Sugemalimab is a fully human immunoglobulin G4 monoclonal antibody. It specifically binds to programmed cell death ligand 1 (PD-L1), thus blocking its ligation with PD-1. PD-L1, when expressed on tumour cells and tumour-infiltrating immune cells, can contribute to the inhibition of an anti-tumour immune response. Binding of PD-L1 to the PD-1 and CD80 (B7.1) receptors found on T-cells and antigen presenting cells suppresses cytotoxic T-cell activity, T-cell proliferation, and cytokine production. Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses without inducing antibody dependent cell-mediated cytotoxicity (ADCC).
The PK of sugemalimab was characterised using population PK (PopPK) analysis with concentration data collected from 1002 participants who received sugemalimab doses in the range of 3 to 40 mg/kg and fixed dose of 1200 mg intravenous every 3 weeks.
Sugemalimab is administered by intravenous infusion and therefore is immediately and completely bioavailable.
Following single- and multiple-doses escalation study of sugemalimab (n=29), sugemalimab exposures (AUC and Cmax) increased in an approximately dose proportional manner within the dosing range of 3 mg/kg to 40 mg/kg, including a fixed dose of 1200 mg intravenous every 3 weeks.
Following multiple intravenous infusions of 1200 mg every 3 weeks (n=16), there was approximately 2-fold accumulation of sugemalimab exposures (i.e., Racc,Cmax and Racc,AUC were 1.74 and 2.00, respectively).
Consistent with a limited extravascular distribution of monoclonal antibodies, the volume of distribution of sugemalimab at steady-state (Vss) from popPK analysis was small, with a geometric mean (CV%) Vss of 5.56 L (21%) in patients with Stage IV NSCLC from Study GEMSTONE-302.
As an antibody, sugemalimab is catabolised through non-specific pathways; metabolism does not contribute to its clearance.
In the PopPK analysis, geometric mean (CV%) of total clearance (CL) after a single dose was estimated to be 0.235 L/day (24.2%) on NSCLC patients from Study GEMSTONE-302. At steady state, the elimination is slightly lower than after a single dose due to target-mediated drug disposition. Geometric mean (CV%) of the elimination half-life (t1/2) estimated from the PopPK model was approximately 17.9 days (25.6%) at the end of cycle 1 in NSCLC patients from Study GEMSTONE-302.
PopPK analysis showed non-statistically significant covariate effects of age (18-78 years) on sugemalimab exposure. The effect of other covariates (albumin, sex, anti-drug antibodies, and tumour type) on the systemic exposure of sugemalimab were not considered clinically meaningful. Based on the results from modelling and simulations, increasing the dosage to 1500 mg Q3W for patients with body weight more than 115 kg is anticipated to achieve comparable exposures to the patients in the pivotal study GEMSTONE-302 that were dosed with 1200 mg Q3W.
The effect of race in participants with advanced solid tumours (including NSCLC) receiving sugemalimab was evaluated by PopPK analysis and no impact of race was identified on the PK of sugemalimab. More specifically, there was no observed PK difference in sugemalimab between Asian and non-Asian participants.
The effect of mild hepatic impairment on sugemalimab PK was evaluated using PopPK analyses. Covariate analysis indicated no statistically significant effect of markers of liver function (AST and ALT) on sugemalimab exposure.
The effect of renal impairment on the clearance of sugemalimab was evaluated using PopPK analyses in participants with mild or moderate renal impairment compared to participants with normal renal function. There was no impact of renal function on PK of sugemalimab.
No carcinogenicity or reproductive toxicity studies have been conducted with sugemalimab.
Based on literature assessment, the PD-L1/PD-1 signalling pathway plays a role in pregnancy by maintaining maternal immune tolerance to the foetus. In a mouse model of pregnancy, blocking PD-L1 signalling can destroy the immune tolerance to the foetus and increase foetal miscarriages. No foetal malformations associated with blocking PD-L1/PD-1 signalling pathway have been reported in the literature, but immune-related diseases have been observed in PD-1 and PD-L1 gene knockout mice. Based on its mechanism of action, foetal exposure to sugemalimab may increase the risk of developing immune-related disorders or altering normal immune responses.
In 4- and 26-week repeat-dose toxicity studies in cynomolgus monkeys, exposure to sugemalimab administered IV once weekly, reveals no special hazard except two ophthalmic observations in high dose females: 1 incidence of retinal depigmentation and 1 case of medium-sized focal cornea opacity at 200 mg/kg, which corresponds to approximately 16-fold and 18-fold the clinical AUC at human recommended clinical dose.
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