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Clinical improvement in psoriasis with specific targeting of interleukin-23

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Abstract

Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being1,2,3. The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg−1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg−1 group and 13 out of 14 subjects in the 10 mg kg−1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

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Figure 1: Tildrakizumab rapidly provides clinical benefit to moderate-to-severe psoriasis patients.
Figure 2: Tildrakizumab resolves altered epithelium in psoriasis patients.
Figure 3: Representative haematoxylin and eosin photomicrographs of sections from lesional and non-lesional skin.
Figure 4: Tildrakizumab diminishes the elevated dermal infiltrate in psoriatic skin.
Figure 5: Identification of IL-23p19-producing cells in psoriatic lesions.
Figure 6: Tildrakizumab inhibits IL-23-associated psoriatic skin gene expression.

Change history

  • 13 May 2015

    A second affiliation was added for author T.K. and affiliations were renumbered accordingly.

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Acknowledgements

The authors thank E. Marcantonio (Merck & Co., Inc.) for his supervision of research and review of this manuscript and J. Pawlowski (Merck & Co., Inc) for editorial and administrative assistance with this manuscript. This study was funded by Merck & Co., Inc.

Author information

Authors and Affiliations

Authors

Contributions

All authors provided substantive suggestions and critically reviewed the manuscript. T.K., E.R., C.B., A.M., E.P.B. and S.K. wrote sections of the initial draft. T.K., E.R., C.B., E.P.B., H.K., T.K.M., A.S.Z., W.M.B., X.S.H., D.M. and S.K. collected/assembled data and/or performed or supervised analyses. T.K., A.H., D.X. and X.S.H. were involved in the design and planning of the study.

Corresponding author

Correspondence to Sauzanne Khalilieh.

Ethics declarations

Competing interests

T.K. and H.K. and E.R. received research support from Merck & Co., Inc. E.R. received travel support from Merck & Co., Inc., and speaker’s fees, travel support, or served on advisory boards for AbbVie, Novartis, Pfizer, Janssen and Amgen. C.B. received travel support from Merck. C.Z. has served as a scientific consultant for Abbvie, Pfizer, Janssen-Cilag, Merck & Co., Inc., Eli Lilly, Takeda and Novartis and clinical study investigator for AbbVie, Amgen, Eli Lilly, Merck & Co., Inc., Takeda and Novartis. T.M. is an employee of Orlando Clinical Research Center, which was contracted by Merck to conduct the trial. E.P.B., A.H., W.M.B., T.K.M., D.X., X.S.H., A.M., A.S.Z., D.M., F.V.A. and S.K. are current or former employees of Merck & Co., Inc, and may own Merck stock. C.B. and E.G. have no competing interests.

Extended data figures and tables

Extended Data Figure 1 Tildrakizumab binds to IL-23, but not IL-12.

a, b, Biacore sensorgrams showing the 37 °C binding kinetics of human IL-23 (a) and human IL-12 (b) to immobilized tildrakizumab as a threefold dilution series from 0.091 to 22.2 nM. The association phase was measured for 220 s followed by a dissociation phase measurement for 1,800 s. The affinity of tildrakizumab for IL-23 is 300 pM.

Extended Data Figure 2 Study flow chart.

Extended Data Table 1 Baseline patient demographics
Extended Data Table 2 Subjects on tildrakizumab who achieved PASI75 and PASI90 on day 112
Extended Data Table 3 Summary of adverse events occurring in 2 or more subjects within a treatment group
Extended Data Table 4 Summary of serious adverse events
Extended Data Table 5 The histopathologic psoriasis severity score
Extended Data Table 6 Antibodies used for immunohistochemistry and immunofluorescence

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Kopp, T., Riedl, E., Bangert, C. et al. Clinical improvement in psoriasis with specific targeting of interleukin-23. Nature 521, 222–226 (2015). https://doi.org/10.1038/nature14175

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