1037846 review-article20212021 TAJ0010.1177/20406223211037846Therapeutic Advances in Chronic DiseaseH Iznardo and L Puig Therapeutic Advances in Chronic Disease Review Dual inhibition of IL-17A and Ther Adv Chronic Dis 2021, Vol. 12: 1–16 IL-17F in psoriatic disease DOI: 10.1177/ https://doi.org/10.1177/20406223211037846 https://doi.org/10.1177/20406223211037846 20406223211037846 © The Author(s), 2021. Article reuse guidelines: Helena Iznardo and Lluís Puig sagepub.com/journals- permissions Abstract: Psoriasis and psoriatic arthritis are chronic immune-mediated disorders with involvement of interleukin (IL)-17 cytokines in their pathogenesis. IL-17A has been considered to be the most biologically active, but IL-17F is also over-expressed in skin and synovial tissues of patients with these diseases. Many therapeutic advances have been made in the past years, but some needs remain unmet. Dual inhibitor and bispecific antibodies simultaneously targeting IL-17A and IL-17F could provide better disease control. Herein we review current evidence on bimekizumab and sonelokimab. The antigen-binding site of bimekizumab neutralizes both IL-17A and IL-17F; phase I, II, and III studies have demonstrated its efficacy and safety in psoriasis and psoriatic arthritis. Sonelokimab is a trivalent nanobody targeting IL-17A and IL-17F; phase I and II studies with this molecule have yielded promising results in psoriasis. Keywords: bimekizumab, dual inhibition, IL-17, IL-17A, IL-17F, psoriasis, psoriatic arthritis, sonelokimab Received: 31 May 2021; revised manuscript accepted: 13 July 2021. Introduction Interleukin-17 cytokines and their Psoriasis is a chronic and recurrent immune-medi- involvement in psoriasis pathogenesis ated, multisystem disorder that affects mainly the The interleukin (IL)-17 family of cytokines con- skin, but entails other domains of involvement and sists of at least six structurally similar cytokines multiple comorbidities.1 Epidemiological studies (IL-17A to F).8 These proinflammatory cytokines show that approximately 3% of the western popula- participate in defence against extracellular bacte- tion suffer from psoriasis.2,3 Psoriasis has a great ria and fungi, and are also involved in promoting impact on quality of life and can be associated with chronic inflammation and autoimmunity.8–10 relevant functional as well as psychosocial impair- IL-17A can exist as a homodimer of two IL-17A ment.4 Psoriatic arthritis (PsA) is a complex chains or as a heterodimer with IL-17F.11,12 inflammatory joint disease, included in the spondy- IL-17F has the highest structural homology with loarthropathy spectrum, and affects approximately IL-17A (close to 50%) and is expressed by the one third of patients, especially those with moderate same immune cell types as IL-17A, mainly T to severe psoriasis.5 PsA produces stiffness, pain and helper (Th)17 cells but also CD8 T cells, natural swelling of joints, and can progress to debilitating killer (NK) cells, lymphoid tissue inducer (LTi) Correspondence to: joint destruction. Enthesitis and dactylitis are cells, type 3 innate lymphoid cells and γδ T cells.8 Lluís Puig Department of observed in 30–50% and 40–50% of patients, IL-17 receptors are composed of five subunits Dermatology, Hospital de respectively.6 Psoriasis manifestations precede the (IL-17RA–RE) in different heterodimeric combi- la Santa Creu i Sant Pau, Sant Antoni Maria Claret, diagnosis of PsA in 85% of patients, although they nations. IL-17A and IL-17F bind to the same 167, Barcelona 08025, can be synchronous or, more rarely, follow.7 This complex of IL-17RA and IL-17RC.13 IL-17RA is Spain lpuig@santpau.cat comprehensive review has been based on a PubMed widely expressed, while the cell type expression of Helena Iznardo search with the search strategy ‘(IL-17A OR other IL-17R family receptors is more restricted. Department of IL-17F) AND (psoriasis OR psoriatic arthritis) On ligand binding, these receptors engage with Dermatology, Hospital de la Santa Creu i Sant Pau, AND (bimekizumab OR sonelokimab OR dual OR cytoplasmic protein ACT1 to enact downstream Universitat Autònoma, bispecific)’, from the start of records. signaling pathways.14 IL-17F is considered to act Barcelona, Spain journals.sagepub.com/home/taj 1 Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage). Therapeutic Advances in Chronic Disease 12 similarly to IL-17A but with less potent effects, as 13 received placebo.36 Bimekizumab pharma- it has less affinity for the IL-17RA/RC complex. cokinetics showed linear correlation with dose However, IL-17F levels are consistently more and its half-life ranged from 17 days (40 mg) to elevated (30-fold higher on average) in psoriatic 22 days (160 mg).36 Five subjects (19.2%) devel- lesional tissues and serum than those of IL-17A,15 oped anti-bimekizumab antibodies during the with similar findings in spondylarthritis patients.16 follow-up period, but pharmacokinetic parame- Several studies have demonstrated the central ters were not affected.36 Rapid and marked skin role of IL-17A and IL-17F in the pathogenesis of improvement was seen from week 2 in patients psoriasis, PsA and spondyloarthritis.17–19 Targeted treated with higher doses (160 mg, 480 mg, and biological therapies directed against IL-17A 640 mg).36 Maximal improvement was reached include secukinumab and ixekizumab – approved between weeks 4 and 6 and was maintained for the treatment of psoriasis, PsA and ankylosing throughout the 20-week study in patients receiv- spondylitis (AS)20,21 – with later addition of the ing bimekizumab ⩾160 mg.36 Maximal psoriasis IL-17RA blocker brodalumab, approved for the area and severity (PASI) score reduction was treatment of psoriasis in USA and Europe22 and >85% in those treated with higher doses psoriasis and PsA in Japan.23 Dual and bispecific (⩾160 mg). Maximal improvement of baseline IL-17A and IL-17F inhibitors have been devel- physician’s global assessment (PGA) score, con- oped following the rationale that neutralization of sisting of 75%, 100%, and 94% reduction, was IL-17A and IL-17F could be more efficacious measured in the 160 mg, 480 mg, and 640 mg than IL-17A neutralization alone,24,25 and the bimekizumab groups, respectively.36 Treatment- clinical data are very promising so far, especially emergent adverse events (TEAEs) were observed for bimekizumab (Table 1). in 84.6% and 76.9% of subjects treated with bimekizumab and placebo, respectively. The majority were mild, with ⩾10% of all subjects Bimekizumab for treatment of psoriasis and receiving bimekizumab presenting with headache, PsA oropharyngeal pain, nasopharyngitis and not clin- Bimekizumab (formerly UCB4940; UCB) is an ically meaningful ECG alterations. Only one seri- immunoglobulin G1 (IgG1) humanized antibody ous adverse effect (AE) occurred, but it was not with strong affinity for IL-17A and IL-17F. classified as treatment related.36 Strictly speaking, bimekizumab is not bispecific, but divalent (two binding sites) with dual speci- BE ABLE 1 (NCT02905006), a 12-week multi- ficity (each one of them binds both IL-17A and center, randomized, double-blind, placebo-con- IL-17F monomers) (Figure 1).26 Preclinical stud- trolled, parallel-group, dose-ranging, phase IIb ies comparing bimekizumab with other IL-17A study in patients with moderate to severe psoria- inhibitors showed the affinity of ixekizumab and sis, demonstrated superior efficacy of bimeki- bimekizumab for IL-17A to be equivalent and zumab versus placebo in all primary (achievement higher than that of secukinumab, whereas the of PASI90 response at week 12) and secondary ability of bimekizumab to neutralize IL-17F was [reduction of at least two categories or the unique.24 Bimekizumab has now completed phase achievement of clear or almost clear skin condi- I, phase II and phase III clinical trials in patients tion as defined by investigator’s global assessment with psoriasis, PsA, AS, and rheumatoid arthritis (IGA) at week 8 and 12, PASI90 response at (RA)27eum and has provided clinically meaningful week 8, PASI75 response at week 12, and improvements in hidradenitis suppurativa.35 PASI100 response at week 12] endpoints.28 Two hundred and fifty patients were randomly assigned to receive subcutaneous bimekizumab every Psoriasis key efficacy and safety data 4 weeks at doses of 64 mg, 160 mg, 160 mg with In the phase I first-in-human, double-blind, pla- 320 mg loading dose, 320 mg, 480 mg, or placebo; cebo-controlled, single-dose, dose-escalating pso- PASI75 and PASI90 responses were more fre- riasis study (NCT02529956), 26 patients with quently observed in the 320 mg group (93% and ‘mild to moderate psoriasis’, defined in the study 79.1%, respectively) compared to placebo (4.8% as ⩽5% of body surface area (BSA), received and 0%, respectively), and the highest PASI100 escalating intravenous doses of bimekizumab response rate (60%) was detected in the group (8 mg, 40 mg, 160 mg, 480 mg and 640 mg) and receiving 160 mg with 320 mg loading dose 2 journals.sagepub.com/home/taj Table 1. Summary of the most relevant currently available efficacy and safety data on bimekizumab and sonelokimab. Drug Disease Trial Active Objective Dose regimen Efficacy Most common AEs comparator BIMEKIZUMAB Psoriasis BE ABLE 1 (NCT02905006) Efficacy and safety PASI90 at Nasopharyngitis, respiratory (n = 250) 12 weeks tract infection and oral (%) candidiasis journals.sagepub.com/home/taj Placebo 0% 64 mg Q4W 46 160 mg Q4W 67 160 mg Q4W (320 mg LD at 75 baseline) 320 mg Q4W 79 480 mg Q4W 72 BE ABLE 2 (NCT03010527) Long-term efficacy and (*) PASI90 at Nasopharyngitis, respiratory (n = 217) safety (extension study 60 weeks tract infection and oral from BE ABLE 1) (%) candidiasis Placebo → 160 Q4W 90 64 mg Q4W 100 160 mg Q4W 80 320 mg Q4W 85 480 mg → 320 Q4W 85 BE READY (NCT03410992) Efficacy and safety PASI90 at IGA0/1 at Nasopharyngitis, oral (n = 435) 16 weeks 16 weeks candidiasis, respiratory (%) (%) tract infection Placebo 1 1 320 mg Q4W 91 93 (Continued) 3 H Iznardo and L Puig 4 Table 1. (Continued) Drug Disease Trial Active Objective Dose regimen Efficacy Most common AEs comparator Be VIVID (NCT03370133) Ustekinumab Efficacy and safety Placebo 5 5 Nasopharyngitis, oral (n = 567) candidiasis, respiratory tract infection BKZ 320 mg Q4W 85 84 Therapeutic Advances in Chronic Disease 12 UST 45/90 mg Q12W 50 53 BE SURE (NCT03412747) Adalimumab Efficacy and safety BKZ 320 mg Q4W until week 86 85 Upper respiratory tract (n = 478) 16 Q8W infections, oral candidiasis, hypertension and diarrhea ADA 40 mg Q2W until week 47 57 24 BKZ BE RADIANT Secukinumab Efficacy and safety PASI100 at PASI100 at Upper respiratory tract (NCT03536884) (n = 743) 16 weeks 48 weeks infections, oral candidiasis, (%) (%) urinary tract infection BKZ 320 mg Q4W 62 67 SEC 300 mg weekly until week 49 46 8 Q4W PsA BE ACTIVE (NCT02969525) Efficacy and safety ACR50 at ACR20 at Nasopharyngitis and oral (n = 206) 12 weeks 12 weeks candidiasis (%) (%) Placebo 7 19 16 mg Q4W 27 54 160 mg Q4W 41 73 160 mg Q4W 320 mg LD at 46 61 baseline) 320 mg Q4W 24 51 BE COMPLETE Efficacy and safety in Ongoing (NCT03896581) (n = 390) anti-TNF inadequate- responders journals.sagepub.com/home/taj (Continued) Table 1. (Continued) Drug Disease Trial Active Objective Dose regimen Efficacy Most common AEs comparator BE OPTIMAL Adalimumab Efficacy and safety Ongoing (NCT03895203) (n = 840) BE VITAL (NCT04009499) Safety (incident AE) Ongoing (n = 1045) journals.sagepub.com/home/taj SONELOKIMAB Psoriasis NCT02156466 (n = 44) Safety/tolerability, Days 1, 15, 29 PASI90 at Pruritus, headache, immunogenicity, 85 days (%) hypertension, pharmacokinetics/ nasopharyngitis, pharmacodynamic and somnolence and bronchitis efficacy Placebo 0 30 mg 50 60 mg 88 120 mg 88 250 mg 100 NCT03384745 (n = 313) Secukinumab Efficacy, safety and (**) IGA 0/1 at Nasopharyngitis, pruritus, tolerability 12 weeks upper respiratory tract (%) infections Placebo 0 30 mg 0, 2, 4, 8 w 48 60 mg 0, 2, 4, 8 w 85 120 mg 0, 2, 4, 8 w 77 120 mg+ 0, 2, 4, 6, 8, 10 w 88 SEC 300 mg 0, 1, 2, 3, 4, 8 w 77 *Patients who achieved PASI90 at week 12 received bimekizumab 64, 160, or 320 mg for an additional 48 weeks (60 weeks in total). Patients receiving placebo in BE ABLE 1 were switched to bimekizumab 160 mg and patients receiving bimekizumab 480 mg were switched to 320 mg. The other dose regimes were maintained. **Thisclinical trial consisted of a 12-week induction period, a 12-week dose escalation period and a 12-week evaluation of response period. Detailed explanation of administration regimes is included in the main text. ADA, adalimumab; AE, adverse effects; BKZ, bimekizumab; LD, loading dose; PsA, psoriatic arthritis; Q4W, every 4 weeks; SEC, secukinumab; UST, ustekinumab. 5 H Iznardo and L Puig Therapeutic Advances in Chronic Disease 12 Figure 1. Schematic representation of bimekizumab and sonelokimab’s molecular structures. (a) Bimekizumab has an antigen-binding site that neutralizes interleukin (IL)-17A, IL-17F and their heterodimers (dual specificity). (b) Sonelokimab is a trivalent camelid nanobody comprised of an N-terminal moiety that binds specifically to IL-17F, a central moiety binding to serum albumin for stabilization and a C-terminal moiety binding IL-17A and IL-17F (bispecific inhibitor). (versus 0% placebo).28 TEAEs were observed in efficacy through week 60 with 80% to 100% 126/208 (61%) of bimekizumab-treated patients achieving PASI90 and 69% to 83% achieving versus 15/42 (36%) of placebo-treated patients, PASI100 and IGA 0.30 Incidence of TEAEs was leading to treatment discontinuation in 4.8% and similar between patients in the bimekizumab 2.4% of patients in the bimekizumab and placebo 160 mg group (88.3%) and 320 mg group groups, respectively. The most common (>5% (83.5%), and lower in the bimekizumab 64 mg patients in any group) TEAEs were nasopharyn- group (66.7%). The majority were mild to mod- gitis, upper respiratory tract infections, arthralgia, erate and the most frequent were oral candidiasis γ-glutamyltransferase increase, neutropenia, rhi- (13.4%) and nasopharyngitis (12.9%). Overall nitis, tonsillitis, hypertension, oral candidiasis, incidence of serious AEs was 6.9% and only one headache, leukopenia, and vomiting. Fungal of them was considered to be related to bimeki- infections were reported in nine (4.3%) of bime- zumab (serum liver enzyme levels increased in a kizumab-treated patients (four out of nine being patient receiving 160 mg).30 No cases of inflam- oral candidiasis). All were localized, superficial matory bowel disease, major adverse cardiovascu- infections of mild or moderate intensity and none lar events, or suicidal ideation or behavior were of them resulted in treatment discontinuation.28 reported.30 Limitations of the study include a There was no apparent dose relationship between relatively short duration of observation, a small TEAEs in patients who discontinued therapy. number of patients in the bimekizumab 64 mg Two patients reported three serious AEs, none of group (n = 15) and selection bias due to with- which were considered related to the study treat- drawal of patients who had not reached PASI75 ment. BE ABLE 2 (NCT03010527) is a phase in the BE ABLE 1 study.30 IIb extension study in which 217 patients from the BE ABLE 1 who achieved PASI90 at week 12 Phase III studies BE READY, BE VIVID, BE received bimekizumab 64, 160, or 320 mg for an SURE and BE RADIANT have also been com- additional 48 weeks (60 weeks in total).30 Initial pleted, with efficacy and safety data supporting PASI90 responders maintained high levels of the therapeutic value of bimekizumab.33,34 6 journals.sagepub.com/home/taj H Iznardo and L Puig Furthermore, the BE SURE and BE RADIANT (270/321), 50% (81/163) and 5% (4/83) of trials have proved superiority and non-inferiority patients in the bimekizumab, ustekinumab [risk of bimekizumab against adalimumab and secuki- difference 35 (95% CI 27–43); p < 0.0001] and numab, respectively.37,38 placebo groups [risk difference 80 (74–86); p < 0.0001], had PASI90, respectively; and 84%, BE READY (NCT03410992) was a 56-week, ran- 53% and 5% of patients in the bimekizumab, domized, double-blinded, placebo-controlled study ustekinumab [risk difference 30 (95% CI 22–39); that consisted of an initial treatment period fol- p < 0.0001] and placebo groups [risk difference lowed by a randomized withdrawal period and 79 (73–85); p < 0.0001) had an IGA response.34 enrolled 435 adults with moderate to severe plaque PASI100 was achieved by 59% of patients in the psoriasis.33 Patients were randomly assigned (4:1) bimekizumab group by week 16, and the response to receive bimekizumab 320 mg (n = 349) every was maintained to study completion, with 65% of 4 weeks or placebo (n = 86) every 4 weeks. patients having complete skin clearance by week Co-primary endpoints were PASI90 and IGA 0/1 52. Serious TEAEs were reported in 6% (24/395) responses at week 16. Bimekizumab-treated and 8% (13/163) of the patients in the bimeki- patients achieving PASI90 at week 16 were ran- zumab group (including those who switched from domly re-allocated (1:1:1) to receive bimekizumab placebo at week 16) and the ustekinumab group, 320 mg every 4 weeks, every 8 weeks, or placebo for respectively. The proportion of TEAEs was simi- weeks 16–56. The study met its co-primary end- lar between bimekizumab and ustekinumab- points of PASI90 (91% of patients receiving bime- treated patients, except for oral candidiasis. kizumab versus 1% receiving placebo) and IGA 0/1 (93% of patients receiving bimekizumab versus 1% In BE SURE (NCT03412747), moderate to receiving placebo) at week 16.33 PASI100 was severe psoriasis patients were randomly assigned achieved by 68% of patients in the bimekizumab (1:1:1) to receive bimekizumab 320 mg every 320 mg every 4 weeks group versus 1% in the pla- 4 weeks (n = 158), bimekizumab 320 mg every cebo group (p < 0.0001). Differences in response 4 weeks until week 16 followed by bimekizumab were observed by week 4, after only one dose of 320 mg every 8 weeks (n = 161) or adalimumab bimekizumab. Responses were maintained through (80 mg at week 0, 40 mg at week 1 and 40 mg week 56 with bimekizumab 320 mg every 8 weeks every 2 weeks until week 23) followed by bimeki- and every 4 weeks. The median time to relapse (loss zumab 320 mg every 4 weeks between weeks 24 of PASI75 response) since randomized allocation and 56 (n = 159).37 Co-primary endpoints were to placebo (at week 16) was 28 weeks (95% confi- met (PASI90 and IGA 0/1 responses compared to dence interval (CI) 24–32, p < 0.0001); TEAEs up adalimumab by week 16), with 86.2% (275/319) to week 16 were reported in 61% (213/349) and and 85.3% (272/319) of bimekizumab-treated 41% (35/86) of patients receiving bimekizumab patients and 47.2% (75/159) and 57.2% (91/159) 320 mg and placebo every 4 weeks, respectively. of those treated with adalimumab showing From week 16 to week 56, TEAEs were reported in PASI90 and IGA 0/1 response, respectively.37 74% (78/106), 77% (77/100) and 69% (72/105) of By week 24, PASI90 and PASI100 response patients receiving bimekizumab 320 mg every rates remained higher for bimekizumab-treated 4 weeks, every 8 weeks or placebo, respectively, and patients as compared to those treated with adali- the safety profile was consistent with that reported mumab (p < 0.001).37 A fast increase in response in previous bimekizumab studies.33 rate was observed after switching from adali- mumab to bimekizumab. By week 56, response BE VIVID (NCT03370133) is a 52-week, multi- rates in adalimumab-switched patients were simi- center, double-blind, active comparator and pla- lar to those in patients who received only bimeki- cebo-controlled phase III trial in which 567 zumab.37 TEAEs were comparable between the patients were randomly assigned (4:2:1) to bime- three treatment groups; the most frequent were kizumab 320 mg every 4 weeks (n = 321), usteki- oral candidiasis, superior respiratory tract infec- numab 45 mg or 90 mg every 12 weeks (n = 163) tions, hypertension and diarrhea.37 From weeks 0 or placebo every 4 weeks (n = 83).34 At week 16, to 24, oral candidiasis and diarrhea occurred patients receiving placebo switched to bimeki- more frequently in the bimekizumab-treated zumab 320 mg every 4 weeks. Co-primary end- groups. Serious AEs were reported in 2.5% points were PASI90 and IGA 0/1 at week 16 (4/158), 0.6% (1/161) and 3.1% (5/159) of (non-responder imputation).34 At week 16, 85% patients treated with bimekizumab every 4 weeks, journals.sagepub.com/home/taj 7 Therapeutic Advances in Chronic Disease 12 bimekizumab every 4 weeks and then every PsA safety and efficacy data 8 weeks and adalimumab, respectively. From In the phase Ib proof-of-concept study weeks 24 to 56 serious AEs were reported in 1.3% (NCT02141763) in patients with moderate to (2/152), 5.4% (8/149) and 6.0% (9/149) of severe adult-onset PsA, 39 patients received dif- patients treated with bimekizumab every 4 weeks, ferent dose regimens of bimekizumab (loading bimekizumab every 4 weeks and then every dose ranging from 80 to 560 mg and maintenance 8 weeks and adalimumab, respectively. No cases doses ranging from 40 to 320 mg) and 14 pla- of adjudicated major adverse cardiovascular cebo.27 Bimekizumab-treated patients experi- events, adjudicated suicidal ideation or behavior, enced rapid improvements for both cutaneous inflammatory bowel disease (IBD), serious hyper- and articular symptoms, detected as soon as week sensitivity reactions, or active tuberculosis among 2 and maintained up to week 20.27 At week 8, patients treated with bimekizumab were observed. 87% (13/15) of patients achieved PASI100 and No unexpected safety concerns appeared in 80% (24/30), and 40% (12/30) achieved at least patients switching from adalimumab to bimeki- 20% and 50% improvement in the American zumab as compared to patients treated only with College of Rheumatology response criteria bimekizumab. The incidence of serious infection (ACR20 and 50, respectively).27 Bimekizumab was similar across treatment groups.37 treatment was not associated with any unexpected safety signals, with two patients in the treatment arm reporting fungal infections.27 This study also In BE RADIANT (NCT03536884) 743 patients included preclinical in vitro experiments showing with moderate to severe plaque psoriasis were that IL-17F induced similar inflammatory randomly assigned (1:1) to receive bimekizumab responses to IL-17A in human skin and joint 320 mg every 4 weeks (n = 373), or secukinumab cells. Furthermore, cytokine responses and neu- 300 mg weekly until week 4, followed by every trophil chemotaxis were suppressed more effec- 4 weeks to week 48 (n = 370).38 At week 16, tively with dual neutralization of IL-17A and patients receiving bimekizumab were re-rand- IL-17F with bimekizumab than with inhibition of omized (1:2) to receive 320 mg every 4 weeks or IL-17A or IL-17F alone.27 every 8 weeks to week 48. The primary end point was met, with 61.7% (230/373) and BE ACTIVE was a 48-week, phase IIb, rand- 48.9% (181/370) of bimekizumab-treated and omized, double-blind, placebo-controlled, dose- secukinumab-treated patients showing PASI100 ranging trial to assess the efficacy and safety of response at week 16, respectively. By week 4, bimekizumab in 206 adult patients with active (⩾3 71% (265/373) of the bimekizumab-treated tender and swollen joints) PsA.32 Patients were patients had a PASI75 response [versus 47.3% randomly assigned (1:1:1:1:1) to receive 16 mg, (175/373) from the secukinumab group].38 160 mg with single 320 mg loading dose, 160 mg, Response rates continued to increase and were 320 mg bimekizumab or placebo via subcutaneous maintained until week 48, with 67% (250/373) injection every 4 weeks for 12 weeks.32 After week and 46.2% (171/370) of bimekizumab and 12, patients on placebo and 16 mg bimekizumab secukinumab-treated patients having PASI100.38 arm were reassigned 1:1 to receive 160 mg or The most frequent AEs were upper respiratory 320 mg bimekizumab. All groups continued to tract infection, oral candidiasis and urinary tract receive treatment every 4 weeks until week 48.32 infection, occurring in more than 5% of patients Primary endpoint was ACR50 response at in any group. Oral candidiasis was more com- 12 weeks, whereas the usual endpoint in PsA trials mon in bimekizumab than in secukinumab- is ACR20 at 24 weeks.39 Patients with previous use treated patients (19.3% and 3%, respectively).38 of one tumor necrosis factor (TNF) inhibitor were Most were mild (36/72) or moderate (34/72) enrolled (19%), as well as those with a history of and none led to treatment discontinuation. The IBD (but no active disease).32 Statistical analysis of rate of serious infections was similar in the two primary response included pairwise comparisons treatment groups. There was one case of new- of each bimekizumab dose versus placebo for onset ulcerative colitis in the bimekizumab group ACR50 at week 12, starting with the highest dose. and one in the secukinumab group. There were The primary endpoint was not met, as the response two cases of adjudicated major adverse cardiac in the 320 mg group did not differ significantly events in the secukinumab group and none in from that in the placebo group [odds ratio (OR) the bimekizumab group. 3.7 (95% CI 1.0–13.7); p = 0.051].32 Exploratory 8 journals.sagepub.com/home/taj H Iznardo and L Puig outcomes with nominal p values included a signifi- maintained until week 108 in 80%/78%/81% of cant ACR50 response at week 12 for every bimeki- week 12 responders.43 Serious AEs occurred in zumab group, with the highest efficacy in the 9.3% of patients, and 8.8% overall withdrew from 160 mg dose with a 320 mg loading dose group the study due to AEs by week 108.43 [OR 9.7 (2.7–34.3); p = 0.0004].32 Significant responses in PASI scores were also obtained at Bimekizumab use in AS and RA has also been week 12 (nominal p values), with 50% of patients explored.29,31 The efficacy and safety of bimeki- in the bimekizumab 160 mg dose with 320 mg zumab in active AS was proved in BE AGILE loading dose group achieving a PASI90 response (NCT02963506), a phase II randomized, double- [OR 12.9 (1.8–60.5); p = 0.0011].32 Response blind, placebo-controlled, dose ranging trial31 with rates increased up to week 24 and thereafter a long-term extension study (NCT03355573), in a remained stable, with no loss of efficacy by week currently ongoing phase II trial comparing bimeki- 48.32 Patient-reported outcomes (PROs) such as zumab with certolizumab pegol (NCT03215277),44 the health assessment questionnaire disability and in a phase III trial for AS (NCT03928743) index (HAQ-DI) and the PsA impact of disease-9 and non-radiographic axial spondyloarthritis (PsAID-9) also showed rapid and sustained (NCT03928704), which is currently recruiting improvement (up to 48 weeks).40 Recently reported participants.45 A proof-of-concept phase IIa study additional data include the Bath Ankylosing (NCT02430909) tested the addition of bimeki- Spondylitis Disease Activity Index (BASDAI) 50 zumab to certolizumab pegol in patients with RA response rates 43% and 56% at week 12 and 48, and inadequate response to the latter. The rapid respectively, for the 93 patients in the bimeki- decrease in disease activity seen at week 12 without zumab 160–320 mg groups.41 Regarding safety, by unexpected or new safety signals encourages fur- week 12 no differences in the frequency of AEs ther study of bimekizumab in RA.29 were found between placebo and the different treatment doses, with 57% (24/42) and 41% Sonelokimab. Sonelokimab (formerly M1095, (68/164) of patients in the placebo and bimeki- MSB0010841, and ALX-0761; Moonlake Immu- zumab groups reporting TEAEs, respectively.32 notherapeutics) is a novel trivalent tandem nano- After reallocation, 74% (151/204) of the patients body that binds specifically to human IL-17F, who received bimekizumab reported AEs between both human IL-17A and IL-17A/F and human weeks 12 and 48; the most frequent were naso- serum albumin (for plasma half-life extension); pharyngitis and respiratory tract infections.32 No thus, it is a bispecific IL-17A and IL-17F inhibi- direct association with bimekizumab dose was tor (Figure 1).25 Compared to common monoclo- found.32 Candida infections were reported in 7% of nal antibodies, nanobodies are smaller molecules patients, not leading to treatment discontinuation with a potential for better tissue penetration.46 in any instance. No cases of IBD were reported. Nine patients (eight receiving bimekizumab) suf- A randomized, double-blind, placebo-controlled fered from serious AEs including drug-induced phase I study of multiple ascending doses of sub- liver injury (one in 320 mg), severe liver enzyme cutaneous sonelokimab has been assessed in 44 elevation (one in 320 mg), hepatitis E infection patients with moderate to severe psoriasis.25 (one in 160 mg), cellulitis (one in 160 mg), mela- Patients were randomly assigned (4:1) into four noma in situ (one in 160 mg), suicidal ideation ascending sonelokimab dose cohorts (30, 60, 120 (one in 160 mg) and neutropenia (one in 320 mg).32 or 240 mg) (n = 8, 8, 8, 9, respectively) or placebo (n = 8). Treatment was administered via subcuta- BE ACTIVE2 (NCT03347110) is the open-label neous injection into the abdominal wall every other extension (OLE) study in which all patients who week through 6 weeks (days 1, 15 and 29).25 completed 48 weeks of the BE ACTIVE trial were Marked decreases in psoriasis inflammatory mark- switched to 160 mg bimekizumab regardless of ers (dermal and epidermal CD3+ cells, epidermal previous treatments.42 After 60 more weeks of thickness and numbers of epidermal Ki67+ cells) OLE treatment (making a total of 108 weeks) and a largely dose-dependent normalization in there were 66.7% ACR50 and 75.4% BSA 0% cutaneous expression of genes coding for IL-17A, responses, with complete resolution of dactilytis IL-17F, CCL20, CXCL1, CXCL8, defensin beta and enthesitis in 65.9% and 77.9% of patients, 4A, lipocalin 2, cathelicidin (LL37), and keratin respectively.43 ACR20/50/70 responses were 16 were observed in sonelokimab-treated patients journals.sagepub.com/home/taj 9 Therapeutic Advances in Chronic Disease 12 by day 43; by day 85, 100% and 56% of patients The primary outcome of the study (proportion of receiving sonelokimab 240 mg achieved PASI90 patients in the sonelokimab groups with an IGA and PASI100 responses, respectively.25 All patients score of 0 or 1 at week 12 compared with the (100%) treated with sonelokimab 240 mg achieved placebo group) was met, with 0/52 in the a sPGA result of minimal or clear with at least a placebo group versus 25/52 [48.1% (34.0–62.4), two-level reduction in static PGA (sPGA) from p < 0.0001] in the sonelokimab 30 mg group, baseline. All these effects were dose-dependent, 44/52 [84.6% (71.9–93.1), p < 0.0001] in the and the largest decrease (95%) in BSA scores was sonelokimab 60 mg group, 41/53 [77.4% (63.8– observed in the cohort receiving sonelokimab 87.7), p < 0.0001] in the sonelokimab 120 mg 240 mg. Rapid onset of improvement was observed, normal load group, 45/51 [88.2% (76.1–95.6), as early as the first week of treatment.25 p < 0.0001] in the sonelokimab 120 mg aug- mented load group, and 41/53 [77.4% (63.8– Results of the phase IIb randomized, double- 87.7), p < 0.0001] in the secukinumab 300 mg blind, placebo-controlled multi-center 12-week group.47 Onset of response was quick, with 31.4% study with an additional 40-week follow-up (16/51) of sonelokimab 120 mg-treated patients assessing the efficacy, safety and tolerability of achieving PASI90 response by week 4. Post-hoc sonelokimab in 313 patients with plaque psoriasis analysis was performed with a combined group of have recently been published (NCT03384745).47 142 patients in the sonelokimab 120 mg normal Patients with stable moderate to severe plaque and load group. Sixty-nine of the 142 patients in psoriasis (IGA ⩾3, BSA ⩾10% and PASI ⩾12) this group had achieved IGA 0 at week 24, so were randomly assigned 1:1:1:1:1 to receive pla- sonelokimab was stopped. Sixty (87%) of them cebo (n = 52), sonelokimab 30 mg (n = 52), relapsed over the subsequent 4–12 weeks. After sonelokimab 60 mg (n = 52), sonelokimab 120 mg restarting sonelokimab, 47 (78.3%) patients re- normal load (induction with administration at achieved IGA 0 status. Regarding safety, AEs weeks 0, 2, 4 and 8) (n = 53), sonelokimab 120 mg occurred in 49.5% (155 of 313) of patients, augmented load (induction with administration with a slightly greater incidence in the sonelo- at weeks 0, 2, 4, 6, 8 and 10) (n = 51) or secuki- kimab groups (51.4%, 107/208) at weeks numab 300 mg (induction period with adminis- 0–12. Common AEs included nasopharyngitis tration at weeks 0, 1, 2, 3, 4 and 8) (n = 53).47 (13.5%), pruritus (6.7%) and upper respiratory This first 12-week placebo-controlled induction tract infections (4.3%). During weeks 12–52, period was followed by a 12-week dose mainte- Candida infections were significantly higher in nance or escalation period, in which patients sonelokimab-treated patients, with 1/53 (1.9%) assigned to the placebo group received in the secukinumab group versus 19/257 (7.4%) sonelokimab 120 mg (at weeks 12, 14, 16, in the sonelokimab groups. Four instances of and then every 4 weeks); patients receiving neutropenia (<1000 cells per µL) resolved quickly sonelokimab 30 mg or 60 mg with IGA score >1 without changes in sonelokimab dosing. One were escalated to 120 mg (every 4 weeks); patients patient with a family history of IBD developed assigned to the sonelokimab 120 mg groups Crohn’s disease while receiving sonelokimab received it at week 12 and then every 8 weeks 30 mg; another patient in the sonelokimab 60 mg (normal load group) or every 4 weeks (augmented group died of cardiopulmonary failure while load); and patients receiving secukinumab 300 mg asleep at home.47 continued to received it every 4 weeks. Finally, a 24-week response assessment or dose-holding Furthermore, sonelokimab also demonstrated period was studied.47 At week 24, patients receiv- improvement of arthritis and X-ray score in a pre- ing sonelokimab 30 mg and 60 mg without dose clinical model of RA.48 escalation, and patients in the two sonelokimab 120 mg groups (including placebo rollover Other bispecific antibodies. Bispecific inhibitors patients) were eligible to stop the study drug. neutralize two different cytokines through two dis- Patients with an IGA score ⩾1 at week 24 contin- tinct binding sites. Those tested for treatment of ued on the same dosage, and those with an IGA psoriasis in clinical trials or animal models include score of 0 were started on placebo. IGA assess- TNF-α/IL-17A inhibitors (COVA322 and ABT- ment was performed every 4 weeks and treatment 122), IL-6/IL-23 inhibitor AZ17, and the IL-17A/ was restarted if patients’ IGA score became ⩾1.47 IL-17F inhibitor afasevikumab (NI-1401).26,48 10 journals.sagepub.com/home/taj H Iznardo and L Puig COVA 322 is a fynomer antibody, resulting from In psoriasis, IL-17A and IL-17F are the main the fusion of a high-affinity IL-17A binding fyno- pro-inflammatory mediators. Currently approved mer to the light chain of the fully human anti- therapies targeting IL-17 include IL-17A inhibi- TNF-α antibody, adalimumab49 and has been tors secukinumab and ixekizumab and anti- explored in a single dose escalation, tolerability, IL-17RA brodalumab. IL-17 blockers have dem- safety, pharmacokinetics and efficacy phase Ib/IIa onstrated superior and faster efficacy compared study in patients with stable chronic moderate to to previous therapies, but primary and secondary severe plaque psoriasis. ABT-122 has been tested therapeutic failure are still relatively frequent.59 in phase II trials for PsA and RA.50,51 Results sug- Some of these non-responder patients can be suc- gest that inhibition of IL-17A does not offer any cessfully switched between IL-17A inhibitors – contribution to TNF-α inhibition, as there were perhaps as a consequence of reinduction – but no differences in efficacy between ABT-122 and others become resistant.60 The broader blockade adalimumab in PsA and RA patients.52 AZ17 was of brodalumab may account for its high efficacy successfully tested in two relevant preclinical in and speed of response, but quick relapses have vivo mouse models, showing greater efficacy in been reported on treatment discontinuation; improving psoriasiform inflammation and epider- increased levels of active IL-17 cytokines on mal thickness, as compared to individual anti-IL-6 blockade of their common receptor subunit or anti-IL-23 antibodies.53 Whereas IL-6 acts early IL-17RA might provide a mechanistic explana- in the initiation phases of Th17 cell differentiation, tion.61 Dual inhibition of IL-17A and IL-17F rep- inducing IL-23 receptor expression, IL-23 is resents a novel approach that has proved to be thought to promote Th17 cell lineage stabilization, effective in multiple models of disease, in both expansion, and maintenance, whereupon stimu- preclinical and clinical studies.36 Bispecific anti- lating production of Th17 cytokines.53 None of bodies might bind preferentially to cells contain- these drugs (COVA322, ABT-122 or AZ17) is ing both targets instead of those expressing only currently being developed for treatment of psoria- one (avidity hypothesis),48 and become an inter- sis and/or PsA. Finally, phase Ia and Ib trials of esting option for patients with IL-17 signaling afasevikumab (NI-1401), a fully human monoclo- pathway-refractory disease.62 nal antibody neutralizing both IL-17A and IL- 17F, have been completed in healthy volunteers In this review we have provided a comprehensive but no results have been released yet.26,48 review of the current available data on bimeki- zumab and sonelokimab, the first inhibitors of both IL-17A and IL-17F (albeit with different Discussion mechanisms of dual and bispecific inhibition, The importance of IL-17 cytokines in psoriasis, respectively) with significant clinical development PsA and other chronic inflammatory diseases has in psoriasis. Accumulating data from phase I, II been widely proved. IL-17A is the leading effec- and III clinical trials have shown the superior effi- tor cytokine in tissue inflammation, autoimmun- cacy of bimekizumab with respect to ustekinumab, ity and host defence, but the role of IL-17F is not adalimumab and secukinumab in psoriasis head- insignificant. A clear example is chronic mucocu- to-head trials. Rapid onset of improvement, with taneous candidiasis caused by a single mutation some patients showing near complete resolution in the IL-17F gene.54 Periodontitis, an inflamma- of psoriasis plaques in 2 weeks, points to the supe- tion of the gingival tissue significantly associated riority of dual IL-17A and IL-17F blockade over with psoriasis and PsA,55 is characterized by neu- IL-12/23, TNF-α and IL-17A blockade as regards trophil infiltration and increased expression of cutaneous manifestations. Maintenance dose IL-17A and IL-17F.56 Furthermore, IL-17A also every 8 weeks has been shown to be effective with plays a key role in vascular inflammation, as bimekizumab, which could offer substantial shown in animal models with monoclonal anti- advantages compared with other IL-17 inhibitors. bodies against IL-17A or IL-17RA and with Interestingly, sustained skin clearance beyond IL-17RA or IL-17A knock-out murine models.57 pharmacokinetic expectations after randomized Moreover, a positive correlation has been found withdrawal, heretofore considered a hallmark of between circulating levels of IL-17 cytokines and specific IL-23 inhibitors, has also been observed severity and progression of carotid artery plaques for bimekizumab: in the randomized withdrawal in patients with atherosclerosis.58 phase of the BE READY trial, the median time to journals.sagepub.com/home/taj 11 Therapeutic Advances in Chronic Disease 12 loss of PASI75 response was 32 weeks after the candidiasis in up to 4% of patients64 and dermato- last dose, and the corresponding value was phyte infections (probably underreported).65 28 weeks for PASI90.33,63 In addition, the efficacy Although most trials excluded patients with a prior of bimekizumab has been tested in patients with history of IBD, there was no increased IBD signal BSA ⩽5.36 Furthermore, in its proof-of-concept with dual IL-17A and IL-17F inhibition compared trial, sonelokimab has shown some of the highest to IL-17A inhibition alone. As for mucocutaneous levels of efficacy so far, achieving PASI90 in 100% candidiasis, both bimekizumab and sonelokimab of patients at day 85.25 Moreover, results from the have shown numerically higher rates of oral can- phase IIb study of sonelokimab suggest a more didiasis than currently approved IL-17 inhibitors, rapid effect and higher peak response than with pointing towards the protective role of IL-17F secukinumab, although formal comparisons can- against mucosal Candida infections.64 Anyhow, not be established.47 Further research will provide most instances of candidiasis were mild to moder- more information on how their different mecha- ate and resolved with topical or oral antifungal nism of action influences the efficacy and safety of treatment. Whether the better efficacy and faster each drug. action of these new molecules compensates for the increased incidence of candidiasis remains to be The role of IL-17 cytokines in PsA has been dem- clarified, but will have to be assessed and discussed onstrated in preclinical trials, with both IL-17A with each patient individually. and IL-17F being able to induce proinflamma- tory cytokines in synoviocytes, periosteum and the skin. Dual neutralization of these cytokines Conclusion resulted in synergy suppressing these activator Throughout this text we have analyzed exten- pathways.27 Despite the encouraging results of sively the current evidence supporting the use of the phase Ib proof-of-concept study,27 BE dual inhibitors of IL-17A and IL-17F in psoria- ACTIVE32 failed its primary endpoint. The dif- sis. The main limitation of this work is that we ference between placebo group and bimekizumab have chosen to perform a comprehensive review 320 mg group in ACR50 response at week 12 was instead of a systematic review. Blockade of very close to statistical significance (p = 0.051); IL-17A and IL-17F with a dual specific agent the ACR50 responses at week 12 with all other (bimekizumab) is likely to provide a fast onset bimekizumab doses were significantly superior and highly efficacious option for treatment of than placebo, albeit with nominal p values: bime- moderate to severe psoriasis and PsA, with a kizumab 16 mg OR 4.2, 95% CI 1.1–15.2, good safety profile and acceptable tolerability. p = 0·032; bimekizumab 160 mg OR 8.1, 95% CI Furthermore, phase II results with sonelokimab, 2.3–28.7, p = 0.0012; bimekizumab 160 mg with a bispecific nanobody, have generated great loading dose OR 9.7, 95% CI 2.7–34.3, expectations. p = 0.0004).32 Furthermore, patients included in the 320 mg bimekizumab group had a higher Author contributions mean tender joint count, mean pain and patient LP: conceptualization, formal analysis, supervi- global assessment of diseases activity scores, with sion, validation, visualization, writing – original a slightly higher mean body mass index than those draft preparation, writing – review and editing. in the other groups.32 The primary endpoint cho- HI: conceptualization, methodology, investiga- sen (ACR50 at week 12) was more ambitious tion, writing – original draft preparation, writing than in other trials of IL-17 inhibitors, and the – review and editing. number of patients in each dose group was small, The associate editor of Therapeutic Advances in accounting perhaps for insufficient statistical Chronic Disease is an author of this paper, there- power.39 Upcoming phase III clinical trials will fore, the peer review process was managed by clarify the optimal dosing, loading dose and treat- alternative members of the board and the submit- ment regimes, and will arguably confirm the ting editor had no involvement in the decision- superiority of dual inhibition of IL-17A and making process. IL-17F over inhibition of IL-17A alone in PsA. Funding Regarding safety, common concerns with IL-17 The authors received no financial support for the inhibitors include the induction or exacerbation of research, authorship, and/or publication of this IBD and fungal infections, mainly mucocutaneous article. 12 journals.sagepub.com/home/taj H Iznardo and L Puig Conflict of interest statement 5. Alinaghi F, Calov M, Kristensen LE, et al. H. Iznardo does not have any potential conflicts Prevalence of psoriatic arthritis in patients with of interest involving the work under consideration psoriasis: a systematic review and meta-analysis for publication. of observational and clinical studies. J Am Acad Dermatol 2019; 80: 251–265.e19. L. Puig has perceived consultancy/speaker’s honoraria from and/or participated in clinical 6. Ritchlin CT, Colbert RA and Gladman DD. trials sponsored by Abbvie, Almirall, Amgen, Psoriatic arthritis. N Engl J Med 2017; 376: Baxalta, Biogen, Boehringer Ingelheim, Celgene, 957–970. Gebro, Janssen, JS BIOCAD, Leo-Pharma, Lilly, 7. Armstrong AW and Read C. Pathophysiology, Merck-Serono, MSD, Mylan, Novartis, Pfizer, clinical presentation, and treatment of psoriasis: a Regeneron, Roche, Sandoz, Samsung-Bioepis, review. JAMA 2020; 323: 1945–1960. Sanofi, and UCB. 8. Iwakura Y, Ishigame H, Saijo S, et al. Functional Receipt of grants/research supports or participa- specialization of interleukin-17 family members. tion in clinical trials (paid to institution): Abbvie, Immunity 2011; 34: 149–162. Almirall, Amgen, Boehringer Ingelheim, Celgene, Janssen, Leo-Pharma, Lilly, Novartis, Pfizer, 9. Nakae S, Nambu A, Sudo K, et al. Suppression Regeneron, Roche, Sanofi, UCB. of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 2003; 171: Receipt of honoraria or consultation fees (paid to 6173–6177. myself): Abbvie, Almirall, Amgen, Baxalta, Biogen, Boehringer Ingelheim, Bristol Myers 10. van Tok MN, van Duivenvoorde LM, Kramer Squibb, Celgene, Fresenius-Kabi, Janssen, JS I, et al. Interleukin-17A inhibition diminishes BIOCAD, Leo-Pharma, Lilly, Mylan, Novartis, inflammation and new bone formation in Pfizer, Regeneron, Roche, Sandoz, Samsung- experimental spondyloarthritis. Arthritis Rheumatol 2019; 71: 612–625. Bioepis, Sanofi, UCB. Participation in a company sponsored speaker’s 11. Wright JF, Guo Y, Quazi A, et al. Identification bureau: Celgene, Janssen, Lilly, Novartis, Pfizer. of an interleukin 17F/17A heterodimer in Stock shareholder: None. activated human CD4+ T cells. J Biol Chem Other support (please specify): None. 2007; 282: 13447–13455. 12. Chang SH and Dong C. 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