C104-05 Results From Phase 1, Randomized, Double-blind, Single and Multiple Ascending Dose Studies Characterizing the Pk, Safety and Tolerability of Orj-001, a Selective β1 Integrin Agonist Peptide in Healthy Volunteers

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