REGKIRONA Concentrate for solution for infusion Ref.[27956] Active ingredients: Regdanvimab

Pharmacotherapeutic group: Antivirals for systemic use
ATC code: not yet assigned

Mechanism of action

Regdanvimab is a recombinant human IgG1 monoclonal antibody that binds to the receptor binding domain (RBD) of the spike(s) protein of SARS-CoV-2 consequently blocking cellular entry and SARS-CoV-2 infection.

Antiviral activity

The in vitro neutralisation activity of regdanvimab against SARS-CoV-2 (BetaCoV/Korea/KCDC03/2020) was assessed by plaque reduction neutralisation test (PRNT) using VeroE6 cells. Regdanvimab neutralised this SARS-CoV-2 strain with an IC₅₀ value of 9.70 ng/mL and an IC₉₀ value of 25.09 ng/mL.

The plaque reduction neutralisation test (PRNT) using authentic SARS-CoV-2 variant virus indicate that regdanvimab retained activity against the Alpha (UK origin/B.1.1.7 lineage), Zeta (Brazilian origin/P.2), Iota (New York origin/B.1.526) and Eta (Nigerian origin/B.1.525) variants. Reduced neutralising activity against Gamma (Brazilian origin/P.1), Beta (South African origin/B.1.351), Epsilon (Californian origin/B.1.427 and B.1.429), Kappa (Indian origin/B.1.617.1) and Delta (Indian origin/B.1.617.2) variants were observed (Table 3). Microneutralisation data using authentic SARSCoV-2 variant virus indicate that regdanivimab retains activity against the Alpha variant and has reduced activity against the Beta and Gamma variants (Table 3).

Table 3. Authentic SARS-CoV-2 and Pseudovirus Neutralisation Data for Regdanvimab:

^a For variants with more than one substitution of concern, only the one(s) with the greatest impact on activity is(are) listed
^b No change: <5-fold reduction in susceptibility
^c Not all isolates of the New York lineage harbours E484K substitution (as of February 2021)
^d The study was conducted using plaque reduction neutralisation test
^e The study was conducted using microneutralisation assay
^f Key substitutions for global variants have been tested in a pseudovirus assay

Antiviral resistance

In vitro virus passaging with authentic SARS-CoV-2 viruses in VeroE6 cells in the presence/absence of regdanvimab identified a S494P amino acid substitution located in the RBD of the spike protein. Pseudovirus assay results with Q493K, Q493R, S494L and S494P showed IC₅₀ above 500 ng/mL.

Clinical efficacy

A Phase 3 of Study CT-P59 3.2 was a randomised, double-blind, placebo-controlled clinical trial studying regdanvimab for the treatment of unvaccinated adult patients with mild to moderate COVID19 and was conducted in multiple countries including the European Union (79.5%), the United States (7.6%) and Asia (0.9%). This study enrolled adult patients who were not hospitalised, had at least one or more symptoms of COVID-19 for ≤7 days, oxygen saturation >94% on room air and not requiring supplemental oxygen therapy and they were enrolled from January 18, 2021 and clinical efficacy endpoints were analysed based on data up to the cut-off date of May 21, 2021. Treatment was initiated after obtaining a positive SARS-CoV-2 viral infection determination.

A total of 1315 patients were randomised in a 1:1 manner to receive a single infusion of regdanvimab at doses of 40 mg/kg (N=656) or placebo (N=659) over 60 minutes.

The primary efficacy endpoint was the proportion of patients with clinical symptoms requiring hospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28. This was analysed in all patients randomly assigned to the study drug, who are at increased risk of progressing to severe COVID-19 and/or hospitalisation (defined as having at least one of the following risk factors for severe COVID-19: age >50 years; BMI >30 kg/m²; cardiovascular disease, including hypertension; chronic lung disease, including asthma; type 1 or type 2 diabetes mellitus; chronic kidney disease, including those on dialysis; chronic liver disease; and immunosuppressed, based on investigator’s assessment).

Among all randomised patients, 66.9% of patients were at increased risk of progressing to severe COVID-19 and/or hospitalisation. Among patients at increased risk of progressing to severe COVID19 and/or hospitalisation, the baseline median age was 54 years (range: 18 to 87); 19.4% of patients aged 65 or older and 4.0% of patients aged 75 or older; 53.6% of patients were male; 88.6% were White, 19.9% were Hispanic or Latino, 0.8% were Asian and 0.8% were Black or African American. The median time from the initial symptom onset was 4 days; mean viral load at baseline was 5.8 log10 copies/mL in the regdanvimab treatment group and 5.9 log10 copies/mL in placebo group. Forty-seven percent and 52.4% of patients had mild and moderate COVID-19, respectively. The most common risk factors were advanced age (age >50 years) (66.1%), cardiovascular disease, including hypertension, (50.3%) and obesity (BMI >30 kg/m²) (47.2%).

Proportion of patients with clinical symptom requiring hospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28

Table 4. Result of Primary Endpoint in Study CT-P59 3.2 (Phase 3):

Note: Clinical symptom which requires hospitalisation, oxygen therapy, or experiencing mortality due to SARS-CoV-2 infection up to Day 28 is included. Criterion of hospitalisation is ≥24 hours of acute care. Criteria of oxygen therapy are at least 24 hours of supplemental oxygen care and SpO2 measure in room air before applying supplemental oxygen showing ≤94%.
^a The difference of proportions between two treatment groups estimated using CMH (CochranMantel-Haenszel) weights, and the 95% stratified Newcombe confidence interval (CI) with CMH weights are presented. Analysis was stratified by Age (≥60 years vs. <60 years), baseline comorbidities (Yes vs. No) and region (United States vs. European Union vs. other).
^b The p-value from stratified CMH test is presented. The CMH test is stratified by age (≥60 years vs. <60 years), baseline comorbidities (Yes vs. No) and region (United States vs. European Union vs. other).

In addition, a total of 3 patients died (1 regdanvimab-treated patient and 2 placebo-treated patients) due to worsening of COVID-19.

Time to Clinical Recovery up to Day 14

Time to clinical recovery was defined as time from study drug administration to the time when symptoms, which were scored as ‘moderate’ or ‘severe’ at baseline reduced to ‘mild’ or ‘absent’, and symptoms scored as ‘mild’ or ‘absent’ at baseline were scored as ‘absent’. Symptoms ‘absent’ in intensity at baseline should maintain as ‘absent’ for at least 48 hours. Symptoms that were absent at baseline but became ‘severe’, ‘moderate’, or ‘mild’ in intensity during the study were considered clinically recovered if it changed back to ‘absent’ for at least 48 hours. Missing symptoms at baseline were considered to be clinically recovered if they were ‘absent’ for at least 48 hours. Symptoms assessed were limited to feeling feverish, cough, shortness of breath or difficulty breathing, sore throat, body pain or muscle pain, fatigue, and headache.

The median time to clinical recovery (at least 48 hours) in all randomised patients who are at increased risk of progressing to severe COVID-19 and/or hospitalisation (as defined above) was significantly shorter for regdanvimab-treated patients as compared to placebo-treated patients (median, 9.27 days vs. not calculated). As less than 50% of the patients in the placebo group achieved clinical recovery up to Day 14, it was not possible to calculate the median time to clinical recovery up to Day 14. However, it can be considered that the patients in the regdanvimab treatment group demonstrated a shortened time to clinical recovery of at least 4.73 days compared to the placebo group assuming the median time to clinical recovery in the placebo-treated patients as a minimum of 14 days. The difference in time to clinical recovery between the treatment groups was statistically significant (p <0.0001 [stratified log-rank test]; clinical recovery ratio [95% CI] = 1.58 [1.31, 1.90]).

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Regkirona in the treatment of Coronavirus disease 2019 (COVID-19) in one or more subsets of the paediatric population (see section 4.2 and section 5.2 for information on paediatric use).