BACKGROUND: Janus-associated kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small molecule inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant production of inflammatory proteins (eg, IL-17). OBJECTIVE: We sought to demonstrate proof of concept in patients with stable plaque psoriasis. METHODS: Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Additional groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream). RESULTS: Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concentrations of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concentration (IC(50)) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation. LIMITATIONS: This study was limited by the relatively short study duration and small sample size. CONCLUSION: Topical INCB018424 is safe, is well tolerated, and exhibits clinical activity in the topical treatment of psoriasis.
RCT Entities:
BACKGROUND: Janus-associated kinases (JAKs) are involved in signal transduction from a variety of cytokines implicated in the pathogenesis of psoriasis, including interleukin (IL)-12, IL-23, and interferon-γ. INCB018424, a small molecule inhibitor of JAK1 and JAK2, inhibits cytokine-induced JAK/signal transducers and activators of transcription signaling and the resultant production of inflammatory proteins (eg, IL-17). OBJECTIVE: We sought to demonstrate proof of concept in patients with stable plaque psoriasis. METHODS:Patients were dosed with vehicle, 0.5% or 1.0% INCB018424 phosphate cream once a day or 1.5% twice a day for 28 days. Additional groups included two active comparators (calcipotriene 0.005% cream or betamethasone dipropionate 0.05% cream). RESULTS: Both the 1% and the 1.5% cream improved lesion thickness, erythema, and scaling and reduced lesion area compared with placebo. A composite lesion score decreased by greater than 50% with the efficacious doses of INCB018424 compared with 32% for vehicle controls. Topical application of INCB018424 was well tolerated with few mild adverse events noted. Mean plasma concentrations of INCB018424 after topical application of 0.5% to 1.5% cream were in the low nanomolar range, representing a fraction (<1%) of the half maximal inhibitory concentration (IC(50)) in whole blood for inhibition of cytokine-stimulated signal transducers and activators of transcription-3 phosphorylation. LIMITATIONS: This study was limited by the relatively short study duration and small sample size. CONCLUSION: Topical INCB018424 is safe, is well tolerated, and exhibits clinical activity in the topical treatment of psoriasis.
Authors: Danny Hung-Chieh Chou; Amedeo Vetere; Amit Choudhary; Stephen S Scully; Monica Schenone; Alicia Tang; Rachel Gomez; Sean M Burns; Morten Lundh; Tamara Vital; Eamon Comer; Patrick W Faloon; Vlado Dančík; Christie Ciarlo; Joshiawa Paulk; Mingji Dai; Clark Reddy; Hanshi Sun; Matthew Young; Nicholas Donato; Jacob Jaffe; Paul A Clemons; Michelle Palmer; Steven A Carr; Stuart L Schreiber; Bridget K Wagner Journal: J Am Chem Soc Date: 2015-06-15 Impact factor: 15.419
Authors: Anna E Kersh; Spencer Ng; Yun Min Chang; Maiko Sasaki; Susan N Thomas; Haydn T Kissick; Gregory B Lesinski; Ragini R Kudchadkar; Edmund K Waller; Brian P Pollack Journal: J Clin Pharmacol Date: 2017-11-14 Impact factor: 3.126
Authors: Luzhou Xing; Zhenpeng Dai; Ali Jabbari; Jane E Cerise; Claire A Higgins; Weijuan Gong; Annemieke de Jong; Sivan Harel; Gina M DeStefano; Lisa Rothman; Pallavi Singh; Lynn Petukhova; Julian Mackay-Wiggan; Angela M Christiano; Raphael Clynes Journal: Nat Med Date: 2014-08-17 Impact factor: 53.440