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Do you know... Which of these drugs is a dual IL-17A/F inhibitor approved for the treatment of both PsO and PsA?
Psoriasis is a chronic, immune-mediated inflammatory disease in which dysregulation of the interleukin (IL)-23/IL-17 axis plays a pivotal role. Genetic and environmental factors trigger keratinocyte stress, initiating an inflammatory cascade that activates plasmacytoid dendritic cells (pDCs) and promotes the release of pro-inflammatory mediators.1,2 This, in turn, leads to activation of myeloid dendritic cells (mDCs) and production of IL-12, IL-23, and tumor necrosis factor (TNF)-α. IL-23 is a key driver of T helper 17 (Th17) responses and induces secretion of IL-17, which stimulates keratinocytes to release antimicrobial peptides, cytokines, and chemokines, thereby driving keratinocyte proliferation and the formation of psoriatic plaques (Figure 1).1,2
Figure 1. The role of the IL-23/IL-17 axis in the pathogenesis of psoriatic disease*
Among the six identified IL-17 isoforms, IL-17A and IL-17F are considered the most pathogenic in psoriasis.4 The interaction between IL-17A/A, IL-17A/F, and IL-17F/F cytokines, and their receptors IL-17RA and IL-17RC, drives the immune response.2 Figure 2 illustrates the therapeutic targets of biologic agents directed against the IL-17/IL-23 pathway. IL-17 pathway inhibition may be achieved through selective inhibition of IL-17A (secukinumab, ixekizumab), blockade of the IL-17RA (brodalumab), or dual inhibition of IL-17A and IL-17F (bimekizumab, sonelokimab, ORKA-002).2,5,6 IL-23 inhibitors act by targeting the shared IL-12/23 p40 subunit (ustekinumab) or the IL-23 p19 subunit (risankizumab, guselkumab, tildrakizumab, icotrokinra).2,7
Figure 2. Therapies targeting the IL-23/IL-17 axis in psoriatic disease*
Several of these biologic agents are approved by the U.S. Food and Drug Administration (FDA) for the treatment of plaque psoriasis (PsO) and psoriatic arthritis (PsA), reflecting their established efficacy and safety profiles in phase III trials (Table 1).16-38 IL-17A inhibitors such as secukinumab and ixekizumab, as well as the IL-17RA blocker brodalumab, are approved for moderate-to-severe PsO, with secukinumab and ixekizumab also indicated for PsA.8–10 The dual IL-17A/IL-17F inhibitor bimekizumab has been more recently approved for both PsO and PsA,11 while sonelokimab and ORKA-002 remain investigational.5,6 Watch a discussion by the PsOPsA Hub Steering Committee to gain further insights into the clinical implications of IL-17A/F dual inhibitors in the treatment of psoriatic disease.
Among IL-23 inhibitors, ustekinumab was the first to gain FDA approval through its dual targeting of IL‑12/23 p40,12 followed by the selective IL‑23p19 inhibitors guselkumab, risankizumab and tildrakizumab in moderate-to-severe PsO, with ustekinumab, guselkumab, and risankizumab also approved for the treatment of active PsA.13–15 Emerging agents like icotrokinra are undergoing clinical development, underscoring the continued evolution of targeted therapy within the IL-23/IL-17 axis.
Table 1. Efficacy of FDA-approved IL-17, IL-12/23, and IL-23 inhibitors for psoriatic disease*
Agent | Trial | Population | Primary endpoints |
IL-17RA inhibitors | |||
Brodalumab | AMAGINE-1 (NCT01708590)16 | Patients with moderate-to-severe PsO (N = 661) | PASI75 at Week 12: sPGA 0/1 at Week 12: |
AMAGINE-2 (NCT01708603)17 | Patients with moderate-to-severe PsO (N = 1,831) | PASI75 at Week 12: sPGA 0/1 at Week 12: | |
AMAGINE-3 (NCT01708629)17 | Patients with moderate-to-severe PsO (N = 1,881) | PASI75 at Week 12: sPGA 0/1 at Week 12: | |
IL-17A inhibitors | |||
Secukinumab | ERASURE (NCT01365455)18 | Patients with moderate-to-severe PsO (N = 738) | PASI75 at Week 12: IGA 0/1 at Week 12: |
FIXTURE (NCT01358578)18 | Patients with moderate-to-severe PsO (N = 1,306) | PASI75 at Week 12: IGA 0/1 at Week 12: | |
FUTURE 1 (NCT01392326)19 | Patients with PsA (N = 606) | ACR20 at Week 24: Secukinumab 150 mg: 50.0% Secukinumab 75 mg: 50.5% Placebo: 17.3% (p < 0.001) | |
FUTURE 2 (NCT01752634)20 | Patients with PsA (N = 397) | ACR20 at Week 24: Secukinumab 300 mg: 54.0% Secukinumab 150 mg: 51.0% Placebo: 15.0% (p < 0.0001) | |
Ixekizumab | UNCOVER-1 (NCT01474512)21 | Patients with moderate-to-severe PsO (N = 1,296) | PASI75 at Week 12: sPGA 0/1 at Week 12: |
SPIRIT-P1 (NCT01695239)22 | Patients with active PsA naïve to biologic therapy (N = 417) | ACR20 at Week 24: Ixekizumab Q2W: 62.1% Ixekizumab Q4W: 57.9% Placebo: 30.2% (p ≤ 0.001) | |
SPIRIT-P2 (NCT02349295)23 | Patients with active PsA and TNFi-IR (N = 363) | ACR20 at Week 24: Ixekizumab Q2W: 48.0% Ixekizumab Q4W: 53.0% Placebo: 20.0% (p < 0.0001) | |
IL-17A/F inhibitors | |||
Bimekizumab | BE READY (NCT03410992)24 | Patients with moderate-to-severe PsO (N = 435) | PASI90 at Week 16: IGA 0/1 at Week 16: |
BE VIVID (NCT03370133)25 | Patients with moderate-to-severe PsO (N = 567) | PASI90 at Week 16: Bimekizumab 320 mg Q4W: 85.0% Ustekinumab 45/90 mg Q12W: 50.0% (p < 0.0001) Placebo: 5.0% (p < 0.0001) IGA 0/1 at Week 16: Bimekizumab 320 mg Q4W: 84.0% Ustekinumab 45/90 mg Q12W: 53.0% (p < 0.0001) Placebo: 5.0% (p < 0.0001) | |
BE SURE (NCT03412747)26 | Patients with moderate-to-severe PsO (N = 478) | PASI90 at Week 16: IGA 0/1 at Week 16: | |
BE OPTIMAL (NCT03895203)27 | Patients with PsA naïve to biologics (N = 852) | ACR50 at Week 16: Bimekizumab 160 mg SC Q4W: 44.0% Placebo: 10.0% (p < 0.0001) | |
BE COMPLETE (NCT03896581)28 | Patients with PsA and TNFi-IR (N = 400) | ACR50 at Week 16: Bimekizumab 160 mg SC Q4W: 43% Placebo: 7.0% (p < 0.0001) | |
IL-12/23 inhibitors | |||
Ustekinumab | PHOENIX 2 (NCT00307437)29 | Patients with moderate-to-severe PsO (N = 1,230) | PASI75 at Week 12: Ustekinumab 45 mg: 66.7% Ustekinumab 90 mg: 75.7% Placebo: 3.7% (p < 0.0001) |
PSUMMIT 1 (NCT01009086)30 | Patients with PsA (N = 615) | ACR20 at Week 24: Ustekinumab 45 mg: 42.4% Ustekinumab 90 mg: 49.5% Placebo: 22.8% (p < 0.0001) | |
PSUMMIT 2 (NCT01077362)31 | Patients with PsA with and without prior exposure to anti-TNF (N = 312) | ACR20 at Week 24: Ustekinumab: 43.8% Placebo: 20.2% (p < 0.001) | |
IL-23 inhibitors | |||
Risankizumab | ultIMMa-1 (NCT02684370)32 | Patients with moderate-to-severe plaque psoriasis (N = 506) | PASI90 at Week 16: sPGA 0/1 at Week 16: |
ultIMMa-2 (NCT02684357)32 | Patients with moderate-to-severe plaque psoriasis (N = 491) | PASI90 at Week 16: sPGA 0/1 at Week 16: | |
KEEPsAKE-1 (NCT03675308)33 | Patients with PsA and csDMARD-IR (N = 964) | ACR20 at Week 24: Risankizumab: 57.3% Placebo: 33.5% (p < 0.001) | |
KEEPsAKE-2 (NCT03671148)34 | Patients PsA and Bio-IR and/or csDMARD-IR (N = 444) | ACR20 at Week 24: Risankizumab: 51.3% Placebo: 26.5% (p < 0.001) | |
Tildrakizumab | reSURFACE 1 (NCT01722331)35 | Patients with chronic PsO (N = 772) | PASI75 at Week 12: Tildrakizumab 200 mg: 62.0% Tildrakizumab 100 mg: 64.0% Placebo: 6.0% (p < 0.0001) PGA 0/1 at Week 12: Tildrakizumab 200 mg: 59.0% Tildrakizumab 100 mg: 58.0% Placebo: 7.0% (p < 0.0001) |
reSURFACE 2 (NCT01729754)35 | Patients with chronic PsO (N = 1,090) | PASI75 at Week 12: Tildrakizumab 200 mg: 66.0% Tildrakizumab 100 mg: 61.0% Placebo: 6.0% (p < 0.0001) Etanercept: 48.0% (p < 0.0001 for 200 mg vs etanercept and p = 0.0010 for 100 mg vs etanercept) PGA 0/1 at Week 12: Tildrakizumab 200 mg: 59.0% Tildrakizumab 100 mg: 55.0% Placebo: 7.0% (p < 0.0001) Etanercept: 48.0% (p = 0.0031 for 200 mg vs etanercept and p = 0.0663 for 100 mg vs etanercept) | |
Guselkumab | VOYAGE 1 (NCT02207231)36 | Patients with moderate-to-severe PsO (N = 837) | IGA 0/1 at Week 16: PASI90 at Week 16: |
VOYAGE 2 (NCT02207244)37 | Patients with moderate-to-severe PsO (N = 992) | IGA 0/1 at Week 16: PASI90 at Week 16: | |
NAVIGATE (NCT02203032)38 | Patients with moderate-to-severe PsO and IR to ustekinumab (N = 871) | Number of visits at which patients achieved IGA 0/1 and ≥2 grade improvement (Week 28–40): Guselkumab: 1.5 Ustekinumab: 0.7 (p < 0.001) | |
ACR20/50, ≥20%/≥50% improvement from baseline in American College of Rheumatology response criteria; csDMARD, conventional synthetic disease-modifying anti-rheumatic drug; IGA 0/1, Investigator's Global Assessment score of 0 (clear) or 1 (almost clear); IR, inadequate response; PASI75/90/100, ≥75%/≥90%/100% improvement from baseline in Psoriasis Area and Severity Index; PsA, psoriatic arthritis; PsO, plaque psoriasis; Q4W, every 4 weeks; Q12W, every 12 weeks; SC, subcutaneous; sPGA 0/1, static Physician’s Global Assessment 0 or 1; TNF, tumor necrosis factor α; TNFi, TNF inhibitor. *Data from Papp et al.,16 Lebwohl et al.,17 Langley et al.,18 Mease et al.,19 McInnes et al.,20 Gordon et al.,21 Mease et al.,22 Nash et al.,23 Gordon et al.,24 Reich et al.,25 Warren et al.,26 McInnes et al.,27 Merola et al.,28 Papp et al.,29 McInnes et al.,30 Ritchlin et al.,31 Gordon et al.,32 Kristensen et al.,33 Östör et al.,34 Reich et al.,35 Blauvelt et al.,36 Reich et al.,37 and Langley et al.38 |
Given the growing number of biologic treatment options for psoriasis, selecting the most appropriate therapy remains a key clinical challenge. Several comparative trials between these agents, as summarized in Table 2, provide valuable insights to guide clinicians in tailoring therapy to individual patient needs. Clinical evidence indicates that IL-17 inhibitors are associated with a more rapid onset of response compared with IL-23 inhibitors, whereas IL-23 blockade demonstrates durable responses.3 In addition, dual inhibition of IL-17A/F appears to offer superior efficacy than with IL-17A inhibition alone.3 In the BE RADIANT trial, bimekizumab administered over 16 weeks achieved greater skin clearance than secukinumab in patients with moderate-to-severe psoriasis (Table 2).39 Although no direct head-to-head trial has evaluated bimekizumab vs secukinumab in PsA, a matching-adjusted indirect comparison suggested a higher likelihood of achieving ACR70 responses with bimekizumab in patients who were biologic-naïve (odds ratio [OR], 2.39; p = 0.008) or those with prior inadequate response to TNF inhibitors (OR, 2.95; p = 0.035).40 However, as IL-17F also plays a role in mucosal immunity, dual IL-17A/F blockade carries an elevated risk of Candida infections than with IL-17A inhibition alone. Accordingly, selection of an appropriate agent should consider individual patient factors, including comorbidities, prior treatment history, and safety profiles.
Table 2. Key head-to-head trials between IL-17/23 inhibitors*
Comparators | Trial | Patient population | Key findings |
Brodalumab vs ustekinumab | AMAGINE-2 (NCT01708603)17 | Patients with moderate-to-severe PsO (N = 1,831) | PASI100 at Week 12: Brodalumab 210 mg: 44.0% Ustekinumab: 22.0% (p < 0.001) |
AMAGINE-3 (NCT01708629)17 | Patients with moderate-to-severe PsO (N = 1,881) | PASI100 at Week 12: Brodalumab 210 mg: 37.0% Ustekinumab: 19.0% (p < 0.001) | |
Guselkumab vs secukinumab | ECLIPSE (NCT03090100)41 | Patients with moderate-to-severe PsO (N = 1,048) | PASI90 at Week 48: Guselkumab: 84.0% Secukinumab: 70.0% (p < 0.0001) |
Ixekizumab vs guselkumab | IXORA-R (NCT03573323)42 | Patients with moderate-to-severe PsO (N = 1,027) | PASI100 at Week 12: Ixekizumab: 41.0% Guselkumab: 25.0% (p < 0.001) |
Risankizumab vs secukinumab | IMMerge (NCT03478787)43 | Patients with moderate-to-severe PsO (N = 327) | PASI90 at Week 52: Risankizumab: 86.6% Secukinumab: 57.1% (p < 0.001) |
Bimekizumab vs secukinumab | BE RADIANT (NCT03536884)39 | Patients with moderate-to-severe PsO (N = 743) | PASI100 at Week 16: Bimekizumab: 61.7% Secukinumab: 48.9% (p < 0.001) |
IL, interleukin; PASI90/100, 90%/100% improvement from baseline in Psoriasis Area and Severity Index; PsA, psoriatic arthritis; PsO, plaque psoriasis. *Data from Lebwohl et al.,17 Reich et al.,39 Reich et al.,41 Blauvelt et al.,42 and Warren et al.43 |
Future research on IL-23/IL-17 inhibitors is focused on leveraging a multi-omics approach to investigate the pathway’s nuanced effects across different cell types and tissues. In addition, there is a need to identify optimal timing for therapy initiation, uncover biomarkers predictive of treatment response, and characterize epigenetic and post-translational modifications influencing disease progression and therapeutic outcomes. These insights may inform personalized treatment strategies, improve prediction of clinical outcomes, and optimize the long-term efficacy and safety of IL-17/IL-23-targeted therapies in psoriatic disease.44
The IL-23/IL-17 axis is central to the pathogenesis of psoriatic disease, and targeting this pathway with biologics has transformed treatment for both PsO and PsA. IL-17 inhibitors offer rapid clinical responses, while IL-23 blockade provides durable outcomes, and dual IL-17A/F inhibition may further enhance efficacy over IL-17 inhibition alone. Future research leveraging multi-omics approaches and biomarker-driven strategies is needed to optimize therapy timing, personalize treatment, and improve long-term efficacy and safety, guiding more precise management of psoriatic disease.
This educational resource is independently supported by UCB. All content was developed by SES in collaboration with an expert steering committee. Funders were allowed no influence on the content of this resource.
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