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 4.
Table 4: Pseudotyped virus-like particle neutralisation data for full sequence or key SARS‑CoV-2 S-protein variant substitutions from variants of interest/concern* with casirivimab and imdevimab alone or together
| Lineage with spike protein substitutions | Key substitutions tested | Reduced susceptibility to casirivimab and imdevimab together | Reduced susceptibility to casirivimab alone | Reduced susceptibility to imdevimab alone |
| B.1.1.7 (UK origin/Alpha) | Full S proteina | no changee | no changee | no changee |
| B.1.351 (South Africa origin/Beta) | Full S proteinb | no changee | 45-fold | no changee |
| P.1 (Brazil origin/Gamma) | Full S proteinc | no changee | 418-fold | no changee |
| B.1.427/B.1.429 (California origin/Epsilon) | L452R | no changee | no changee | no changee |
| B.1.526 (New York origin/Iota)f | E484K | no changee | 25-fold | no changee |
| B.1.617.1/B.1.617.3 (India origin/Kappa) | L452R+E484Q | no changee | 7-fold | no changee |
| B.1.617.2/ AY.3 (India origin/Delta) | L452R+T478K | no changee | no changee | no changee |
| AY.1/AY.2g (India origin/Delta [+K417N]) | K417N+L452R+ T478Kd | no changee | 9-fold | no changee |
| B.1.621/B.1.621.1(Colombia origin/Mu) | R346K, E484K, N501Y | no changee | 23-fold | no changee |
| C.37 (Peru origin/Lambda) | L452Q+F490S | no changee | no changee | no changee |
| B.1.1.529/BA.1 (Omicron) | Full S proteinh | >1013-fold | >1732-fold | >754-fold |
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 interest/concern 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 5 for a comprehensive list of authentic SARS-CoV-2 Variants of Concern/Interest assessed for susceptibility to casirivimab and imdevimab alone and together.
| Lineage with spike protein substitution | Reduced susceptibility to casirivimab and imdevimab together | Reduced susceptibility to casirivimab alone | Reduced susceptibility to imdevimab alone |
B.1.1.7 (UK origin/alpha) |
no changea | no changea | no changea |
| B.1.351 (South Africa origin/beta) | no changea | 5-fold | no changea |
| P.1 (Brazil origin/Gamma) | no changea | 371-fold | no changea |
| B.1.617.1 (India origin/Kappa) | no changea | 6-fold | no changea |
| B.1.617.2 (India origin/Delta) | no changea | no changea | no changea |
a No change: ≤ 5-fold reduction in susceptibility.
M-PL-00002072
References:
- Summary of Product Characteristic https://www.roche.pl/content/dam/rochexx/roche-pl/roche_poland_rwd/pl_PL/documents/SmPC/Ronapreve_1332.pdf
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