Efficacy of Tildrakizumab Across Different Body Weights in Moderate-to-Severe Psoriasis Over 5 Years : Pooled Analyses from the reSURFACE Pivotal Studies

Tildrakizumab (TIL), a monoclonal antibody that selectively targets interleukin-23p19, has been approved for the treatment of moderate-to-severe plaque psoriasis. According to the European Medicines Agency Summary of Product Characteristics, the recommended dose is 100 mg, but a 200 mg dose can be used in patients with certain characteristics, such as a high disease burden or body weight (BW) ≥ 90 kg. Fixed one-dose biological therapies tend to become less effective in patients with high BW. This post-hoc study describes the long-term efficacy of TIL across different BWs in pivotal clinical trials. A 5-year pooled analysis of two double-blind, randomised, controlled phase III trials-reSURFACE 1 and 2-was performed. Efficacy measures were the proportions of the patients with an absolute Psoriasis Area and Severity Index (PASI) of < 3 and < 1 and a Dermatology Life Quality Index (DLQI) of 0/1. The study population included patients randomised to TIL 100 mg or TIL 200 mg who received ≥ 1 TIL dose up to week 12 (part 1 of the trial) or up to week 28 (part 2) and patients who were responders (≥ 75% improvement in PASI) to TIL 100 or TIL 200 mg at week 28 and who were maintained on the same dose up to week 244. Efficacy was evaluated by analysing BW subgroups at weeks 28, 52 and 244. Missing data were analysed using multiple imputation. Safety was assessed in the all-patients-as-treated population. The proportions of TIL-treated patients with PASI < 3 and < 1 (up to week 244) and DLQI 0/1 (up to week 52) were similar for patients with BW < 90 or ≥ 90 kg, regardless of dose. Patients ≥ 120 kg had greater efficacy outcomes at the 200 mg dose. Safety outcomes were similar regardless of treatment dose and weight (< 120/≥ 120 kg). In patients with BW ≥ 120 kg, TIL 200 mg is more efficacious than TIL 100 mg, with similar favourable safety profiles obtained regardless of dose and BW group. ClinicalTrials.gov NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2)

TYK2 inhibition and its potential in the treatment of chronic inflammatory immune diseases

Immune-mediated chronic inflammatory diseases have emerged as a leading cause of morbidity and mortality in Western countries over the last decades. Although multiple putative factors have been suspected to be causally related to the diseases, their overarching etiology remains unknown. This review article summarizes the current state of scientific knowledge and understanding of the role of non-receptor tyrosine kinases, with a special focus on the Janus kinase TYK2 in autoimmune and immune mediated diseases as well as on the clinical properties of its inhibition. A panel of experts in the field discussed the scientific evidence and molecular rationale for TYK2 inhibition and its clinical application. Reviewing this meeting, we aim at providing an integrated overview of the clinical profile of TYK2 inhibition and its potential in targeted pharmacological therapy of chronic autoimmune and immune-mediated diseases, with a special focus on inflammatory diseases of the skin

Price variability of TNF-α inhibitor biosimilars among European countries

Dear Editor, The treatment of psoriasis has been revolutionized by biological drugs. Despite their excellent efficacy and safety, their high cost represents a hindrance to a wider and early us

Optimizing Anti-Inflammatory and Immunomodulatory Effects of Corticosteroid and Vitamin D Analogue Fixed-Dose Combination Therapy

Abstract: Fixed-dose combination topical therapy with corticosteroid and vitamin D analog provides effective treatment and possible long-term management of psoriasis. The anti-inflammatory and immunomodulatory effects of corticosteroids and vitamin D analogs in treating psoriasis are well investigated; their complementary effects lead to the disruption of the inflammatory feedback loop underlying psoriasis pathogenesis. Recent preclinical data showed that combination therapy is more effective than monotherapies of the active ingredients in preventing activation of resting pro-inflammatory cells, inducing immunomodulation, reducing inflammatory responses by regulating T cell production, and normalizing keratinocytes. The increased understanding of the mechanism of action of fixed-dose combination therapy from preclinical studies is supported by several clinical studies. As the efficacy of topical therapy is correlated with the skin penetration of the active ingredients, new drug delivery systems have been developed. The fixed-dose combination Cal/BD aerosol foam creates a modified supersaturated formulation when applied to the skin, which is maintained for at least 26 h in the laboratory setting. Clinical studies have demonstrated superior efficacy of fixed-dose combination calcipotriol (Cal) 50 µg/g and betamethasone dipropionate (BD) 0.5 mg/g aerosol foam compared with monotherapies of the active ingredients. Furthermore, Cal/BD aerosol foam has shown significantly improved efficacy compared with more traditional formulations, such as Cal/BD ointment and gel, in other studies. Calcipotriol also mitigates risks associated with betamethasone dipropionate and vice versa, resulting in the favorable safety profile observed with fixed-dose combination treatment. Recent data also suggest that fixed-dose combination treatment could provide long-term management of psoriasis, although further clinical investigations are needed. Overall, these data support the value of fixed-dose combination therapy of corticosteroid and vitamin D analog and highlight the added potential of innovative drug delivery for the treatment of psoriasis. Funding: LEO Pharma

Oligonucleotides suppress PKB/Akt and act as superinductors of apoptosis in human keratinocytes

DNA oligonucleotides (ODN) applied to an organism are known to modulate the innate and adaptive immune system. Previous studies showed that a CpG-containing ODN (CpG-1-PTO) and interestingly, also a non-CpG-containing ODN (nCpG-5-PTO) suppress inflammatory markers in skin. In the present study it was investigated whether these molecules also influence cell apoptosis. Here we show that CpG-1-PTO, nCpG-5-PTO, and also natural DNA suppress the phosphorylation of PKB/Akt in a cell-type-specific manner. Interestingly, only epithelial cells of the skin (normal human keratinocytes, HaCaT and A-431) show a suppression of PKB/Akt. This suppressive effect depends from ODN lengths, sequence and backbone. Moreover, it was found that TGFα-induced levels of PKB/Akt and EGFR were suppressed by the ODN tested. We hypothesize that this suppression might facilitate programmed cell death. By testing this hypothesis we found an increase of apoptosis markers (caspase 3/7, 8, 9, cytosolic cytochrome c, histone associated DNA fragments, apoptotic bodies) when cells were treated with ODN in combination with low doses of staurosporin, a well-known pro-apoptotic stimulus. In summary the present data demonstrate DNA as a modulator of apoptosis which specifically targets skin epithelial cells

Five-year analysis from the ESPRIT 10-year postmarketing surveillance registry of adalimumab treatment for moderate to severe psoriasis

BackgroundESPRIT is an ongoing, 10-year, observational registry, evaluating long-term safety and effectiveness of adalimumab treatment in routine clinical practice for patients with moderate to severe, chronic plaque psoriasis.ObjectivesInitial 5-year results are reported.MethodsTwo populations were analyzed: the “all-treated” population received 1 or more adalimumab doses in registry, continuing adalimumab treatment from a current prescription or previous study participation, and included the “new-prescription” population initiating adalimumab 4 weeks or earlier preregistry entry.ResultsData were collected from September 26, 2008, through November 30, 2013, for all-treated (n = 6059), which included new-prescription (n = 2580, 42.6%); median registry exposure was 765 and 677 days, respectively. In all-treated, rate (events per 100 patient-years of total adalimumab exposure [E/100PY]) of serious treatment-emergent adverse events (inside or outside of the registry) was 4.3 E/100PY, serious infection 1.0 E/100PY, malignancies 0.9 E/100PY (nonmelanoma skin cancers 0.6 E/100PY; melanomas <0.1 E/100PY). Standardized mortality ratio was 0.30 (95% confidence interval 0.19-0.44). Physician Global Assessment clear or minimal (effectiveness parameter) was achieved by 57.0% at 12 months and 64.7% at 60 months of treatment.LimitationsObservational data are subject to outcome-reporting bias.ConclusionNo new safety signals were observed with adalimumab treatment during this initial 5-year registry review. Observed number of deaths was below expected. As-observed effectiveness remained stable through 60 months

Long-term topical management of psoriasis: the road ahead

AbstractTopical therapies have been available for the treatment of psoriasis for several decades. Despite this and the availability of several types of topicals, with varying potency, and numerous ..

Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: results from two phase III, randomized, double-blinded, placebo-controlled trials

Lebrikizumab, a high-affinity IgG-4 monoclonal antibody targeting interleukin (IL)-13, selectively prevents the formation of the IL-13Ra1/IL-4Ra heterodimer receptor signalling complex. Lebrikizumab demonstrated rapid, dose-dependent efficacy and an acceptable safety profile in patients with moderate-to-severe atopic dermatitis (AD) in a phase IIb trial (NCT03443024). Here, we report 16-week efficacy and safety outcomes of lebrikizumab monotherapy in patients with AD from two ongoing 52-week, randomized, double-blinded, placebo-controlled phase III trials – ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Eligible patients with moderate-to-severe AD [adults and adolescents (12–17 years of age, weighing ≥40 kg)] were randomized 2: 1 to subcutaneous lebrikizumab 250 mg or placebo every 2 weeks. Efficacy analyses included proportions of patients achieving Investigator’s Global Assessment (IGA) 0/1, Eczema Area and Severity Index (EASI)-75 and Pruritus Numerical Rating Scale (NRS) ≥ 4-point improvement from baseline (P ≥ 4) at week 16. Nonefficacy-related missing data were imputed by multiple imputation. In ADvocate1, proportions of patients treated with lebrikizumab 250 mg (n = 283) and placebo (n = 141) achieving IGA 0/1 at week 16 were 43.0% and 12.8% (P \u3c 0.001); EASI-75 responses were 59.3% and 16.4% (P \u3c 0.001); P ≥ 4 proportions were 46.3% and 12.7% (P \u3c 0.001), respectively. In ADvocate2 (lebrikizumab, n = 281; placebo, n = 146), corresponding proportions for IGA 0/1 were 33.1% and 10.9% (P \u3c 0.001); EASI-75 responses were 50.8% and 18.2% (P \u3c 0.001); P ≥ 4 proportions were 38.3% and 11.3% (P \u3c 0.001), respectively. The percentage of patients reporting ≥1 TEAE was comparable in ADvocate1 (lebrikizumab, 45.4%; placebo, 51.1%) and ADvocate2 (lebrikizumab 53.0%; placebo 66.2%). Data from two ongoing pivotal phase III trials suggest that lebrikizumab 250 mg Q2W provides an efficacious treatment option with an acceptable safety profile for patients with moderate-to-severe AD

Evaluation of Nomacopan for Treatment of Bullous Pemphigoid:A Phase 2a Nonrandomized Controlled Trial

Importance: Bullous pemphigoid is a difficult-to-treat autoimmune blistering skin disease that predominantly affects older adults and is associated with an increased mortality rate. Objective: To examine the safety and therapeutic potential of nomacopan, an inhibitor of leukotriene B4and complement C5, in patients with bullous pemphigoid. Design, Setting, and Participants: This multicenter, single-group, phase 2a nonrandomized controlled trial was conducted in the dermatology departments of universities in the Netherlands and Germany. Participants were enrolled between September 2018 and April 2020. Older adult patients (aged ≥55 years) with mild to moderate, new-onset or relapsing bullous pemphigoid were recruited into the study. Interventions: Patients received nomacopan, 90 mg, subcutaneously on day 1 and 30 mg subcutaneously daily until day 42. Main Outcomes and Measures: The primary end point was the proportion of patients with grade 3 to 5 (severe) adverse events associated or possibly associated with nomacopan. Secondary end points included mean absolute and percentage changes in the Bullous Pemphigoid Disease Area Index (BPDAI) activity score, the BPDAI pruritus score, and the patient-reported outcome measures Dermatology Life Quality Index (DLQI) and Treatment of Autoimmune Bullous Disease Quality of Life (TABQOL). Results: A total of 9 patients (median [range] age, 75 [55-85] years) with bullous pemphigoid were included in the trial, of whom 5 were women (55.6%). No serious adverse events associated with nomacopan were found. The mean (90% CI) BPDAI activity score decreased from 32.0 (8.7) points on day 1 to 19.6 (9.0) points on day 42. Seven of 9 patients (77.8%) responded to nomacopan with a reduction in the BPDAI activity score of at least 8 points between days 1 and 42; in 3 responders, the reduction was 80% or greater. On day 42, the mean (90% CI) BPDAI pruritus score had decreased by 6.8 (4.6) points from 17.6 (4.0) points on day 1. The mean (90% CI) DLQI score decreased from 11.3 (4.2) points at baseline to 6.4 (3.8) points by day 42, and the mean (90% CI) TABQOL score decreased from 14.6 (5.4) points at baseline to 10.3 (5.0) points on day 42. Conclusions and Relevance: Results of this nonrandomized controlled trial suggest that nomacopan can be well tolerated in older patients with bullous pemphigoid and may have therapeutic benefits for suppressing acute flares of this disease. A larger, placebo-controlled randomized clinical trial is warranted to confirm this safety profile and to establish nomacopan as a new therapeutic option for bullous pemphigoid. Trial Registration: ClinicalTrials.gov Identifier: NCT04035733

Secukinumab demonstrates sustained efficacy in clearing skin and improving patient-reported outcomes in patients with moderate-to-severe psoriasis through 2 years of treatment : Results from the CLEAR study

Altres ajuts: The authors thank Dhaval Gupta, MPH (Novartis Healthcare Pvt Ltd, India), and Jackie L. Johnson, PhD (Novartis Ireland Ltd), for providing medical writing support, which was funded by Novartis Pharma AG, Basel, Switzerland, in accordance with Good Publication Practice guidelines (http://www.ismpp.org/gpp3)