Selective Inhibition of Tyrosine Kinase 2 With Deucravacitinib (BMS-986165) Compared With Janus Kinase 1−3 Inhibitors Anjaneya Chimalakonda, James Burke,* Lihong Cheng, Ian Catlett, Aditya Patel, Jun Shen, Ihab G. Girgis, Subhashis Banerjee, John Throup Bristol Myers Squibb, Princeton, NJ, USA *Employee at the time the analysis was conducted. Background • Tyrosine kinase 2 (TYK2), an intracellular kinase involved in the pathogenesis of immune-mediated inflammatory diseases (IMIDs), regulates signaling and functional responses downstream of the interleukin (IL)-12, IL-23, and Type I interferon receptors1 • Deucravacitinib (BMS-986165) is an oral, selective, allosteric TYK2 inhibitor with a unique mode of binding to the less-well-conserved pseudokinase domain rather than to the conserved active site in the catalytic domain1 — This unique mode of binding provides high functional selectivity for TYK2 vs other tyrosine kinases in cellular and other in vitro assays1 — Allosteric inhibition may provide robust efficacy and a differentiated safety profile vs other kinases due to decreased toxicity • In a 12-week, placebo-controlled, Phase 2 trial in patients with moderate to severe plaque psoriasis, the proportion of patients who achieved a 75% or greater improvement from baseline in the Psoriasis Area and Severity Index (PASI 75) at Week 12 (primary endpoint) was significantly higher with deucravacitinib 3 mg twice daily (BID; 69%), 6 mg BID (67%), and 12 mg once daily (QD; 75%) vs placebo (7%; P<0.001).2 Deucravacitinib also had a favorable safety profile including no significant changes in laboratory parameters2 • Deucravacitinib is currently being evaluated in multiple IMIDs including plaque psoriasis, psoriatic arthritis, inflammatory bowel disease, and lupus Objective • To compare the selectivity of deucravacitinib vs the approved Janus kinase (JAK) inhibitors tofacitinib, upadacitinib, and baricitinib, at clinically relevant doses and plasma concentrations Methods • In vitro whole blood assays that measure activity of TYK2, JAK 1/3, and JAK2 pathways were developed (Table 1) • Half-maximal inhibition concentrations (IC50) of deucravacitinib, tofacitinib, upadacitinib, and baricitinib were determined using these assays, as well as Hill coefficients for inhibition Table 1. In vitro whole blood assays for JAK 1−3 and TYK2 inhibitors Signaling kinase Stimulant Endpoint JAK 1/3 IL-2 STAT5 phosphorylation in T cells JAK2 TPO STAT3 phosphorylation in platelets TYK2 IL-12 IFN-γ production in cells IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; TYK, tyrosine kinase. • Pharmacokinetic (PK) profiles were simulated using parameters derived from published population PK models for tofacitinib, upadacitinib, and baricitinib3-6 and from internal analyses for deucravacitinib — PK parameters, including maximum plasma concentration (Cmax), average plasma concentration (Cave), and minimum plasma concentration (Cmin), were calculated • Plasma concentrations of deucravacitinib, tofacitinib, upadacitinib, and baricitinib were plotted relative to their whole blood IC50 values — If the whole blood IC50 value was higher than the Cmax value, the fold difference between the IC50 and Cmax values was calculated • Additionally, key exposure parameters (Cmax, Cave, and Cmin) of these agents were plotted relative to their individual whole blood IC50 values • Average percent inhibition of JAK 1−3 and TYK2 signaling was calculated using the following equation based on the average drug concentration, whole blood IC50, and the Hill coefficient — Percent inhibition = 100/(1+[(IC50/X)^H]) where X is the average drug concentration and H is the Hill coefficient • Given that in vitro assays were conducted in whole blood, no adjustments for plasma protein binding differences were considered in this evaluation. Additionally, the blood to plasma concentration ratio of these agents is close to 1 (range, 1.16−1.32).7 Therefore, no adjustments were considered Conclusions • This analysis confirms that deucravacitinib is a highly selective, allosteric TYK2 inhibitor with minimal or no activity against JAK 1−3 • Selective TYK2 inhibition is consistent with the reduced potential for treatment-related toxicities (eg, laboratory parameter abnormalities, gut perforation, thrombosis) in deucravacitinib-treated patients, effects generally associated with JAK 1−3 inhibitors2,10,11 • Conversely, the JAK 1−3 inhibitors included in this analysis (tofacitinib, upadacitinib, and baricitinib) did not exhibit TYK2 inhibition. Hence, the undesirable adverse effects associated with these agents as noted above are unlikely to be related to TYK2 inhibition • These results suggest that deucravacitinib is in a distinct therapeutic class compared with inhibitors of the closely related intracellular signaling kinases, JAKs 1−3 • Ongoing trials in plaque psoriasis (NCT03624127, NCT03611751, NCT04167462, NCT03924427, and NCT04036435) and other IMIDs will provide additional safety information about deucravacitinib Presented at the 2020 Fall Clinical Dermatology Conference; October 29−November 1; virtual meeting and at Las Vegas, Nevada http://www.globalbmsmedinfo.com This poster may not be reproduced without written permission from the author of this poster. Results In vitro whole blood IC50 • Based on in vitro whole blood IC50 values (Table 2), deucravacitinib had greater selectivity for TYK2 compared with JAK 1/3 or JAK2 • In contrast, tofacitinib, upadacitinib, and baricitinib demonstrate more potent inhibition of JAK 1/3 and JAK2 compared with TYK2. Whole blood IC50 values for tofacitinib, upadacitinib, and baricitinib are within range of values reported in the published literature8 Table 2. In vitro whole blood IC50 values for JAK 1−3 and TYK2 inhibitors Whole blood IC50 (95% CI), nM Signaling kinase readout Tofacitinib Baricitinib Upadacitinib Deucravacitinib JAK 1/3 (IL-2−induced pSTAT5) 17 (15−19) 11 (8.7−13) 7.8 (6.5−9.5) 1646 (1446−1872) JAK2 (TPO−induced pSTAT3) 217 (182−258) 32 (28−36) 41 (36−47) >10,000 (—) TYK2 (IL-12−induced IFN-γ release) 5059 (3767−7026) 2351 (1834−2980) 3685 (2346−6208) 40 (29−55) IC50, half-maximal inhibitory concentration; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and activator of transcription; TPO, thrombopoietin; TYK, tyrosine kinase. Daily percent inhibition by JAK 1−3 and TYK2 inhibitors • At clinically relevant concentrations, deucravacitinib inhibited TYK2 by >50% over 24 hours and exerted minimal effects (<2% inhibition) against JAK 1−3 (Figure 1). This indicates that deucravacitinib is a selective TYK2 inhibitor and does not modulate the JAK 1−3 pathways • Tofacitinib, upadacitinib, and baricitinib exhibited varying degrees of inhibition against JAK 1/3 (daily average inhibition, 70%−94%) and JAK2 (23%−67%) and no meaningful inhibition against TYK2 (<2%) Figure 1. Daily percent inhibition by JAK 1−3 and TYK2 inhibitors 0 25 50 75 100 2 mg 4 mg 5 mg 10 mg 15 mg 30 mg 6 mg QD 12 mg QD D ai ly i n h ib it io n , % JAK 1/3 JAK2 TYK2 Baricitinib Tofacitinib Upadacitinib Deucravacitinib (TYK2i) JAK, Janus kinase; QD, once daily; TYK2i, tyrosine kinase 2 inhibitor. JAK 1−3 and TYK2 inhibitor plasma concentrations and whole blood IC50 • At clinically relevant doses, deucravacitinib plasma concentrations were higher than the TYK2 whole blood IC50 value for a considerable portion (8−16 hours) of the 24-hour dosing interval and considerably lower than the JAK 1−3 IC50 values throughout the dosing interval (Figure 2) • Deucravacitinib Cmax values remained approximately 9- to 18-fold lower than the JAK 1/3 IC50 and approximately >52- to 109-fold lower than the JAK2 IC50. In contrast, tofacitinib, upadacitinib, and baricitinib plasma concentrations were higher than JAK 1/3 IC50 values over most of the dosing interval but were considerably lower than TYK2 IC50 values • Additionally, upadacitinib and baricitinib plasma concentrations exceeded JAK2 IC50 values over part of the dosing interval, especially at higher doses Figure 2. JAK 1−3 and TYK2 inhibitor plasma concentrations over time and whole blood IC50 17-fold 31-fold 33-fold 9-fold >52-fold 10 100 1000 10,000 0 6 12 18 24 P la sm a co n ce n tr at io n ( n M ) Time (hours) 10 100 1000 10,000 0 6 12 18 24 P la sm a co n ce n tr at io n ( n M ) Time (hours) 0 6 12 18 24 P la sm a co n ce n tr at io n ( n M ) Time (hours) 10 100 1000 10,000 0 6 12 18 24 P la sm a co n ce n tr at io n ( n M ) Time (hours) 1 10 100 1000 10,000 Baricitinib Tofacitinib Upadacitinib Deucravacitinib (TYK2) JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 5 mg BID 15 mg QD2 mg QD 6 mg QD 10 mg BID 30 mg QD4 mg QD 12 mg QD Arrows and fold-increase values pertain to the highest approved dose for each agent. Tofacitinib 10 mg BID is approved for treating ulcerative colitis but not for rheumatoid arthritis.9 Tofacitinib, upadacitinib, and baricitinib: margins to TYK2 inhibitor IC50 are provided for the highest approved dose. BID, twice daily; IC50, half-maximal inhibitory concentration; JAK, Janus kinase; QD, once daily; TYK, tyrosine kinase 2. JAK 1−3 and TYK2 inhibitor pharmacokinetic parameters and whole blood IC50 • At clinically relevant doses, deucravacitinib Cmax, Cave, and Cmin were higher than or close to the TYK2 IC50 value, but were considerably lower than JAK 1/3 and JAK2 IC50 values (Figure 3) • Cmax, Cave, and Cmin values for tofacitinib, upadacitinib, and baricitinib were many-fold lower than TYK2 IC50 values, but were above or within range of JAK 1/3 and JAK2 IC50 values Figure 3. JAK 1−3 and TYK2 inhibitor pharmacokinetic parameters and whole blood IC50 1 10 100 1000 10,000 Cmax (nM) Cave (nM) Cmin (nM) P la sm a co n ce n tr at io n ( n M ) 2 mg QD 4 mg QD JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 1 10 100 1000 10,000 Cmax (nM) Cave (nM) Cmin (nM) P la sm a co n ce n tr at io n ( n M ) 5 mg QD 10 mg QD JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 1 10 100 1000 10,000 Cmax (nM) Cave (nM) Cmin (nM) P la sm a co n ce n tr at io n ( n M ) 15 mg QD 30 mg QD JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 1 10 100 1000 10,000 Cmax (nM) Cave (nM) Cmin (nM) P la sm a co n ce n tr at io n ( n M ) 6 mg QD 12 mg QD JAK 1/3 IC50 JAK2 IC50 TYK2 IC50 Baricitinib Tofacitinib Upadacitinib Deucravacitinib TYK2 BID, twice daily; Cave, average plasma concentration; Cmax, maximum plasma concentration; Cmin, minimum or trough plasma concentration; IC50, half-maximal inhibitory concentration; JAK, Janus kinase; QD, once daily; TYK2i, tyrosine kinase 2 inhibitor. References 1. Burke JR et al. Sci Transl Med. 2019;11:1-16. 2. Papp K et al. N Engl J Med. 2018;379:1313-1321. 3. Girgis IG et al. Presented at: Triennial Meeting of the Skin Inflammation and Psoriasis International Network; April 25-27, 2019; Paris, France. 4. Klünder B et al. Clin Pharmacokinet. 2019;58:1045-1058. 5. Xie R et al. Int J Clin Pharmacol Ther. 2019;57:464- 473. 6. Zhang X et al. CPT Pharmacometrics Syst Pharmacol. 2017;6:804-813. 7. Dowty ME et al. Pharmacol Res Perspect. 2019;7:e00537. 8. McInnes IB et al. Arthritis Res Ther. 2019;21:183. 9. Xeljanz [package insert]. New York, NY: Pfizer Inc.; 2019. 10. Winthrop KL. Nat Rev Rheumatol. 2017;13:234-243. 11. Gadina M et al. Rheumatology (Oxford). 2019;58:i4-i16. Acknowledgments • This analysis was sponsored by Bristol Myers Squibb. Professional medical writing from Ann Marie Fitzmaurice, PhD and editorial assistance were provided by Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, and were funded by Bristol Myers Squibb Relationships and Activities • AC, LC, JS, IC, AP, IGG, SB, JT are employees and shareholders of Bristol Myers Squibb; JB was an employee and shareholder of Bristol Myers Squibb at the time the analysis was conducted