Psoriasis is a chronic, immune-mediated inflammatory skin disease that affects up to 3% of the population and is associated with diseases including chronic lung disease, diabetes, liver disease, cardiovascular disease, chronic kidney disease, and rheumatic diseases There is a significant correlation. The burden of disease is not just a physical manifestation, it has significant social and psychological factors that lead to a negative impact on the quality of life. Advances in basic immunology have enhanced our understanding of the pathogenesis of psoriasis, and promoted the development of targeted therapies for key proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin (IL) -17A And IL-23. Although targeting the TNF-dependent pathway has already shown positive reactions in patients with psoriasis, newly developed drugs targeting IL-23 / T-helper 17 cells have achieved greater efficacy. T-helper 17 cells are a key driver of psoriasis. Despite these advances, achieving complete removal of skin lesions and maintaining this level is still challenging; in addition, in these therapies, several safety issues have been noted, including injection site reactions, fungal infections (especially Candida) Infection) and inflammatory bowel disease (IBD) aggravation and new onset. Therefore, treatments that show more efficient and less safety issues can provide patients with additional benefits.
In the IL-17 cytokine family, the most extensive research has focused on IL-17A. Among the currently available treatments that target the IL-17 pathway, 2 drugs specifically inhibit IL-17A, and the third targets IL-17RA. IL-17RA is IL-17A, IL-17C, IL-25 and IL The receptor subunit used by 17F. Although IL-17A and IL-17F are the closest relatives in the IL-17 family, in history, the role of IL-17F has not been widely studied. IL-17F and IL-17A have more than 50% structural homology and overlapping biological pro-inflammatory functions, suggesting that IL-17F plays an important role in psoriasis. Evidence from preclinical studies indicates that both IL-17A and IL-17F are expressed in skin lesions and inflammatory synovium in patients with psoriatic arthritis (PsA). Compared with simply blocking IL-17A, double neutralization of IL-17A and IL-17F leads to a decrease in the expression levels of inflammation-related genes and cytokines, and an increase in the suppression of disease-related gene expression. Immune cell migration. These data support the theoretical basis for targeting IL-17A and IL-17F. To this end, bimelizumab, a humanized monoclonal IgG1 antibody, is designed to effectively and selectively neutralize the biological functions of IL-17A and IL-17F. In addition, in preclinical models, both IL-17A and IL-17F have been shown to cooperate with TNF to stimulate the production of key pro-inflammatory cytokines and amplify tissue inflammation. Compared with IL-17A blocking alone, the double neutralization of IL-17A and IL-17F leads to a reduction in the expression levels of inflammation-related genes and cytokines, and greater inhibition of disease-related immune cell migration. These data support the theoretical basis for targeting IL-17A and IL-17F. To this end, the humanized IgG1 monoclonal antibody bimekizumab was designed to effectively and selectively neutralize the biological functions of IL-17A and IL-17F.
method
This is a randomized, double-blind, placebo-controlled, parallel group, and dose range study (NCT02905006), recruiting 6 countries (Canada, Czech Republic, Hungary, Japan, Poland and the United States). All patients who have stopped or did not participate in the extended study (NCT03010527) will need to complete a 20-week safety follow-up after taking the final dose of study drug. The study was conducted in accordance with the principles of the Helsinki Declaration and the International Conference on Good Clinical Practice Coordination and Guidance. Obtained approval from the Independent Agency Review Committee.
The criteria for eligible patients were age ≥18 years, diagnosed with moderate-severe plaque psoriasis over 6 months, PASI score ≥12, psoriatic lesions accounted for more than 10% of body surface area, the investigator ’s global assessment (IGA ) With a score of more than 3 (5-point scale), and patients who are going to receive systemic psoriasis treatment or phototherapy. Psoriasis treatment or phototherapy. Patients who had received anti-IL-17 treatment within 6 months or had been exposed to psoriasis or other biological therapies of PsA, apparently uncontrolled neuropsychiatric disorders, history of suicide attempts, or suicidal thoughts were excluded (severe use of electronic suicide) Degree evaluation scale). For other appendices and exclusion criteria, see the supplementary appendix (available at http://www-jad.org). All patients provided written informed consent in accordance with local requirements.
Patients were randomly divided into 6 groups (1: 1: 1: 1: 1: 1) and received bimekizumab every 4 weeks at doses of 64 mg, 160 mg, 160 mg (baseline loading dose of 320 mg), 320 mg, 480 mg or placebo. An interactive voice or network response system is used to assign eligible patients to a treatment plan based on a randomized schedule established by an independent biostatistician who is not involved in the design or analysis of the study. Treatment allocation is stratified by geographic area and previous biological exposure.
Bimekizumab is provided in single-use vials containing 160 mg / mL. Due to the different presentation methods, in order to ensure that the study is blinded, bimekizumab and placebo injections are prepared and administered by non-blind, dedicated researchers at the study site (Supplementary Appendix).
Process
Treatment was performed at baseline, weeks 4 and 8, with 3 subcutaneous injections (see supplementary materials). Efficacy and safety were evaluated at baseline and weeks 1, 2, 4, 6, 8, and 12 Security is monitored by an external data monitoring committee.
Result
The primary efficacy endpoint was PASI90 at week 12. The secondary efficacy endpoints were PASI90 at week 8, PASI75 and PASI100 at week 12, and IGA at weeks 8 and 12 considered effective (defined as complete improvement or most improvement. Compared with the baseline level, there were 2 or more aspects. Improvement). Safety monitoring during the study included recording the frequency and severity of adverse events (AE) (based on the common terminology standard for adverse events), serious AEs, suicidal ideation and behavior (through the Columbia Suicide Severity Rating Electronic Scale), and depression and anxiety ( (Assessed by the Hospital Anxiety and Depression Scale). In addition, we use electrocardiogram to assess the patient's heart function, measure vital signs, and perform physical examinations and laboratory tests.