Interleukin Inhibitors in Brief

February 25, 2015

Agents that target the TH17-interleukin pathway show promise in psoriatic arthritis, as alternatives for patients who don't benefit from TNFα blockers. This slide show describes their mode of action and potential.

Interleukin inhibitors, especially those targeting IL-17 and IL-23, show promise as alternatives in treating psoriatic arthritis. These slides summarize their actions and their clinical potential, with hyperlinks to the relevant publications in the captions.

Two agents that target the interleukin pathway (secukinumab and ustekinumab) are already approved in the US, the latter for psoriatic arthritis. More are on the way. In a recent review (see citation below), Philip Mease MD described their actions and potential. The basics are summarized in these slides, with hyperlinks to the underlying studies.
Inhibition of interleukin-17, interleukin-23 and the TH17 cell pathway in the treatment of psoriatic arthritis and psoriasis.Curr Opin Rheumatol. 2015;27(2):127-33. doi: 10.1097/BOR.0000000000000147.

TH17 cells respond to infections and fungi, releasing a range of cytokines including interleukins that trigger inflammation.

The TH17 pathway is key in the pathogenesis of psoriatic arthritis and related spondyloarthropathies. Levels of these cells correlate with disease activity.

Six agents that target the TH17 pathway are directed at psoriasis or psoriatic arthritis. Two (secukinumab and ustekinumab) have been approved by the FDA. The others (brodalumab, ixekizumab, guselkumab, and tildrakizumab) are in various stages of clinical trials.

These inhibitors of the TH17 cytokines IL17 and IL23 have good safety profiles, and may serve as first-line biologics or as second-line treatments for patients who cannot take or have not benefitted from TNF inhibitors.

The two PSUMMIT trials of the IL-23 inhibitor ustekinumab led to its FDA approval for treatment of psoriatic arthritis.
Ustekinumab, an anti-IL-12/23 p40 monoclonal antibody, inhibits radiographic progression in patients with active psoriatic arthritis: results of an integrated analysis of radiographic data from the phase 3, multicentre, randomised, double-blind, placebo-controlled PSUMMIT-1 and PSUMMIT-2 trialsAnn Rheum Dis. 2014; 73:1000-6. doi: 10.1136/annrheumdis-2013-204741

Secukinumab, an IL-17A inhibitor, is approved for treatment of psoriasis. Its approval was based on the two FUTURE trials.
Secukinumab, a Human Anti-Interleukin-17A Monoclonal Antibody, Improves Active Psoriatic Arthritis: 24-Week Efficacy and Safety Data from a Phase 3 Randomized, Multicenter, Double-Blind, Placebo-Controlled Study Using Subcutaneous Dosing>Late breaking oralpresentation at: ACR/ARHP Annual Meeting, Boston, MA, USA, 2014.

Brodalumab, which targets the IL-17 receptor, shows promise against both psoriasis and psoriatic arthritis.
Brodalumab, an AntiâInterleukin-17âReceptor Antibody for PsoriasisN Engl J Med. 2012; Mar 29;366(13):1181-9. doi: 10.1056/NEJMoa1109017.
Brodalumab, an Anti-IL17RA Monoclonal Antibody, in Psoriatic ArthritisN Engl J Med. 2014; Jun 12;370(24):2295-306. doi: 10.1056/NEJMoa1315231

Ixekizumab, another IL-17A inhibitor, is in phase 2 testing for psoriasis.
Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis.N Engl J Med. 2012; 366(13):1190-9. doi: 10.1056/NEJMoa1109997.

Guselkumab, an IL-23 blocker, has shown promise against psoriasis in Phase 1 testing.
Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasisJ Allergy Clin Immunol. 2014;133(4):1032-40. doi: 10.1016/j.jaci.2014.01.025.

Tildrakizumab, another IL-23 inhibitor, has completed dose-ranging studies against psoriasis. New and emerging therapies in psoriasisSemin Cutan Med Surg. 2014;33(2 Suppl 2):S37-41. doi: 10.12788/j.sder.0066.