EVUSHELD Solution for injection Ref.[49908] Active ingredients: Tixagevimab and Cilgavimab

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies
ATC code: J06BD03

Mechanism of action

Tixagevimab and cilgavimab are two recombinant human IgG1 monoclonal antibodies, with amino acid substitutions in the Fc regions, to extend antibody half-life and to reduce antibody effector function and potential risk of antibody-dependent enhancement of disease (see section 5.3). Tixagevimab and cilgavimab can simultaneously bind to non-overlapping regions of the spike protein receptor binding domain (RBD) of SARS-CoV-2. Tixagevimab, cilgavimab and their combination bind to spike with equilibrium dissociation constants of KD = 2.76 pM, 13.0 pM and 13.7 pM, respectively, blocking its interaction with the human ACE2 receptor, resulting in a blockade of virus entry. Tixagevimab, cilgavimab and their combination blocked RBD binding to the human ACE2 receptor with IC₅₀ values of 0.32 nM (48 ng/mL), 0.53 nM (80 ng/mL) and 0.43 nM (65 ng/mL), respectively.

Antiviral activity

In a SARS-CoV-2 virus neutralisation assay on Vero E6 cells, tixagevimab, cilgavimab and their combination neutralised SARS-CoV-2 (USA-WA1/2020 isolate) with EC₅₀ values of 60.7 pM (9 ng/mL), 211.5 pM (32 ng/mL) and 65.9 pM (10 ng/mL), respectively. These in-vitro values correlate with in-vivo clinically effective serum concentrations of 2.2 µg/mL of EVUSHELD.

Antiviral resistance

SARS-CoV-2 or recombinant vesicular stomatitis virus encoding SARS-CoV-2 spike protein (pseudovirus) were serially passaged in cell cultures in the presence of tixagevimab or cilgavimab individually, or tixagevimab and cilgavimab in combination. Escape variants were identified following passage with cilgavimab, but not with tixagevimab or tixagevimab and cilgavimab in combination.

In neutralisation assays using recombinant SARS-CoV-2 pseudoviruses harbouring individual spike substitutions identified in circulating SARS-CoV-2, variants with reduced susceptibility to tixagevimab alone included those with F486S (>600-fold) and F486V (121- to 149-fold) and variants with reduced susceptibility to cilgavimab alone included those with R346I (>200-fold), K444E (>200-fold), K444Q (>200-fold) and K444R (>200-fold).

Tixagevimab and cilgavimab in combination retained full to nearly full neutralisation activity against pseudovirus and/or live virus SARS-CoV-2 variant strains harbouring all spike substitutions identified in Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1) Delta (B.1.617.2) and Delta [+K417N] (AY.1/AY.2), and Omicron (BA.2) variants of concern. Pseudotyped VLPs expressing spike protein and authentic SARS-CoV-2 Omicron BA.1 variant (B.1.1.529) and Omicron BA.1.1 (B.1.1.529 [+R346K]) showed reduced susceptibility to tixagevimab and cilgavimab in combination (Table 3).

Data collection is ongoing to better understand how small reductions in activity seen in authentic SARS-CoV-2 or pseudotyped VLP assays may correlate with clinical outcomes.

Table 3. Pseudovirus and authentic SARS-CoV-2 neutralisation data for SARS-CoV-2 variant substitutions with tixagevimab and cilgavimab together:

^a Range of reduced in-vitro potency across multiple sets of co-occurring substitutions and/or testing labs using research-grade assays; mean fold change in half maximal inhibitory concentration (IC₅₀) of monoclonal antibody required for a 50% reduction in infection compared to wild type reference strain.
^b Pseudoviruses expressing the entire SARS-CoV-2 spike variant protein and individual characteristic spike substitutions except L452Q were tested including Alpha (+L455F, E484K, F490S, Q493R, and/or S494P), and Delta (+K417N) harbouring additional indicated RBD substitutions that are no longer detected or detected at extremely low levels within these lineages.
^c Authentic SARS-CoV-2 expressing the entire variant spike protein were tested including Alpha (+E484K or S494P) harbouring additional indicated RBD substitutions that are no longer detected or detected at extremely low levels within these lineages.
ND, not determined; RBD, receptor binding domain.

It is not known how pseudovirus or authentic SARS-CoV-2 neutralisation susceptibility data correlate with clinical outcome.

In PROVENT, sequencing data collected at illness visits was available for 21 participants with COVID-19 infection (6 who received tixagevimab and cilgavimab and 15 placebo). At an allele fraction ≥25%, 14 participants were infected with variants of concern or variants of interest, including 8 participants with Alpha (B.1.1.7) (8 placebo), 1 participant with Beta (B.1.351) (1 who received tixagevimab and cilgavimab), 3 participants with Delta (B.1.617.2) (3 placebo), and 2 participants with Epsilon (B.1.429) (2 who received tixagevimab and cilgavimab). Additional spike protein RBD substitutions detected at an allele fraction ≥3% included V503F in the tixagevimab and cilgavimab group.

It is possible that resistance-associated variants to tixagevimab and cilgavimab together could have cross-resistance to other monoclonal antibodies targeting the RBD of SARS-CoV-2. Tixagevimab and cilgavimab together retained activity against pseudoviruses harbouring individual SARS-CoV-2 spike substitutions (E484D/K/Q, F490S, Q493R, S494P, K417E/N, D420N, K444Q, V445A, Y453F, L455F, N460K/S/T, F486V, and Q493K) identified in neutralisation escape variants of other monoclonal antibodies targeting the RBD of SARS-CoV-2 spike protein.

Pharmacodynamic effects

In PROVENT, following an intramuscular dose of 150 mg tixagevimab and 150 mg cilgavimab, neutralising antibody GMT at 7 (n=891), 28 (n=954) and 57 (n=43) days post-dose were similar to those observed in the Phase I healthy volunteer study and were 16-, 22-, and 17-fold higher, respectively, than the GMT measured in convalescent plasma from COVID-19 patients (GMT=30.8).

Immunogenicity

In PROVENT through Day 183, treatment-emergent anti-tixagevimab, anti-cilgavimab and antiEVUSHELD antibodies were detected in 0.8% (6/716), 1.1% (7/644) and 1.3% (10/743) ADAevaluable participants who received EVUSHELD. No evidence of an association of ADA with any impact on efficacy or safety has been observed.

Clinical efficacy

PROVENT

PROVENT is an ongoing Phase III, randomised (2:1), double-blind, placebo-controlled clinical trial studying EVUSHELD for the pre-exposure prophylaxis of COVID-19 in adults ≥18 years of age. Enrolled participants were individuals considered to be at increased risk for inadequate response to active immunisation (due to age ≥60 years, co-morbidity, pre-existing chronic illness, immunocompromised, or intolerant of vaccination) or at increased risk of SARS-CoV-2 infection (due to their location or circumstances at time of enrolment, for example health care workers including staff for long-term care facilities, working in high risk industrial settings or living with high density proximity, including students in dormitories and military barracks). Participants received either 150 mg of tixagevimab and 150 mg of cilgavimab or placebo, administered as two separate intramuscular injections. The study excluded participants with a history of laboratory-confirmed SARS-CoV-2 infection or SARS-CoV-2 antibody positivity at screening.

The baseline demographics were well balanced across the EVUSHELD and placebo arms. The median age was 57 years (with 24% of participants aged 65 years or older and 4% of participants aged 75 years or older), 46% of participants were female, 73% were White, 3% were Asian, 17% were Black/African American, and 15% were Hispanic/Latino. Of the 5 197 participants, 78% had baseline co-morbidities or characteristics associated with an increased risk for severe COVID-19, including obesity (42%), diabetes (14%), cardiovascular disease (8%), cancer, including a history of cancer (7%), chronic obstructive pulmonary disease (5%), chronic kidney disease (5%), chronic liver disease (5%), immunosuppressive medications (3%) and immunosuppressive disease (<1%).

The primary analysis included 5 172 participants who were SARS-CoV-2 RT-PCR-negative at baseline, of which 3 441 received EVUSHELD and 1 731 received placebo. EVUSHELD significantly (p-value<0.001) reduced the risk of SARS-CoV-2 RT-PCR-positive symptomatic illness (COVID-19) when compared to placebo (Table 4). The median follow-up time post-administration was 83 days.

Table 4. Incidence of COVID-19:

CI = Confidence Interval, N = number of participants in analysis.
^a Primary endpoint, a participant was defined as a COVID-19 case if their first case of SARS-CoV-2 RT-PCR-positive symptomatic illness occurred after administration and prior to Day 183.
^b 150 mg tixagevimab and 150 mg cilgavimab.

Efficacy was consistent across pre-defined sub-groups including age, gender, ethnicity and baseline co-morbidities or characteristics associated with an increased risk for severe COVID-19.

Among participants who received EVUSHELD there were no severe/critical COVID-19 events (defined as SARS-CoV-2 RT-PCR-positive symptomatic illness characterised by a minimum of either pneumonia [fever, cough, tachypnoea or dyspnoea, and lung infiltrates] or hypoxemia [SpO₂ <90% in room air and/or severe respiratory distress] and a WHO Clinical Progression Scale score of 5 or higher) compared to one event (0.1%) among participants who received placebo.

An additional data cut-off was conducted to provide post-hoc updated safety and efficacy analyses; the median follow-up was 6.5 months for participants in both the EVUSHELD and placebo arms. The relative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 83% (95% CI 66-91), with 11/3 441 (0.3%) events in the EVUSHELD arm and 31/1 731 (1.8%) events in the placebo arm, see Figure 1). Among participants who received EVUSHELD there were no severe/critical COVID-19 events compared to five events among participants who received placebo.

In exploratory analyses of all participants who received EVUSHELD or placebo, including 25 participants who were subsequently found to have been SARS-CoV-2 RT-PCR-positive at baseline, the relative risk reduction of SARS-CoV-2 RT-PCR-positive symptomatic illness was 78% (95% CI 59-88), with 14/3 460 (0.4%) events in the EVUSHELD arm and 31/1 737 (1.8%) events in the placebo arm at a median follow-up of 6.5 months.

Figure 1. Kaplan Meier: Cumulative Incidence of Symptomatic COVID-19:

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with EVUSHELD in one or more subsets of the paediatric population in the prophylaxis of COVID-19 (see section 4.2 for information on paediatric use).