Nemolizumab is a humanised IgG2 monoclonal antibody that inhibits interleukin-31 (IL-31) signalling by binding selectively to interleukin-31 receptor alpha (IL-31 RA). IL-31 is a naturally occurring cytokine that is involved in pruritus, inflammation, epidermal dysregulation, and fibrosis. Nemolizumab inhibited IL-31-induced responses including the release of proinflammatory cytokines and chemokines.
In atopic dermatitis clinical studies, nemolizumab was found to modulate gene expression related to the pathophysiology of atopic dermatitis, with a primary impact on immune system processes, by decreasing the inflammatory and proliferative profile of specific immune cells (T-cells and monocytes/macrophages) without leading to immunosuppression.
In prurigo nodularis clinical studies, nemolizumab was found to modulate molecular processes related to the pathophysiology of prurigo nodularis, with impact on pruritus, inflammation, epidermal differentiation and fibrosis.
Anti-drug antibodies (ADA) were very commonly detected. No evidence of ADA impact on pharmacokinetics, efficacy or safety was observed.
Following an initial subcutaneous dose of 60 mg in patients with AD or PN, the population PK estimated mean (SD) peak concentration (Cmax) was 6.7 (2.20) μg/mL by approximately 6 days post dose.
Following multiple doses in subjects with atopic dermatitis, the population PK estimated mean (SD) steady-state trough concentrations of nemolizumab were 2.63 (1.27) μg/mL for 30 mg administered Q4W and 0.74 (0.44) μg/mL for 30 mg administered Q8W.
Following multiple doses in subjects with prurigo nodularis, the population PK estimated mean (SD) steady-state trough concentrations of nemolizumab 3.04 (1.23) μg/mL in patients with body weight <90 kg for 30 mg administered Q4W; and 3.66 (1.63) μg/mL in patients with body weight ≥90 kg for 60 mg administered Q4W.
In both atopic dermatitis and prurigo nodularis population, steady state concentrations of nemolizumab were achieved by week 4 after a 60 mg loading dose and by week 12 without a loading dose.
A loading dose is proposed for subjects with PN with body weight <90 kg. However, for subjects with body weight ≥90 kg no loading dose is proposed because the 60 mg dose was sufficient to achieve similar steady-state concentrations of nemolizumab as the 30 mg dose (with 60 mg loading dose) after the second dose (at Week 8).
Based on a population PK analysis, the apparent volume of distribution (V/F) was 7.67 L.
Specific metabolism studies were not conducted because nemolizumab is a protein. Nemolizumab is expected to be metabolised into small peptides by catabolic pathways.
Nemolizumab is expected to be degraded in the same manner as endogenous IgG. In the population PK analysis, the terminal elimination half-life (SD) of nemolizumab was estimated to be 18.9 (4.96) days and apparent systemic clearance (Cl/F) was estimated to be 0.26 L/day.
After a single dose, nemolizumab exhibited linear pharmacokinetics with exposures increasing in dose-proportional manner between 0.03 and 3 mg/kg. After multiple doses, nemolizumab systemic exposure increased in an approximately dose-proportional manner across the SC dose range up to 30 mg. There was a slight decrease in bioavailability by 9% with the 60 mg SC dose.
Gender, age (range 12 to 85 years for AD, and 18 to 84 years for PN), and ethnicity did not have a clinically relevant effect on the pharmacokinetics of nemolizumab.
Nemolizumab, as a monoclonal antibody, is not expected to undergo significant hepatic elimination. No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of nemolizumab. Mild to moderate hepatic impairment was not found to affect the PK of nemolizumab determined by population PK analysis. No data are available in patients with severe hepatic impairment.
Nemolizumab, as a monoclonal antibody, is not expected to undergo significant renal elimination. No clinical studies have been conducted to evaluate the effect of renal impairment on the pharmacokinetics of nemolizumab. Population PK analysis did not identify mild or moderate renal impairment as having a clinically meaningful influence on the systemic exposure of nemolizumab. Very limited data are available in patients with severe renal impairment.
Nemolizumab exposure was lower in subjects with higher body weight.
Atopic dermatitis:
The difference in systemic exposure due to body weight had no clinically meaningful impact on efficacy. Dose adjustment based on body weight is not needed.
Prurigo nodularis:
The variability in systemic exposure due to body weight had a clinically meaningful impact on skin lesion efficacy as assessed by IGA response but not on pruritus improvement and does require dose adjustment in subjects with PN.
Atopic dermatitis:
In the population PK analysis, no clinically relevant difference in the pharmacokinetics of nemolizumab was estimated in paediatric subjects 12-17 years of age compared to adults. Dose adjustment in this population is not recommended.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology and repeated dose toxicity.
The mutagenic potential of nemolizumab has not been evaluated; however monoclonal antibodies are not expected to alter DNA or chromosomes.
Carcinogenicity studies have not been conducted with nemolizumab. Evaluation of the available evidence related to IL-31 inhibition and animal toxicology data does not suggest carcinogenic potential.
No effects on fertility parameters were observed in sexually mature cynomolgous monkeys after a long-term subcutaneous treatment with nemolizumab. In the group of dams treated with 25 mg/kg of nemolizumab every two weeks from early organogenesis to delivery, a slight increase in the incidence of offspring death was observed during the early postnatal period. The dams exposures (AUC) were 43- or 34-fold higher than human exposure at maximum recommended human dose in AD or PN patients respectively. A relation of this finding to nemolizumab cannot be excluded.
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