Sipavibart is a recombinant human IgG1 monoclonal antibody that provides passive immunisation by binding the SARS-CoV-2 spike protein receptor binding domain (RBD). Sipavibart is long-acting, with amino acid substitutions to extend antibody half-life (YTE) and to reduce antibody effector function and potential risk of antibody-dependent enhancement of disease (TM). Sipavibart binds to the spike protein RBD of SARS-CoV-2 (BA.2) with equilibrium dissociation constant of KD = 20.95 pM, blocking RBD binding to the human ACE2 receptor. This results in a blockade of virus entry.
In a SARS-CoV-2 pseudovirus neutralisation assay, sipavibart had antiviral activity through direct neutralisation.
Treatment-emergent anti-drug antibodies (ADA) were uncommonly (0.8% (5/604)) detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed. However, data are still limited.
Following a single dose, sipavibart demonstrated approximately dose proportional increase in serum exposure as doses increased in the range of 300 mg to 600 mg for intramuscular injection or 300 mg to 1 200 mg for intravenous infusion.
Following a single 300 mg intramuscular dose of sipavibart in the anterolateral thigh, the geometric mean (geometric coefficient of variation (CV%)) of the maximum serum concentration (Cmax) of sipavibart was 48.0 (25.2%) μg/ml. The median time (range) to Cmax was 7.5 (3.9, 53) days.
Based on population PK analysis, the estimated absolute bioavailability of sipavibart following intramuscular administration in the anterolateral thigh is 80.7%.
Following the first and second dose of 300 mg sipavibart administered intramuscularly in the anterolateral thigh, the geometric mean serum sipavibart concentrations (CV%) at one-month post-dose were 29.8 (36.2%) μg/ml and 30.8 (54.3%) μg/ml, respectively. Doses were administered 6 months apart.
Following a single infusion of 300 mg and 1 200 mg sipavibart (infusion rate: 50 mg/min), the geometric mean (CV%) serum concentration of sipavibart at 20 minutes post-infusion was 101.6 (7.6%) μg/ml and 452.1 (25.8%) μg/ml, respectively.
The geometric mean (CV%) apparent volume of distribution for sipavibart was 6.3 (19.4%) L following a single 300 mg intramuscular administration in the anterolateral thigh.
Based on population PK analysis, the estimated central and peripheral volume of distribution (relative standard error, RSE%) for sipavibart was 4.6 (1.3%) L and 0.4 (19.6%) L, respectively, following intravenous administration.
Sipavibart is expected to be degraded into small peptides and component amino acids via catabolic pathways in the same manner as endogenous IgG antibodies.
Following a single 300 mg intramuscular dose in the anterolateral thigh, the geometric mean (CV%) clearance of sipavibart was 0.053 (43.1%) L/day, and the estimated mean terminal elimination half-life (standard deviation) of sipavibart was 87.3 (26.5) days.
Based on population PK analysis, the estimated clearance (RSE%) of sipavibart following intravenous administration was 0.044 (0.9%) L/day.
No specific studies have been conducted to examine the effects of renal impairment on the PK of sipavibart.
Sipavibart has a molecular weight (MW) of approximately 148 kDa and is not expected to be excreted intact in the urine. Renal impairment is not expected to significantly affect the exposure of sipavibart. Similarly, dialysis is not expected to impact the PK.
No specific studies have been conducted to examine the effects of hepatic impairment on the PK of sipavibart.
Sipavibart is expected to be catabolised by multiple tissues through proteolytic degradation into amino acids and recycling into other proteins, therefore hepatic impairment is not expected to affect the PK of sipavibart.
Exposure to sipavibart in older adults ≥65 years of age (n=233) was comparable to that in younger adults 18 to <65 years of age (n=354).
The recommended dose regimen is expected to result in comparable serum exposures of sipavibart in adolescents 12 years of age or older who weigh at least 40 kg as observed in adults, since adults with similar body weight have been included in the clinical studies with sipavibart.
There were no clinically meaningful differences in serum exposures to sipavibart based on sex, age (12 to 85 years of age), race, or ethnicity.
Carcinogenesis, mutagenesis, and reproductive toxicology studies with sipavibart have not been conducted.
Non-clinical data reveal no special hazard for humans based on studies of tissue binding and a repeat dose toxicity study in cynomolgus monkeys, including assessment of safety pharmacology and local tolerance.
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