Abstract Rationale Repeated injury to alveolar epithelial cells (AECs) and abnormal repair responses may be key triggers of idiopathic pulmonary fibrosis. Demonstration that β1 integrin-deficient AECs induce inflammation and lung tissue destruction, suggests a critical role for β1 integrin in alveolar homeostasis in the lung. In the therapeutic bleomycin model of pulmonary fibrosis, ORJ-001, a β1 integrin agonist peptide, showed reduction in established lung fibrosis and regeneration of alveolar epithelium, providing scientific basis to initiate development of ORJ-001 as a treatment for IPF. In 4-week toxicology studies, the No Observed Adverse Effect Level (NOAEL) was 500mg/kg/day and 200mg/kg/day in mice and monkeys, respectively. Methods ORJ-001 was administered to 64 healthy volunteers in either single (100, 200, 300, 400mg or placebo) or multiple (200, 300, 400mg or placebo QD, 5 days; 400mg or placebo QW, 4 weeks) subcutaneously. Each dose cohort consisted of 8 subjects (6 active: 2 placebo). Safety assessments included analyses of adverse events, laboratory tests, vital signs, electrocardiograms and presence of anti-drug antibodies (ADA). The pharmacokinetic profile of ORJ-001 was assessed at multiple timepoints up to 12 hours post-dose. A physiologically based pharmacokinetic (PBPK) model was developed and utilized to predict an optimal dose range for future Phase 2 studies. Results In the single ascending dose (SAD) study, treatment-emergent adverse events (TEAEs) were reported in 100% and 62.5% of subjects in the overall active and pooled placebo arms, respectively. Ninety-six percent and 4% of all TEAEs were of mild and moderate severity, respectively. In the multiple ascending dose (MAD) study, TEAEs occurred in 92% overall active vs. 100% pooled placebo arms. The most common TEAEs reported were injection site reactions and no serious adverse events or clinically relevant laboratory changes were observed in either SAD or MAD studies; all titer values for ADA were negative. Peak plasma concentrations of ORJ-001 were reported between 0.5 hours to 0.67 hours across all dose cohorts and the plasma level steadily declined over the next 4 hours. PBPK modeling predicted the exposures achieved in the range of 200-400mg in humans are expected to be effective, based on the exposures achieved in the efficacy range tested in the bleomycin mouse models. Conclusions The safety profile of ORJ-001 in healthy volunteers was consistent with nonclinical studies and, supported by PBPK modeling, enables Phase 2 clinical development. This abstract is funded by: Oorja Bio, NIBEC
Pena et al. (Fri,) studied this question.