Abstract C103: Preclinical and clinical safety and tolerability evaluation 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

Abstract Glutathione S-transferase Pi (GSTP) has an important role in detoxification and anti-oxidative damage responses. Additionally, GSTP has a chaperone function that regulates key oncogenic pathways such as the KRAS and JNK pathways (E Laborde, 2010). Since alternative or redundant pathways could compensate for the incomplete inhibition of a single kinase, targeting multiple pathways could lead to more effective therapy. NBF-006 is a novel drug product containing a GSTP siRNA encapsulated within a proprietary lipid nanoparticle (LNP). It has been designed to deliver siRNA to tumors of the lung and common sites of metastatic spread (liver and marrow). As GSTP downregulation leads to inhibition of KRAS signaling through modulation of both MAPK and PI3K pathways, NBF-006 is being developed to treat KRAS mutant tumors. Preclinical studies have demonstrated activity across KRAS mutations, as well as efficacy in orthotopic non-small cell lung cancer (NSCLC) models. Immune toxicities have been recognized as safety concerns associated with LNP therapeutics. The safety assessment of NBF-006 was conducted both preclinically and clinically. In vitro preclinical toxicity studies included hemolysis in hRBC samples, cytokine release in hPBMCs, and TLR activation in human THP1 cells. GLP-compliant general toxicity studies were conducted in both mice and cynomolgus monkeys, IV administration, once a week, for 5 weeks. Complement splits were measured in the monkey study to assess any immune-related responses. Safety pharmacology parameters were also conducted in monkeys. The mouse was slightly more sensitive than monkeys to NBF-006, and the highest non-seriously toxic dose level in mice was 20 mg/kg/week, which yielded a good safety margin to proceed for a Phase I clinical trial. The highest dose level tested in monkeys was of 18 mg/kg/week and was well tolerated by the monkeys. Immunological assessments were conducted during Phase 1 dose escalation and expansion in patients with NSCLC, pancreatic cancer, or colorectal cancer. NBF-006 was administered by IV infusion over 70 minutes, once a week, for 4 weeks followed by a 2-week rest period. Clinical symptoms and reactions were monitored, and lab tests were conducted according to the protocol, including CBC, complement split products (Bb, C3a, C5a, and CH50), cytokines (IL-6, IL-1β, IFNg, and TNFα), and anti-drug antibodies against the LNPs. Dose-dependent increases in C3a and Bb of 1.2 and 1.6 mg/kg were observed following NBF-006 administration at doses ranging from 0.15 to 1.6 mg/kg. The increases were transient at either 10 minutes or 1 hour after the end of the infusion. Due to lack of corresponding increases in C5a or decreases in CH50, transient elevations of C3a and Bb were not considered clinically significant. In summary, NBF-006 was well tolerated in both animal species and patients: 20 mg/kg/week was the non-seriously toxic dose level in mice; the highest dose level of 18 mg/kg/week tested in monkeys was the NOAEL; and 1.6 mg/kg/week was the highest dose level evaluated in humans. Citation Format: Jian Liu, Cima Cina, Douglas Kornbrust, Sonya Zabludoff. Preclinical and clinical safety and tolerability evaluation 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 C103.