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In two trials in patients with moderate-to-severe plaque psoriasis, the anti–interleukin-17A monoclonal antibody secukinumab was more effective than placebo and etanercept. Infectious complications occurred more often with secukinumab than with placebo. Psoriasis is a chronic, immune-mediated inflammatory skin disease that is associated with substantial impairment of physical and psychological quality of life. 1 , 2 Our understanding of the pathogenesis of psoriasis was advanced by the discovery of the class of type 17 helper T (Th17) cells, which regulates innate and adaptive immunity. The proinflammatory cytokine interleukin-17A is the primary effector of Th17 cells, but it is also produced by other cell types in psoriatic lesions, including γδ T cells, neutrophils, and possibly mast cells. 3 – 7 Interleukin-17A stimulates keratinocytes to secrete chemokines and other proinflammatory mediators that recruit additional inflammatory cells, including neutrophils, . . .

In a trial involving 255 patients with moderate-to-severe plaque psoriasis, the oral interleukin-23–receptor antagonist peptide JNJ-77242113 showed a dose–response relationship and greater efficacy than placebo within 16 weeks.

A proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis. Antibody treatment of psoriasis Sauzanne Khalilieh and colleagues report a proof-of-concept phase I clinical trial which demonstrates that targeting the pro-inflammatory cytokine interleukin-23 (IL-23) with tildrakizumab, an antibody that binds to the p19 subunit of IL-23, leads to symptomatic improvement of disease in patients with moderate to severe psoriasis. The antibody is well tolerated, suggesting that selective targeting of IL-23 merits further study. Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being 1 , 2 , 3 . The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg −1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg −1 group and 13 out of 14 subjects in the 10 mg kg −1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25 bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control. Impaired interleukin-2 production and regulatory T cell dysfunction is implicated in multiple autoimmune diseases. Here, in two phase lb trials, the authors show that rezpegaldesleukin, a Treg-selective pegylated IL-2, is safe and improves symptoms in patients with atopic dermatitis or psoriasis.

This study aims to compare the efficacy of IL-17 and IL-23 biologics in the treatment of plaque psoriasis (Psoriasis vulgaris) in patients with metabolic syndrome (MetS) and to explore the effects of different biologics on metabolic indicators, particularly regarding the differences in efficacy during long-term treatment. This is a randomized controlled clinical trial involving 120 moderates to severe plaque psoriasis patients, of which 60 have metabolic syndrome and 60 do not. The patients were randomly assigned to three groups: IL-17 biologics group, IL-23 biologics group, and cyclosporine control group. Treatment lasted for three months, with evaluation indicators including psoriatic lesion assessment (PASI score), blood glucose levels, lipid profile (triglycerides, HDL-C), inflammatory markers (CRP, ESR, IL-6), etc. Patients were assessed at baseline, after one month, and after three months of treatment for both clinical efficacy and changes in metabolic indicators. Both IL-17 and IL-23 biologics demonstrated superior efficacy compared to cyclosporine in treating plaque psoriasis. After one month and three months of treatment, PASI scores in the IL-17 and IL-23 groups were significantly lower than in the control group, and the therapeutic effects were more pronounced ( P  < 0.05). The IL-17 and IL-23 groups also showed better improvements in blood glucose, blood lipids (TG and HDL-C), and inflammatory markers (CRP, ESR, IL-6) compared to the control group. After three months of treatment, fasting blood glucose, fasting insulin, triglycerides, and CRP levels were significantly lower in the IL-17 and IL-23 groups than in the control group ( P  < 0.05). Metabolic syndrome had some impact on treatment outcomes, with the efficacy of IL-17 and IL-23 biologics being lower in patients with metabolic abnormalities compared to those without metabolic syndrome. However, the IL-23 biologic showed less impact from metabolic syndrome. IL-17 biologics had a rapid effect in the short term, while IL-23 biologics demonstrated superior efficacy in long-term treatment, particularly at the three-month mark, where both efficacy and metabolic improvements were better than the IL-17 group. Both IL-17 and IL-23 biologics are more effective than cyclosporine in treating plaque psoriasis and can improve metabolic indicators in patients. Although metabolic syndrome impacts the efficacy of IL-17 biologics, IL-23 biologics are less affected by metabolic syndrome and demonstrate better long-term efficacy. Therefore, IL-23 biologics are recommended for long-term treatment in plaque psoriasis patients with metabolic syndrome.

Background Palmoplantar pustulosis (PPP), a refractory skin disease characterized by repeated eruptions of sterile pustules and vesicles on palms and/or soles, involves interleukin-17 pathway activation. Brodalumab, a fully human anti-interleukin-17 receptor A monoclonal antibody, is being investigated for use in PPP treatment. Objective The aim was to assess the efficacy and safety of brodalumab in Japanese PPP patients with moderate or severe pustules/vesicles. Methods A phase 3, randomized, double-blind, placebo-controlled trial was conducted between July 2019 and August 2022, at 41 centers in Japan. Patients aged 18–70 years with a diagnosis of PPP for ≥ 24 weeks, a PPP Area Severity Index (PPPASI) score of ≥ 12, a PPPASI subscore of pustules/vesicles of ≥ 2, and inadequate response to therapy were included. Participants were randomized 1:1 to receive brodalumab 210 mg or placebo, subcutaneously (SC) at baseline, weeks 1 and 2, and every 2 weeks (Q2W) thereafter until week 16. Changes from baseline to week 16 in the PPPASI total score (primary endpoint) and other secondary skin-related endpoints and safety endpoints were assessed. Results Of the 126 randomized patients, 50 of 63 in the brodalumab group and 62 of 63 in the placebo group completed the 16-week period. Reasons for discontinuation were adverse event ( n = 6), withdrawal by patient/parent/guardian ( n = 3), progressive disease ( n = 3), and lost to follow-up ( n = 1) in the brodalumab group and Good Clinical Practice deviation ( n = 1) in the placebo group. Change from baseline in the PPPASI total score at week 16 was significantly higher ( p = 0.0049) with brodalumab (least-squares mean [95% confidence interval {CI}] 13.73 [10.91–16.56]) versus placebo (8.45 [5.76–11.13]; difference [95% CI] 5.29 [1.64–8.94]). At week 16, brodalumab showed a trend of rapid improvement versus placebo for PPPASI-50/75/90 response (≥ 50%/75%/90% improvement from baseline) and Physician’s Global Assessment 0/1 score: 54% versus 24.2%, 36.0% versus 8.1%, 16.0% versus 0.0%, and 32.0% versus 9.7%, respectively. Infection was the dominant treatment-emergent adverse event (TEAE); the commonly reported TEAEs were otitis externa (25.4%/1.6%), folliculitis (15.9%/3.2%), nasopharyngitis (14.3%/4.8%), and eczema (14.3%/12.9%) in the brodalumab/placebo groups, respectively. The severity of most TEAEs reported was Grade 1 or 2 and less frequently Grade ≥ 3. Conclusions Brodalumab SC 210 mg Q2W demonstrated efficacy in Japanese PPP patients. The most common TEAEs were mild infectious events. Trial Registration NCT04061252 (Date of Trial Registration: August 19, 2019)

Type 1 cytokines are overexpressed in psoriatic plaques. This trial evaluated a monoclonal antibody against interleukin-12 and interleukin-23 in patients with psoriasis. Response rates at 12 weeks were significantly higher in patients treated with interleukin-12/23 monoclonal antibody than in those treated with placebo. Four percent of patients who received interleukin-12/23 monoclonal antibody and 1% of those who received placebo had serious adverse events. Larger studies of longer duration are needed to assess the effectiveness and safety of interleukin-12/23 monoclonal antibody for psoriasis. In patients with psoriasis, response rates at 12 weeks were significantly higher in those treated with interleukin-12/23 monoclonal antibody than in those treated with placebo. Psoriasis is a chronic inflammatory skin disorder affecting 2 to 3% of the world's population. 1 , 2 Psoriasis affects the physical and emotional well-being of patients, and its effect on quality of life is similar to that seen with other major medical diseases. 3 Significant unmet need remains for safe, highly effective, and convenient treatments. Aberrant type 1 immune responses have been linked to the pathogenesis of psoriasis, 4 – 7 and cytokines that elicit these immune responses (e.g., interleukin-12 and interleukin-23) may represent appropriate therapeutic targets. 8 Interleukin-12 p40 is overexpressed in psoriasis plaques, 9 and preclinical studies implicate this cytokine in the pathogenesis of . . .

The objective of this study was to demonstrate that BCD-057 is similar to innovator adalimumab (iADA) in terms of efficacy, safety, and pharmacokinetics in steady state in the target population of patients with moderate to severe plaque psoriasis (NCT02762955). Patients were randomized in 1:1 ratio to receive 80 mg of BCD-057 or iADA at week 0 and 40 mg thereafter every other week from week 1. At week 24 patients from iADA group were re-randomized (1:1) to continue iADA or to be switched to BCD-057. The primary efficacy endpoint was 75% improvement in Psoriasis Area and Severity Index from baseline (PASI 75), secondary endpoints included PASI percent improvement and relative change in affected Body Surface Area (BSA) from baseline at weeks 16, 24, 33, and 55. Safety was assessed through monitoring of adverse events (AEs) and antidrug antibodies. Pharmacokinetics was evaluated at steady state. Overall, 346 adult patients were included in the study (174/172 patients in BCD-057/iADA arms, respectively). At week 16 PASI 75 was achieved by 60.34% and 63.37% of patients in BCD-057 and iADA arms, respectively (p = 0.5622). Bounds of the calculated 95% confidence interval (CI) for the difference between PASI 75 responses in arms [-13.26%; 7.2%] fall within the equivalence margin [-15% to 15%] demonstrating equivalent efficacy of BCD-057 and iADA. At week 55 81.61%, 85.56%, and 80.49% of patients in BCD-057, iADA and iADA/BCD-057 arms achieved PASI 75. Comparison of the secondary endpoints did not show significant differences between arms. A comparable pharmacokinetics was shown at steady state. Safety profiles and proportions of patients with antidrug antibodies were similar between arms. The switch from the iADA to BCD-057 did not affect the immunogenicity profile. Obtained data demonstrate that BCD-057 and iADA are highly similar in clinical efficacy, pharmacokinetics, safety, and immunogenicity in patients with moderate to severe plaque psoriasis.

ObjectiveThis post hoc analysis compared the immunogenicity of the biosimilar adalimumab-adbm (Cyltezo) with the adalimumab reference product (RP; Humira) across indications, including rheumatoid arthritis (RA), Crohn’s disease (CD) and plaque psoriasis (PsO), and by patient sex in the VOLTAIRE trials programme.MethodsIn each active-comparator randomised controlled trial (RCT), immunogenicity was assessed at various time points by the proportion of patients with antidrug antibodies (ADAs) and neutralising antibodies (nAbs), using acid dissociation followed by electrochemiluminescence assay. Assay sensitivity was 50 ng/mL, and drug tolerance was ≥30 µg/mL (free drug) at the low positive control level.ResultsMinor differences in immunogenicity parameters (ADAs, ADA titres and nAbs) were evident between adalimumab-adbm and adalimumab RP across these three immune-mediated inflammatory diseases (IMIDs). The proportion of ADA-positive and nAb-positive patients increased from baseline over time in all three RCTs, as expected, and was similar in the RA and CD RCTs but with higher numbers of ADA-positive and nAb-positive patients reported in the PsO trial. Subgroup analysis by patient sex showed the same trend.ConclusionsDifferences among the RCTs may partially be explained by concomitant background therapy (methotrexate) in the RA trial, stable doses of azathioprine, 6-mercaptopurine or methotrexate in 36% of patients with CD and absence of background therapy in the PsO RCT. The analyses further confirm the biosimilarity of adalimumab-adbm with the adalimumab RP across IMIDs and provide supporting evidence that adalimumab-adbm is an interchangeable biosimilar with consistent clinical results in patients originally treated with the RP.Trial registration numbersVOLTAIRE-RA (NCT02137226; EudraCT 2012-002945-40); VOLTAIRE-CD (NCT02871635; EudraCT 2016-000612-14); VOLTAIRE-PsO (NCT02850965; EudraCT 2016-000613-79).