Dataset Information

Exposure-Response Relationships for Efficacy and Safety of Risankizumab in Phase II and III Trials in Psoriasis Patients.

ABSTRACT: Risankizumab has demonstrated efficacy in phase III trials in patients with moderate-to-severe plaque psoriasis. The exposure-response relationships for risankizumab efficacy (Psoriasis Area and Severity Index (PASI)75, PASI90, PASI100, and static Physician's Global Assessment (sPGA)0/1) at week 16 (N = 1,732) and week 52 (N = 598) as well as safety (incidence of any adverse event, serious adverse event, infection and infestation, or serious infection) over up to 52 weeks were characterized using the data from risankizumab phase II and III clinical trials in patients with moderate-to-severe plaque psoriasis. Impact of clinically relevant covariates was evaluated. Risankizumab phase III regimen (150 mg subcutaneously at weeks 0, 4, and every 12 weeks thereafter) achieved the plateau of the exposure-efficacy relationships with model-estimated PASI90 and sPGA0/1 response probabilities of 77%, and 87%, respectively, at week 16 and 85%, and 88%, respectively, at week 52. There was no apparent relationship between risankizumab plasma exposure and the evaluated safety variables.

SUBMITTER: Khatri A

PROVIDER: S-EPMC7006881 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Exposure-Response Relationships for Efficacy and Safety of Risankizumab in Phase II and III Trials in Psoriasis Patients.

Khatri Amit A Suleiman Ahmed A AA Polepally Akshanth R AR Othman Ahmed A AA Othman Ahmed A AA

Clinical pharmacology and therapeutics 20190926 2

Risankizumab has demonstrated efficacy in phase III trials in patients with moderate-to-severe plaque psoriasis. The exposure-response relationships for risankizumab efficacy (Psoriasis Area and Severity Index (PASI)75, PASI90, PASI100, and static Physician's Global Assessment (sPGA)0/1) at week 16 (N = 1,732) and week 52 (N = 598) as well as safety (incidence of any adverse event, serious adverse event, infection and infestation, or serious infection) over up to 52 weeks were characterized usin ...[more]

PMID: 31355921

Similar Datasets

Project description:Background and objectivesRisankizumab 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.MethodsPlasma 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 mixed-effects modeling. The model was qualified using bootstrap and simulation-based diagnostics.ResultsA 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%.ConclusionsRisankizumab 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.

Project description:ImportanceRisankizumab selectively inhibits interleukin 23, a cytokine that contributes to psoriatic inflammation.ObjectiveTo evaluate the efficacy and safety of risankizumab vs placebo and continuous treatment vs withdrawal in adults with moderate to severe plaque psoriasis.Design, setting, and participantsMultinational, phase 3, randomized, double-blind, placebo-controlled trial conducted from March 6, 2016, to July 26, 2018. A total of 507 eligible patients had stable moderate to severe chronic plaque psoriasis for 6 months or longer, body surface area involvement greater than or equal to 10%, Psoriasis Area and Severity Index (PASI) greater than or equal to 12, and a static Physician's Global Assessment (sPGA) score greater than or equal to 3. Intention-to-treat analysis was conducted.InterventionsPatients were randomized (4:1, interactive response technology) to risankizumab, 150 mg, subcutaneously, or placebo at weeks 0 and 4 (part A1). All patients received risankizumab at week 16. At week 28, patients randomized to risankizumab who achieved an sPGA score of 0/1 were rerandomized 1:2 to risankizumab or placebo every 12 weeks (part B).Main outcomes and measuresCo-primary end points for the part A1 phase included proportions of patients achieving greater than or equal to 90% improvement in PASI (PASI 90) and sPGA score of 0/1 at week 16. The PASI measures severity of erythema, infiltration, and desquamation weighted by area of skin involvement over the head, trunk, upper extremities, and lower extremities; scores range from 0 (no disease) to 72 (maximal disease activity). The sPGA assesses average thickness, erythema, and scaling of all psoriatic lesions; scores range from 0 (clear) to 4 (severe), with 0/1 indicating clear or almost clear. Primary and secondary end points in part B included proportion of rerandomized patients achieving an sPGA score of 0/1 at week 52 (primary) and week 104 (secondary).ResultsOf 563 patients screened, 507 were randomized to risankizumab (n = 407) or placebo (n = 100). Most patients were men (356 [70.2%]); median age was 51 years (interquartile range, 38-60 years). At week 16, 298 patients (73.2%) in the treatment group vs 2 patients (2.0%) receiving placebo achieved a PASI 90 response, and 340 patients (83.5%) receiving risankizumab vs 7 patients (7.0%) receiving placebo achieved sPGA 0/1 scores (placebo-adjusted differences: PASI 90: 70.8%; 95% CI, 65.7%-76.0%; sPGA 0/1: 76.5%; 95% CI, 70.4%-82.5%; P < .001 for both). At week 28, 336 responders were rerandomized to risankizumab (n = 111) or treatment withdrawal (n = 225). At week 52, the sPGA 0/1 score was achieved by 97 patients (87.4%) receiving risankizumab vs 138 patients (61.3%) receiving placebo. At week 104, the sPGA 0/1 score was achieved by 90 patients (81.1%) receiving risankizumab vs 16 patients (7.1%) receiving placebo (placebo-adjusted differences: week 52: 25.9%; 95% CI, 17.3%-34.6%; week 104: 73.9%; 95% CI, 66.0%-81.9%; P < .001 for both). Rates of treatment-emergent adverse events were similar between risankizumab (186 [45.7%]) and placebo (49 [49.0%]) in part A1 and remained stable over time.Conclusions and relevanceRisankizumab showed superior efficacy compared with placebo through 16 weeks and treatment withdrawal through 2 years. Risankizumab was well tolerated, with no unexpected safety findings during the 2-year trial.Trial registrationClinicalTrials.gov Identifier: NCT02672852.

Project description:Biological targeted therapy serves as a new alternative treatment for psoriasis due to its minimal side effects. This study is aimed at examining the drug effectiveness and safety of risankizumab and ustekinumab for psoriasis treatment, so as to provide a reference for clinical decision-making. Databases from Embase, Web of Science, PubMed, and Cochrane Library were gathered, starting from inception to March 1, 2022, for randomized controlled trials regarding risankizumab and ustekinumab for psoriasis treatment. All retrieved articles were carefully selected in strict accordance with a set of inclusion and exclusion criteria. Stata 15.0 and RevMan 5.4 were applied to perform meta-analysis and risk of bias assessment. A total of two trials with three NCTs were selected, with 384 participants in the risankizumab group and 140 participants in ustekinumab. Meta-analysis showed that in the long-term and short-term PASI100, risankizumab was more effective than ustekinumab (RR = 2.27, 95% CI (1.77, 2.90), p < 0.05; RR = 2.33, 95% CI (1.75, 3.08), p < 0.05). In PASI90, RR = 1.77, 95% CI (1.54, 2.03), and p < 0.05 and RR = 1.72, 95% CI (1.48, 2.00), and p < 0.05. In short-term PASI75, RR = 1.23, 95% CI (1.13, 1.34), and p < 0.05. In sPGA of 0, the results at week-16 and week-52 showed that risankizumab was significantly more effective than ustekinumab (RR = 2.24, 95% CI (1.67, 3.01), p < 0.05; RR = 2.30, 95% CI (1.80, 2.95), p < 0.05). Risankizumab was significantly more effective than ustekinumab in improving the quality of life and PSS scores (RR = 1.48, 95% CI (1.26, 1.75), p < 0.05; RR = 2.01, 95% CI (1.41, 2.85), p < 0.05). Nevertheless, risankizumab and ustekinumab did not show significant difference in the incidence of adverse responses (RR = 1.02, 95% CI (0.75, 1.39), p > 0.05). Risankizumab was more effective than ustekinumab for the treatment of psoriasis. The adverse reactions of both risankizumab and ustekinumab were similar and could be tolerated. Risankizumab might be a better alternative option for their treatment.

Project description:Nowadays, the vaccination with COVID-19 vaccines is being promoted worldwide, professionals and common people are very concerned about the efficacy and safety of COVID-19 vaccines. No published systematic review and meta-analysis has assessed the efficacy and safety of the COVID-19 vaccines based on data from phase III clinical trials. Therefore, this study has estimated the efficacy and safety of COVID-19 vaccines and the differences between vaccine types. PubMed, Embase, the Cochrane Library, CNKI, Wanfang, medRxiv databases and two websites were used to retrieve the studies. Random-effects models were used to estimate the pooled efficacy and safety with risk ratio (RR). A total of eight studies, seven COVID-19 vaccines and 158,204 subjects were included in the meta-analysis. All the vaccines had a good preventive effect on COVID-19 (RR = 0.17, 95% CI: 0.09-0.32), and the mRNA vaccine (RR = 0.05, 95% CI: 0.03-0.09) was the most effective against COVID-19, while the inactivated vaccine (RR = 0.32, 95% CI: 0.19-0.54) was the least. In terms of safety, the risk of overall adverse events showed an increase in the vaccine group after the first (RR = 1.46, 95% CI: 1.03-2.05) or second (RR = 1.52, 95% CI: 1.04-2.20) injection. However, compared with the first injection, the risk of local (RR = 2.64, 95% CI: 1.02-6.83 vs. RR = 2.25, 95% CI: 0.52-9.75) and systemic (RR = 1.33, 95% CI: 1.21-1.46 vs. RR = 1.59, 95% CI: 0.84-3.01) adverse events decreased after the second injection. As for the mRNA vaccine, the risk of overall adverse events increased significantly, compared with the placebo, no matter whether it was the first (RR = 1.83, 95% CI = 1.80-1.86) or the second (RR = 2.16, 95% CI = 2.11-2.20) injection. All the COVID-19 vaccines that have published the data of phase III clinical trials have excellent efficacy, and the risk of adverse events is acceptable. The mRNA vaccines were the most effective against COVID-19, meanwhile the risk and grade of adverse events was minimal, compared to that of severe symptoms induced by COVID-19.

Dataset Information

Exposure-Response Relationships for Efficacy and Safety of Risankizumab in Phase II and III Trials in Psoriasis Patients.

Publications

Exposure-Response Relationships for Efficacy and Safety of Risankizumab in Phase II and III Trials in Psoriasis Patients.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets