Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials

Reich, Kristian; Papp, Kim; Blauvelt, Andrew; Tyring, Stephen K.; Sinclair, Rodney; Thaçi, Diamant; Nograles, Kristine; Mehta, Anish; Cichanowitz, N.; Li, Qing; Liu, Kenneth; Rosa, Carmen La; Green, Stuart; Kimball, Alexa B.

doi:10.1016/s0140-6736(17)31279-5

Cited by 462 publications

(551 citation statements)

References 44 publications

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“…These results indicate that disruption of the IL-23/Th17 immune signaling axis is sufficient to reverse the aberrant epidermal signaling networks induced by CARD14 GoF mutation. Thus, CARD14 GoF drives IL-23emediated psoriatic skin disease, and targeting of IL-23p19 in this mouse model is a rapid and effective therapeutic option, consistent with reports from phase III clinical trials in patients with plaque-type psoriasis (Nakamura et al, 2017;Papp et al, 2017;Reich et al, 2017).…”

Section: Neutralization Of the T Helper Type 17-polarizing Cytokine Isupporting

confidence: 83%

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Mellett

Meier

Mohanan

et al. 2018

Journal of Investigative Dermatology

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Rare autosomal dominant mutations in the gene encoding the keratinocyte signaling molecule CARD14, have been associated with an increased susceptibility to psoriasis, but the physiological impact of CARD14 gain-offunction mutations remains to be fully determined in vivo. Here, we report that heterozygous mice harboring a CARD14 gain-of-function mutation (Card14DE138) spontaneously develop a chronic psoriatic phenotype with characteristic scaling skin lesions, epidermal thickening, keratinocyte hyperproliferation, hyperkeratosis, and immune cell infiltration. Affected skin of these mice is characterized by elevated expression of anti-microbial peptides, chemokines, and cytokines (including T helper type 17 cell-signature cytokines) and an immune infiltrate rich in neutrophils, myeloid cells, and T cells, reminiscent of human psoriatic skin. Disease pathogenesis was driven by the IL-23/IL-17 axis, and neutralization of IL-23p19, the key cytokine in maintaining T helper type 17 cell polarization, significantly reduced skin lesions and the expression of antimicrobial peptides and proinflammatory cytokines. Therefore, hyperactivation of CARD14 alone is sufficient to orchestrate the complex immunopathogenesis that drives T helper type 17-mediated psoriasis skin disease in vivo.

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Section: Neutralization Of the T Helper Type 17-polarizing Cytokine Isupporting

confidence: 83%

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Mellett

Meier

Mohanan

et al. 2018

Journal of Investigative Dermatology

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“…Other IL-23 blockers include guselkumab, recently approved for treating psoriasis, [9] and tildrakizumab, [10] which is being developed for the same indication. Secukinumab and ixekizumab, both IL-17 inhibitors, were also efficacious against several autoimmune inflammatory disorders [11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

et al. 2018

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Background and Objectives Risankizumab is a humanized anti-interleukin-23 monoclonal antibody in development for the treatment of several inflammatory diseases. This work characterized the pharmacokinetics of risankizumab and evaluated covariates that may affect its exposures using phase I and II trial data in subjects with psoriasis and Crohn's disease. Methods Plasma concentration measurements from a phase I study and a phase II study in subjects with psoriasis (n = 157; single doses of 0.01-5 mg/kg intravenously, 0.25-1 mg/kg subcutaneously, and 18 mg subcutaneously, and multiple doses of 90 and 180 mg subcutaneously), and a phase II study in subjects with Crohn's disease (n = 115; doses of 200 or 600 mg intravenously every 4 weeks followed by 180 mg subcutaneously every 8 weeks) were analyzed using non-linear mixedeffects modeling. The model was qualified using bootstrap and simulation-based diagnostics. Results A two-compartment model with first-order absorption and elimination described the pharmacokinetics of risankizumab. Considering the body weight and baseline albumin central tendency differences between disease populations, risankizumab clearance, steady-state volume of distribution, and terminal-phase elimination half-life were estimated to be approximately 0.35 L/day, 11.7 L, and 27 days, respectively, for a typical 90-kg subject with psoriasis with an albumin level of 42 g/L, and 0.31 L/day, 8.45 L, and 22 days, respectively, for a typical 65-kg subject with Crohn's disease with an albumin level of 37 g/L. Risankizumab absolute subcutaneous bioavailability and absorption rate constant were 72% and 0.18 day −1 , respectively. Inter-individual variability for clearance was 37%. Conclusions Risankizumab displayed pharmacokinetic characteristics typical for an IgG1 monoclonal antibody with no apparent target-mediated disposition. Accounting for the effects of body weight and baseline albumin explained the small differences in the pharmacokinetics of risankizumab between psoriasis and Crohn's disease, with no further differences between the patient populations. Electronic supplementary materialThe online version of this article (https ://doi.org/10.1007/s4026 2-018-0704-z) contains supplementary material, which is available to authorized users. Key PointsA robust two-compartment model with dose-and timeindependent pharmacokinetic parameters was developed to characterize the disposition of risankizumab, an antiinterleukin-23 monoclonal antibody, in subjects with plaque psoriasis and Crohn's disease.Of the factors evaluated (demographics, disease population, laboratory values, and anti-drug antibody development), only body weight and baseline albumin level were statistically correlated with risankizumab clearance. Body weight had a modest effect on risankizumab exposure while albumin had no meaningful impact.After accounting for differences in body weight and baseline albumin levels between psoriasis and Crohn's disease patient populations, no significant differences in the pharmacokinetics of ri...

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“…However, etanercept is expensive, with the price being 10 times higher compared with conventional drugs [1]. In addition, although clinical outcomes are improved in a great proportion of psoriasis patients with etanercept treatment, some patients still did not achieve clinical response to etanercept [8-10]. Therefore, identifying factors correlated with clinical response to etanercept is greatly needed.…”

Section: Introductionmentioning

confidence: 99%

Depression Symptoms Predict Worse Clinical Response to Etanercept Treatment in Psoriasis Patients

2018

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Background/Aims: This study aimed to investigate the predicting values of depression and anxiety symptoms for clinical response to etanercept treatment in psoriasis patients. Methods: A total of 85 psoriasis patients who received 6 months of etanercept treatment were consecutively enrolled in this prospective cohort study. The Psoriasis Area and Severity Index (PASI) score was evaluated at month 0 (M0), M1, M3, and M6, and the corresponding PASI 75/90 response at each visit was assessed. Also, anxiety and depression symptoms were assessed by the Hospital Anxiety and Depression Scale (HADS) at M0, M1, M3, and M6. Results: Depression symptoms were observed to correlate with female gender (p = 0.004), longer disease duration (p = 0.018), and higher PASI score (p < 0.001), and anxiety symptoms were seen to be associated with female gender (p = 0.017), larger psoriasis-affected body surface area (p = 0.049), and higher PASI score (p = 0.017) in psoriasis patients. After etanercept treatment, HADS-Depression (HADS-D) and HADS-Anxiety (HADS-A) scores were both decreased at M1, M3, and M6 (all p < 0.001) compared with M0. Most importantly, baseline depressed patients presented with a lower PASI 75 response rate at M3 (p = 0.014) and M6 (p = 0.005), and a reduced PASI 90 response rate at M6 (p = 0.045) compared with baseline non-depressed patients. Furthermore, multivariate logistic regression analyses revealed that depression symptoms at baseline were an independent predictive factor for the lower possibility of both PASI 75 response (p = 0.048) and PASI 90 response (p = 0.048) achievements at M6 in psoriasis patients. However, no correlation of baseline anxiety symptoms with PASI 75/90 responses was observed. Conclusion: Depression symptoms at baseline independently predict a worse clinical response to etanercept treatment in psoriasis patients.

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Tildrakizumab versus placebo or etanercept for chronic plaque psoriasis (reSURFACE 1 and reSURFACE 2): results from two randomised controlled, phase 3 trials

Cited by 462 publications

References 44 publications

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

993 CARD14 gain-of-function mutation alone is sufficient to drive IL-23/IL-17-mediated psoriasiform skin inflammation in vivo

Population Pharmacokinetics of the Interleukin-23 Inhibitor Risankizumab in Subjects with Psoriasis and Crohn’s Disease: Analyses of Phase I and II Trials

Depression Symptoms Predict Worse Clinical Response to Etanercept Treatment in Psoriasis Patients

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