Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis

Kim Papp; Kenneth Gordon; Diamant Thaçi; Akimichi Morita; Melinda Gooderham; Peter Foley; Ihab G. Girgis; Sudeep Kundu; Subhashis Banerjee

doi:10.1056/NEJMoa1806382

Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis

Kim Papp^*, Kenneth Gordon, Diamant Thaçi, Akimichi Morita, Melinda Gooderham, Peter Foley, Ihab G. Girgis, Sudeep Kundu, Subhashis Banerjee

^*Corresponding author for this work

Institute of Inflammation Medicine

352 Citations (Scopus)

Abstract

BACKGROUND Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis. METHODS We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis). RESULTS A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P = 0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment. CONCLUSIONS Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838.).

Original language	English
Journal	New England Journal of Medicine
Volume	379
Issue number	14
Pages (from-to)	1313-1321
Number of pages	9
ISSN	0028-4793
DOIs	https://doi.org/10.1056/NEJMoa1806382
Publication status	Published - 04.10.2018

Funding

The trial was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonisation guidelines for Good Clinical Practice, and local regulations. An institutional review board or independent ethics committee at each site approved the protocol, consent form, and any other written information provided to patients. Patients provided written informed consent before trial entry. The trial was sponsored by Bristol-Myers Squibb, which designed the trial, provided the trial drug and placebo, conducted blinded safety monitoring, developed the analysis plan, analyzed the results, and funded professional writing assistance. A contract research organization (ICON, Dublin) conducted the trial under the direction of the sponsor, and medical writers paid by the sponsor wrote the first draft of the manuscript. All the authors had full access to the trial data, reviewed and approved the manuscript before submission, and vouch for the adherence of the trial to the protocol, the completeness and accuracy of the data and analyses, and the reporting of adverse events. There were confidentiality agreements between the authors and the sponsor. Supported by Bristol-Myers Squibb.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Areas and Centers

Academic Focus: Center for Infection and Inflammation Research (ZIEL)

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10.1056/NEJMoa1806382

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title = "Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis",

abstract = "BACKGROUND Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis. METHODS We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75\% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis). RESULTS A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75\% or greater reduction in the PASI score was 7\% (3 of 45 patients) with placebo, 9\% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P = 0.49 vs. placebo), 39\% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69\% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67\% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75\% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment. CONCLUSIONS Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838.).",

author = "Kim Papp and Kenneth Gordon and Diamant Tha{\c c}i and Akimichi Morita and Melinda Gooderham and Peter Foley and Girgis, \{Ihab G.\} and Sudeep Kundu and Subhashis Banerjee",

year = "2018",

month = oct,

day = "4",

doi = "10.1056/NEJMoa1806382",

language = "English",

volume = "379",

pages = "1313--1321",

journal = "New England Journal of Medicine",

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T1 - Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis

AU - Papp, Kim

AU - Gordon, Kenneth

AU - Thaçi, Diamant

AU - Morita, Akimichi

AU - Gooderham, Melinda

AU - Foley, Peter

AU - Girgis, Ihab G.

AU - Kundu, Sudeep

AU - Banerjee, Subhashis

PY - 2018/10/4

Y1 - 2018/10/4

N2 - BACKGROUND Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis. METHODS We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis). RESULTS A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P = 0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment. CONCLUSIONS Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838.).

AB - BACKGROUND Tyrosine kinase 2 (TYK2) signaling pathways, which mediate cytokine signaling, are implicated in the pathophysiology of psoriasis. Selective inhibitors of TYK2 may be effective in treating psoriasis. METHODS We conducted a phase 2, double-blind trial of a TYK2 inhibitor, BMS-986165, in adults with moderate-to-severe psoriasis, excluding patients with a previous lack of response to agents targeting cytokine signaling through the same tyrosine kinase pathway. Patients were randomly assigned to receive the drug orally at a dose of 3 mg every other day, 3 mg daily, 3 mg twice daily, 6 mg twice daily, or 12 mg daily or to receive placebo. The primary end point was a 75% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 12 (higher scores indicate greater severity of psoriasis). RESULTS A total of 267 patients received at least one dose in an intervention group of the trial. At week 12, the percentage of patients with a 75% or greater reduction in the PASI score was 7% (3 of 45 patients) with placebo, 9% (4 of 44 patients) with 3 mg of BMS-986165 every other day (P = 0.49 vs. placebo), 39% (17 of 44 patients) with 3 mg daily (P<0.001 vs. placebo), 69% (31 of 45 patients) with 3 mg twice daily (P<0.001 vs. placebo), 67% (30 of 45 patients) with 6 mg twice daily (P<0.001 vs. placebo), and 75% (33 of 44 patients) with 12 mg daily (P<0.001 vs. placebo). There were three serious adverse events in patients receiving the active drug, as well as one case of malignant melanoma 96 days after the start of treatment. CONCLUSIONS Selective inhibition of TYK2 with the oral agent BMS-986165 at doses of 3 mg daily and higher resulted in greater clearing of psoriasis than did placebo over a period of 12 weeks. Larger and longer-duration trials of this drug are required to determine its safety and durability of effect in patients with psoriasis. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT02931838.).

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DO - 10.1056/NEJMoa1806382

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JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 14

ER -

Phase 2 trial of selective tyrosine kinase 2 inhibition in psoriasis

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