ENFLONSIA Solution for injection Ref.[116536] Active ingredients: Clesrovimab

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies
ATC code: J06BD10

Mechanism of action

Clesrovimab is a fully human immunoglobulin G1 kappa (IgG1κ) neutralising monoclonal antibody with a triple amino acid substitution (YTE) in the Fc region which increases binding to the neonatal Fc receptor leading to an extended serum half-life. Clesrovimab provides passive immunity by targeting the RSV outer membrane fusion (F) protein to prevent viral entry into cells.

Clesrovimab binds to a conserved epitope on antigenic site IV on the fusion F protein. Clesrovimab binds to RSV pre-fusion F glycoprotein and post-fusion F glycoprotein with equilibrium dissociation constant values (KD) of 71 pM and 480 pM, respectively.

RSV A and B isolates were equipotently neutralised by clesrovimab in vitro.

Pharmacodynamic effects

Antiviral activity

An in vitro infection neutralisation assay was used to determine clesrovimab potency against RSV strains A and B using HEp-2 cells. In the laboratory, clesrovimab neutralised RSV strain A and B with an IC50 ± SD of 6.0 ± 4.3 and 3.0 ± 2.0 ng/mL, respectively. Clesrovimab was assessed for its ability to neutralise 47 RSV clinical isolates using a similar in vitro assay, with IC50 values ranging from 0.18 ng/mL to 11.11 ng/mL for RSV A and 0.58 ng/mL to 29.65 ng/mL for RSV B. The clinical isolate panel consisted of a broad range of clinical RSV isolated between years 1987 and 2016. Recent clinical isolates (RSV A and RSV B) from 2016 through 2021 were equipotently neutralised by clesrovimab as compared to the reference RSV strains. Clesrovimab neutralises the virus without the requirement of Fc effector function.

Antiviral resistance

In cell culture

Monoclonal antibody-resistant viral mutants (MARMs) were identified after serial infection in cell culture of RSV A or RSV B. Four RSV strain A MARMs for clesrovimab were generated after 6 rounds of serial infection. The 4 MARM viruses were subjected to an additional 3 rounds of serial infection prior to being processed for characterisation. The 4 RSV A MARMs were sequenced and found to have substitutions located in the binding epitope region reported for clesrovimab, G446E, S443P and K445N, S443P and G446E, or S443P. An in vitro assay confirmed that clesrovimab was not able to neutralise the 4 MARMs. One RSV B MARM was identified after 9 rounds of serial infection. The RSV B MARM was found to have a substitution located in the binding epitope region reported for clesrovimab, S443P.

In surveillance studies

In sequences reported in the GenBank database, the RSV binding epitope for clesrovimab was highly conserved (99.8%). Thirteen clesrovimab epitope variants were identified, including 1 variant, I432T, identified in 5 RSV A and 1 RSV B samples (0.04%). This variant was shown to reduce clesrovimab neutralising activities by 4 times (RSV A) and 1.6 times (RSV B). The I432T variant demonstrated reduced fitness as compared to the wild type virus. Two RSV A MARMs were identified with a substitution at position 446 (G446E). This substitution was found in 3 GenBank variant RSV A F sequences (0.02%) in the database. The in vitro data for the RSV A MARM virus with the G446E substitution suggest reduced viral fitness compared to wild type RSV strain A and are less likely to dominate in circulation in subsequent seasons compared to wild type.

In a global surveillance study conducted between 2019 and 2023 in 8 countries, which included both the Northern and Southern hemispheres, the clesrovimab binding site was highly conserved (100%). There were 652 RSV positive clinical samples collected from individuals of various ages. Of these, the 555 RSV positive sequenced clinical samples consisted of 300 RSV A (54%) and 255 RSV B (46%). There were no sequence variants identified in the clesrovimab binding site.

In clinical studies

Resistance substitutions were not associated with the development of RSV-associated disease in Study 004 and Study 007. Viral genotypic testing of RSV positive nasal swabs demonstrated that the majority of the clesrovimab binding site (IV) substitutions affected residue G446, resulting in the following substitutions: G446E, G446R or G446W (RSV A) and G446E or G446R (RSV B). The G446E substitution was previously found in the GenBank database and RSV MARM study. In Study 004, there was 1 case of RSV-associated hospitalisation (RSV A) with the G446W substitution. There were no cases of RSV-associated medically attended lower respiratory infection (MALRI) associated with any G446 substitution. In Study 007, 1 case of RSV-associated MALRI (RSV A) and 1 case of RSV-associated severe MALRI (RSV B) in clesrovimab participants within 2 weeks of dosing carried the G446R substitution. No G446 substitutions were found in the placebo or palivizumab treatment arm.

Cross-resistance

Clesrovimab neutralised both palivizumab and nirsevimab resistant isolates. Clesrovimab was 5.2 times and 1.7 times more potent on the N262Y RSV A and RSV B palivizumab resistant clinical isolate strains, as compared to RSV A and B reference strains, respectively. Nirsevimab resistant mutants of RSV B strains (N208S, I64T+K68E, I64T+K68E+I206M+Q209R) observed in the clinic were equipotently neutralised by clesrovimab as compared to RSV B wild type control virus. The potency against L204S+I206M+Q209R+S211N RSV B mutant was undeterminable due to insufficient growth of the virus.

Immunogenicity

In Study 004 and Study 007, 12.0% (124/1033) and 13.0% (34/261) of participants who received clesrovimab were anti-drug antibodies (ADA)-positive through Day 240, respectively. There was no identified impact of ADA on pharmacokinetics, RSV serum neutralising activity, or safety of clesrovimab during RSV season 1. The impact of ADA on efficacy could not be established.

Clinical efficacy

The efficacy and safety of clesrovimab were evaluated in preterm and full-term infants in the clinical studies 004 and 007.

Efficacy against RSV-associated MALRI, hospitalisation, and severe MALRI in neonates and infants entering their first RSV season (Study 004)

Study 004 was a Phase 2b/3, randomised, double-blind placebo-controlled, multicentre study conducted in 22 countries from the Northern and Southern hemispheres to evaluate the efficacy of clesrovimab in healthy early and moderate preterm infants (≥29 to <35 weeks GA) and late preterm and full-term infants (≥35 weeks GA). Participants were randomised 2:1 to receive a 105 mg dose of clesrovimab (n=2 412, including 422 early and moderate preterm infants) or saline placebo (n=1 202, including 209 early and moderate preterm infants) by intramuscular injection.

Among participants who received clesrovimab or saline placebo, the median age of infants was 3.1 months (range: 0 to 12 months); 14.9% were ≤1 month of age; 34.5% were >1 to ≤3 months; 30.6% were >3 to ≤6 months; 20.1% were >6 months; and 51.1% were male. Of these participants, 17.5% were GA ≥29 to <35 weeks and 82.5% were GA ≥35 weeks. The median body weight was 5.8 kg (range: 1.6 to 11.9 kg). The racial distribution was as follows: 45.2% were White; 26.6% were Asian; 13.8% were Black or African American; 12.2% were multi-racial and 1.9% were American Indian or Alaska Native; 28.1% were of Hispanic or Latino ethnicity.

The primary endpoint was the incidence of RSV-associated MALRI characterised as cough or difficulty breathing and requiring ≥1 indicator of LRI (wheezing, rales/crackles) or severity (chest wall in-drawing/retractions, hypoxemia, tachypnoea, dehydration due to respiratory symptoms) through 150 days after dosing. Medically Attended (MA) includes all healthcare professional visits in settings such as outpatient clinic, clinical study site, emergency department, urgent care centre, and/or hospital. The statistical criterion for success required the lower bound of the 95% CI of efficacy to be greater than 25%.

RSV-associated hospitalisation through 150 days after dosing and RSV-associated MALRI through 180 days after dosing were also evaluated as secondary endpoints. RSV-associated hospitalisation was defined as hospitalisation for respiratory symptoms with a positive test for RSV. For RSV-associated hospitalisation through 150 days, the statistical criterion for success required the lower bound of the 95% CI of efficacy to be greater than 0%.

RSV-associated severe MALRI, a pre-specified exploratory endpoint, characterised by 1) cough or difficulty breathing and 2) severe hypoxemia or the need for supplemental oxygen or mechanical ventilatory support, was evaluated through 150 days after dosing.

All efficacy endpoints evaluated required an RSV positive RT-PCR nasopharyngeal (NP) sample.

Table 2 displays the efficacy results for RSV-associated disease endpoints, in order of increasing severity, in preterm and full-term infants from Days 1 through 150 post-dose.

Table 2. Incidence of RSV-associated disease in preterm and full-term infants Days 1 through 150 Post-dose (Study 004):

n=Number of participants eligible for inclusion in the full analysis set population.
^* Based on relative risk reduction vs placebo. Estimate and 95% CI of efficacy were estimated from the modified Poisson regression with robust variance method.
^† Pre-specified multiplicity controlled; p-value <0.001
^‡ An exploratory analysis evaluated RSV-associated LRI hospitalisation characterised by cough or difficulty breathing and requiring ≥1 indicator of LRI or severity in hospitalised infants with an RSV positive RT PCR NP sample (5 cases/2398 in the clesrovimab arm and 27 cases/1201 in the placebo arm; endpoint not multiplicity controlled). The estimated efficacy was 90.9% (95% CI: 76.2, 96.5).
^§ Exploratory efficacy endpoint, not multiplicity controlled.

Subgroup analyses of the primary efficacy endpoint of RSV-associated MALRI by gestational age, chronological age, body weight, sex, race and region showed results consistent with the overall population.

When analysed through 180 days after dosing, the efficacy estimate for RSV-associated MALRI (requiring ≥1 indicator of LRI or severity) was 59.5% (95% CI: 43.3, 71.1).

The incidence rates of RSV-associated MALRI (requiring ≥ 1 indicator of LRI or severity) in the second season in the absence of additional prophylaxis (Days 365 through 515 post-dose) were similar between recipients of clesrovimab (53 events/1008 participants, incidence = 0.055 over 5 months) and placebo (26 events/501 participants, incidence = 0.054 over 5 months).

Efficacy against RSV-associated MALRI and hospitalisation in infants at increased risk of severe RSV disease entering their first RSV season (Study 007)

Study 007 is a phase 3, randomised, partially blind, palivizumab controlled, multicentre study conducted in 27 countries from the Northern and Southern hemispheres to evaluate the safety, efficacy and pharmacokinetics of clesrovimab in early (<29 weeks GA) or moderate preterm infants (≥29 to ≤35 weeks GA), and infants with chronic lung disease of prematurity or congenital heart disease of any GA, who are at increased risk for severe RSV disease entering in their first RSV season. Participants were randomised to receive clesrovimab (n=446, including 176 infants with chronic lung disease (CLD) of prematurity or haemodynamically significant congenital heart disease (CHD) and 270 early or moderate preterm infants (≤35 weeks GA) without CLD of prematurity or CHD), or palivizumab (n=450, including 175 infants with CLD of prematurity or CHD and 275 early or moderate preterm infants (≤35 weeks GA) without CLD of prematurity or CHD) by intramuscular injection. Participants randomised to clesrovimab received a single 105 mg dose on Day 1 followed by a dose of placebo one month later; palivizumab was administered on Day 1 and every month thereafter for a total of 3 to 5 doses of 15 mg/kg.

Among participants who received clesrovimab or palivizumab, the median age of infants was 2.5 months (range: 0 to 12 months); 14.3% were ≤1 month of age; 44.3% were >1 to ≤3 months; 30.6% were >3 to ≤6 months; 10.8% were >6 months; and 49.8% were male. Of these participants, 27.9% had CLD, 11.3% had CHD, 5.6% were GA less than 29 weeks with neither CLD nor CHD and 55.2% were GA greater than or equal to 29 weeks with neither CLD nor CHD. The median body weight was 3.3 kg (range: 1.1 to 9.6 kg). The racial distribution was as follows: 52.2% were White; 18.1% were Asian; 15.4% were Black or African American; 12.2% were multi-racial, and 1.3% were American Indian or Alaska Native; 31.7% were of Hispanic or Latino ethnicity.

The efficacy of clesrovimab in infants at increased risk for severe RSV disease was established by extrapolation of efficacy of clesrovimab from Study 004 to Study 007 based on pharmacokinetic exposure (see section 5.2). In Study 007, the incidence rate of RSV-associated MALRI (requiring ≥1 indicator of LRI or severity) through 150 days after dosing was 3.6% (95% CI: 2.0, 6.0; 14 cases/443 in analysis set) in the clesrovimab arm and 3.0% (95% CI: 1.6, 5.3; 12 cases/437 in the analysis set) in the palivizumab arm. The incidence rate of RSV-associated hospitalisation through 150 days after dosing was 1.3% (95% CI: 0.4, 3.0; 5 cases/443 in analysis set) in the clesrovimab arm and 1.5% (95% CI: 0.6, 3.3; 6 cases/437 in analysis set) in the palivizumab arm.

Duration of protection

Based on clinical efficacy data from Study 004, the duration of protection offered by a single dose of clesrovimab could extend through 6 months but the observation is limited by a low event incidence that occurred after 5 months post-dose.