Regdanvimab

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). Microneutralisation data using authentic SARS-CoV-2 variant virus indicate that regdanivimab retains activity against the Alpha variant and has reduced activity against the Beta and Gamma variants (Table).

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.

Absorption and distribution

Following the administration of the recommended dose regimen (a single dose of 40 mg/kg) in COVID-19 patients, the mean (CV%) C_max level was 1017 µg/mL (27%).

The mean (CV%) apparent volume of distribution at steady-state (V_ss) after intravenous administration of regdanvimab 40 mg/kg was 83 mL/kg (26%) in COVID-19 patients.

Elimination

Regdanvimab is expected to be degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. No major age- or weight-related differences in clearance or volume of distribution were observed in COVID-19 patients.

In studies with COVID-19 patients, the mean (CV%) clearance of regdanvimab 40 mg/kg was 0.20 mL/hr/kg (24%).

In patients with COVID-19, the mean (CV%) terminal half-life for 40 mg/kg of regdanvimab was 17 days (37%).

Linearity

Based on the PK analysis in healthy subjects, regdanvimab was approximately dose proportional in terms of maximal and systemic exposure (C_max, AUC_0-last, and AUC_0-inf) over the dose range of 10 mg/kg to 80 mg/kg.

Other special populations

Elderly

Based on pharmacokinetic subgroup analyses, there is no difference in pharmacokinetics of regdanvimab in elderly patients compared to younger patients.

Paediatric patients

The pharmacokinetics of regdanvimab in paediatric patients has not been evaluated.

Hepatic and renal impairment

The pharmacokinetics of regdanvimab has not been evaluated in patients with renal and/or hepatic impairment. Regdanvimab is not eliminated intact in the urine, thus renal impairment is not expected to affect the exposure of regdanvimab.

Non-clinical data revealed no special hazard for humans based on conventional studies of tissue crossreactivity and repeated dose toxicity.

In a 3-week repeat-dose toxicity study in cynomolgus monkeys, transient moderate to marked decreases in neutrophils and haematology parameter changes were observed in 20% of animals at a dose of about 9 times the human clinical exposure.

In the TCR studies with regdanvimab using human adult, neonatal, and cynomolgus tissues, specific positive stainings in meningeal arachnoid cap cells in the brain and/or spinal cord tissues were observed. These findings were not associated with neurological symptoms and histopathological findings in the toxicity study, indicating that this TCR finding is less likely to have clinical relevance.

Carcinogenicity, genotoxicity and reproductive toxicology studies have not been conducted with regdanvimab.