Crovalimab is a recombinant humanised immunoglobulin G1 (IgG1)-based monoclonal antibody that specifically binds with high affinity to component 5 (C5) of the complement system, inhibiting its cleavage into C5a and C5b and thus preventing the formation of the membrane attack complex (MAC). Crovalimab causes terminal complement activity inhibition. In patients with PNH, crovalimab inhibits terminal complement-mediated intravascular haemolysis.
In clinical studies with PNH patients, a concentration-dependent inhibition of terminal complement activity following treatment with crovalimab was observed. Terminal complement activity (CH50 as measured by Liposome Immunoassay [LIA]) inhibition was achieved immediately by the end of the initial crovalimab infusion and was generally sustained through the duration of crovalimab treatment.
Similarly, mean free C5 concentrations decreased to low levels (<0.0001 g/L) in comparison to baseline and remained low throughout the treatment period.
Free C5 and CH50 levels were similar between paediatric and adult patients treated with crovalimab.
The pharmacokinetics of crovalimab have been characterised both in healthy volunteers and in patients with PNH. The pharmacokinetics were characterised using non-linear mixed effects pharmacokinetic analysis methods, based on a pooled database composed of 9 healthy volunteers and 210 and 211 treatment-naïve patients and patients who switched from previous treatment with another C5 inhibitor to crovalimab, respectively.
The concentration-time course of crovalimab is best described using a two-compartment open model with first-order elimination and a first order subcutaneous absorption constant. To describe the transient increase in clearance due to the formation of Type III immune complexes observed in patients who switched from treatment with another C5 inhibitor to crovalimab, an additional time-varying clearance parameter, which decreases exponentially with time, was added. At steady state, exposure is expected to be similar between treatment naïve and switch patients.
The absorption rate constant was estimated to be 0.126 day -1 [CV%: 38.3]. Following subcutaneous administration, the bioavailability was estimated at 83.0% [CV%: 116].
The central volume of distribution was estimated to be 3.23 L [CV%: 22.4] and the peripheral volume of distribution was estimated as 2.32 L [CV%: 70.6].
The small volume of distribution indicates that crovalimab is likely to be distributed mainly in serum and/or in vascular rich tissues.
The metabolism of crovalimab has not been directly studied. IgG antibodies are mainly catabolised by lysosomal proteolysis and then eliminated from or reused by the body.
The clearance was estimated to be 0.0791 L/day [CV%: 20.6]. The terminal half-life of crovalimab was estimated as 53.1 days [CV%: 39.9], which is longer compared to other humanised IgG antibodies. This long half-life is consistent with the recycling properties of crovalimab.
No pharmacokinetic studies with crovalimab have been conducted in special populations. Bodyweight was shown to be a significant covariate, with clearances and volumes of distribution increasing and crovalimab exposure decreasing as bodyweight increases. Therefore, posology of crovalimab is based on the bodyweight of the patient.
After inclusion of bodyweight in the model, the population pharmacokinetics analyses in patients with PNH showed that age (13–85 years) and gender did not meaningfully influence the pharmacokinetics of crovalimab. No further dose adjustment is required.
Race/ethnicity was also shown not to have an impact on the pharmacokinetics of crovalimab; however, data are limited in Black patients and therefore not considered conclusive in this population.
No dedicated studies have been conducted to investigate the pharmacokinetics of crovalimab in patients aged ≥65 years, however 46 (10.9%) elderly PNH patients were enrolled in clinical studies, including 35 patients aged 65-74 years, 10 patients aged 75-84 years, and 1 patient aged ≥85 years. The data obtained in PNH clinical studies indicates that exposure in patients aged ≥65 years is comparable to that of younger patients in other age groups, however, due to the limited data in patients ≥85 years, the pharmacokinetics of crovalimab in those subjects is unknown.
No dedicated studies have been conducted to investigate the pharmacokinetics of crovalimab in patients with renal impairment, however the data obtained in PNH clinical studies (62 [14.7%] patients with mild renal impairment, 38 [9%] patients with moderate renal impairment, and 4 [1%] patients with severe renal impairment) indicate that exposure in patients with mild, moderate, or severe renal impairment is comparable to that of patients without renal impairment. However, limited data were obtained for patients with severe renal impairment in PNH clinical studies.
No dedicated studies have been conducted in patients with hepatic impairment, however data obtained in PNH clinical studies indicate that exposure in patients with mild hepatic impairment (46 [11%] as graded based on alanine aminotransferase levels) are comparable to that of patients without hepatic impairment. Limited pharmacokinetic data were available in PNH patients with moderate (0 [0%]) to severe (1[0.23%]) hepatic impairment, therefore the impact of moderate or severe hepatic impairment on the pharmacokinetics of crovalimab is unknown and no dose recommendation can be provided.
Data obtained in 12 paediatric patients (13-17 years old) in the PNH clinical studies indicates that exposure in paediatric patients 12 years of age or older with a weight of 40 kg and above was found to be comparable to that of adult patients.
Non-clinical data revealed no special hazard related to crovalimab treatment for humans based on conventional studies of, repeated dose toxicity (including safety pharmacology endpoints), and toxicity to reproduction and development.
No dedicated studies have been performed to establish the genotoxic potential of crovalimab. Monoclonal antibodies are not expected to interact directly with DNA or other chromosomal material.
No studies have been performed to establish the carcinogenic potential of crovalimab. Assessment of available evidence related to pharmacodynamic effects and animal toxicology data do not indicate carcinogenic potential of crovalimab.
Repeated administration of crovalimab to pregnant cynomolgus monkeys during the gestation period induced no maternal toxicity and did not affect pregnancy outcome. No effects on the viability, growth and development of the infants were observed during the 6-month postnatal period.
No effects on female or male reproductive organs were observed in cynomolgus monkeys following repeated administration of crovalimab for up to 6 months. Separate animal fertility studies have not been conducted with crovalimab.
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