Depemokimab targets human IL-5 with a binding affinity of 10.5 pM, thereby blocking the binding to the IL-5 receptor alpha expressed on the cell surface with picomolar potency (IC50 4 pM) in vitro. Depemokimab contains a triple amino acid substitution (YTE) in the fragment crystallisable (Fc) region which increases binding to the neonatal Fc receptor and thereby extends the half-life when compared to the IgG1 wildtype.
IL-5 is a pleiotropic cytokine with established impact on eosinophils and other immune and structural cells. In severe asthma, inhibition of IL-5 has demonstrated an improvement in epithelial integrity, mucus plugging and reduction in tissue remodelling. However, the mechanism of action has not been definitively established.
In a clinical pharmacology study with mild-to-moderate asthma patients, a single 100 mg subcutaneous dose of depemokimab produced a rapid reduction in blood eosinophil count. Blood eosinophils were reduced by 54% compared to placebo 24 hours after dosing, which was the first post-dose assessment.
In the asthma and CRSwNP phase 3 studies, these reductions were sustained over the treatment period and blood eosinophil count reductions at week 52 were 79% and 85% compared to placebo, respectively.
Depemokimab exhibited approximately dose-proportional pharmacokinetics over a dose range of 10 to 300 mg in patients with asthma following subcutaneous administration. After subcutaneous administration of 100 mg depemokimab every 6 months, the average concentrations (%CV) at steady state were 5.9 mcg/mL (28%) and 5.2 mcg/mL (27%) in asthma and CRSwNP patients, respectively. The Week 26 trough concentrations were 1.2 mcg/mL (37%) and 1.0 mcg/mL (36%) in asthma and CRSwNP patients, respectively.
Following a single subcutaneous administration (doses ranging from 2 to 300 mg), maximum observed plasma concentrations (Cmax) were achieved at a median time ranging from 8 to 14 days. After a single subcutaneous administration of 100 mg depemokimab, the average Cmax (%CV) was 12.2 mcg/mL (16%).
Following two repeat subcutaneous administrations once every 6 months, achieving steady-state conditions, the depemokimab accumulation was negligible (<10%).
Following a single subcutaneous administration of depemokimab, the mean apparent volume of distribution is 6 to 9 L.
Depemokimab is a monoclonal antibody which is catabolised by ubiquitous proteolytic enzymes not restricted to hepatic tissue.
Following a single subcutaneous administration of depemokimab, the geometric mean terminal half-life ranged from 38 to 53 days, with geometric mean apparent clearance values ranging from 0.081 to 0.16 L/day.
Population pharmacokinetic analyses indicated that exposure to depemokimab decreases with increasing body weight. Weight was the major determinant of depemokimab exposure, and satisfied conventional allometry with coefficients of 0.841 for CL/F and 0.887 for V/F, typical for a mAb such as depemokimab. Over the body weight range of 54 to 108 kg (corresponding to the 5th to 95th percentiles), the difference in all exposure metrics was less than 1.3-fold. Thus, the magnitude of effect of body weight on depemokimab exposure is not considered clinically relevant within this body weight range. At high body weights (140-160 kg) the exposure may be decreased 2-fold. For such patients, reduced efficacy cannot be excluded.
Population pharmacokinetic analyses indicated there was no clinically relevant effect of gender or race on depemokimab pharmacokinetics.
Available pharmacokinetic data in elderly patients (≥65 years old, N=176) across all clinical studies showed that depemokimab pharmacokinetics were similar between adult patients and patients aged 65 years and older (up to 93 years), based on the population pharmacokinetic analysis.
No formal studies have been conducted to investigate the effect of renal impairment on the pharmacokinetics of depemokimab. Based on population pharmacokinetic analyses, no dose adjustment is required in patients with impaired renal function. Data are limited (n=2) in patients with an eGFR <30 mL/min/1.73m², but CL/F values of these two patients fell within the range of patients with normal renal function.
Renal impairment is not expected to have a significant impact on clearance as depemokimab is not cleared renally.
No formal studies have been conducted to investigate the effect of hepatic impairment on the pharmacokinetics of depemokimab. Since depemokimab is degraded by widely distributed proteolytic enzymes, not restricted to hepatic tissue, changes in hepatic function are unlikely to have any effect on the elimination of depemokimab. Based on population pharmacokinetic analysis, baseline hepatic function biomarkers (alanine aminotransferase [ALT], aspartate aminotransferase [AST] and bilirubin) had no clinically relevant effect on depemokimab apparent clearance.
Asthma:
There are limited pharmacokinetic data available in the paediatric population (15 adolescent patients with asthma). The pharmacokinetics of depemokimab in adolescents aged 12 to 17 years were similar to adults and key pharmacokinetics parameters are presented in the following table.
Derived secondary pharmacokinetics parameters in patients who received depemokimab 100 mg subcutaneously every 26 weeks in the pooled SWIFT-1 and SWIFT-2 studies:
| Parameter - geometric mean (%CV) | Adolescents N=15 | Adults N=479 | Overall N=494 |
| AUCtau,ss (mcg*day/mL) | 1051 (31) | 1082 (28) | 1081 (28) |
| Cav,ss (mcg /mL) | 5.8 (31) | 5.9 (28) | 5.9 (28) |
| Cmax,26-52 (mcg/mL) | 14.6 (30) | 13.6 (28) | 13.6 (28) |
| Tmax,26-52 (day) | 10.8 (9) | 13.7 (18) | 13.6 (18) |
| Ctrough,week52 (mcg/mL) | 1.1 (39) | 1.3 (38) | 1.3 (38) |
| t1/2 (days) | 44.7 (9) | 48.7 (10) | 48.6 (10) |
AUCtau,ss; area under the concentration-time curve during a dosing interval at steady state, Cav,ss; average concentration during a dosing interval, Cmax,26-52; maximum concentration during the second dosing interval, Tmax,26-52; time to maximum concentration during the second dosing interval, Ctrough,week52; trough concentration at the end of the second administration, t1/2; half-life
The pharmacokinetics of depemokimab have not been established in paediatric patients with asthma aged less than 12 years of age.
There is a clear relationship between depemokimab pharmacokinetics and reduction in blood eosinophil counts (pharmacodynamics) with maximum achievable reduction of around 85% and a half-maximal effective concentration (EC50) of 0.19 mcg/mL. The concentration associated with 90% of maximal effect (EC90) was 0.75 mcg/mL.
Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity with safety pharmacology endpoints.
No genotoxicity, carcinogenicity or reproductive toxicology studies have been conducted with depemokimab.
In animal studies targeting IL-5 signaling pathways (e.g. knockout animal data and class effects), there were no developmental effects observed.
Male and female fertility are unlikely to be affected based upon no adverse histopathological findings in the reproductive organs from cynomolgus monkeys at exposures sufficiently in excess of the maximum human exposure. Mating and reproductive performance were unaffected in male and female CD-1 mice receiving an analogous antibody, which inhibits the activity of murine IL-5.
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