Abstract 7165: Clinical population pharmacokinetic (popPK) analysis of NBF-006, a novel siRNA inhibitor of glutathione-S-transferase P (GSTP) encapsulated in a lipid nano particle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC)
Authors: Hall Michael P. , O'Brien Zhihong , Chen Xi , Hendrix Angelean , Brenes-Coto Stacy , Zabludoff Sonya 
Published: March 2024

Abstract
GSTP has an important role in detoxification and antioxidative damage response. Additionally, GSTP has a chaperone function that regulates multiple oncogenic pathways such as KRAS and JNK. Since alternative pathways could compensate for the inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy.
NBF-006 is a drug product comprised of GSTP siRNA encapsulated within a novel LNP. It is designed to deliver siRNA to localized and metastatic lung tumors.
Unlike other well-established drug modalities, there is a general need for increased understanding of the PK of RNA therapeutics. For NBF-006, we present popPK analysis of patients who have undergone treatment in a Phase I (a/b) clinical study. A primary goal of popPK modeling is to identify PK parameters and sources of variability in a population. Other goals include correlating drug exposures with administered doses through identification of predictive covariates in a target population and establishing whether fixed dosing as opposed to weight-based dosing can be utilized in future clinical studies. Ultimately this analysis will help to inform decision-making for dosing regimens in future clinical trial designs and to better predict PK variability across populations.
A total of 48 advanced NSCLC (N=38), pancreatic (N=5), or colorectal cancer (N=5) patients received 4 doses (QW) of NBF-006 by infusion at 0.15, 0.3, 0.6, 1.2 or 1.6 mg/kg followed by a 2-week rest period. In all studies, serial blood samples were collected at weeks 1 and 4. Plasma concentrations of siRNA were determined by hybridization ELISA. PopPK analysis was performed to characterize NBF-006 PK and to explore intrinsic and extrinsic covariate effects that could affect NBF-006 exposure.
The analysis included 695 quantifiable PK observations. A popPK model with two-compartment disposition and linear elimination adequately described the PK profile of NBF-006. Exploratory data analysis of dose-normalized PK profiles suggested that exposure increased proportionally with increasing dose from 0.15 to 1.6 mg/kg. Little to no apparent accumulation nor exposure reduction was observed between weeks 1 and 4. The impact of individual patient covariates, including body weight, baseline ALT, sex, KRAS mutation, cancer type and race, was assessed on PK parameters. None of the covariates evaluated had a significant effect on NBF-006 clearance or central distribution volume (Vc) in the model. Vc showed a slight positive trend with higher body weight, but was not statistically significant.
A popPK model was successfully developed for NBF-006. No covariates were identified that impact NBF-006 exposure. The lack of a relationship of exposure with body weight suggests the potential to use fixed dosing in future clinical studies.
Citation Format: Michael P. Hall, Zhihong O'Brien, Xi Chen, Angelean Hendrix, Stacy Brenes-Coto, Sonya Zabludoff. Clinical population pharmacokinetic (popPK) analysis of NBF-006, a novel siRNA inhibitor of glutathione-S-transferase P (GSTP) encapsulated in a lipid nano particle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7165.