Artikel
Efficacy of tyrosine kinase 2 (TYK2) inhibition in immune-mediated diseases with an oral, selective TYK2 inhibitor, BMS-986165
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Veröffentlicht: | 8. Oktober 2019 |
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Gliederung
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Background: BMS-986165 is an oral, selective inhibitor of TYK2, an intracellular kinase that activates STAT-dependent cytokine signalling pathways (including interleukin [IL]-23 and Type I interferons) involved in the pathophysiology of psoriasis (PsO) [1], psoriatic arthritis (PsA), and systemic lupus erythematosus (SLE) [2], BMS-986165 was evaluated initially in a prototypic IL-23–dependent condition, PsO.
Methods: Phase 2 trial (NCT02931838): adults with PsO for ≥6 months and moderate to severe disease were randomised to placebo or BMS-986165 (3mg every other day [QOD], 3mg every day [QD], 3mg twice daily [BID], 6mg BID, 12mg QD) for 12 weeks. Pain was assessed by American College of Rheumatology joint pain visual analogue scale (VAS) in patients with baseline musculoskeletal symptoms.
Results: At Week 12 (primary endpoint), 67–75% of patients achieved Psoriasis Area and Severity Index 75 at doses ≥3mg BID, versus 7% with placebo (P<0.001; (Figure 1A [Fig. 1]) [3]. Pain scores (VAS) in patients with musculoskeletal symptoms showed dose-dependent improvements from baseline: ~70% decrease in pain at Week 12 (Figure 1B [Fig. 1]) in patients receiving doses ≥3mg BID. Adverse events were generally mild to moderate: reported in 51% (placebo), 59% (3mg QOD), 55% (3mg QD), 64% (3mg BID), 80% (6mg BID) and 77% (12mg QD) of patients; most common were nasopharyngitis, headache, nausea, diarrhea. There were no opportunistic infections, herpes zoster cases, or blood abnormalities characteristic of Janus kinase 1–3 inhibition (changes in neutrophils, lymphocytes, haemoglobin, cholesterol).
Conclusion: BMS-986165 demonstrated significant efficacy and was well tolerated in patients with moderate to severe PsO. These clinical data provide rationale for ongoing investigations in PsO (Phase 3 trials POETYK PsO-1/2; NCT03624127, NCT03611751) and other immune-mediated diseases that could be TYK2-dependent, including SLE and PsA. PAISLEY (NCT03252587) is an ongoing, multicentre, randomised, placebo-controlled, double-blind Phase 2 study enrolling ~360 adults with SLE (196 sites/18 countries; (Figure 2 [Fig. 2]). Primary objective: assess the effect of BMS-986165 on SLE Responder Index-4 response at Week 32 in patients on stable background therapy. A monitored review of medically appropriate disease activity scoring and corticosteroids tapering is included. A 180-patient, multicentre, randomised, placebo-controlled, double-blind Phase 2 study in PsA (NCT03881059) is enrolling; primary endpoint is Week 16 ACR20.
References
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- Harden JL, Krueger JG, Bowcock AM. The Immunogenetics of Psoriasis: A Comprehensive Review. J Autoimmun. 2015;64:66-73.
- 2.
- Yao Y, Richman L, Morehouse C, de los Reyes M, Higgs BW, Boutrin A, White B, Coyle A, Krueger J, Kiener PA, Jallal B. Type I Interferon: Potential Therapeutic Target for Psoriasis? PLoS One. 2008;16;3(7):e2737.
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- Papp K, Gordon K, Thaçi D, Morita A, Gooderham M, Foley P, Girgis IG, Kundu S, Banerjee S. Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med. 2018;379(14):1313-1321.