RALEIGH, N.C. – At 2 weeks after psoriasis patients received their first dose of the investigational interleukin-17 inhibitor ixekizumab, their gene expression pattern resembled that of healthy controls.
At the annual meeting of the Society for Investigative Dermatology, Dr. James G. Krueger presented a translational medicine study aimed at defining the impact that turning off IL-17 signaling has on pathological tissue structures, molecular pathways, and biomarkers.
Dr. James G. Krueger
His conclusion: "I think these data suggest IL-17 is the central cytokine driving pathogenesis in psoriasis," said Dr. Krueger of Rockefeller University in New York.
Eight psoriasis patients received a subcutaneous 150-mg dose of ixekizumab at weeks 0, 2, and 4 and underwent skin biopsies at weeks 0, 2, and 6. He compared their inflammatory gene expression profiles 2 weeks into treatment vs. those obtained from 15 psoriasis patients 2 weeks after beginning treatment with etanercept (at 50 mg twice weekly for 12 weeks).
IL-17 blockade with ixekizumab proved to have a greater impact on the expression of inflammatory genes known to be associated with psoriasis than did tumor necrosis factor inhibition via etanercept. Ixekizumab resulted in greater-than-75% normalization of expression of 643 of these inflammatory genes, compared with 104 with etanercept.
The structural result of IL-17 blockade was reversal by week 6 of the epidermal hyperplasia that is the hallmark of psoriasis, he added.
Two of the eight patients on the ixekizumab 150-mg regimen achieved PASI 75 (that is, a 75% improvement from baseline on the Psoriasis Area and Severity Index) in 2 weeks. That’s remarkably fast improvement, Dr. Krueger noted. By week 6, all eight patients had achieved PASI 75.
Another point in favor of IL-17’s being a central cytokine driving psoriasis is that ixekizumab shut down not only the IL-17A target genes downstream, but also genes controlling the production of key cytokines located upstream, including interferon-gamma and IL-22, he noted.
Phase III trials investigating ixekizumab for psoriasis are underway. The drug is also being investigated for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.
Dr. Krueger is a consultant to Eli Lilly, which funded the study and is developing ixekizumab as a treatment for psoriasis.