A multicentre randomized double-blind placebo-controlled phase III study of the efficacy and safety of xeligekimab (GR1501) in patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Xeligekimab (GR1501) is a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A and has shown potential efficacy in treating moderate-to-severe psoriasis in preliminary trials. OBJECTIVES: To evaluate the efficacy and safety of xeligekimab in Chinese patients with moderate-to-severe psoriasis. METHODS: A total of 420 Chinese patients were randomized to 200 mg xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by an extension of the treatment schedule to xeligekimab every 4 weeks for a further 40 weeks. Efficacy was assessed by evaluating achievement of Physician Global Assessment (PGA) 0/1 and 75%, 90% and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90 and PASI 100, respectively). The safety profile was also evaluated. RESULTS: At week 12, PASI 75, PASI 90 and PASI 100 were achieved in 90.7%, 74.4% and 30.2% of patients in the xeligekimab group vs. 8.6%, 1.4% and 0% of patients in the placebo group, respectively. PGA 0/1 was achieved in 74.4% patients in the xeligekimab group and 3.6% of patients in the placebo group. PASI 75 and PGA 0/1 were maintained until week 52. No unexpected adverse events were recorded. CONCLUSIONS: Xeligekimab showed high efficacy and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis.

Psoriasis is a skin disease characterized by scaly and raised patches of skin on any part of the body. The condition can be caused by a combination of how a person's immune system works, their genes and their environment. A cytokine is a substance secreted by certain cells of the immune system that have an effect on other cells. One such cytokine, called IL-17A, has been associated with different inflammatory diseases, including psoriasis. We conducted a large trial in Chinese people with moderate-to-severe psoriasis to look at the efficacy (ability to produce the intended result) and safety of a medicine called xeligekimab (known as a 'monoclonal antibody') which works by targeting IL-17A. We randomly assigned 420 Chinese patients to receive 200 mg of xeligekimab every 2 weeks or a 'placebo' (no active medicine) for the first 12 weeks. We extended the treatment schedule of xeligekimab to every 4 weeks for a further 40 weeks. To assess how the medicine worked, we measured people's psoriasis symptoms and severity. To assess how safe the medicine was, we looked at the side-effects (or 'adverse events'). The results of this trial showed that xeligekimab improved people's psoriasis and itching starting at week 4 of receiving treatment, and more than 60% of people achieved improvement or remission by week 6, which was sustained up to week 52. The safety of xeligekimab was similar to another medicine classed as a monoclonal antibody (called secukinumab) and there were no new or unexpected adverse events reported. Overall, our findings suggest that xeligekimab is a safe and effective medicine for the treatment of psoriasis in Chinese people.

Safety, tolerability, pharmacokinetics and efficacy of HB0017, a humanized monoclonal antibody that targets interleukin-17A, in healthy participants and patients with moderate-to-severe plaque psoriasis.

BACKGROUND: Several interleukin (IL)-17 inhibitors have been approved for the treatment of moderate-to-severe plaque psoriasis (PsO). There is still scope for the development of affordable treatments for PsO. OBJECTIVES: To assess, in a phase Ia study, the safety, tolerability and pharmacokinetics (PK) of HB0017, a humanized monoclonal antibody that targets IL-17A, in healthy participants and patients with moderate-to-severe plaque PsO; and, in a phase Ib study, to assess the efficacy of HB0017 in patients with moderate-to-severe plaque PsO. METHODS: The phase Ia study (NCT04505033) was a randomized double-blind placebo-controlled dose-escalation study in healthy participants. Each cohort of 10 volunteers was randomly assigned to receive either a single dose of HB0017 (50 mg, 150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. The phase Ib study (NCT05442788) was a randomized double-blind placebo-controlled dose-escalation study in enrolled patients with moderate-to-severe plaque PsO. Each cohort of 10 patients was randomly assigned to receive either multiple doses of HB0017 (150 mg, 300 mg or 450 mg) or the matching placebo at a ratio of 4 : 1. RESULTS: HB0017 demonstrated dose-proportional linear PK and was tolerated across the dose range assessed. In the phase Ia and Ib studies, participants in both the HB0017 and placebo groups experienced treatment-emergent adverse events (69% vs. 87%, 96% vs. 100%, respectively). HB0017 demonstrated clinically meaningful effects in patients with moderate-to-severe plaque PsO. PASI 75 [≥ 75% improvement in Psoriasis Area and Severity Index (PASI)], PASI 90 (≥ 90% improvement in PASI) and static Physician Global Assessment (sPGA) 0/1 (i.e. 'clear' or 'almost clear') responses were 100% for the HB0017 300-mg group, with maximal improvements (100% or near 100% reductions from baseline) in PASI score observed at week 12, while the duration of effect was evident up to week 20. There was no clinical response in any participant in the placebo group in the phase Ib study. CONCLUSIONS: Overall, HB0017 showed acceptable safety and tolerability in both healthy participants and patients with moderate-to-severe plaque PsO. An encouraging signal of efficacy with a longer half-life provides HB0017 with the potential to be added to the currently available range of biologics targeting IL-17A.

Efficacy, Safety and Pharmacokinetics of IL-17 Monoclonal Antibody Injection (AK111) in Patients with Moderate-to-Severe Plaque Psoriasis: A Randomized, Double-Blinded, Placebo-Controlled Phase Ib Multidose Escalation Clinical Study.

OBJECTIVES: To evaluate the safety, tolerability, immunogenicity, and induced expression of skin biomarkers of AK111 injection after multiple administrations in subjects with moderate-to-severe plaque psoriasis. METHODS: This study is a randomized, double-blinded, placebo-parallel-controlled study using a dose escalation mode of multiple doses. A total of 48 subjects were sequentially randomized to receive each AK111 dose regimen (75 mg, 150 mg, 300 mg, 450 mg) or the corresponding placebo. All subjects were treated with the study drug at weeks 0, 1, 4, and 8 and were unblinded at week 12, with the placebo group ending and the AK111 group being followed up to 20 weeks. RESULTS: At week 12, compared with placebo, the percentage of subjects achieving Psoriasis Area and Severity Index 75 (PASI75) and static Physician Global Assessment (sPGA) 0/1 in the AK111 75 mg-450 mg dose groups was significantly increased, and higher PASI90 was achieved in the 150 mg, 300 mg, and 450 mg dose groups than in the 75 mg group. All efficacy indicators were maintained at week 20. The incidence of treatment-emergent anti-drug antibodies (ADAs) was 0% (0/48). Neutralizing antibodies (NAbs) were not detected in any subject. The proportion of subjects who reported any treatment-emergent adverse event (TEAE) was 75.0% in the AK111 group, similar to the 66.7% in the placebo group. The most commonly reported adverse events were hyperglycemia, elevated blood pressure, and hypokalemia. The AK111 pharmacokinetics showed approximate dose proportionality with regard to the maximum observed concentration (Cmax) and area under the curve from 0 to the time of the last quantifiable concentration (AUC0-t) following subcutaneous injection doses of 150-450 mg. CONCLUSIONS: After moderate-to-severe plaque psoriasis subjects received multiple subcutaneous AK111 injections of 150-450 mg, AK111 exposure increased in a roughly dose-proportional relationship. AK111 was safe and tolerable. In subjects with moderate-to-severe plaque psoriasis, AK111 demonstrated encouraging preliminary efficacy, which was sustained for a relatively long time after the last dose administration. CLINICAL TRIAL REGISTRATION: The clinical trial identification number is NCT05504317.

[The number of regulatory T cells in spleen and serum-related cytokines increase in mouse model of psoriasis induced by imiquimod].

Objective To explore the role of regulatory T cells (Tregs) and its related cytokines in mouse model of psoriasis induced by imiquimod. Methods Female BALB/c mice were divided into control group and model group of psoriasis induced by imiquimod, with ten mice in each group. The psoriasis model was established by smearing imiquimod cream on the back of mice. HE staining was performed to observe the pathological changes of skin tissues. Flow cytometry was used to detect the number of Tregs in spleen and the levels of serum IL-10 and TGF-ß1 was detected by ELISA. Results The mouse model of psoriasis was successfully established. Compared with the control group, the percentage of Tregs in spleen of the mouse model group significantly increased, and the levels of serum IL-10 and TGF-ß1 also increased. Conclusion The number of Tregs and related cytokines increase in mouse model of psoriasis.

Culture of amelanotic melanocytes derived from human fetal hair follicles.

Human melanocyte stem cells (MSCs) or melanoblasts are not well-investigated owing to the devoid of suitable culture system. Establishing cell lines of MSCs and/or their progenies from human hair follicles will provide a better opportunity to satisfy clinical needs and to enable a deeper understanding of hair-related diseases. In the present study, we cultured melanocytes derived from human fetal hair follicles, perform immunocytochemistry and Fontana Masson staining on them, and employed atomic force microscopy (AFM) and scanning electron microscopy to observe their subtle morphologies. The results show that the cultured melanocytes have a bipolar or tripolar appearance, which obviously differ from cultured epidermal melanocytes. Compared to cells derived from adult human hair follicles, these cells display a high proliferative capability and exhibit a clonal growth behavior. At the second passage, all these cells were positive for immunocytochemical staining with the NKI/beteb monoclonal antibody and Fontana Masson staining. Under AFM, the cells exhibited rounded, oval, triangular, or quadrangular perikarya, from which two or three dendrites arose. The dendritic arbor was not homogeneous but appeared as spindle-shaped dendritic swellings, knob-like processes, without any filopodia arising from the dendrites or the cell body. Without using a feeder layer, we successfully obtained the clonal growth of melanocytes from human fetal HFs, suggesting that the medium was suitable for the growth of MSCs and their progenies.

Increased frequencies of Th17 and Th22 cells in the peripheral blood of patients with secondary syphilis.

T-helper (Th) 17 and the more recently identified Th22 cells are of great importance in host defense against pathogens, but can also be responsible for chronic inflammatory disorders. However, the roles of the two cell subsets in syphilis remain elusive. In this study, we show that the frequencies of Th17 and Th22 cells are significantly increased in the peripheral blood of patients with secondary syphilis (SS). A significant positive correlation is observed between Th17 and Th22 cells, whereas a negative correlation exists between Th17 and Th1 cells. Moreover, the frequency of Th17 cells has a significant positive correlation with the plasma interleukin 6 (IL-6) or IL-1ß levels, and the frequency of Th22 cells is positively correlated with the IL-6 or IL-23 levels. Finally, the elevated frequencies of Th17 and Th22 cells are positively associated with plasma C-reactive protein levels. Our results suggest that Th17 and Th22 cells may be implicated in the pathogenesis of the SS.