Anti-IL-23 Phase II Data for Psoriasis: A Review
October 2015 | Volume 14 | Issue 10 | Original Article | 1093 | Copyright © October 2015
Kourosh Beroukhim BS,a Melissa J. Danesh BS,b Catherine Nguyen BS,c Annemieke Austin MD,b John Koo MD,b and Ethan Levin MDb
aDepartment of Dermatology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA
bDepartment of Dermatology, University of California, San Francisco School of Medicine, San Francisco, CA
cDepartment of Dermatology, University of California, Irvine School of Medicine, Irvine, CA
BACKGROUND: Monoclonal antibodies that target both Interleukin (IL)-12 and IL-23 have shown great efficacy in the treatment of psoriasis.
Recent evidence suggests that IL-23 serves a more critical role than IL-12 in the pathogenesis of psoriasis, leading to the development
of monoclonal antibodies that specifically target IL-23.
METHODS: We reviewed the results of the phase II clinical trials for the anti-IL-23 agents tildrakizumab and guselkumab, in order to assess
the efficacy and safety profile of each agent.
RESULTS: By week 16, the proportion of patients achieving Physician Global Assessment (PGA) score of clear (0) or minimal (1) and Psoriasis Area and Severity Index (PASI 75) was above 70% among the most efficacious dosage of each agent (P< 0.001 compared to placebo for all agents). The safety profiles of the agents were similar, with the most frequently reported adverse events of nasopharyngitis,
upper respiratory infections, cough, and headache.
CONCLUSION: The anti-IL-23 agents demonstrated a rapid clinical improvement and favorable short-term safety profile. The results of the phase II trials support IL-23 as an essential target in psoriasis treatment. J Drugs Dermatol.
Psoriasis is a common immune-mediated skin disorder, estimated to affect 3-4% of the United States population.1 The pathogenesis of psoriasis is a multifactorial, resulting
from a combination of genetic susceptibility and environmental
or endogenous triggers. The majority of genes implicated
in the etiology of psoriasis involve components of the cutaneous inflammatory cascade.2,3 Key cytokines involved in the pathogenesis of psoriasis include tumor necrosis factor alpha
(TNFa), interleukin (IL)-12, IL-22, IL-17, and IL-23.2,4-7
The IL-12 family of cytokines comprises four heterodimeric cytokines
that share sequence homology.8 These include IL-12, which is composed of the p35 and p40 subunits, and IL-23, which is composed of the p19 and p40 subunits.8 Prior to the identification
of IL-23, the abundance of the p40 subunit mRNA in psoriatic lesions led to the initial theory that IL-12 was the key cytokine in driving psoriasis pathogenesis.9 This belief was further corroborated
by the clinical efficacy of ustekinumab, a p40 subunit antibody that was thought to improve psoriasis severity by inhibiting
IL-12 activity.9 Following the discovery of IL-23, it became apparent that ustekinumab also targets IL-23, which shares the p40 subunit with IL-12.9 Mounting evidence since then suggests that IL-23 serves a more critical role than IL-12 in the cutaneous inflammatory cascade leading to the clinical manifestation of psoriasis.6,8,10-14 Of note, there is an elevation of mRNA levels of both IL-23 subunits (p19 and p40) in psoriasis lesions compared to nonlesional skin, whereas there is no rise in mRNA levels of
p35, which is unique to IL-12.10,15-18 This implies that IL-23 is more important than IL-12 in the pathogenesis of psoriasis.
IL-23 is a cytokine primarily produced by activated CD11c+ dendritic cells in the skin. IL-23 induces naïve T cell differentiation
into TH17 cells, which subsequently release IL-17A, IL-17F, and IL-22, among other cytokines. These cytokines then act on keratinocytes to promote changes culminating in the clinical manifestation of psoriasis.19 The observations that IL-23 protein expression is upregulated in psoriatic lesions, and that the IL-23 pathway is independently sufficient to drive the psoriasis phenotype,
suggest that IL-23 is critical to the pathophysiology of psoriasis.16,19,20
According to surveys conducted by the National Psoriasis Foundation
between 2003 and 2011, a significant portion of patients with psoriasis remain undertreated relative to the severity of their disease, leading to high dissatisfaction rates among patients. 21-23 Thus, there is a need for new therapies with enhanced long-term efficacy and safety profiles that provide additional options, especially to patients with generalized psoriasis. The newest biologic agents are targeted IL-23 pathway inhibitors, two of which are currently in phase III clinical trials. Tildrakizumab,
a humanized, monoclonal antibody, and Guselkumab, a fully human monoclonal antibody, both act to neutralize IL-23 by targeting the unique p19 subunit of the cytokine.24 In the following article, we will review the results of the pivotal phase