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 (IC 50 ) for BMS-986165, Tofa, Upa, and Bari were determined. The whole blood IC 50 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 >IC 50 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 IC 50 value for a considerable part of the dosing interval. Additionally, the maximal plasma concentration (C max ) of BMS-986165 was approximately >9- to 18-fold lower than the JAK 1/3 whole blood IC 50 value and >52- to >109-fold lower than JAK2/2 whole blood IC 50 , indicating lack of meaningful inhibition of the JAK 1-3 pathways by BMS-986165 at therapeutic doses. At clinically relevant doses, projected C max values of Tofa, Upa, and Bari were many-fold lower than TYK2 IC 50 , 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

Methotrexate (MTX), a substrate of organic anion transporter 1 and 3, is an immunosuppressive agent recommended for the treatment of steroid-dependent ulcerative colitis and active/relapsing Crohn’s disease.1,2 BMS-986165, an oral selective TYK2 inhibitor, has demonstrated efficacy and acceptable safety in patients with moderate to severe plaque psoriasis,3 and is under investigation in moderate to severe Crohn’s disease (LATTICE; NCT03599622), among other chronic autoimmune diseases. There is a potential for co-administration of BMS-986165 with MTX in many of these diseases. The objectives of this study were to evaluate the effects of BMS-986165 on the pharmacokinetics (PK; primary objective) and safety and tolerability (secondary objective) of MTX on co-administration. This was a Phase 1, open-label, single-sequence study in healthy male volunteers. Subjects aged 18–50 years with a body mass index (BMI) of 18–32 kg/m2 received a single oral (po) dose of MTX 7.5 mg on Day (D) 1 and D12 and BMS-986165 12 mg po from D8 to D14. Blood samples were collected after each treatment to determine the PK of MTX and BMS-986165. Safety evaluations (adverse events [AEs], physical and skin examinations, vital signs, electrocardiograms, laboratory tests) were performed during the course of the study. Overall, 10 subjects were treated (mean [standard deviation] age 33.6 [7.06] years, BMI 24.9 [2.31] kg/m2), all of whom completed the study. Following co-administration of MTX + BMS-986165, MTX geometric mean maximum concentration (Cmax) and total exposure (area under the curve extrapolated to infinity [AUCINF]) increased by ~11% and 4%, respectively, compared with MTX alone (Table). The 90% confidence intervals (CIs) for the geometric least-square mean ratios for Cmax and AUCINF were contained within the no-effect boundary of 0.80–1.25. There were no serious AEs, deaths, or AEs leading to discontinuation. All treatment-emergent AEs were mild and resolved spontaneously. Table. PK parameters for MTX and MTX + BMS-986165. BMS-986165 at steady state had no clinically meaningful effect on the PK of a single dose of MTX. MTX alone or in combination with BMS986165 was safe and well tolerated in this study. Reference 1. Harbord M, et al. (2017) J Crohn’s Colitis. 2. Gomollón F, et al. (2017) J Crohn’s Colitis. 3. Papp K, et al. (2018) N Engl J Med.

Cyclosporine is a dual breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) inhibitor. Current treatment guidelines for inflammatory bowel disease include cyclosporine for steroid-refractory ulcerative colitis.1,2 BMS-986165, an oral selective TYK2 inhibitor, has demonstrated efficacy and acceptable safety in patients with moderate to severe plaque psoriasis,3 and is under investigation in moderate to severe Crohn’s disease (LATTICE; NCT03599622) among other chronic autoimmune diseases. The current study assessed the effect of cyclosporine co-administration on the PK and safety/tolerability of BMS-986165. In this Phase 1, open-label, single-sequence drug–drug interaction study (NCT03419910), healthy male subjects aged 18–50 years with a body mass index (BMI) of 18–32 kg/m2 received a once-daily, pharmacologically relevant, oral (po) dose of BMS-986165 on Days (D) 1–5, followed by a single dose of BMS-986165 + cyclosporine 500 mg po on D6. On PK sampling days, doses were administered after an overnight fast of ≥10 h. Blood samples were collected on D5 and D6 to determine the PK of BMS-986165 and cyclosporine. Overall, 20 subjects (mean [standard deviation] age 30.3 [7.0] years, BMI 26.0 [3.2] kg/m2) were treated and evaluable for safety; 2 (10%) withdrew due to adverse events (AEs; pyrexia) before D5 PK sampling. Cyclosporine co-administration with BMS-986165 had no clinically meaningful effect on peak and total BMS-986165 exposures (16% increase in maximum concentration and 29% increase in area under the curve over 24 h; Table) or its key metabolites. Median (min, max) time to maximum concentration for BMS-986165 was 2.5 (1, 4) h on D5 and 2.5 (2, 8) h on D6. There were no serious AEs or deaths. All treatment-emergent AEs were considered mild and resolved by study end. Table. Effect of concomitant cyclosporine administration on BMS-986165 PK in PK-evaluable subjects (n = 18). Cyclosporine, a dual BCRP and P-gp inhibitor, has no clinically meaningful effect on the PK of BMS-986165. Therefore, drugs inhibiting P-gp or BCRP (eg, cyclosporine, among others), are not expected to meaningfully impact the PK of BMS-986165. BMS-986165 alone or in combination with cyclosporine was well tolerated in healthy subjects in this study. References 1. Harbord M, et al. J Chrons Colitis. 2017. 2. Kornbluth A, et al. Am J Gastroenterol 2010. 3. Papp K, et al. N Engl J Med. 2018.

Myostatin is a negative regulator of skeletal muscle. Genetic ablation or pharmacologic inhibition of myostatin results in increased skeletal muscle size in several species including human. Reducing myostatin is a potential therapeutic approach for skeletal muscle diseases such as Duchenne's muscular dystrophy (DMD). BMS-986089 is an anti-myostatin adnectin (engineered scaffold based on the 10th fibronectin type III domain) that exhibits high affinity for myostatin (Kd = 0.17–0.45 nM) and inhibits myostatin and GDF-11 second messenger signaling in cells (IC50s = 0.06–1 nM and 0.09–0.7 nM, respectively). In male SCID mice (to avoid immunogenic responses), four weekly sub-cutaneous (SC) doses (0.1–100 mpk) of BMS-986089 produced dose- and time-dependent increases in lower limb muscle volume (MRI) of up to approximately 30%. In male rats, a single SC administration of BMS-98089 (0.3−25 mpk) produced time- and dose-dependent increases in lower limb muscle volume that reached a maximum of up to 16%, 15 days post-dose. In male cynomolgus monkeys, four weekly SC doses (0.3–25 mpk) of BMS-986089 produced dose- and time-dependent increases in lower limb muscle volume of up to approximately 5%. In each study serum free myostatin was suppressed in a dose and time dependent manner. These data support further development of BMS-986089 in diseases such as DMD.