Summary
Background
Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin‐13, a key driver of atopic dermatitis (AD).
Objectives
To evaluate the efficacy and ...safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate‐to‐severe AD who were candidates for systemic therapy.
Methods
This was a double‐blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator’s Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks.
Results
At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% difference (95% confidence interval): 12·4% (2·9–21·9); P = 0·015 and EASI 75: 56·0% vs. 35·7% 20·2% (9·8–30·6); P < 0·001. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups.
Conclusions
Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate‐to‐severe AD.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
In clinical practice, biologics are commonly initiated as add‐on therapy to topical corticosteroids (TCS).
Tralokinumab is a fully human monoclonal antibody that binds specifically to the IL‐13 cytokine with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with TCS showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
This is the first phase III trial evaluating a targeted anti‐IL‐13 biologic in combination with TCS.
These data demonstrate that tralokinumab plus TCS can achieve significant improvements in AD signs and symptoms and quality of life, as well as exert a steroid‐sparing effect.
Response with tralokinumab in combination with TCS was maintained over 32 weeks.
Tralokinumab may be considered a targeted biological treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online
Summary
Background
Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin‐13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II ...studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms.
Objectives
To evaluate the efficacy and safety of tralokinumab monotherapy in adults with moderate‐to‐severe AD who had an inadequate response to topical treatments.
Methods
In two 52‐week, randomized, double‐blind, placebo‐controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate‐to‐severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo. Primary endpoints were Investigator’s Global Assessment (IGA) score of 0 or 1 at week 16 and ≥ 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16. Patients achieving an IGA score of 0 or 1 and/or EASI 75 with tralokinumab at week 16 were rerandomized to tralokinumab Q2W or every 4 weeks or placebo, for 36 weeks. The trials were registered with ClinicalTrials.gov: NCT03131648 and NCT03160885.
Results
At week 16, more patients who received tralokinumab vs. placebo achieved an IGA score of 0 or 1: 15·8% vs. 7·1% in ECZTRA 1 difference 8·6%, 95% confidence interval (CI) 4·1–13·1; P = 0·002 and 22·2% vs. 10·9% in ECZTRA 2 (11·1%, 95% CI 5·8–16·4; P < 0·001) and EASI 75: 25·0% vs. 12·7% (12·1%, 95% CI 6·5–17·7; P < 0·001) and 33·2% vs. 11·4% (21·6%, 95% CI 15·8–27·3; P < 0·001). Early improvements in pruritus, sleep interference, Dermatology Life Quality Index, SCORing Atopic Dermatitis and Patient‐Oriented Eczema Measure were observed from the first postbaseline measurements. The majority of week 16 tralokinumab responders maintained response at week 52 with continued tralokinumab treatment without any rescue medication (including topical corticosteroids). Adverse events were reported in 76·4% and 61·5% of patients receiving tralokinumab in ECZTRA 1 and ECZTRA 2, respectively, and in 77·0% and 66·0% of patients receiving placebo in ECZTRA 1 and ECZTRA 2, respectively, in the 16‐week initial period.
Conclusions
Tralokinumab monotherapy was superior to placebo at 16 weeks of treatment and was well tolerated up to 52 weeks of treatment.
What is already known about this topic?
Atopic dermatitis (AD) is a chronic interleukin (IL)‐13‐mediated disease.
There is a need for safe and effective long‐term treatment options for AD.
Tralokinumab is a fully human monoclonal antibody that binds specifically to IL‐13 with high affinity, thereby preventing receptor interaction and subsequent downstream signalling.
Tralokinumab combined with topical corticosteroids showed early and sustained efficacy and safety in a 12‐week, phase IIb trial in moderate‐to‐severe AD.
What does this study add?
These are the first pivotal phase III trials demonstrating that by specifically targeting IL‐13 alone, patients can achieve significant improvements in AD signs and symptoms and quality of life, and maintain these improvements over time without the requirement for topical corticosteroids.
These trials provide evidence that tralokinumab offers a long‐term, well‐tolerated treatment option for patients with moderate‐to‐severe AD.
Linked Comment: Morra and Drucker. Br J Dermatol 2021; 184:386–387.
Plain language summary available online
Summary
Background
High‐mobility group box 1 protein (HMGB1) belonging to endogenous danger signals prolongs eosinophil survival and acts as a chemoattractant.
Objective
The authors evaluated the ...role of HMGB1 in the pathogenesis of asthma characterized by eosinophilic airway inflammation.
Methods
Firstly, HMGB1 expressions in induced sputum obtained from human asthmatics were determined. This was followed by an evaluation of the role of HMGB1 in a murine model of asthma using anti‐HMGB1 antibodies. Then the effect of HMGB1 on the receptor of advanced glycation end products (RAGE) expressions on CD11b‐CD11c+ cells isolated from a murine model of asthma were measured to elucidate the mechanisms involved.
Results
Sputum HMGB1 expressions were markedly higher in asthmatics than in normal controls, and were positively correlated with sputum eosinophilia and sputum TNF‐α, IL‐5 and IL‐13 expressions. In a murine model of asthma, HMGB1 expressions in lung tissue and HMGB1 levels in bronchoalveolar lavage fluid were significantly elevated and eosinophilic airway inflammation, non‐specific airway hyperresponsiveness, and pathological changes were attenuated by blocking HMGB1 activity. Furthermore, we found that enhanced RAGE expressions on CD11b‐CD11c+ also significantly decreased when HMGB1 activity was blocked.
Conclusion and Clinical Relevance
Our findings suggest that HMGB1 plays a key role in the pathogenesis of clinical and experimental asthma characterized by eosinophilic airway inflammation.
Summary
Background
Drug survival (time to drug discontinuation) has recently emerged as an important parameter reflecting the long‐term therapeutic performance in a real‐life setting. Biologic drug ...survival in psoriasis is mainly limited by a gradual loss of efficacy over time. Previous studies have been limited by small patient population size and short observation times and yielded discrepant survival times for different biologics.
Objectives
To calculate the long‐term drug survival for adalimumab, etanercept, infliximab and ustekinumab in a large cohort of real‐life patients with psoriasis vulgaris and to analyse the factors that influence drug survival.
Patients and methods
Data were extracted from the prospective registry DERMBIO covering all patients with psoriasis vulgaris treated with biologic agents in the academic centres in Denmark. Drug survival was analysed using the Kaplan–Meier method. The influence of different covariates on drug survival was analysed by Cox regression.
Results
Included in the analysis were 1867 treatment series (adalimumab n = 774, etanercept n = 449, infliximab n = 253, ustekinumab n = 391) administered in 1277 patients for up to 10 years. Drug survival was significantly longer for ustekinumab than for anti‐tumour necrosis factor (TNF)‐α agents (P < 0·001). Etanercept had the shortest survival time median survival 30 months, 95% confidence interval (CI) 25·1–34·9 whereas adalimumab and infliximab had comparable survival rates (59 months, 95% CI 45·6–72·4; 44 months, 95% CI 33–54·9, respectively). Survival was longer in men odds ratio (OR) 1·51, 95% CI 1·31–1·74 vs. women and in patients who had not previously received any biologic agent (OR 1·24, 95% CI 1·05–1·46). Loss of efficacy accounted for 67% of all drug discontinuations.
Conclusions
Ustekinumab has a significantly longer drug survival than the anti‐TNF‐α agents. Switching from one biologic to another is associated with an impairment of drug survival. Preventing loss of efficacy is a major area of medical need in the biologic therapy of psoriasis and the strategies that improve drug survival should be further investigated.
What's already known about this topic?
Gradual loss of efficacy of biologic agents has been observed during long‐term treatment of psoriasis.
Previous studies have had limited numbers of patients and short observation times and showed conflicting data.
What does this study add?
This is the largest study to date, comprising 1277 patients followed for up to 10 years.
Long‐term drug survival depends on the drug (ustekinumab > adalimumab = infliximab > etanercept), sex (men > women) and previous exposure to another biologic.
Glaucoma: challenges and opportunities Kalloniatis, Michael; Bui, Bang B; Phu, Jack
Clinical and experimental optometry
107, Številka:
2
Journal Article
1-2-(2,4-Dimethylphenyl-sulfanyl)-phenyl-piperazine (Lu AA21004) is a human (h) serotonin (5-HT)(3A) receptor antagonist (K(i) = 3.7 nM), h5-HT(7) receptor antagonist (K(i) = 19 nM), h5-HT(1B) ...receptor partial agonist (K(i) = 33 nM), h5-HT(1A) receptor agonist (K(i) = 15 nM), and a human 5-HT transporter (SERT) inhibitor (K(i) = 1.6 nM) (J Med Chem 54:3206-3221, 2011). Here, we confirm that Lu AA21004 is a partial h5-HT(1B) receptor agonist EC(50) = 460 nM, intrinsic activity = 22% using a whole-cell cAMP-based assay and demonstrate that Lu AA21004 is a rat (r) 5-HT(7) receptor antagonist (K(i) = 200 nM and IC(50) = 2080 nM). In vivo, Lu AA21004 occupies the r5-HT(1B) receptor and rSERT (ED(50) = 3.2 and 0.4 mg/kg, respectively) after subcutaneous administration and is a 5-HT(3) receptor antagonist in the Bezold-Jarisch reflex assay (ED(50) = 0.11 mg/kg s.c.). In rat microdialysis experiments, Lu AA21004 (2.5-10.0 mg/kg s.c.) increased extracellular 5-HT, dopamine, and noradrenaline in the medial prefrontal cortex and ventral hippocampus. Lu AA21004 (5 mg/kg per day for 3 days; minipump subcutaneously), corresponding to 41% rSERT occupancy, significantly increased extracellular 5-HT in the ventral hippocampus. Furthermore, the 5-HT(3) receptor antagonist, ondansetron, potentiated the increase in extracellular levels of 5-HT induced by citalopram. Lu AA21004 has antidepressant- and anxiolytic-like effects in the rat forced swim (Flinders Sensitive Line) and social interaction and conditioned fear tests (minimal effective doses: 7.8, 2.0, and 3.9 mg/kg). In conclusion, Lu AA21004 mediates its pharmacological effects via two pharmacological modalities: SERT inhibition and 5-HT receptor modulation. In vivo, this results in enhanced release of several neurotransmitters and antidepressant- and anxiolytic-like profiles at doses for which targets in addition to the SERT are occupied. The multimodal activity profile of Lu AA21004 is distinct from that of current antidepressants.
Pancreas disease (PD), caused by salmonid alphavirus subtype 3 (SAV3), emerged in Norwegian aquaculture in the 1980s and is now endemic along the south‐western coast. In 2011, the first cases of PD ...caused by marine salmonid alphavirus subtype 2 (SAV2) were reported. This subtype has spread rapidly among the fish farms outside the PD‐endemic zone and is responsible for disease outbreaks at an increasing numbers of sites. To describe the geographical distribution of salmonid alphavirus (SAV), and to assess the time and site of introduction of marine SAV2 to Norway, an extensive genetic characterization including more than 200 SAV‐positive samples from 157 Norwegian marine production sites collected from May 2007 to December 2012 was executed. The first samples positive for marine SAV2 originated from Romsdal, in June 2010. Sequence analysis of the E2 gene revealed that all marine SAV2 included in this study were nearly identical, suggesting a single introduction into Norwegian aquaculture. Further, this study provides evidence of a separate geographical distribution of two subtypes in Norway. SAV3 is present in south‐western Norway, and marine SAV2 circulates in north‐western and Mid‐Norway, a geographical area which since 2010 constitutes the endemic zone for marine SAV2.
Infectious salmon anaemia (ISA) is an important viral disease causing economic losses and reduced welfare in farmed Atlantic salmon. Here, we present a spatio-temporal stochastic model for the spread ...of ISA between and within marine aquaculture farms. The model is estimated on historical production data for all marine salmonid farms in Norway from 2004 to February 2019. In this time 142 outbreaks of ISA occurred. We find that transmission from infected neighbouring farms accounts for around 50% of the infections, whereas transmission from “non-specified sources” accounts for around 40%. We hypothesise that the most important of the latter are viruses mutating from the non-virulent ISAV HPR0 to the virulent ISAV HPRdel. The model is used for scenario simulation, or what-if analysis, to investigate the effects of potential strategies to combat ISA, including screening, vaccination and culling. Changing from the current strategy of culling farms with detected ISA-outbreaks to mandatory screening and culling when virus is detected will reduce the fraction of cohorts with a clinical ISA outbreak from 3.8 to 0.36%. Introducing mandatory vaccination would have approximately the same effect as the current stamping-out strategy. The scenario simulation is a useful tool for deciding on appropriate mitigation measures.
Cardiomyopathy syndrome (CMS) is a severe cardiac disease affecting Atlantic salmon Salmo salar L. The disease was first recognized in farmed Atlantic salmon in Norway in 1985 and subsequently in ...farmed salmon in the Faroe Islands, Scotland and Ireland. CMS has also been described in wild Atlantic salmon in Norway. The demonstration of CMS as a transmissible disease in 2009, and the subsequent detection and initial characterization of piscine myocarditis virus (PMCV) in 2010 and 2011 were significant discoveries that gave new impetus to the CMS research. In Norway, CMS usually causes mortality in large salmon in ongrowing and broodfish farms, resulting in reduced fish welfare, significant management‐related challenges and substantial economic losses. The disease thus has a significant impact on the Atlantic salmon farming industry. There is a need to gain further basic knowledge about the virus, the disease and its epidemiology, but also applied knowledge from the industry to enable the generation and implementation of effective prevention and control measures. This review summarizes the currently available, scientific information on CMS and PMCV with special focus on epidemiology and factors influencing the development of CMS.
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