected residue G446 (RSV A: G446E, G446R or G446W; and RSV B: G446E or G446R), and were seen at >50% VAF in at least one participant each.¹ G446E, G446R, and G446W substitutions are resistance-associated, with G446E and G446W conferring >2,941-fold (RSV A) or >1,299-fold (RSV B) loss of susceptibility to clesrovimab-cfor, and G446R conferring >1,563-fold (RSV A) loss of susceptibility to clesrovimab-cfor (RSV B not assessed).¹ Other binding site substitutions seen in clesrovimab-cfor-treated participants at <10% VAF were RSV B: F435S, S443L, G446V, and V447I (no cell culture neutralization data available).¹ In Trial 007, RSV infections with binding site substitutions at >50% VAF included RSV A (G446W) and RSV B (G446E and G446R), in clesrovimab-cfor-treated participants.¹ For Trials 004 and 007, there was no clear association of binding site substitutions seen in RSV infections and RSV-associated Medically Attended Lower Respiratory Infection (MALRI) or hospitalization.¹ However, for substitutions seen at high VAF% from Days 1 to 150 post-dose, one participant in Trial 004 with RSV A G446W substitution had RSV-associated hospitalization, and one participant in Trial 007 with RSV B G446R substitution had RSV-associated severe MALRI and hospitalization.¹

Cross-resistance:No cross-resistance was seen for RSV variants harboring palivizumab or nirsevimab resistance-associated substitutions in cell culture neutralization assays.¹ Clesrovimab-cfor did not lose activity against RSV A or RSV B clinical isolates with palivizumab resistance-associated substitution N262Y, or recombinant RSV B with nirsevimab resistance-associated substitutions N208S, I64T+K68E, or I64T+K68E+I206M+Q209R, which were observed in clinical trials of nirsevimab.¹ Not all nirsevimab resistance-associated substitutions have been assessed for cross-resistance with clesrovimab.¹ Both nirsevimab and palivizumab neutralized RSV A and B variants harboring clesrovimab resistance-associated substitutions G446E or G446W in cell culture.¹

Advice to Patients

• Advise the child’s caregiver to read the FDA-approved patient labeling¹

• 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 infant experiences a hypersensitivity reaction to clesrovimab ¹

• Advise the caregiver that the infant will receive clesrovimab-cfor by IM injection by a healthcare provider ¹

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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