Casirivimab and imdevimab

Casirivimab (IgG1κ) and imdevimab (IgG1λ) are two recombinant human monoclonal antibodies which are unmodified in the Fc regions. Casirivimab and imdevimab bind to non-overlapping epitopes of the spike protein receptor binding domain (RBD) of SARS-CoV-2. This prevents RBD binding to the human ACE2 receptor, so preventing virus entry into cells.

In-vitro antiviral activity

In a SARS-CoV-2 virus neutralisation assay in Vero E6 cells, casirivimab, imdevimab, and casirivimab and imdevimab together neutralised SARS-CoV-2 (USA-WA1/2020 isolate) with EC₅₀ values of 37.4 pM (0.006 μg/mL), 42.1 pM (0.006 μg/mL), and 31.0 pM (0.005 μg/mL) respectively.

Resistance

There is a potential risk of treatment failure due to the development of viral variants that are resistant to casirivimab and imdevimab administered together.

The neutralising activity of casirivimab, imdevimab and casirivimab and imdevimab together was assessed against S protein variants, including known Variants of Concern/Interest, variants identified in in vitro escape studies, and variants from publicly available SARS-CoV-2 genome data obtained from the Global Initiative on Sharing All Influenza Data (GISAID). Casirivimab and imdevimab neutralising activity against the Variants of Concern/Interest are shown in Table 1.

Table 1. Pseudotyped virus-like particle neutralisation data for full sequence or key SARSCoV-2 S-protein variant substitutions from variants of concern/interest* with casirivimab and imdevimab alone or together:

^a Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: del69-70, del145, N501Y, A570D, D614G, P681H, T716I, S982A, D1118H.
^b Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: D80Y, D215Y, del241-243, K417N, E484K, N501Y, D614G, A701V.
^c Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, V1176F
^d For AY.1: Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: (T19R, G142D, E156G, F157-, F158-, K417N, L452R, T478K, D614G, P681R, D950N).
^e No change: ≤5-fold reduction in susceptibility. f Not all isolates of the New York lineage harbor the E484K substitution (as of February 2021).
^g Commonly known as “Delta plus”.
^h Pseudotyped VLP expressing the entire variant spike protein was tested. The following changes from wild-type spike protein are found in the variant: A67V, del69-70, T95I, G142D/del143-145, del211/L212I, ins214EPE, G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H, T547K, D614G, H655Y, N679K, P681H, N764K, D796Y, N856K, Q954H, N969K, L981F.
^* Variants of concern/interest as defined by the Centers for Disease Control and Prevention (CDC, 2021) {https://www.cdc.gov/coronavirus/2019-ncov/variants/variant-info.html}

See Table 2 for a comprehensive list of authentic SARS-CoV-2 Variants of Concern/Interest assessed for susceptibility to casirivimab and imdevimab alone and together.

Table 2. Neutralisation data for authentic SARS-CoV-2 variants of concern/interest with casirivimab and imdevimab alone or together:

^a No change: ≤5-fold reduction in susceptibility.

Both casirivimab and imdevimab exhibited linear and dose-proportional PK across the intravenous (150 to 4 000 mg of each monoclonal antibody) and subcutaneous (300 and 600 mg of each monoclonal antibody) dose ranges evaluated in clinical studies.

Mean peak concentration (C_max), area under the curve from 0 to 28 days (AUC_0-28) and concentration at 28 days after dosing (C₂₈) for casirivimab and imdevimab were comparable after either a single 1 200 mg (600 mg of each monoclonal antibody) intravenous dose (182.7 mg/L, 1 754.9 mg.day/L, 37.9 mg/L, respectively for casirivimab, and 181.7 mg/L, 1 600.8 mg.day/L, 27.3 mg/L, respectively for imdevimab), or a single 1 200 mg (600 mg of each monoclonal antibody) subcutaneous dose (52.5 mg/L, 1 121.7 mg.day/L, 30.5 mg/L, respectively for casirivimab, and 49.2 mg/L, 1 016.9 mg.day/L, 25.9 mg/L, respectively for imdevimab).

For the intravenous regimen of 8 000 mg (4 000 mg of each monoclonal antibody) in patients who require oxygen supplementation, the mean peak concentration (C_max), area under the curve from 0 to 28 days (AUC_0-28) and concentration at 28 days after dosing (C₂₈) for casirivimab and imdevimab were 1 046 mg/L, 9280 mg.day/L, 165.2 mg/L, respectively for casirivimab, and 1 132 mg/L, 8789 mg.day/L, 136.2 mg/L, respectively for imdevimab, after a single intravenous dose.

For the pre-exposure prophylaxis intravenous and subcutaneous regimens at monthly administration of 300 mg each for casirivimab and imdevimab following an initial (loading) dose of 600 mg each for casirivimab and imdevimab, the median predicted casirivimab and imdevimab trough serum concentrations at steady state are similar to observed mean day 29 concentrations in serum for a single subcutaneous dose of casirivimab and imdevimab 1 200 mg (600 mg of casirivimab and 600 mg of imdevimab).

Absorption

Casirivimab and imdevimab administered as a single intravenous dose results in peak serum concentrations at the end of infusion. The median (range) time to reach maximum serum concentration of casirivimab and imdevimab (T_max) estimates following a single subcutaneous dose of 600 mg of each monoclonal antibody are 6.7 (range 3.4-13.6) days and 6.6 (range 3.4-13.6) days for casirivimab and imdevimab, respectively. After a single subcutaneous dose of 600 mg of each monoclonal antibody, casirivimab and imdevimab had an estimated bioavailability of 71.8% and 71.7%, respectively.

Distribution

The total volume of distribution estimated via population pharmacokinetic analysis was 7.072 L and 7.183 L for casirivimab and imdevimab, respectively.

Biotransformation

As human monoclonal IgG1 antibodies, casirivimab and imdevimab are expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG.

Elimination

The mean (5^th, 95^th percentile) serum elimination half-lives after a 600 mg dose of each monoclonal antibody were 29.8 (16.4, 43.1) days and 26.2 (16.9, 35.6) days, respectively, for casirivimab and imdevimab. The mean (5^th, 95^th percentile) clearances were 0.188 (0.11, 0.30) and 0.227 (0.15, 0.35), respectively, for casirivimab and imdevimab.

For patients who require supplemental oxygen, the mean (5^th, 95^th percentile) serum elimination halflives after a 4 000 mg dose of each monoclonal antibody were 21.9 (12.4, 36.9) days and 18.8 (11.7, 29.4) days, respectively, for casirivimab and imdevimab. The mean (5^th, 95^th percentile) clearances were 0.303 (0.156, 0.514) and 0.347 (0.188, 0.566), respectively, for casirivimab and imdevimab.

Paediatric population

For adolescent patients with COVID-19 (12 years of age and older and weighing at least 40 kg in COV-2067) receiving a single 1200 mg IV dose, the mean ± SD concentration at the end of infusion and at 28 days after dosing was 172 ± 96.9 mg/L and 54.3 ± 17.7 mg/L for casirivimab and 183 ± 101 mg/L and 45.3 ± 13.1 mg/L for imdevimab.

For adolescents not infected with SARS-CoV-2 (12 years of age and older and weighing at least 40 kg in COV-2069) receiving a single 1200 mg SC dose, the mean ± SD concentration 28 days after dosing was 44.9 ± 14.7 mg/L for casirivimab and 36.5 ± 13.2 mg/L for imdevimab.

The pharmacokinetics of casirivimab and imdevimab in children <12 years of age has not yet been established.

The pharmacokinetics of casirivimab and imdevimab in children <18 years of age who require supplemental oxygen has not yet been established.

Elderly

In the population PK analysis, age (18 years to 96 years) was not identified as a significant covariate on PK of casirivimab and imdevimab.

Renal impairment

Casirivimab and imdevimab are not expected to undergo significant renal elimination due to their molecular weight (>69 kDa).

Hepatic impairment

Casirivimab and imdevimab are not expected to undergo significant hepatic elimination.

Carcinogenicity, genotoxicity, and reproductive toxicology studies have not been conducted with casirivimab and imdevimab. Antibodies such as casirivimab and imdevimab are not expected to display genotoxic or carcinogenic potential. In tissue cross-reactivity studies with casirivimab and imdevimab using human and monkey adult tissues and human foetal tissues, no binding was detected.

In a toxicology study in cynomolgus monkeys, non-adverse liver findings (minor transient increases in AST and ALT) were observed.