Secukinumab was the first IL-17A inhibitor approved in 2015 for treatment of patients with psoriasis, and about one year later secukinumab was also approved for PsA. It is a fully human anti-IL-17A IgG1 monoclonal antibody that selectively binds and neutralizes IL-17A. The IL-17 cytokine family comprises six members, IL-17A-F. Both IL-17A and IL-17F are secreted by Th17-cells and other immune cells, as described previously. Interleukin-17A is about 10–30-fold more potent than IL-17F, whereas the IL-17A/IL-17F heterodimer has intermediate activity [98
In phase III studies, the proportion of patients who achieved PASI75 at week 12 was 75.9–86.7% with secukinumab 300 mg (administered once weekly for 4 weeks starting at week 0, then every 4 weeks) and 0–4.9% with placebo [99
]. A post-hoc analysis including Japanese patients only, showed similar responses [99
]. Head-to-head studies demonstrated secukinumab to be superior compared with both etanercept and ustekinumab [99
]. Although the difference in PASI75 response was only small for the comparison of secukinumab to ustekinumab. Contrary, the difference was more pronounced when measuring the proportion of patients achieving a ≥PASI90 response [102
]. After 52 weeks of treatment, the proportions of patients (secukinumab versus ustekinumab) with a PASI90 response were 76% versus 61% and the proportions with a PASI100 response were 46% versus 36% [102
]. Already at week 1, PASI75 response rates were significantly higher for secukinumab compared with ustekinumab, and at week 4 the proportion of patients achieving PASI75 with secukinumab was 50.0% compared with 20.6% with ustekinumab [102
Conclusively, compared with older biologics, secukinumab has a faster onset of action. The drug is highly effective, and compared with ustekinumab, secukinumab has higher PASI90—and PASI100 response rates.
Pooled safety data from 10 phase II and phase III studies have shown that secukinumab was comparable to etanercept over 1 year. An exception was a higher rate of uncomplicated mucocutaneus candida infections in patients treated with secukinumab compared with etanercept [104
Ixekizumab is a humanized IgG4 anti-IL-17A monoclonal antibody, which like secukinumab neutralizes IL-17A. FDA approved ixekizumab for treatment of psoriasis in 2016 [105
]. Ixekizumab is not yet approved for PsA, but is undergoing clinical development [106
Results from two independent phase III studies in psoriasis were reported in the same publication, and showed similar results. PASI75 responses reported for the treatment regimen of ixekizumab 160 mg as starting dose followed by 80 mg every 2 weeks were 87.3% and 89.7% at week 12 (for some patients, effect was seen as early as week 1), and was significantly higher than both placebo (7.3% and 2.4%) and treatment with etanercept (53.4% and 41.6%). Results on PASI90 and PASI100 were also significantly higher compared with placebo and etanercept ((PASI90: ixekizumab = 68.1% and 70.7%; placebo = 3.1% and 0.6%; etanercept = 25.7% and 18.7%), (PASI 100: ixekizumab = 37.1% and 40.5%; placebo = 0% and 0.6%; etanercept = 7.3% and 5.3%)) [30
]. Combined long-term data from the two phase III studies (UNCOVER 2 and 3) as well as a third phase III study (UNCOVER 1) were published in 2016, and showed in general that >70% maintained treatment responses (PASI75 responses for UNCOVER 1 and 2 and PASI90 responses for UNCOVER 3) up to week 60 with ixekizumab 80 mg every 4 weeks as extension dose [108
]. In Japanese patients with psoriasis results from a phase III study on ixekizumab have been even better. However, the study was only based on 78 patients with moderate to severe psoriasis, and designed as an open-label study with no placebo or control group. After 12 weeks of treatment almost all patients achieved PASI75 (98.7%) and 83.3% achieved PASI90 [109
]. Results from an extension of this study showed that at week 52, 92.3% had a PASI75 response and 80.8% had a PASI90 response [110
More sub-analyses that underline the effectiveness and usability of ixekizumab have been conducted on the basis of the former phase III trials and published separately: High treatment response has been demonstrated after switching to ixekizumab in etanercept non-responders [111
]. The difficult to treat psoriasis areas, hands and feet, were improved by treatment with ixekizumab [112
]. Treatment with ixekizumab has also been shown to improve patient-reported work productivity, measured by the Work Productivity and Activity Impairment Psoriasis score [113
Safety data is available from seven phase I-III studies of patients treated with ixekizumab (12-week induction period and 60 weeks of maintenance). In the first 12-week period comparison with etanercept was eligible and showed similar safety profile, but with a higher frequency of uncomplicated mucocutaneus candida infections. Also, the exposure-adjusted incidence rate of injection site pain was higher in patients treated with ixekizumab every two weeks compared with etanercept. The maintenance period showed no unexpected safety issues [114
The IL-17 receptor family comprises five receptor subunits IL-17RA–IL-17RE. Brodalumab is a fully human anti-IL-17RA IgG2 monoclonal antibody and thereby blocks IL-17 family members that act via IL-17RA, including IL-17A, IL-17A/F, IL-17F, IL17-C, and IL-17E (IL-25) [115
]. Like IL-17A, IL-17F has been ascribed a pro-inflammatory role in psoriasis, e.g., through induction of IL-6 and IL-8 in keratinocytes and regulation of CCL20 and human beta-defensin-2 [117
]. Expression of IL-17C, but not IL-25, is increased in psoriatic lesions, which indicates a less important role for IL-25 in psoriasis [116
Compared with secukinumab and ixekizumab that target IL-17A alone, the ability of brodalumab to block the effects of more IL-17 cytokines involved in psoriasis by interacting with IL-17RA may contribute to higher efficacy. However, no head-to-head studies have been conducted for the comparisons of brodalumab against secukinumab or ixekizumab.
Three phase III studies have been completed (AMAGINE 1–3), where results from AMAGINE 2 and 3 were published together. At week 12, the proportion of patients achieving a PASI75 response with brodalumab 210 mg every other week (2 doses on week 1) was very similar among the three phase III trials, 83–86%, versus placebo 3–8% [121
]. Efficacy compared with ustekinumab was measured at the level of a PASI100 achievement at week 12, and was significantly in favor of brodalumab (PASI100: brodalumab, AMAGINE 2 and 3: 44% and 37%. Ustekinumab, AMAGINE 2 and 3: 22% and 19%). Patients receiving brodalumab were re-randomized after the initial 12 weeks to four different dosing regimens (patients were stratified on i.a. response at week 12), where inadequate responders received rescue therapy from week 16 with brodalumab 210 mg every other week. In AMAGINE 2 and 3, 90% and 91% respectively, remained in the study at week 52. Treatment with the highest dose of brodalumab, 210 mg every other week, from week 12 to 52 (including placebo switched to treatment), >60% had a static PGA score of 0 or 1 (clear or almost clear skin) at week 54 (missing data and patients with inadequate response were imputed as non-responders) [121
]. There was no significant difference in adverse events and severe adverse events compared with placebo or ustekinumab, however mucocutaneus candida infections were more often seen in patients receiving brodalumab compared with ustekinumab and placebo [121
In Japanese patients a phase II randomized, placebo-controlled study have been conducted with a PASI75 response of 94.6% at week 12 [123
In AMAGINE 1 and 2, two patients in each study committed suicide while on brodalumab [121
]. Because events of suicidal ideation and behavior were registered in the clinical trials with brodalumab, additional monitoring for suicidal ideation and depression were implemented as wells as a retrospective data review. A total of six patients committed suicide during the clinical trial program (including trials for PsA and rheumatoid arthritis). A FDA advisory committee was set up to bring light upon the concern about a causative relation between brodalumab and suicide. The committee emphasized the fact that among patients with psoriasis, baseline prevalence of depression was increased, and compared with the general population individuals with psoriasis have higher hazard ratios for depression, anxiety, and suicidality. It was also mentioned, that in the clinical studies, patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiated the brodalumab program from most other biologic studies in psoriasis. No biological mechanism has been described for an association between brodalumab and development of suicidal behavior.
In February 2017, brodalumab was approved by the FDA. However, because of the observed cases of suicidal ideation and behavior, the label includes a boxed warning. Furthermore, the drug is only available through a restricted program under a Risk Evaluation and Mitigation Strategy called the Siliq REMS Program. This program ensures that both pharmacies, prescribers and patients are informed about the risk of depression and suicidality and the preventive strategy if symptoms occur [124
]. However, in 2016 brodalumab had already received approval in Japan, and in May 2017 the European Medical Agency has recommended the approval of brodalumab without remarks to the European Commission [125
Il-17 inhibitors are all highly effective treatments for psoriasis with a rapid onset of action. So far, no head-to-head studies have been conducted to compare the three IL-17 inhibitors on the market. In terms of safety, they are all labeled with an increased risk of infection, most frequently mild infections (e.g., upper respiratory tract infection and candida infections). Manageable mucocutaneous candida infection is associated with all the IL-17 inhibitors, which is probably due to the key role of IL-17 in the host defense against fungi [127
]. Like TNF-α inhibitors and ustekinumab, it is recommended to screen patients for and treat latent TB before initiating therapy with an IL-17 inhibitor. There have been no results so far from clinical studies, that indicate an association between IL-17 inhibitors and development of active TB. However, the relationship is difficult to examine from these studies, as patients with active TB were excluded and latent TB was treated before initiating treatment with an IL-17 inhibitor [129
Neutropenia was observed in patients receiving an IL-17 inhibitor, which is in accordance with previous studies that indicate IL-17 to play a role in the regulation of peripheral neutrophils [130
]. In patients treated with secukinumab for a 52-week period, 77% of newly developed or worsening neutropenia was grade 1 [104
]. In patients treated with ixekizumab week 0–60, 8.6% developed grade 1 neutropenia [108
]. In addition, in patients treated with brodalumab week 0–52, 0.4 per 100 patient-years developed grade 1 or 2 neutropenia [122
]. For all the three IL-17 inhibitors, grade 3 and 4 neutropenia were rare (0–0.5%). Neutropenia was often seen to resolve and was generally not associated with concurrent infection.
A warning about an association between the IL-17 inhibitors and exacerbation of existing Crohn’s disease has also been included in the labels.
Brodalumab is labeled with relatively more frequent, but mild adverse events compared with secukinumab and ixekizumab, including arthralgia, headache, fatigue, and oropharyngeal pain [131
One phase III study examining effect and safety of brodalumab in patients with PsA was terminated due to sponsors decision (www.clinicaltrial.gov
accessed June 2017: NCT02029495). Another phase III study has been completed, but results have not yet been published (www.cinicaltrial.gov
accessed June 2017: NCT02024646).
Only limited long-term safety data is available for the IL-17 inhibitors and so post-marketing surveillance should be performed for any adverse events associated with the use of these new biologics.