Leaflet ENFLONSIA 105mg solution for injection in pre-filled syringe

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies,

ATC code: J06BD10

Clesrovimab is a fully human immunoglobulin G1 kappa (IgG1κ) neutralising monoclonal antibodywith 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 bytargeting 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. Clesrovimabbinds to RSV pre-fusion F glycoprotein and post-fusion F glycoprotein with equilibrium dissociationconstant values (KD) of 71 pM and 480 pM, respectively.

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

An in vitro infection neutralisation assay was used to determine clesrovimab potency against RSVstrains A and B using HEp-2 cells. In the laboratory, clesrovimab neutralised RSV strain A and B withan IC50 ± SD of 6.0 ± 4.3 and 3.0 ± 2.0 ng/mL, respectively. Clesrovimab was assessed for its abilityto neutralise 47 RSV clinical isolates using a similar in vitro assay, with IC50 values ranging from0.18 ng/mL to 11.11 ng/mL for RSV A and 0.58 ng/mL to 29.65 ng/mL for RSV B. The clinicalisolate panel consisted of a broad range of clinical RSV isolated between years 1987 and 2016. Recentclinical isolates (RSV A and RSV B) from 2016 through 2021 were equipotently neutralised byclesrovimab as compared to the reference RSV strains. Clesrovimab neutralises the virus without therequirement of Fc effector function.

Monoclonal antibody-resistant viral mutants (MARMs) were identified after serial infection in cellculture of RSV A or RSV B. Four RSV strain A MARMs for clesrovimab were generated after6 rounds of serial infection. The 4 MARM viruses were subjected to an additional 3 rounds of serialinfection prior to being processed for characterisation. The 4 RSV A MARMs were sequenced andfound 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 wasnot able to neutralise the 4 MARMs. One RSV B MARM was identified after 9 rounds of serialinfection. The RSV B MARM was found to have a substitution located in the binding epitope regionreported for clesrovimab, S443P.

In surveillance studies

In sequences reported in the GenBank database, the RSV binding epitope for clesrovimab was highlyconserved (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 clesrovimabneutralising activities by 4 times (RSV A) and 1.6 times (RSV B). The I432T variant demonstratedreduced fitness as compared to the wild type virus. Two RSV A MARMs were identified with asubstitution 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 G446Esubstitution suggest reduced viral fitness compared to wild type RSV strain A and are less likely todominate in circulation in subsequent seasons compared to wild type.

In a global surveillance study conducted between 2019 and 2023 in 8 countries, which included boththe 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, the555 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.

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 themajority of the clesrovimab binding site (IV) substitutions affected residue G446, resulting in thefollowing 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) and1 case of RSV-associated severe MALRI (RSV B) in clesrovimab participants within 2 weeks ofdosing carried the G446R substitution. No G446 substitutions were found in the placebo orpalivizumab treatment arm.

Clesrovimab neutralised both palivizumab and nirsevimab resistant isolates. Clesrovimab was5.2 times and 1.7 times more potent on the N262Y RSV A and RSV B palivizumab resistant clinicalisolate strains, as compared to RSV A and B reference strains, respectively. Nirsevimab resistantmutants of RSV B strains (N208S, I64T+K68E, I64T+K68E+I206M+Q209R) observed in the clinicwere equipotently neutralised by clesrovimab as compared to RSV B wild type control virus. Thepotency against L204S+I206M+Q209R+S211N RSV B mutant was undeterminable due to insufficientgrowth of the virus.

In Study 004 and Study 007, 12.0% (124/1033) and 13.0% (34/261) of participants who receivedclesrovimab were anti-drug antibodies (ADA)-positive through Day 240, respectively.

There was no identified impact of ADA on pharmacokinetics, RSV serum neutralising activity, orsafety of clesrovimab during RSV season 1. The impact of ADA on efficacy could not be established.

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

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

Study 004 was a Phase 2b/3, randomised, double-blind placebo-controlled, multicentre studyconducted in 22 countries from the Northern and Southern hemispheres to evaluate the efficacy ofclesrovimab in healthy early and moderate preterm infants (≥ 29 to < 35 weeks GA) and late pretermand full-term infants (≥ 35 weeks GA). Participants were randomised 2:1 to receive a 105 mg dose ofclesrovimab (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 was3.1 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 was5.8 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 ordifficulty breathing and requiring ≥ 1 indicator of LRI (wheezing, rales/crackles) or severity (chestwall in-drawing/retractions, hypoxemia, tachypnoea, dehydration due to respiratory symptoms)through 150 days after dosing. Medically Attended (MA) includes all healthcare professional visits insettings such as outpatient clinic, clinical study site, emergency department, urgent care centre, and/orhospital. The statistical criterion for success required the lower bound of the 95% CI of efficacy to begreater than 25%.

RSV-associated hospitalisation through 150 days after dosing and RSV-associated MALRI through180 days after dosing were also evaluated as secondary endpoints. RSV-associated hospitalisation wasdefined as hospitalisation for respiratory symptoms with a positive test for RSV. For RSV-associatedhospitalisation through 150 days, the statistical criterion for success required the lower bound of the95% CI of efficacy to be greater than 0%.

RSV-associated severe MALRI, a pre-specified exploratory endpoint, characterised by 1) cough ordifficulty breathing and 2) severe hypoxemia or the need for supplemental oxygen or mechanicalventilatory 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 increasingseverity, 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 through150 Post-dose (Study 004)

RSV-Associated Clesrovimab Placebo

Endpoint (n=2 398) (n=1 201)

Efficacy (95% CI)*

Incidence Incidence

Number Numberrate rateof cases of casesover 5 months over 5 months

MALRI (requiring60.4% (44.1, 71.9)†≥ 1 indicator of 60 0.026 74 0.065

LRI or severity)

Hospitalisation‡84.2% (66.6, 92.6)†9 0.004 28 0.024

Severe MALRI§2 0.001 12 0.01 91.7% (62.9, 98.1)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 Poissonregression 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 andrequiring ≥1 indicator of LRI or severity in hospitalised infants with an RSV positive RT PCR NP sample (5 cases/2398 inthe clesrovimab arm and 27 cases/1201 in the placebo arm; endpoint not multiplicity controlled). The estimated efficacy was90.9% (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 overallpopulation.

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 thesecond season in the absence of additional prophylaxis (Days 365 through 515 post-dose) were similarbetween recipients of clesrovimab (53 events/1008 participants, incidence = 0.055 over 5 months) andplacebo (26 events/501 participants, incidence = 0.054 over 5 months).

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

Study 007 is a phase 3, randomised, partially blind, palivizumab controlled, multicentre studyconducted in 27 countries from the Northern and Southern hemispheres to evaluate the safety, efficacyand 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 ofany 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 lungdisease (CLD) of prematurity or haemodynamically significant congenital heart disease (CHD) and270 early or moderate preterm infants (≤ 35 weeks GA) without CLD of prematurity or CHD), orpalivizumab (n=450, including 175 infants with CLD of prematurity or CHD and 275 early ormoderate preterm infants (≤ 35 weeks GA) without CLD of prematurity or CHD) by intramuscularinjection. Participants randomised to clesrovimab received a single 105 mg dose on Day 1 followed bya dose of placebo one month later; palivizumab was administered on Day 1 and every month thereafterfor a total of 3 to 5 doses of 15 mg/kg.

Among participants who received clesrovimab or palivizumab, the median age of infants was2.5 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 and55.2% were GA greater than or equal to 29 weeks with neither CLD nor CHD. The median bodyweight 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 byextrapolation of efficacy of clesrovimab from Study 004 to Study 007 based on pharmacokineticexposure (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; 14cases/443 in analysis set) in the clesrovimab arm and 3.0% (95% CI: 1.6, 5.3; 12 cases/437 in theanalysis set) in the palivizumab arm. The incidence rate of RSV-associated hospitalisation through150 days after dosing was 1.3% (95% CI: 0.4, 3.0; 5 cases/443 in analysis set) in the clesrovimab armand 1.5% (95% CI: 0.6, 3.3; 6 cases/437 in analysis set) in the palivizumab arm.

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