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4th September 2023
Delays in gut microbiome maturation in young children are uniformly associated with distinct allergic diagnoses at five years of age, according to the findings of a study by Canadian researchers.
The study, which was published in the journal Nature Communications, revealed how specific gut microbiome features and early life influences are associated with children developing any of four common allergies: atopic eczema, asthma, food allergy and/or allergic rhinitis.
It is possible, therefore, that these findings could lead to methods for predicting whether a child would develop an allergic disease. They could also form the foundation of strategies to prevent them from developing, especially given that food allergies in particular continue to be a major source of life-threatening reactions in children.
Courtney Hoskinson, PhD candidate at the University of British Columbia (UBC) and the study‘s lead author said: ‘Typically, our bodies tolerate the millions of bacteria living in our guts because they do so many good things for our health. Some of the ways we tolerate them are by keeping a strong barrier between them and our immune cells and by limiting inflammatory signals that would call those immune cells into action.‘
‘We found a common breakdown in these mechanisms in babies prior to the development of allergies.‘
In the study, researchers evaluated the four clinically distinct allergic diseases diagnosed at five years of age in the large, deeply characterised CHILD cohort study. The team adopted a multi-omics approach to profile infant stool collected at study visits scheduled for ages three months and one year.
The study used a deeply phenotyped cohort of 1,115 children. A total of 523 participants could be defined as a ‘healthy‘ control group in that they did not develop allergic sensitisation at any time in their life up to five years of age.
Some 592 children had been diagnosed by an expert physician at the five-year scheduled visit with one or more allergic disorders: atopic eczema (n = 367), asthma (n = 165), food allergy (n = 136) and allergic rhinitis (n = 187). There were gut microbiome features uniformly associated with these allergic diagnoses at five years of age.
When evaluating the association between early-life factors and a diagnosis of allergic disease at age five, male sex, a history of either maternal of paternal atopy and antibiotic usage before age one were all significantly linked with an increased risk of developing an allergic disease.
In contrast, breastfeeding up to age six months and self-identifying as Caucasian were negatively associated with an allergy diagnosis.
Dr Stuart Turvey, professor in the department of pediatrics at UBC, investigator at British Columbia Children‘s Hospital Research Institute and co-senior author on the study, added: ‘There are a lot of potential insights from this robust analysis. From these data we can see that factors such as antibiotic usage in the first year of life are more likely to result in later allergic disorders, while breastfeeding for the first six months is protective. This was universal to all the allergic disorders we studied.
‘Developing therapies that change these interactions during infancy may therefore prevent the development of all sorts of allergic diseases in childhood, which often last a lifetime.‘
17th August 2023
JAK inhibitors are known to increase the risk of major adverse cardiovascular events when used in rheumatoid arthritis, but does this elevated risk also apply when this class of drugs is used in atopic eczema? Clinical writer Rod Tucker investigates.
Since the 1990s, the treatment of severe rheumatoid arthritis (RA) has centred on biologics such as tumour necrosis factor (TNF) inhibitors. However, a better understanding of cell signalling pathways and, in particular, intracellular signal transduction, led to the development of alternative therapies, one of which being oral Janus kinase (JAK) inhibitors. Several of these have been approved for use in RA since 2011.
What’s more, as JAK inhibitors disrupt intracellular signalling through a variety of cytokine and haematopoietic growth factor receptors, this mode of action suggests the drug class may have a much wider role in a number of immune-mediated inflammatory diseases. As such, approvals for JAK inhibitors in Crohn‘s disease, psoriasis and atopic eczema have been seen in recent years.
Despite their apparent effectiveness in RA, a recent post-marketing study has raised safety concerns over JAK inhibitors compared to TNF inhibitors. The Oral Rheumatoid Arthritis Trial (ORAL) was a randomised, post-authorisation, non-inferiority trial designed to evaluate the safety and efficacy of the JAK inhibitor tofacitinib compared to a TNF inhibitor such as etanercept or adalimumab. It focused on patients with RA who were aged 50 or older and had at least one additional cardiovascular risk factor.
The findings were somewhat disturbing. JAK inhibitor use led to a significantly higher incidence of both major adverse cardiovascular events (MACE) and cancers compared to a TNF inhibitor, even though the efficacies were broadly similar.
The ORAL trial served to highlight how JAK inhibitors may increase the risk of MACE when used in patients with RA who are already at an elevated risk due to their condition. Indeed, a meta-analysis of 24 studies with over 111,000 RA patients estimated a 50% higher risk of cardiovascular mortality.
So, with three JAK inhibitors (upadacitinib, baricitinib and abrocitinib) approved for atopic eczema, and representing an important and promising development for its treatment, should dermatologists be concerned over the risk of MACE when using this class of drugs?
Before considering whether JAK inhibitors might increase the risk of adverse cardiovascular sequelae in those with atopic eczema, its worth exploring whether atopic eczema, itself an inflammatory condition, is linked to a higher risk of MACE. After all, such a risk is theoretically possible, given the emerging evidence of the pivotal role of inflammation in the development and progression of both cardiac and vascular diseases.
The current evidence of an association between atopic eczema and MACE is equivocal. Some work, for instance, clearly demonstrates that atopic eczema is associated with increased risk of myocardial infarction compared to the general population. In contrast, another study found no such independent association in women.
Nevertheless, pooling data from several studies does suggest a positive relationship. For example, a 2018 meta-analysis of 15 studies, which included over 3.5 million participants, did show that atopic eczema was independently associated with an increased risk of stroke and myocardial infarction, especially in male subjects and those with more severe disease.
In addition, a recent Danish study, looked at what happened to patients over time following a diagnosis of atopic eczema. It included over 40,000 atopic eczema patients and an equal number of matched controls and found that adults were at a significantly higher risk of experiencing a subsequent cardiovascular disease.
Finally, a UK prospective study including 387,439 patients with atopic eczema followed for over five years, concluded that severe active atopic eczema was associated with an increased risk of cardiovascular outcomes.
While prospective studies are subject to confounding, Mendelian randomisation studies, are able to provide an estimate causality without the influence of confounders. One such study showed that asthma and atopic eczema were causal risk factors for heart failure and suggested that the underlying inflammatory nature of both diseases was a major contributory factor.
As ever, things are never that straightforward. In a recent bidirectional Mendelian randomisation study, it was found that there was no robust association between cardiovascular disease and atopic eczema.
In trying to establish if there was a higher risk of MACE in patients with atopic eczema prescribed a JAK inhibitor, researchers recently undertook a systematic review and meta-analysis. The findings were published in July 2023 in the British Journal of Dermatology and included phase 2b or 3 randomised controlled trials and controlled cohort studies.
The primary outcome was the occurrence of MACE, which the researchers defined as a composite of acute coronary syndrome (ACS), ischaemic stroke and CV death.
A total of 23 studies were included in the analysis. Very few cases of MACE were found, leading the researchers to suggest that JAK inhibitors may have little-to-no effect on the occurrence of MACE in patients with atopic eczema compared to placebo. However, they did add the caveat that the evidence was uncertain.
In addition, MACE generally occurred in patients at a high cardiovascular risk and not in the younger, healthy patients typically seen in routine clinical practice.
Further and reassuring evidence of the absence of a possible association with MACE comes from real-world studies on the use of JAK inhibitors in atopic eczema. There have been at least four such studies, none of which have identified any cases of MACE, even though some have been conducted in patients with more severe disease.
Although patients with atopic eczema may have a higher risk of MACE, this is more likely to occur either in those with severe disease or for patients at a greater risk of cardiovascular disease. Over time, pharmacovigilance data will no doubt shed further light on the level of risk associated with JAK inhibitors.
For now, the European Medicines Agency (EMA) issued advice in January 2023 on the use of JAK inhibitors in all chronic inflammatory disorders, including atopic eczema. This recommended avoiding against the use of a JAK inhibitor in those aged 65 years or above, in patients at an increased risk of major cardiovascular problems, smokers and individuals at a higher risk of cancer, unless there are no suitable alternatives.
For most patients with atopic eczema, JAK inhibitors represent a potentially game-changing addition to a dermatologist’s armamentarium for their treatment. Provided that clinicians heed the current safety guidance, those prescribed a JAK inhibitor for atopic eczema have much to gain but without the attendant risk of MACE.
5th July 2023
Amlitelimab has met its primary endpoint of an improvement in disease severity of atopic dermatitis in a recent phase 2b dose-ranging trial, its manufacturer Sanofi has announced.
Amlitelimab provided statistically significant improvements in signs and symptoms of moderate-to-severe atopic dermatitis in adults whose disease could not be adequately controlled with topical medications or where topical medications are not a recommended treatment approach.
A non-depleting IgG4 human anti-OX40L monoclonal antibody, amlitelimab’s OX40–OX40L interaction appears to play a central role in the pathogenesis of atopic dermatitis. The drug binds to OX40L and in doing so, blocks its interactions with OX40, thus restoring immune homeostasis between pro-inflammatory and anti-inflammatory T-cells. Consequently, the drug offers a potential first-in-class novel antibody therapy for patients with moderate to severe atopic dermatitis.
Amlitelimab (formerly KY1005) was found in a pharmacokinetic study to reduce skin redness, indicating its potential as a novel pharmacological treatment in immune-mediated disorders. Earlier work revealed how amlitelimab leads to a significant reduction of interleukin-13 levels with a corresponding reduction in dermatitis disease severity. Furthermore, the drug also improves disease severity through targeting interleukin-22.
The latest information released by Sanofi relates to STEAM-AD – a phase 2b, double blind, five-arm study assessing amlitelimab in adult participants with moderate to severe atopic dermatitis. While the company did not provide specific details, it did report that amlitelimab had enrolled 390 people from several countries. The primary endpoint was the percentage change in the Eczema Area and Severity Index score from baseline at 16 weeks.
The detailed efficacy and safety results from the trial are to be presented in a future scientific forum and, as amlitelimab is currently under clinical investigation, the safety and efficacy have not yet been evaluated by regulatory authorities.
Dr Naimish Patel, head of global development, immunology and inflammation at Sanofi, said: ‘While we have made significant strides in the treatment of atopic dermatitis, there are patients who are still in need of new options.
‘We believe that the results from this Phase 2b study with amlitelimab support our perspective that targeting OX40-Ligand has the potential to provide a first and best-in-class treatment option that addresses type 2 and non-type 2 inflammation to meet the individual needs of people living with atopic dermatitis and other chronic inflammatory diseases.
‘We look forward to advancing into a larger Phase 3 clinical development programme and continuing to drive momentum in our immunology pipeline to deliver first or best-in-class treatments.’
22nd June 2023
Topical roflumilast is being increasingly trialled for a number of skin conditions but how effective is it, and will it take centre stage in the field of dermatology? Rod Tucker investigates.
Oral roflumilast is licensed for maintenance treatment in severe chronic obstructive pulmonary disease. Its mode of action relates to the suppression of inflammation, but this benefit extends far beyond respiratory diseases.
Roflumilast inhibits the enzyme phosphodiesterase 4 (PDE4), which hydrolyses cyclic adenosine monophosphate (cAMP), a secondary messenger within cells that is involved in many biological processes in the body. With research suggesting that higher levels of cAMP supress inflammation, PDE4 inhibitors effectively suppress the production of inflammatory markers.
PDE4 inhibitors have become a promising class of drugs with a potential role in a number of therapy areas such as pulmonary, dermatological and neurological diseases. To date, there are two further PDE inhibitors available: apremilast, which is an established oral therapy for psoriasis, and crisaborole, a topical agent used to treat atopic eczema.
But how effective is topical roflumilast in the management of skin diseases?
Topical roflumilast 0.3% has gained gained FDA approval for use in patients with plaque psoriasis. In the two trials leading to FDA approval, disease severity was assessed by a score of ‘clear’ or ‘almost clear’ and a two-point improvement on the Investigator Global Assessment (IGA) scale. This endpoint was achieved by 41.5% and 36.7% of patient treated with topical roflumilast compared to 5.8% and 7.1% with placebo.
In addition, roflumilast has also been found to significantly improve symptoms of scalp psoriasis. But, an added bonus for the drug, is that it is also effective and approved for psoriasis affecting intertriginous sites. Management of intertriginous, or inverse, psoriasis, is a therapeutic challenge, as noted by a recent systemic review which concluded that there is a lack of good quality evidence upon which to base treatment recommendations.
Although clinically distinct from psoriasis, seborrhoeic eczema is associated with an inflammatory milieu characterised by several cytokines. In a recent phase 2a, double-blind, vehicle-controlled trial, researchers investigated the efficacy of a roflumilast 0.3% foam in patients with the condition. Participants assigned to roflumilast saw significant improvements in the IGA score (73.8%) compared the the vehicle group (40.9%), and there were also signification reductions in pruritus.
PDE4 inhibition is also a potentially valuable target in atopic eczema, as demonstrated by crisaborole, which is a proven effective treatment. However, a recent turn of events has provided the manufacturer of topical roflumilast, Arcutis Biotherapeutics, with a distinct advantage in the topical treatment of atopic eczema, particularly in Europe.
In the UK, NICE has not provided a recommendation for the use of Pfizer’s crisaborole in atopic eczema, after the manufacturer withdrew its evidence submission. Similarly, in 2022, the marketing authorisation for crisaborole in the EU was withdrawn. As a result, the drug, is not recommended in the 2022 European guidelines on the management of atopic eczema.
Nevertheless, the position adopted by the UK and EU is in sharp contrast to the US, where the most recent iteration of the American Academy of Dermatology guidelines on atopic eczema do include a recommendation to use crisaborole.
Although roflumilast now has an advantage over crisaborole in the European market, initial findings for the drug in atopic eczema were disappointing. The results of a phase 2 proof-of-concept trial using two strengths of the drug (0.15% and 0.05%) found that neither strength improved Eczema Area and Severity Index (EASI) scores compared to the vehicle cream.
In contrast, the most recent data are more encouraging. In an abstract that combined two phase 3 trials in patients with atopic eczema, those assigned to roflumilast 0.15% cream achieved a significantly higher treatment success (p < 0.0001) compared to vehicle in both trials.
Arcutis Biotherapeutics appears to have great ambitions for its drug. Some work with the PDE4 inhibitor apremilast, demonstrated an ability to control the progression of vitiligo. Moreover, given that vitiligo is mediated via oxidative stress and that roflumilast is able to reduce oxidative stress, the drug may also be of value in this condition.
In preliminary work, it was shown that roflumilast enhanced melanin synthesis when combined with forskolin, a cAMP stimulator, but only exhibited a slight influence on melanogenesis when used alone. Although this indicates a potential role in vitiligo, which is reflected on the manufacturer’s website, this is not an active area of research.
Finally, with evidence from a trial demonstrating that apremilast improved disease severity in papulopustular rosacea, a trial of roflumilast in facial papulopustular rosacea is currently recruiting patients.
There is now mounting evidence to suggest that topical roflumilast has the potential to make an important impact on the treatment landscape of psoriasis, seborrhoeic and atopic eczema and possibly rosacea. But exactly where the drug might sit in the treatment ladder for these conditions is uncertain given the absence of studies with active comparators.
Nonetheless, any effective addition to the clinician’s therapeutic armamentarium in the fight against skin diseases is to be welcomed. With Arcutis Biotherapeutics having only just begun its journey with topical roflumilast, it remains to be seen whether the drug will ultimately achieve the status of a dermatological panacea.
12th June 2023
UVB phototherapy (UVBP) for the treatment of atopic eczema in adults does not increase the risk of cutaneous cancers, according to a retrospective analysis.
Published in the Journal of the American Academy of Dermatology, Taiwanese researchers retrospectively assessed whether UVBP use in adults with atopic eczema elevated the risk of cutaneous cancers.
The team undertook a nationwide, population-based cohort study from 2001-18 to estimate the risk of developing both non-melanoma skin cancer and melanoma. They excluded patients under 20 years of age, those with a prior diagnosis of skin cancer and individuals who had received PUVA therapy. The cohort of patients who had received UVBP were then matched 4:1 to a group of atopic eczema patients who had not received phototherapy.
The researchers calculated the number of UVBP sessions for each patient and adjusted their analysis for a number of covariates including immunosuppressant therapy.
After exclusion, a total of 1,241 patients in the UVBP group were matched to 4,964 patients in the non-UVBP group. For the entire cohort, mean age was 42.4 years and 65.8% were men.
Compared to those not receiving UVBP, there was no overall and significant increased risk of skin cancer in the phototherapy group (adjusted Hazard ratio, aHR = 0.91, 95% CI 0.35 – 2.35). Similarly, there was no increased risk of either non-melanoma skin cancer (aHR = 0.80, 95% CI 0.29 – 2.26) or cutaneous melanoma (aHR = 0.80, 95% CI 0.08 – 7.64).
In addition, the risk of either form of cutaneous cancer was not increased when analysed based on the number of UVBP sessions.
UVBP is a recommended second-line treatment following failure of first-line treatment in patients with atopic eczema. While the existing literature suggests that longer-term use of UVBP does not increase the risk of cancer, this evidence is derived from patients with psoriasis. Consequently, whether this treatment modality is also safe in the longer term among those with atopic eczema remains uncertain.
25th April 2023
Tralokinumab targets interleukin-13 (IL-13) and appears to be both effective and tolerable in adolescents aged 12-17 with moderate-to-severe atopic eczema.
Adolescent atopic eczema gives rise to a negative impact on patient’s quality of life. There is already good evidence to suggest that IL-13 creates inflammation in atopic eczema.
Tralokinumab specifically neutralises IL-13 and therefore reduces inflammation. Previous work has demonstrated efficacy for the drug adults with moderate-to-severe atopic eczema. However, it remains uncertain whether tralokinumab is effective for adolescents with moderate-to-severe disease.
The current randomised, double-blinded, placebo-controlled enrolled adolescents aged 12-17 years with moderate-to-severe atopic eczema. Individuals received monotherapy with tralokinumab either 150 mg or 300 mg, or matching placebo, every two weeks for 16 weeks.
The primary endpoint was an Investigator’s Global Assessment (IGA) score of 0 or 1 (clear/almost clear) at week 16.
An alternative primary endpoint was a 75% or higher improvement in EASI (i.e. an EASI 75). Those meeting the primary outcome at week 16 continued in a maintenance phase until week 52.
There were 289 participants with a median age of 15 years (51.6% male). Some 97 participants were given 150 mg of tralokinumab, and 98 were assigned to 300 mg of tralokinumab.
At week 16, significantly more patients receiving tralokinumab had an IGA of 0 or 1 than placebo: 21.4% (150 mg) and 17.5% (300 mg) vs 4.3% for placebo (p < 0.01 and p = 0.002 respectively).
In addition, 28.6% of tralokinumab 150 mg patients had an EASI75, as did 27.8% of the tralokinumab 300 mg group. Only 6.4% of those in the placebo arm achieved EASI75.
Larger improvements were seen for both doses of the drug compared to placebo for itch and quality of life scores.
At week 52, 62.9% of all tralokinumab participants maintained their IGA score of 0 or 1 with doses administered either every two or four weeks. The drug was tolerable with a similar proportion of adverse events in all three arms.
The researchers concluded that tralokinumab therefore appears effective for adolescents with moderate-to-severe atopic eczema.
Citation
Paller AS et al. Efficacy and Safety of Tralokinumab in Adolescents With Moderate to Severe Atopic Dermatitis: The Phase 3 ECZTRA 6 Randomized Clinical Trial. JAMA Dermatol 2023.
11th April 2023
UK and Japanese researchers have shown that among infants with atopic eczema, enhanced treatment, i.e., to both clinically affected and unaffected skin, is more effective at preventing hen’s egg allergy than conventional or reactive treatment, applied only to clinically affected areas.
There appears to be an increase in the prevalence of food allergy in some areas of the world, thus highlighting the need for better strategies for prevention, diagnosis and therapy. For example, one study of Japanese children found a caregiver-reported immediate food allergy prevalence of 7.6% in children aged 1, with hen egg allergy being the most common at 5.4%. The presence of atopic eczema is associated with the development of food allergies, with a suggestion that infants with early eczema onset (within the first 1 – 4 months after birth) have an increased risk of developing food allergy at 3 years of age. Given the relationship between atopic eczema and food allergies, researchers wondered if early treatment of the disease could reduce the subsequent development of allergies. One retrospective analysis showed that early aggressive use of topical corticosteroids to shorten the duration of atopic eczema in infants, was associated with decreased development of food allergy by 24 months of age.
Based on the findings of this retrospective analysis, in the current study, researchers conducted a randomised controlled trial. Infants aged 7-13 weeks with atopic eczema were treated with topical steroids and randomised 1:1 to enhanced early skin treatment or conventional reactive treatment, i.e., applying topical corticosteroids only to areas of clinically affected skin. The team set the primary outcome as the proportion of immediate hen’s egg allergy confirmed by oral food challenge at 28 weeks of age.
Enhanced early treatment and the development of hen’s egg allergy
A total of 640 children were included, 318 of whom were assigned to enhanced early treatment. Two-thirds (66%) of children in the enhanced group were aged 7 to 10 weeks at enrolment.
Enhanced treatment significantly reduced hen’s egg allergy compared with the conventional treatment (31.4% vs. 41.9%, p = 0.0028). However, a higher proportion of infants in the enhanced group experienced serious adverse events (5.3% vs 1.9%). In addition, the intervention reduced mean body weight and height when assessed at week 28.
The authors concluded that while enhanced control of atopic eczema appeared to reduce hen’s egg allergy, the treatment protocol of this trial should be modified in order to avoid the adverse effects of topical corticosteroids.
Citation
Yamamoto-Hanada K et al. Enhanced early skin treatment for atopic dermatitis in infants reduces food allergy. J Allergy Clin Immunol 2023
28th March 2023
Two identical randomised, double-blind, placebo-controlled trials have shown that treatment with lebrikizumab alone in patients 12 years of age and older with moderate to severe atopic eczema led to a significant improvement in disease severity.
Although atopic eczema affects approximately 20% of children, the condition persists in around 7% of adults. Moreover, atopic eczema has a huge negative impact on the quality of life of sufferers and can even increase the risk of suicide ideation.
While it has been recognised in recent years that elevated levels of both interleukin-4 and interleukin-13 (IL-13) are implicated in the pathophysiology of the disease, it has been recently demonstrated that IL-13 is the primary up-regulated cytokine in skin biopsy samples from patients with atopic eczema. The monoclonal antibody, lebrikizumab exerts selective antagonism of IL-13 and which is sufficient to control atopic eczema and improve patient’s quality of life.
In fact, a recent, randomised, phase 3 trial demonstrated the benefit of lebrikizumab when combined with topical steroids in adolescents and adults with moderate to severe atopic eczema. However, whether lebrikizumab is effective alone is currently unclear and was the objective of the current study.
The current publication includes the findings from two identical phase 3 trials, ADvocate1 and ADvocate2, in which patients with moderate-to-severe atopic eczema, aged 12 years and older, were randomised 2:1 to either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks.
The primary outcome was based on an Investigator’s Global Assessment (IGA) score of 0 or 1 (indicating clear (0) or almost clear (1)), with a reduction of at least 2 points from baseline and was assessed after 16 weeks. The main secondary outcome was a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response), whereas other measures included assessments of itch and of itch interference with sleep.
Lebrikizumab and atopic eczema disease severity
In the first trial, 424 patients with a mean age of 35.5 years (51.8% female) were randomised to lebrikizumab (283) or placebo with similar demographics in the second trial.
In the first trial, the primary outcome occurred in 43.1% of those assigned to lebrikizumab group and in 12.7% placebo patients and this difference was statistically significant (p < 0.001). In addition, a significant difference was seen in the EASI-75 response (58.8% vs 16.2%, p < 0.001). Similar and significant findings were observed in the second trial.
In both trials, a significantly higher proportion of patients given lebrikizumab group also achieved reductions in pruritus and improvements in sleep loss scores.
The authors concluded that 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic eczema.
Citation
Silverberg JI et al. Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis. N Eng J Med 2023.
30th January 2023
The manufacturer Regeneron described how data from a study in The Lancet, showed that Dupixent treatment plus topical corticosteroids (hydrocortisone 1%) was effective in children under 6 years of age.
The Lancet trial enrolled and randomised 162 children aged 6 months to 6 years, to the drug or placebo. In the trial, participants were included if they had an Investigator’s Global Assessment (IGA) score of 3 – 4, which represents moderate to severe disease.
The drug was given at a dose based on the bodyweight. For instance, if > 5 kg but < 15 mg, a dose of 200 mg was given once every 4 weeks and for children weighing > 15 kg but < 30 kg, a dose of 300 mg was given. The primary endpoint was set as the proportion of participants with an IGA score of 0 or 1 (i.e., clear or almost clear) skin after 16 weeks.
At week 16, there was a 24% difference in IGA scores between Dupixent and placebo and which was statistically significant (p < 0.0001). The study also observed that the drug’s safety profile was generally in line with what might be expected.
The press release describes how in practice, 85 to 90% of children will develop atopic eczema before the age of 5 years and in Europe alone, it is estimated that up to 80,000 children aged between 6 months and 5 years have uncontrolled severe atopic dermatitis and might therefore benefit from a trial of systemic therapy.
According to the EMA, Dupixent will now be indicated for the treatment of severe atopic dermatitis in children 6 months to 11 years and who are candidates for systemic therapy.
The drug was approved for the same paediatric population by the FDA in June 2022.
19th January 2023
Lebrikizumab in combination with low to mid-potency topical corticosteroids is an effective therapeutic approach for adults with moderate to severe atopic eczema according to the results of a randomised, placebo-controlled trial by an international research group.
Atopic eczema (AE) is a chronic, relapsing and remitting skin disease which, according to one UK-based study, affects up to 16.5% of children aged 2 years and 2.8% of adults aged 30-39. Moderate to severe disease symptoms include intense itch, sleep disturbance together with skin pain, affecting sleep, daily activities and occurs in 28.9% and 11% of adults, respectively. Both emollients and topical corticosteroids (topical steroids) are used to manage mild to moderate disease whereas systemic therapy and or phototherapy is recommended for those with more severe disease. In recent years, biologic therapies such as dupilumab have emerged for the treatment of individuals with moderate to severe disease.
Another recently introduced biologic is the monoclonal antibody lebrikizumab, which targets interleukin (IL)-13, a pro-inflammatory Th2 cytokine central to AE pathogenesis and which is an important driver of the clinical manifestations of AE. Although lebrikizumab has been shown to provide a rapid and dose-dependent efficacy across a broad range of clinical manifestations in adult patients with moderate to severe AE, no studies have examined the value of the drug in combination with topical steroids, which is reflective of real-life practice.
Consequently, in the current study, researchers randomised eligible patients, i.e., with a diagnosis of moderate-to-severe AE, 2:1 to lebrikizumab and topical steroids or placebo and topical steroids. An initial lebrikizumab loading dose of 500 mg was administered subcutaneously, at baseline and week 2, followed by 250 mg once every two weeks. The primary efficacy endpoint was the percentage of patients with an investigator’s Global Assessment scale (IGA) score of 0 or 1 (i.e., clear or almost clear) and a 2 or more point improvement from baseline at week 16. A key secondary objective was the percentage of patients achieving 75% improvement in EASI (EASI-75) at week 16.
Lebrikizumab and atopic eczema outcomes
A total of 211 patients with mean age of 37.2 years (48.8% female) were randomised to lebrikizumab and topical steroids (145) or placebo and steroids.
After 16 weeks of treatment, an IGA score of 0 or 1 with a 2-point or more reduction from baseline was achieved by 41.2% of those receiving lebrikizumab compared to 22.1% on placebo (p = 0.01), although a statistically significant difference was observed as early as week 8.
There was also a significantly higher proportion of lebrikizumab patients achieving an EASI75 (69.5% vs 42.2%, p < 0.01) and this time, a statistically significant difference was achieved and maintained from as early as week 4 and maintained through week 16.
The authors concluded on how lebrikizumab in combination with topical steroids was superior to topical steroids alone, adding how safety data was consistent with previously reported AE trials.
Citation
Simpson EL et al. Efficacy and Safety of Lebrikizumab in Combination With Topical Corticosteroids in Adolescents and Adults With Moderate-to-Severe Atopic DermatitisA Randomized Clinical Trial (ADhere). JAMA Dermatol 2023
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