Translation of IL-17 inhibition into clinical practice

There is currently an unmet need in the treatment of SpA [39]. Traditional disease-modifying antirheumatic drugs (e.g., methotrexate) are ineffective in spinal inflammatory arthritis and AS. While the TNF-α inhibitors etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab have all demonstrated efficacy in AS and PsA, a substantial proportion of patients either do not respond at all or respond inadequately, while some patients are unable to tolerate these drugs [15, 39–41]. In recent years, other therapies used to treat RA have been investigated in AS, including the IL-1 receptor antagonist anakinra, the IL-6 inhibitor tocilizumab, the anti-CD20 antibody rituximab, and the costimulatory pathway inhibitor abatacept. However, none of these agents have demonstrated a meaningful clinical benefit in patients with AS [41].

It has been recognized that biologic agents with mechanisms of action other than TNF inhibition, which acts upstream of newer agents, would provide valuable alternatives for the treatment of SpA. However, until very recently there was a lack of alternatives to TNF-α inhibitors [39]. That changed with the approval of the IL-12/IL-23 antagonist ustekinumab, the phosphodiesterase 4 inhibitor apremilast, and the IL-17A inhibitor secukinumab for the treatment of PsA, and with the approval of secukinumab for the treatment of AS. Now, when patients fail to respond to one biologic due to lack of efficacy or poor tolerability, switching to another biologic with a different mechanism of action can be an effective treatment strategy [42, 43].

When choosing a biologic agent in SpA, it is reasonable to consider preclinical findings that support the mechanistic rationale for targeting IL-17A. IL-17A seems to be a more downstream effector of SpA pathogenesis than other cytokines (i.e., IL-23, TGF-β, IL-6, and IL-1β), which act upstream to trigger differentiation of Th17 cells in entheses and synovial tissue. Once activated, these Th17 cells stimulate production of downstream effector cytokines including IL-17 and IL-22, which contribute to inflammation, bone erosion, and bone fusion [2, 7, 9, 12, 27, 28, 33]. In addition to the good efficacy observed in SpA with this strategy, such downstream targeting may also be beneficial for patients with refractory SpA and those who are otherwise intolerant to other biologic therapies.

As clinical development programs for IL-17A inhibitors have progressed, findings from large-scale randomized controlled trials have supported the translation of IL-17A inhibition in SpA from bench to bedside. Positive findings have been observed in clinical studies of IL-17A inhibitors in psoriasis, PsA, and AS [44–49].

The IL-17A inhibitor secukinumab is approved for the treatment of moderate-to-severe plaque psoriasis. In phase 3 clinical studies, secukinumab consistently provided substantial meaningful improvements in the signs and symptoms of moderate-to-severe chronic plaque psoriasis [44, 49]. In the pivotal ERASURE and FIXTURE studies, more than half of patients who received secukinumab 300 mg experienced a 90% improvement in Psoriasis Area and Severity Index (PASI90) scores at week 12, compared with 1% with placebo (ERASURE) and 21% with etanercept (FIXTURE) [44]. In the CLEAR phase 3 study, secukinumab 300 mg demonstrated superiority compared with ustekinumab for the primary endpoint of PASI90 at week 16 (79.0% vs 57.6% response rates, respectively; p < 0.0001) [49].

The IL-17A inhibitor ixekizumab was recently approved for the treatment of moderate-to-severe plaque psoriasis. In the UNCOVER-2 and UNCOVER-3 randomized controlled phase 3 studies, up to 71% of patients treated with ixekizumab achieved PASI90 at week 12, compared with 0.6% to 3.1% with placebo, and 18.7% to 25.7% with etanercept [45].

The anti-IL-17RA monoclonal antibody brodalumab was in late-stage development for the treatment of moderate-to-severe plaque psoriasis. Results of the phase 3 AMAGINE-1 study showed that, at week 12, PASI90 was achieved by 43% of patients treated with brodalumab 140 mg and by 70% of patients treated with brodalumab 210 mg, compared with 1% of patients in the placebo group [50]. In the AMAGINE-2 and AMAGINE-3 studies, brodalumab 210 mg demonstrated higher efficacy compared with ustekinumab based on week 12 PASI90 responses (70% vs 47% in AMAGINE-2, and 69% vs 48% in AMAGINE-3) [51]. However, the future of brodalumab development is uncertain based on observed events of suicidal ideation and behavior during clinical development [52].

In early 2016, secukinumab received US Food and Drug Administration (FDA) approval for the treatment of active PsA. In the large-scale FUTURE 1 and FUTURE 2 phase 3 studies, patients received placebo or intravenous (IV) or subcutaneous (SC) induction dosing of secukinumab followed by SC maintenance dosing [46, 48]. At week 24 in FUTURE 1, at least 20% improvement in American College of Rheumatology response criteria (ACR20) responses were observed in 50% of patients receiving secukinumab 150 mg, 51% receiving secukinumab 75 mg, and 17% of patients receiving placebo (p < 0.001 for both comparisons with placebo) [48]. At week 24 in FUTURE 2, which had a mixed population of TNF-naive and TNF-experienced patients, ACR20 was achieved by 54% of patients receiving secukinumab 300 mg (p < 0.0001), 51% receiving secukinumab 150 mg (p < 0.0001), 29% receiving secukinumab 75 mg (p = 0.0399), and 15% of patients receiving placebo [46]. These improvements were sustained through 52 weeks of treatment [46, 48].

In the phase 3 SPIRIT-P1 trial of a TNF-naive population, significantly more patients achieved ACR20 with ixekizumab 80 mg once every 2 weeks (62%) and ixekizumab 80 mg once every 4 weeks (58%) than with placebo (30%; both p ≤ 0.001) [53]. A clinical trial of ixekizumab in biologic-experienced patients with active PsA is ongoing ({"type":"clinical-trial","attrs":{"text":"NCT02349295","term_id":"NCT02349295"}}NCT02349295).

Secukinumab also recently received FDA approval for the treatment of active AS. In a randomized, double-blind, phase 2 study, 59% of patients treated with secukinumab achieved rapid, meaningful clinical improvement in AS symptoms compared with 24% of patients who received placebo [54]. These improvements were maintained for up to 2 years in patients who continued in an open-label extension of this study [55]. The benefits of secukinumab in patients with AS were confirmed in the phase 3 MEASURE 1 and MEASURE 2 studies [47]. In these randomized controlled trials, patients received placebo, or IV or SC loading doses of secukinumab followed by SC maintenance dosing. In MEASURE 1 and MEASURE 2, respectively, at least 20% improvement in Assessment of SpondyloArthritis International Society (ASAS20) response rates at week 16 were 61% in both studies in the secukinumab 150 mg group, 60% and 41% in the secukinumab 75 mg group, and 29% and 28% for patients who received placebo [47]. Improvement in signs and symptoms of AS occurred rapidly with secukinumab and were sustained over time. Secukinumab was also associated with improvements in physical functioning and health-related quality of life compared with placebo [47].

Studies of ixekizumab in biologic treatment-naive (COAST-V) and treatment-experienced (COAST-W) patients with AS are ongoing ({"type":"clinical-trial","attrs":{"text":"NCT02696785","term_id":"NCT02696785"}}NCT02696785 and {"type":"clinical-trial","attrs":{"text":"NCT02696798","term_id":"NCT02696798"}}NCT02696798).

As suggested by basic research studies characterizing the different roles of IL-17A in RA and SpA [38], results from clinical studies of IL-17A inhibitors in RA indicate that these agents may have limited therapeutic efficacy in this patient population [56, 57]. In separate phase 2 studies of secukinumab and ixekizumab in patients with RA, ACR20 response rates differed across the dose ranges studied, without a consistent dose–response relationship [56, 57]. In a 16-week phase 2 study of secukinumab, ACR20 response rates ranged from 36% to 54% in the active-treatment arms, compared with 34% with placebo [56]. In a second 52-week phase 2 study of secukinumab, ACR20 response rates were not significantly different between secukinumab and placebo (42.9% vs 40.9%), but significant improvements were observed in the secukinumab arm based on 28-joint Disease Activity Score (DAS28), global assessments of disease activity, pain assessments, and high-sensitivity C-reactive protein levels [58].

Among biologic treatment-naive patients in a phase 2 study of ixekizumab, ACR20 response rates ranged from 43% to 70%, compared with 35% for placebo. In this study, ACR20 response rates were significantly higher with ixekizumab 80 mg and 180 mg compared with placebo for patients with prior inadequate response to TNF-α inhibitors [57]. Patients in this study were eligible to enter a 48-week open-label extension. Patients in the extension who experienced clinical improvements during the initial 16-week study generally maintained these improvements through week 64 [59].

Based on findings from these phase 2 studies, it cannot be ruled out that a subset of patients with RA may experience clinical benefits from treatment with IL-17A inhibitors. However, a recent study investigating the relationship between genetic biomarkers and secukinumab treatment response in patients with RA found that the human leukocyte antigen (HLA)-DRB1*04 and HLA-DRB1* shared epitope allelic groups were not predictive of treatment response [60].

IL-17A inhibitors have been shown to have good overall safety profiles [61]. In psoriasis clinical trials, secukinumab’s side-effect profile was similar to that of the TNF-α inhibitor etanercept and the IL-12/IL-23 antagonist ustekinumab, with no safety signals indicating an increased risk for serious adverse events of interest, including malignancy, infection, or induction of autoimmune diseases [44, 49]. In placebo-controlled studies of secukinumab in PsA and AS, the incidence and types of adverse events were similar between secukinumab and placebo, with a small increased risk for infections, including candidiasis [46–48]. Similarly, in the UNCOVER-2 and UNCOVER-3 psoriasis clinical studies, rates of serious adverse events were low and similar with ixekizumab and etanercept, and a small number of Candida infections were reported [45].