AB0018 TNFΑ RS1800629 POLYMORPHISM: WHAT ABOUT ITS ASSOCIATION WITH CLINICAL MANIFESTATIONS AND ANTI-TNFΑ THERAPY? DATA FROM A SERIES OF ITALIAN PATIENTS WITH BEHÇET SYNDROME

Background: BMS-986165 is an oral, selective inhibitor of tyrosine kinase 2 (TYK2) with a unique mode of binding to the pseudokinase domain of the enzyme rather than the active site within the kinase domain. This unique mode of binding provides high functional selectivity for TYK2 versus other tyrosine kinases (TYKs) in cellular and other in vitro assays.1 This approach may provide robust efficacy with a differentiated safety profile due to decreased off-target activity on other kinases. In a 12-week, placebo-controlled Phase 2 trial in patients with moderate to severe plaque psoriasis,2 BMS-986165 had a favorable safety profile, and 67%–75% of patients achieved Psoriasis Area and Severity Index 75 (PASI 75) after 12 weeks at doses ≥3 mg twice daily versus 7% with placebo. BMS-986165 is currently under investigation in multiple autoimmune disorders such as psoriatic arthritis, psoriasis, and systemic lupus erythematosus. Objectives: To understand the selectivity of BMS-986165 compared with JAK inhibitors, such as tofacitinib (Tofa), upadacitinib (Upa), and baricitinib (Bari), at clinically relevant doses and plasma concentrations. Methods: In vitro whole blood assays were developed to measure the activity of common pairings of JAKs (JAK 1/3, JAK2/2, and TYK2/JAK2) and concentrations providing half-maximal inhibition (IC50) for BMS-986165, Tofa, Upa, and Bari were determined. The whole blood IC50 values were plotted against pharmacokinetic profiles of these agents at approved doses and/or doses evaluated in their respective Phase 2/3 trials. The time that concentrations were >IC50 and projected average daily inhibition were evaluated. Results: At clinically relevant doses and exposures, BMS-986165 plasma concentrations were higher than the TYK2 whole blood IC50 value for a considerable part of the dosing interval. Additionally, the maximal plasma concentration (Cmax) of BMS-986165 was approximately >9- to 18-fold lower than the JAK 1/3 whole blood IC50 value and >52- to >109-fold lower than JAK2/2 whole blood IC50, indicating lack of meaningful inhibition of the JAK 1-3 pathways by BMS-986165 at therapeutic doses. At clinically relevant doses, projected Cmax values of Tofa, Upa, and Bari were many-fold lower than TYK2 IC50, indicating minimal or no meaningful inhibition of the TYK2 pathway. As expected, Tofa, Upa, and Bari had varying degrees of inhibition against JAK1/3 (daily average inhibition range: 70%–94%) and JAK2/2 pathways (daily average inhibition range: 24%–67%) at clinically relevant doses and exposures. Conclusion: These results demonstrate the high TYK2 functional selectivity of BMS-986165 at clinically relevant doses and plasma concentrations compared with Tofa, Upa, and Bari and indicate that BMS-986165 is in a different class compared with JAK 1–3 inhibitors. Ongoing studies in psoriasis and other conditions may confirm the expected safety of BMS-986165 based on the above results. The daily average inhibition of JAK1 and JAK2 likely explains some common laboratory observations and adverse events reported for the JAK1–3 inhibitors. References: [1]Burke JR et al. Sci Transl Med. 2019 Jul 24;11(502); eaaw1736. [2]Papp K et al. N Engl J Med. 2018;379(14):1313-1321. Acknowledgments: This study was sponsored by Bristol-Myers Squibb. Editorial assistance was provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and was funded by Bristol-Myers Squibb. Disclosure of Interests: Anjaneya Chimalakonda Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, James Burke Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Lihong Cheng Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Joann Strnad Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Ian Catlett Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Aditya Patel Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Jun Shen Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Ihab Girgis Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, Subhashis Banerjee Shareholder of: AbbVie, Bristol-Myers Squibb, Lily, Pfizer, Employee of: Bristol-Myers Squibb (current); AbbVie, Lily, Pfizer (past), John Throup Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb