(S-098) Population Pharmacokinetic Modeling of Rezpegaldesleukin after Subcutaneous Dosing to Account for Variability Across Multiple Patient Populations with Autoimmune Diseases

Hong Lu – Nektar Therapeutics; Sung Min Park – Allucent; Yi Liu – Nektar Therapeutics; Christie Fanton – Nektar Therapeutics; Alex MacDonald – Allucent; Jonathan Zalevsky – Nektar Therapeutics

Objectives: Rezpegaldesleukin (REZPEG) is an IL-2 receptor (IL-2R) pathway agonist designed to stimulate the expansion and function of regulatory T cells (Tregs). REZPEG utilizes the approved recombinant human IL-2 (rhIL-2) aldesleukin sequence with stable, covalently attached polyethylene glycol (PEG) moieties which extend the half-life and confer a selectivity for Treg stimulation over conventional T cells (Tcons) compared with rhIL-2 [1]. As compared to unPEGylated rhIL-2, REZPEG has reduced binding affinity for IL-2Rβ, resulting in a different binding selectivity for cells expressing IL-2Rβ versus IL-2Rα, and renders Tregs with high-affinity (IL-2Rαβγ) receptors more sensitive than Tcons to activation by REZPEG [2]. Nektar Therapeutics is developing REZPEG as a potential treatment for inflammatory diseases by therapeutic restoration of the Treg compartment. The objective of this work is to: 1) characterize clinical PK of REZPEG after subcutaneous administration and identify variability sources; 2) quantify relationships between relevant covariates and REZPEG exposure across multiple therapeutic indications; and 3) perform exposure simulations in key patient subgroups.

Methods: PK and clinical data were pooled from 5 Phase 1/2 studies in healthy subjects and patients with systemic lupus erythematosus, atopic dermatitis (AD), or ulcerative colitis. A population PK (PopPK) model was performed using NONMEM® (v7.4.4) with structural models (one- vs. two-compartment) assessed. Covariate selection used a forward addition and backward elimination. A prediction-corrected visual predictive check (pcVPC) was conducted to evaluate the model performance, and the parameter uncertainty was assessed via nonparametric bootstrap.

Covariates evaluated were disease condition, formulation, injection site locations and injection volume, age, sex, race/ethnicity, body weight, and renal and hepatic function biomarkers. For the current population model, simulations were performed to quantify the impact of the selected covariates on REZPEG exposures.

Results: The PK of REZPEG was adequately described by a one-compartment model with first-order absorption and elimination. Population estimates of CL/F and Vc/F in an adult of 75 kg were 0.42 L/day and 6.15 L, with inter-individual variability of 33.3% and 32.4%, respectively. Body weight was a significant predictor of both apparent clearance and volume of distribution. Weight-based dosing is expected to reduce inter-patient exposure variability.

Creatinine clearance (CRCL) was a predictor of CL/F. The simulation at CRCL levels (mild, moderate and severe renal impairment) of 60, 30 and 15 mL/min (vs. 134 mL/min) showed Cmax increases of 13%, 28% and 46% and AUC increases of 15%, 34% and 55%, respectively. These results supported conducting a dedicated renal impairment study in future development.

No significant effects on REZPEG PK were found for disease condition, formulation, injection site locations or injection volume, age, gender, race/ethnicity or hepatic biomarkers.

Conclusions: The integrated population PK model supports the weight-based dose levels and regimens currently being evaluated in the phase 2b studies of REZPEG in atopic dermatitis and alopecia areata.

Citations: [1] Fanton C et al, Selective expansion of regulatory T cells by NKTR-358 in healthy volunteers and patients with systemic lupus erythematosus, J Transl Autoimmun 2022 Mar 28:5:100152. doi: 10.1016/j.jtauto.2022.100152.
[2] Silverberg JI et al, The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebocontrolled phase 1b trials. Nat Commun. 2024 Oct 25;15(1):9230. doi: 10.1038/s41467-024-53384-1.

Keywords: Rezpegaldesleukin, PopPK, Weight-based-dosing