Icotrokinra induces early and sustained pharmacodynamic responses in phase IIb study of patients with moderate-to-severe psoriasis
David Strawn, James G. Krueger, Robert Bissonnette, Kilian Eyerich, Laura K. Ferris, Amy S. Paller, Andreas Pinter, Dylan Richards, Elizabeth Y. Chen, Kate Paget, Daniel Horowitz, Roohid Parast, Joshua J. Rusbuldt, Jocelyn Sendecki, Sunita Bhagat, Lynn P. Tomsho, Ching-Heng Chou, Marta E. Polak, Brice E. Keyes, Emily Bozenhardt, Yuan Xiong, Wangda Zhou, Cynthia DeKlotz, Paul Newbold, Dawn M. Waterworth, Megan Miller, Takayuki Ota, Ya-Wen Yang, Monica W.L. Leung, Lloyd S. Miller, Carolyn A. Cuff, Bradford McRae, Darren Ruane, Arun K. Kannan
David Strawn, James G. Krueger, Robert Bissonnette, Kilian Eyerich, Laura K. Ferris, Amy S. Paller, Andreas Pinter, Dylan Richards, Elizabeth Y. Chen, Kate Paget, Daniel Horowitz, Roohid Parast, Joshua J. Rusbuldt, Jocelyn Sendecki, Sunita Bhagat, Lynn P. Tomsho, Ching-Heng Chou, Marta E. Polak, Brice E. Keyes, Emily Bozenhardt, Yuan Xiong, Wangda Zhou, Cynthia DeKlotz, Paul Newbold, Dawn M. Waterworth, Megan Miller, Takayuki Ota, Ya-Wen Yang, Monica W.L. Leung, Lloyd S. Miller, Carolyn A. Cuff, Bradford McRae, Darren Ruane, Arun K. Kannan
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Clinical Research and Public Health Clinical Research Dermatology Inflammation

Icotrokinra induces early and sustained pharmacodynamic responses in phase IIb study of patients with moderate-to-severe psoriasis

Abstract

BACKGROUND Icotrokinra is the first and only targeted oral peptide that selectively binds the IL-23 receptor with high affinity to precisely inhibit IL-23 signaling. Icotrokinra demonstrated high rates of complete skin clearance and durable disease control in the phase IIb trial, FRONTIER-1, and its long-term extension, FRONTIER-2, in participants with moderate-to-severe plaque psoriasis. This study evaluated systemic and skin pharmacodynamic response of icotrokinra and its relationship to clinical response in FRONTIER participants.METHODS FRONTIER-1 participants received icotrokinra or placebo for 16 weeks. FRONTIER-2 followed participants for up to 1 year of treatment; placebo participants transitioned to icotrokinra after week 16. Systemic pharmacodynamic changes were assessed in serum through week 52. Skin pharmacodynamic changes were assessed using transcriptomic analysis of skin biopsies and protein quantification in tape-strip samples through week 16.RESULTS Icotrokinra dose-dependently reduced serum levels of the IL-23/IL-17 axis and psoriasis disease biomarkers through week 52, with maximal reductions observed with the highest 100 mg twice-daily dose. Proteomic analyses showed icotrokinra selectively blocked IL-23–driven inflammation without broader impacts on circulating proteins, including serum IL-23 levels. Sixteen weeks of icotrokinra, but not placebo, reduced expression of psoriasis-associated genes in lesional skin. Icotrokinra treatment also reduced psoriasis-relevant proteins in week 16 lesional skin tape-strips to levels comparable to nonlesional samples.CONCLUSION Icotrokinra induced a dose-dependent pharmacodynamic response, with early (week 4) and sustained (week 52) reductions in biomarkers of IL-23 pathway activation and psoriasis disease severity, which correlated with clinical response.TRIAL REGISTRATION ClinicalTrials.gov: NCT05223868, NCT05364554.FUNDING Johnson & Johnson.

Authors

David Strawn, James G. Krueger, Robert Bissonnette, Kilian Eyerich, Laura K. Ferris, Amy S. Paller, Andreas Pinter, Dylan Richards, Elizabeth Y. Chen, Kate Paget, Daniel Horowitz, Roohid Parast, Joshua J. Rusbuldt, Jocelyn Sendecki, Sunita Bhagat, Lynn P. Tomsho, Ching-Heng Chou, Marta E. Polak, Brice E. Keyes, Emily Bozenhardt, Yuan Xiong, Wangda Zhou, Cynthia DeKlotz, Paul Newbold, Dawn M. Waterworth, Megan Miller, Takayuki Ota, Ya-Wen Yang, Monica W.L. Leung, Lloyd S. Miller, Carolyn A. Cuff, Bradford McRae, Darren Ruane, Arun K. Kannan

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Figure 4

Protein changes in skin among participants receiving icotrokinra and placebo.

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Protein changes in skin among participants receiving icotrokinra and pla...
(A) BD-2 protein levels in skin of participants receiving icotrokinra compared with placebo at weeks 0 and 16. Comparisons of BD-2 protein levels (pg of BD-2/μg of total protein) between lesional and nonlesional skin and between week 0 and week 16 were performed using an unpaired t test. BD-2 protein levels were significantly reduced after 16 weeks of icotrokinra but not with placebo. (B–E) Protein expression measured by Olink Explore HT comparing (B) lesional versus nonlesional skin at week 0, (C) lesional skin from icotrokinra-treated participants at week 16 versus week 0, and (D) lesional skin from icotrokinra-treated participants at week 16 versus nonlesional skin at week 0. Psoriasis-relevant proteins were upregulated at week 0 in lesional skin compared with nonlesional, and they were downregulated after 16 weeks of icotrokinra, bringing protein expression to levels comparable to nonlesional skin. (E) GSVA scores of protein sets in skin of placebo- and icotrokinra-treated FRONTIER-1 participants and healthy volunteers. Skin from icotrokinra-treated participants was more similar to nonlesional than lesional skin. *Nominal P < 0.05 based on unpaired t test. (B–D) Log2 FC = 1 or –1 and adjusted P value = 0.05 thresholds are depicted with dotted lines. Enrichment statistics were based on Benjamini-Hochberg procedure. aBD-2 pg/mL: total μg/mL. bAverage of 100 mg BID and placebo (PBO) nonlesional skin at week 0. cHealthy control (HC) skin tape-strip samples were obtained from sponsor healthy donor program at Johnson & Johnson (Protocol NOCOMPOUNDNAP1001). DEFB4, defensin beta 4; BID, twice daily; NFKB, nuclear factor κB; NL, nonlesional; PI, peptidase inhibitor; RQ, relative quantification; Th, T helper cells; TNF, tumor necrosis factor; W, week.