6.1.4. Risankizumab

Risankizumab is expected to have quick efficacy, based on the results of the phase 1 trial during which rapid and durable clearing of skin lesions was demonstrated in Ps patients [109]. Risankizumab is a humanized IgG1 monoclonal antibody that selectively inhibits the IL-23 p19 subunit. In the head-to-head trial of risankizumab and ustekinumab for Ps patients, risankizumab demonstrated significantly greater improvement in the PASI score at week 12, and this efficacy was maintained up to week 48 [110]. In this study, a 50% reduction of VAS score caused by arthritis was also reported in both the ustekinumab and risankizumab groups.

As for PsA, a phase 2 trial demonstrated the primary end point of ACR20 response at week 16 was superior in the risankizumab-treated patients, and this efficacy was maintained at week 24 [111].

On the other hand, risankizumab demonstrated no significant effectiveness against active AS. A total of 159 patients with untreated active AS were included in the study. A roughly 40% improvement in Assessment in SpondyloArthritis International Society (ASAS40) score at week 12 was attained in 25.5%, 20.5%, and 15.0% of subjects in the 18 mg, 90 mg, and 180 mg risankizumab groups, respectively, compared with 17.5% of subjects in the placebo group [112].

#### *6.2. Anti IL-17*

#### 6.2.1. Secukinumab

Secukinumab is a fully human monoclonal IgG1 antibody that selectively inhibits IL-17A. After the phase 3 studies demonstrated its significant efficacy in 2015 [113,114], secukinumab received FDA approval for the treatment of AS and PsA in 2016. In other phase 3 trials, secukinumab also showed efficacy in delaying radiographic changes in AS patients whose illness was unable to be controlled by or was contraindicated by TNF-inhibitors [115], and a sustained, long-time efficacy in patients with AS was also reported [116,117]. With an extension of the phase 3 trial (FUTURE 2) [114], the long-term effects of secukinumab in PsA were also demonstrated [118,119]. In addition, a head-to-head comparison study of secukinumab and adalimumab involving a first-line biological monotherapy (EXCEED) trial demonstrated that the ACR 20 response at week 52 was 67% in the secukinumab group and 62% in the adalimumab group (OR, 1.30; 95%CI, 0.98–1.72; *p* = 0.0719). Although the difference was not statistically significant in terms of the ACR20 response, a higher treatment retention rate and better improvement in PASI was reported, which suggests that secukinumab is a useful option for the treatment of AS [120].

#### 6.2.2. Ixekizumab

Ixekizumab is a humanized IgG4 monoclonal antibody that neutralizes IL-17A in contrast to secukinumab, which is an IgG1 monoclonal antibody. This structural difference characterizes the higher affinity of ixekizumab to IL-17 [121]. For the treatment of Ps, ixekizumab showed a superior short-term outcome compared to secukinumab [122,123]. In a phase 3 clinical trial (SPRIT-P1) [124], ACR20 response at week 24 was superior in the ixekizumab group (60.3%) compared to placebo (30.1%), and an extension of the study revealed the long-term persistent efficacy, safety, and inhibition of radiographic progression [125]. As for the treatment of AS, ixekizumab also demonstrated a superior response of ASAS40 at week 16 compared to placebo (ixekizumab: 52%, placebo: 18%) [126]. Ixekizumab received approval by the FDA for the treatment of PsA in 2017, radiographic axial SpA in 2019, and non-radiographic axial SpA in 2020. The comparison between ixekizumab and adalimumab in the treatment of PsA demonstrated that the effects related to joint improvement in ACR20/50/70 response were comparable, but ixekizumab had a greater response for skin manifestations (PASI) [127].

#### 6.2.3. Netakimab

Netakimab (BCD-085) is a novel recombinant IgG1 anti-IL-17 monoclonal antibody with a modified complementarity determining region (CDR) and Fc-fragment, which results in a higher affinity of IL-17 to the Fab fragment of netakimab [128,129].

A phase 3 trial for PsA (NCT03598751: PATERA study) [130,131] is in progress and is expected to generate new evidence in support of the use of netakimab in SpA treatment.

#### 6.2.4. Brodalumab

IL-17 receptor (IL-17R) is a heterodimer of IL17-RA and IL-17RC. Brodalumab is a humanized IgG2 monoclonal antibody that binds to IL-17RA and inhibits IL-17A, IL-17A/F, IL-17F/F, and IL-17E [132]. A phase 2 clinical study on PsA patients demonstrated that ACR20 response rates at week 12 in the

140 mg and 280 mg brodalumab groups were 37% and 39%, respectively, as compared with 18% among the placebo group [133]. A study with brodalumab for AS was discontinued because of suicidality being one of the adverse events that developed during the trial [134] although no causal relationship between suicidality and brodalumab treatment was confirmed [135].

#### 6.2.5. Bimekizumab

Bimekizumab is a humanized IgG1 monoclonal antibody with dual neutralization effects of both IL-17A and IL-17F [136]. A phase 2b dose-ranging trial (BE ACTIVE study) [137] and one for AS (BE AGILE study) [138] demonstrated the short-term efficacy of bimekizumab for PsA. In the BE ACTIVE study, the ACR50 response at week 12 was greater in the 16 mg (27%), 160 mg (41%), and 320 mg bimekizumab (24%) groups than in the placebo group (7%) [137]. In addition, the primary end point (ASAS40 at week 12) was achieved in all of the bimekizumab-treated groups (16 mg: 29.5%, 64 mg: 42.6%, 160 mg: 46.7%, and 320 mg: 45.9%) compared with placebo (13.3%) [138].
