Pos0373 Phase 1 Clinical Trial Evaluating the Pharmacokinetics and Pharmacodynamics of a Novel Il-17a and Baff Dual Antagonist in Sjogren’s Syndrome

Background: Sjogren's syndrome (SS) is a chronic autoimmune disorder characterized by inflammation of the lacrimal and salivary glands. Histopathological analysis has previously confirmed increased numbers of activated T and B cells in the glands. Sjogren's patients have increased levels of antibodies directed against SS Antigen A (SSA) or SS Antigen B (SSB). B cell activating factor (BAFF) plays a significant role in B cell survival and the generation of autoantibodies. Additionally, BAFF levels have previously been shown to be elevated in the circulating blood as well as inflamed salivary glands. IL-17 is pleiotropic cytokine that drives autoimmunity through the induction of inflammatory cytokines, chemokines, and other mediators. Furthermore, several studies have demonstrated increased levels of IL-17 in the plasma, saliva, and tears of SS patients. Taken together, these data suggest dual antagonism of BAFF and IL-17 as a potential treatment for SS. Objectives: To evaluate the safety, tolerability, pharmacokinetic, and pharmacologic activity of tibulizumab (LY3090106; ZB-106) in a Phase 1, parallel-group, randomized, double blind placebo controlled, multiple ascending dose clinical trial in patients with SS. Methods: Participants between the ages of 18 and 65 were screened for a confirmed diagnosis of SS and the presence of either anti-SSA or anti-SSB antibodies prior to enrollment. All participants provided written informed consent prior to enrollment in the trial. Enrolled participants subcutaneously received tibulizumab (30mg Q4W, 100mg Q4W, 300mg Q4W, 300mg Q2W) for 12 weeks followed by another 12-week follow-up period. Serum samples were collected throughout the trial for the assessment of target engagement (circulating levels of IL-17A and BAFF), pharmacokinetics, anti-tibulizumab antibodies (ADA), and exploratory biomarkers. Results: Twenty-five participants with physician-diagnosed SS meeting the inclusion/exclusion criteria were enrolled in this Phase 1 study. 92% (23 out of 25) of the participants were female and 88% (22 out of 25) were non-Hispanic. Of the 25 participants enrolled, 21 participants received at least one dose of tibulizumab while 4 participants received at least one placebo treatment. In participants receiving tibulizumab, the serum levels of both BAFF and IL-17A increased as expected. At doses of 100mg Q4W and above, the concentrations of BAFF and IL-17A appeared to plateau, suggesting maximum target engagement. Additionally, treatment with tibulizumab reduced the levels of circulating exploratory biomarkers including total B cell counts and CXCL1 levels. PK/PD modeling determined the subcutaneous bioavailability to be approximately 62.9% and the tmax between 5 – 8 days post dose. Throughout the course of the study, only one tibulizumab-treated participant (30mg Q4W) had a treatment emergent-ADA. Conclusion: Overall, this clinical trial demonstrated that tibulizumab was well-tolerated and that the combined neutralization of IL-17A and BAFF disrupts two key pathways involved in disease pathogenesis. These results suggest that tibulizumab may provide significant benefit to those with IL-17A and B cell-mediated autoimmune diseases, including SS, and warrants further exploration in larger clinical trials. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: Michael Howell ZuraBio, ZuraBio, Kiran Nistala ZuraBio, ZuraBio, Parisa Faghihi ZuraBio, ZuraBio, Abid Sattar ZuraBio, Someit Sidhu ZuraBio, ZuraBio.