Abstract C101: Preclinical and clinical pharmacokinetics (PK) of NBF-006, a novel siRNA inhibitor of glutathione-s-transferase P (GSTP) encapsulated in a lipid nanoparticle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC)
Authors: Hall Michael , O'Brien Zhihong , Zabludoff Sonya 
Published: December 2023

Abstract
Background: GSTP has an important role in detoxification and anti-oxidative damage response. Additionally, GSTP has a chaperone function that regulates multiple key oncogenic pathways such as KRAS and JNK. Since alternative or redundant 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 preclinical PK data in healthy mice and monkeys, prediction of human doses, and phase 1 clinical PK data.
Methods: Preclinical PK studies were performed by intravenous bolus injection of NBF-006 once weekly for 1 month at 5, 20, and 40 mg/kg in mice and 6, 12, and 18 mg/kg in cynomolgus monkeys. Human drug exposures were predicted based upon simple allometry. For the phase 1 clinical study, a total of 48 advanced NSCLC, pancreatic, or colorectal cancer patients received 4 weekly doses 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 a hybridization ELISA. Non-compartmental PK analysis (NCA) was performed with the resulting concentration-time data. Results: In mice, terminal elimination half-life (t1/2) of plasma siRNA ranged between 3.69 to 9.04 hr, clearance (CL) ranged between 3.61 and 5.81 mL/hr/kg, and volume of distribution (Vd) ranged between 23.5 and 57.4 mL/kg. In cynomolgus monkeys, t1/2 ranged between 8.22 and 28.2 hr, CL ranged between 1.38 and 3.97 mL/hr/kg, and Vd ranged between 31.7 to 83.3 mL/kg. Exposure (maximal plasma concentration, Cmax, and area under the curve, AUC) increased with increasing dose in both species and was generally dose proportional. Following weekly administration of NBF-006, no apparent accumulation or reduction of siRNA exposure was observed. Human PK exposures were well-predicted within 2-fold accuracy at clinically studied doses. Clinically, NCA demonstrated consistent slow CL and low Vd with a mean t1/2 of 41 (± 13) hours. Exposure showed dose proportionality from 0.15 to 1.2 mg/kg. At 1.6 mg/kg, exposure was not statistically different than that of 1.2 mg/kg. No accumulation risk potential was identified following the current dosing regimen. Moreover, exposure was not reduced after repeat dosing in any dose group.
Conclusions: Preclinical PK profiling enabled initial characterization of the in vivo disposition of NBF-006 and prediction of human PK and doses. In patients, repeated administration of NBF-006 was well-tolerated up to 1.6 mg/kg. Exposure appeared to be dose proportional through 1.2 mg/kg. Neither exposure reduction nor accumulation was observed.
Citation Format: Michael Hall, Zhihong O'Brien, Sonya Zabludoff. Preclinical and clinical pharmacokinetics (PK) of NBF-006, a novel siRNA inhibitor of glutathione-s-transferase P (GSTP) encapsulated in a lipid nanoparticle (LNP), for treatment of advanced non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C101.