Rationale and Early Clinical Data on IL-17 Blockade in Psoriasis

Steven M Nwe; Amanda H Champlain; Kenneth B Gordon

Disclosures

Expert Rev Clin Immunol. 2013;9(7):677-682. 

In This Article

Clinical Validation of the Role of the IL-23/Th17 Pathway in Psoriasis

The validation of this pathway has, in large part been a result of the successful use of specifically targeted biologic therapy against cytokines involved in the IL-23/TH17 pathway for the treatment of psoriasis. Psoriasis lends itself well to the study of various cytokine-targeted biologic therapies as clinical response to therapy can be evaluated visually and for the most part, noninvasively. The Psoriasis Area and Severity Index (PASI) is an efficacy measurement that combines the body surface area involvement of four regions of the body (head, trunk, upper extremities and lower extremities) and the severity of erythema, induration (plaque thickness) and desquamation (or scale) to calculate a score ranging from 0 to 72.[47] It is the most frequently used end point measure in psoriasis, and the PASI75 refers specifically to a 75% reduction in PASI score over time. This tool has helped to visually quantify the efficacy of biologic targets for use in psoriasis and have helped to illustrate the role of the IL-23/Th17 pathway in the immunopathogenesis of psoriasis.

TNF-α inhibitors including adalimumab, etanercept and infliximab remain the most common targeted therapy for patients with moderate to severe plaque psoriasis.[48] Their successful use in psoriasis has also driven further studies to test targets along the same pathway. Ustekinumab, an antibody targeting the IL-12p40 subunit common to both IL-12 and IL-23 cytokines has also met with success. Phase III trials of ustekinumab found that patients treated with the drug at 45 or 90 mg for 12 weeks achieved a PASI75 of 67 and 76%, respectively, compared with 4% in the placebo group.[49] Additional studies comparing TNF-α-directed therapies (in this case etanercept) against ustekinumab showed increased efficacy in the ustekinumab group.[50] While these data are definitely promising, not all therapeutics for psoriasis have met with completely positive results. Briakinumab, a monoclonal antibody also targeting the IL-12p40 subunit, proved superior to both etanercept and methotrexate in Phase III trials.[51–54] However, the data also linked the drug to a potential increase in major cardiovascular adverse events (MACE). A total of 5 MACE occurred in the briakinumab treated group versus zero in the placebo group. Although a meta-analysis of both ustekinumab and briakinumab Phase II and III trials failed to show a statistically significant increases in major cardiovascular adverse events, the withdrawal of briakinumab FDA and EMA approval by the pharmaceutical sponsor has raised very important issues of the risk:benefit ratios of current and future biologic therapies.[55] It also highlighted the very real possibility that while biologic therapies attempt to target specific points of the pathway, and in doing so target key body systems (in this case, the skin), they may also affect other body systems, oftentimes in a negative way.

The relative success of therapies targeting the IL-23/Th17 has not stopped investigators from continuing to hone in on therapeutic targets within the system that will maximize the therapeutic benefit while minimizing side effects. Not only would successful use of such biologics help further validate the current theory of psoriasis pathogenesis, but it would provide an additional therapeutic modality available to those suffering from the disease itself. One of the more promising targets recently has been the point of contact between IL-17 and the IL-17 receptor. Murine models have observed that IL-17 receptor deficient mice are less likely to develop laboratory-induced psoriasis-like lesions than their counterparts.[56] In addition, while IL-22 and the IL-17 family are both common to the Th17 pathway, there is evidence that they have distinctive roles, with IL-17 being implemented in its proinflammatory effects.[44] Early positive trials testing the efficacy of IL-17 blockade in key inflammatory diseases similar to psoriasis have also driven further studies, while two studies looking at the efficacy of IL-22 blockade in the treatment of psoriasis failed to meet primary end points and were terminated.[39,57,58] Currently, three different drugs that attempt to modify the interaction of IL-17 and its receptor are being tested for clinical efficacy in the moderate to severe plaque psoriasis population: brodalumab, ixekizumab and secukinumab.

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