Safety and Tolerability of NIM-1324, an Oral, Once-daily LANCL2 Agonist, in a Randomized, Double-Blind, Placebo-Controlled Phase 1 Study in Normal Healthy Volunteers

Background. Systemic lupus erythematosus is a complex disease in which the immune system is dysfunctional at multiple levels including impaired regulatory responses, altered self-antigen processing and increased autoantibody production. LANCL2 is a novel therapeutic target that has been first targeted by a gut-restricted compound, omilancor, currently in clinical development for inflammatory bowel diseases. NIM-1324 functions through similar LANCL2-dependent immunometabolic mechanisms, increasing the suppressive capacity and stability of regulatory CD4+ T cells (Treg) while also supporting the metabolic demands of autophagy in phagocytes. The preclinical efficacy of NIM-1324 has been validated in NZB/W, MRL, and pristane-induced models of lupus and the preclinical safety has been demonstrated up to a NOAEL of 1,000 mg/kg/d.

Methods. Oral NIM-1324 was evaluated for safety and tolerability in normal healthy volunteers (n = 56) in a randomized, double-blind, placebo-controlled trial. Volunteers were randomized into five single ascending dose cohorts (250 – 1500 mg, p.o.) and three multiple ascending dose cohorts (250 – 1500 mg QD for seven days, p.o.). Safety and tolerability were assessed by adverse event (AE) reporting, vital signs, ECG, hematology, and clinical chemistry. Blood concentrations of NIM-1324 were measured. Whole blood gene expression and serum cytokines were analyzed as markers of target engagement.

Results. Single and seven-day dosing with NIM-1324 did not result in and SAEs or increases in total AE rates in individual dose cohorts and overall pooled active group relative to placebo. Oral NIM-1324 dosing did not result in any clinically significant findings by biochemistry, coagulation, ECG, hematology, or urinalysis. NIM-1324 was rapidly absorbed after oral dosing and did not accumulate over the seven-day dosing period. Plasma exposure of NIM-1324 was observed to scale in a dose-proportional manner within the range of 250 to 1000 mg/d. Using a whole blood transcriptomic signature developed during preclinical efficacy testing, NIM-1324 upregulated the mRNA expression of genes associated with mitochondrial metabolism and downregulated markers of phagocyte activation. The magnitude of effect in the 250 mg cohort was like those observed preclinically at maximally effective doses.