Anti-IL-17 Agents for Psoriasis: A Review of Phase III Data
March 2016 | Volume 15 | Issue 3 | Original Article | 311 | Copyright © March 2016
Benjamin Farahnik BA,a Kourosh Beroukhim BS,b Mio Nakamura MD,c Michael Abrouk BS,d Tian Hao Zhu BA,e Rasnik Singh BS,b Kristina Lee BA,c Tina Bhutani MD,c and John Koo MDc
aUniversity of Vermont College of Medicine, Burlington, VT
bDavid Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA
cUniversity of California – San Francisco, Department of Dermatology, Psoriasis and Skin Treatment Center, San Francisco, CA
dUniversity of California, Irvine, School of Medicine, Irvine, CA
eUniversity of Southern California Keck School of Medicine, Los Angeles, CA
BACKGROUND: Studies investigating the molecular basis of psoriasis have established the central roles of TNFa, interleukin (IL)-12, IL-22 and IL-23, and now there is increasing evidence that IL-17 plays a vital role in the complex pathophysiology of this disease. Preclinical and phase II studies of medications targeting IL-17 and its receptor have thus far proved to be promising.
METHODS: We reviewed the results of the phase III clinical trials for the anti-IL-17 agents secukinumab, ixekizumab and brodalumab in order to assess the efficacy and safety profile of each agent.
RESULTS: By week 12, the proportion of patients reaching a 75% improvement from baseline Psoriasis Area and Severity Index (PASI 75) was comparable between the different agents (secukinumab 83%, ixekizumab 89%, and brodalumab 85%). The safety profiles of the agents were similar with the most frequently reported adverse events of nasopharyngitis, upper respiratory infections, headache, and injection site reaction.
CONCLUSION: The anti-IL-17 agents demonstrated a rapid and robust clinical improvement accompanied by a favorable short-term safety profile. The results of the phase III trials continue to reinforce the theory that the IL-17 pathway is an essential target in psoriasis treatment.
J Drugs Dermatol.
Psoriasis is a common chronic inflammatory skin condition that affects 3-4% of the adult United States population. 1 The pathogenesis of psoriasis is multifactorial and thought to be due to a combination of genetic susceptibility, immune dysregulation, and environmental factors. The majority of genes implicated in the etiology of psoriasis include components of the cutaneous inflammatory cascade. Key cytokines involved in the pathogenesis of psoriasis include tumor necrosis factor alpha (TNFa), interleukin (IL)-12, IL-22, and IL-23. 2
There is increasing evidence that IL-17 also plays a critical part in the molecular pathway of psoriasis.3 IL-17 is a proinflammatory cytokine produced primarily by type 17 helper (TH17) T cells and is a downstream product of IL-23 4, another cytokine targeted by a currently approved biologic agent, ustekinumab.5 IL- 17 contributes to the activation and recruitment of neutrophils and the stimulation of psoriasis angiogenesis.6,7 The findings of elevated levels of IL-17 in psoriatic lesions and in the serum of patients with psoriasis further support the role of IL-17 in the pathophysiology of psoriasis. 8,9
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. 12 Untreated psoriasis is associated with severe impairment of social, occupational, and overall well-being, with physical and emotional impact that increases with disease severity.10,11 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 approved by the FDA for the treatment of psoriasis are targeted IL-17 pathway inhibitors, three of which have completed phase III clinical trials. Secukinumab, a fully human monoclonal antibody, and ixekizumab, a humanized monoclonal antibody, act by directly binding and neutralizing the IL-17A cytokine. Brodalumab is a human monoclonal antibody that decreases the downstream effect of all subtypes of IL-17 by antagonizing the IL-17 receptor. In the following article, we review the results of the pivotal phase III data regarding the efficacy and safety of these three anti-IL-17 agents in patients with moderate-to-severe plaque psoriasis.
We reviewed the published results of the phase III clinical trials for secukinumab, brodalumab, and ixekizumab in order to determine the percentage of patients with psoriasis who had a positive response to the biologic therapy (ie, achieved