RONAPREVE Solution for injection/infusion Ref.[107202] Active ingredients: Casirivimab and imdevimab

Pharmacotherapeutic group: Immune sera and immunoglobulins, antiviral monoclonal antibodies
ATC code: J06BD07

Mechanism of action

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 5.

Table 5. 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 6 for a comprehensive list of authentic SARS-CoV-2 Variants of Concern/Interest assessed for susceptibility to casirivimab and imdevimab alone and together.

Table 6. 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.

Clinical efficacy

Treatment of COVID-19

COV-2067

COV-2067 was a randomised, double-blinded, placebo-controlled clinical trial evaluating casirivimab and imdevimab for the treatment of subjects with COVID-19 (symptomatic with SARS-CoV-2 detected by quantitative reverse transcription polymerase chain reaction [RT-qPCR]) who did not require supplemental oxygen and were at increased risk of progression to severe disease.

In Phase 3 Cohort 1 of this trial, subjects not previously vaccinated against SARS-CoV-2 were randomised within 7 days of symptom onset to a single intravenous infusion of 600 mg of casirivimab and 600 mg of imdevimab (n=1 347), 1 200 mg of casirivimab and 1 200 mg of imdevimab (n=2 036) or placebo (n=2 009).

Subjects in Phase 3 Cohort 1 had at least one protocol-listed risk factor for developing severe COVID19 (these included age >50 years, obesity defined as BMI ≥ 30 kg/m², cardiovascular disease including hypertension, chronic lung disease including asthma, type 1 and 2 diabetes mellitus, chronic kidney disease including those on dialysis, chronic liver disease, pregnancy and immunosuppressed).

The median age was 50 years (with 13.1% of subjects aged 65 years or older) and 51.4% of the subjects were female. Baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab and placebo treatment groups.

The primary endpoint was the proportion of subjects with ≥1 COVID-19-related hospitalisation or allcause death through Day 29.

Table 7. Summary of primary endpoint phase 3 results from study COV-2067:

mFAS: modified full analysis set included those subjects with a positive SARS-CoV-2 RT-qPCR result from nasopharyngeal (NP) swab at randomisation, and with at least one risk factor for severe COVID-19.

The median time to symptom resolution, as recorded in a trial-specific daily symptom diary, was reduced from 13 days with placebo to 10 days with both doses of casirivimab and imdevimab (p<0.0001).

RECOVERY

RECOVERY is an ongoing multi-centre, randomised, controlled, open-label platform study, evaluating the efficacy and safety of potential treatments in hospitalised subjects with COVID-19. RECOVERY enrolled hospitalised subjects on no oxygen, low or high flow oxygen therapy, noninvasive or invasive ventilation and ECMO. In this trial, 9 785 subjects in the United Kingdom (UK) were randomised to a single IV infusion of 4 000 mg of casirivimab and 4 000 mg of imdevimab plus usual care (n=4 839) or usual standard of care alone (n=4 946; herein after referred to as usual care alone). Subjects could receive between 0 and 4 treatments on top of usual standard of care.

Subjects had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and were enrolled regardless of the respiratory support required. Baseline serology test results were used to define analysis populations.

At baseline, the mean age was 62 years (with 30% of subjects aged 70 years or older, 11 adolescents ≥12 and <18 years old were included) and 63% of the subjects were male. Baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab, and usual care alone, treatment groups. Subjects were enrolled in the study when the B.1.1.7 (alpha) variant was the dominant variant in the UK. Respiratory support received by subjects included 7% on no supplemental oxygen, 61% on simple oxygen, 26% on non-invasive ventilation, and 6% on invasive ventilation (including 17 subjects on ECMO). In subjects who were seronegative at baseline, 10% were on no supplemental oxygen at baseline, 66% were on simple oxygen, 21% were on non-invasive ventilation, and 2% were on invasive ventilation (including one subject on ECMO). Approximately 94% of all randomised subjects received corticosteroids as part of background standard care.

The primary endpoint was 28-day all-cause mortality in all randomised subjects who were seronegative at baseline. The results are shown in Table 8.

Table 8. Summary of primary endpoint results from study RECOVERY:

In seropositive subjects, the 28-day all-cause mortality was 16% (410/2 636) in the casirivimab+imdevimab arm and 15% (384/2 636) in the usual care alone arm (rate ratio 1.09 [95% CI: 0.94, 1.25]).

In seronegative subjects aged ≥80 years, 28-day all-cause mortality was 54.5% (126/231) and 57.5% (134/233) in the casirivimab+imdevimab and usual care alone arms, respectively (rate ratio 0.97 [95% CI: 0.76, 1.25]). Statistical testing of the secondary endpoint was performed outside of the hierarchy and is, therefore, considered descriptive.

The secondary endpoint of discharge alive from hospital within 28 days was more common in the allrandomised seronegative population treated with casirivimab and imdevimab compared with usual care alone (64% vs. 58%; rate ratio 1.19 [95% CI: 1.09, 1.31]), with a 4-day shorter median duration of hospital stay (13 days vs. 17 days).

Among the all-randomised seronegative population not on invasive mechanical ventilation at baseline, treatment with casirivimab and imdevimab was associated with a lower risk of progressing to the composite endpoint of invasive mechanical ventilation or death (31% vs. 37%; risk ratio 0.83 [95% CI: 0.75, 0.92]).

COV-2066

COV-2066 was a randomised, double-blinded, placebo-controlled clinical trial evaluating casirivimab and imdevimab for the treatment of hospitalised subjects with COVID-19 on low flow oxygen devices (e.g. by face mask or nasal cannula) or no supplemental oxygen. In this phase ⅔ trial, 1 197 subjects had a positive SARS-CoV-2 RT-qPCR result at baseline and were randomised 1:1:1 to a single intravenous infusion of 1 200 mg of casirivimab and 1 200 mg of imdevimab (n=406), 4 000 mg of casirivimab and 4 000 mg of imdevimab (n=398), or placebo (n=393), with all subjects receiving casirivimab and imdevimab, or placebo in addition to the usual standard of care for COVID-19. The overall sample size was smaller than anticipated due to the early study termination following several months of low recruitment rates. Overall, similar effects were observed in patients on no supplemental oxygen or on low flow oxygen devices for casirivimab and imdevimab 2 400 mg, and casirivimab and imdevimab 8 000 mg doses, indicating an absence of a dose effect in this population. These dose groups were combined when compared to the placebo group for the efficacy analysis.

At baseline, the median age was 62 years (with 44% of subjects aged 65 years or older), and 54% of the subjects were male, 43% of the subjects were seronegative, 48% were seropositive and 9% had an unknown serostatus. Baseline respiratory support received by subjects included 44% on no supplemental oxygen and 56% on low flow oxygen devices. Prior to randomisation, approximately 33% of subjects received remdesivir and 50% received systemic corticosteroids as part of background usual care. Baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab and placebo treatment groups.

The primary virologic efficacy endpoint was time weighted average (TWA) daily change from baseline in viral load (log10 copies/mL) through day 7, measured by RT-qPCR in NP swab samples, in subjects who were seronegative and had a positive SARS-CoV-2 RT-qPCR result at baseline.

Treatment with casirivimab and imdevimab for the combined doses group resulted in a statistically significant reduction in the LS mean viral load (log10 copies/mL) compared to placebo (-0.28 log10 copies/mL/day for casirivimab and imdevimab; p=0.0172).

The primary clinical endpoint was the proportion of subjects who died or went on mechanical ventilation in those with a positive SARS-CoV-2 RT-qPCR result. Treatment with casirivimab and imdevimab for the combined doses group resulted in a reduced proportion of subjects with a high viral load who died or went on mechanical ventilation from day 6 to day 29, but the endpoint did not achieve statistical significance (relative risk reduction [RRR] 25.5% [95% CI: -16.2%, 52.2%]; p=0.2048).

Treatment with casirivimab and imdevimab for the combined doses group resulted in a 47.1% RRR (95% CI: 10.2%, 68.8%) in the proportion of seronegative subjects who died or went on mechanical ventilation from day 6 to day 29.

In a post hoc analysis of all randomized seronegative subjects aged ≥ 80 years, all-cause mortality from day 1 to day 29 was 18.1% (19/105 subjects) and 30.0% (18/60 subjects) in the casirivimab+imdevimab (combined doses) and placebo arms, respectively (risk ratio 0.60 [95% CI: 0.34, 1.06]).

Prevention of COVID-19

COV-2069 was a randomised, double-blind, placebo-controlled clinical trial that compared 600 mg casirivimab and 600 mg imdevimab given subcutaneously to placebo for prevention of COVID-19 in asymptomatic household contacts of symptomatic individuals infected with SARS-CoV-2 (index cases). Subjects had not been previously vaccinated against SARS-CoV-2.

Subjects were randomised 1:1 to casirivimab and imdevimab or placebo within 96 hours of collection of the first index case sample that gave a positive result (RT-qPCR) for SARS-CoV-2.

Randomised subjects with a negative SARS-CoV-2 RT-qPCR test result at baseline were assigned to Cohort A and those with a positive SARS-CoV-2 RT-qPCR test result were assigned to Cohort B.

Cohort A

The primary analysis population included subjects who were SARS-CoV-2 RT-qPCR negative and seronegative at baseline. Subjects who were seropositive or who had undetermined/missing baseline serology were excluded from the primary efficacy analysis.

For the primary analysis population at baseline, the median age was 44 years (with 9% of subjects ages 65 years or older) and 54% of the subjects were female. The baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab and placebo treatment groups.

The primary endpoint was the proportion of subjects who developed symptomatic RT-qPCRconfirmed COVID-19 through Day 29. There was a statistically significant 81% risk reduction in the development of COVID-19 with casirivimab and imdevimab treatment versus placebo. In a sensitivity analysis that included all RT-qPCR negative subjects at baseline, regardless of baseline serological status, there was a statistically significant 82% risk reduction in development of COVID-19 with casirivimab and imdevimab treatment compared to placebo.

Table 9. Primary analysis of study COV-2069, Cohort A:

¹ The confidence interval (CI) with p-value is based on the odds ratio (casirivimab and imdevimab group vs placebo group) using logistic regression model with the fixed categorical effects of treatment group, age group (age in years: ≥12 to <50 and ≥50), and region (US vs ex-US).

Cohort B

The primary analysis population included asymptomatic subjects who were SARS-CoV-2 RT-qPCR positive and seronegative at baseline.

For the primary analysis population at baseline, the median age was 40 years (with 11% of subjects ages 65 years or older) and 55% of the subjects were female. The baseline demographics and disease characteristics were well balanced across the casirivimab and imdevimab and placebo treatment groups.

The primary efficacy endpoint was the proportion of subjects who developed RT-qPCR-confirmed COVID-19 through Day 29. There was a 31% risk reduction in the development of COVID-19 with casirivimab and imdevimab treatment vs. placebo. In a sensitivity analysis that included all RT-qPCR positive subjects at baseline, regardless of baseline serological status, there was a 35% risk reduction in RT-qPCR-confirmed COVID-19 with casirivimab and imdevimab treatment compared to placebo.

Table 10. Primary analysis study COV-2069, Cohort B:

¹ The confidence interval (CI) with p-value is based on the odds ratio (casirivimab and imdevimab group vs placebo group) using logistic regression model with the fixed categorical effects of treatment group, age group (age in years: ≥12 to <50 and ≥50), and region (US vs ex-US).